22016685|t|A novel missense mutation Asp506Gly in Exon 13 of the F11 gene in an asymptomatic Korean woman with mild factor XI deficiency.
22016685|a|Factor XI (FXI) deficiency is a rare autosomal recessive coagulation disorder most commonly found in Ashkenazi and Iraqi Jews, but it is also found in other ethnic groups. It is a trauma or surgery-related bleeding disorder, but spontaneous bleeding is rarely seen. The clinical manifestation of bleeding in FXI deficiency cases is variable and seems to poorly correlate with plasma FXI levels. The molecular pathology of FXI deficiency is mutation in the F11 gene on the chromosome band 4q35. We report a novel mutation of the F11 gene in an 18-year-old asymptomatic Korean woman with mild FXI deficiency. Pre-operative laboratory screen tests for lipoma on her back revealed slightly prolonged activated partial thromboplastin time (45.2 sec; reference range, 23.2-39.4 sec). Her FXI activity (35%) was slightly lower than the normal FXI activity (reference range, 50-150%). Direct sequence analysis of the F11 gene revealed a heterozygous A to G substitution in nucleotide 1517 (c.1517A>G) of exon 13, resulting in the substitution of aspartic acid with glycine in codon 506 (p.Asp506Gly). To the best of our knowledge, the Asp506Gly is a novel missense mutation, and this is the first genetically confirmed case of mild FXI deficiency in Korea.
22016685	26	35	Asp506Gly	ProteinMutation	p|D|506|G
22016685	1109	1118	c.1517A>G	DNAMutation	c|A|1517|G
22016685	1206	1217	p.Asp506Gly	ProteinMutation	p|D|506|G
22016685	1254	1263	Asp506Gly	ProteinMutation	p|D|506|G

21850008|t|Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.
21850008|a|The mutation pattern of mitochondrial DNA (mtDNA) in mainland Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) has been rarely reported, though previous data suggested that the mutation pattern of MELAS could be different among geographically localized populations. We presented the results of comprehensive mtDNA mutation analysis in 92 unrelated Chinese patients with MELAS (85 with classic MELAS and 7 with MELAS/Leigh syndrome (LS) overlap syndrome). The mtDNA A3243G mutation was the most common causal genotype in this patient group (79/92 and 85.9%). The second common gene mutation was G13513A (7/92 and 7.6%). Additionally, we identified T10191C (p.S45P) in ND3, A11470C (p. K237N) in ND4, T13046C (p.M237T) in ND5 and a large-scale deletion (13025-13033:14417-14425) involving partial ND5 and ND6 subunits of complex I in one patient each. Among them, A11470C, T13046C and the single deletion were novel mutations. In summary, patients with mutations affecting mitochondrially encoded complex I (MTND) reached 12.0% (11/92) in this group. It is noteworthy that all seven patients with MELAS/LS overlap syndrome were associated with MTND mutations. Our data emphasize the important role of MTND mutations in the pathogenicity of MELAS, especially MELAS/LS overlap syndrome.
21850008	727	733	A3243G	DNAMutation	m|A|3243|G
21850008	856	863	G13513A	DNAMutation	m|G|13513|A
21850008	909	916	T10191C	DNAMutation	m|T|10191|C
21850008	918	924	p.S45P	ProteinMutation	p|S|45|P
21850008	934	941	A11470C	DNAMutation	m|A|11470|C
21850008	943	951	p. K237N	ProteinMutation	p|K|237|N
21850008	961	968	T13046C	DNAMutation	m|T|13046|C
21850008	970	977	p.M237T	ProteinMutation	p|M|237|T
21850008	1124	1131	A11470C	DNAMutation	m|A|11470|C
21850008	1133	1140	T13046C	DNAMutation	m|T|13046|C

22104738|t|Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria.
22104738|a|A 3-year-old Chinese boy presented with prominent clinical features of malonic aciduria, including developmental delay, short stature, brain abnormalities and massive excretion of malonic acid and methylmalonic acid. Molecular characterization by DNA sequencing analysis and multiplex ligation-dependent probe amplification of the MLYCD gene revealed a heterozygous mutation (c.920T>G, p.Leu307Arg) in the patient and his father and a heterozygous deletion comprising exon 1 in the patient and his mother. The missense mutation (c.920T>G) was not found in 100 healthy controls and has not been reported previously. Our findings expand the number of reported cases and add a novel entry to the repertoire of MLYCD mutations.
22104738	466	474	c.920T>G	DNAMutation	c|T|920|G
22104738	476	487	p.Leu307Arg	ProteinMutation	p|L|307|R
22104738	619	627	c.920T>G	DNAMutation	c|T|920|G

22295085|t|Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas.
22295085|a|BACKGROUND: Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior. METHODOLOGY/PRINCIPAL FINDINGS: NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study. CONCLUSIONS/SIGNIFICANCE: The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth.

22174939|t|RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients.
22174939|a|Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial).Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5' untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.

21943124|t|A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome.
21943124|a|BACKGROUND: Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event. CASE PRESENTATION: We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents. CONCLUSIONS: Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.

21779184|t|Detection of a-thalassemia-1 Southeast Asian and Thai type deletions and b-thalassemia 3.5-kb deletion by single-tube multiplex real-time PCR with SYBR Green1 and high-resolution melting analysis.
21779184|a|BACKGROUND: Prevention and control of thalassemia requires simple, rapid, and accurate screening tests for carrier couples who are at risk of conceiving fetuses with severe thalassemia. METHODS: Single-tube multiplex real-time PCR with SYBR Green1 and high-resolution melting (HRM) analysis were used for the identification of a-thalassemia-1 Southeast Asian (SEA) and Thai type deletions and b-thalassemia 3.5-kb gene deletion. The results were compared with those obtained using conventional gap-PCR. DNA samples were derived from 28 normal individuals, 11 individuals with a-thalassemia-1 SEA type deletion, 2 with a-thalassemia-1 Thai type deletion, and 2 with heterozygous b-thalassemia 3.5-kb gene deletion. RESULTS: HRM analysis indicated that the amplified fragments from a-thalassemia-1 SEA type deletion, a-thalassemia-1 Thai type deletion, b-thalassemia 3.5-kb gene deletion, and the wild-type b-globin gene had specific peak heights at mean melting temperature (T(m)) values of 86.89   , 85.66   , 77.24   , and 74.92   , respectively. The results obtained using single-tube multiplex real-time PCR with SYBR Green1 and HRM analysis showed 100% consistency with those obtained using conventional gap-PCR. CONCLUSIONS: Single-tube multiplex real-time PCR with SYBR Green1 and HRM analysis is a potential alternative for routine clinical screening of the common types of a- and b-thalassemia large gene deletions, since it is simple, cost-effective, and highly accurate.

21640722|t|Xeroderma pigmentosum variant: complementary molecular approaches to detect a 13 base pair deletion in the DNA polymerase eta gene.
21640722|a|Deficiencies of DNA polymerase eta-an enzyme mediating replication past UV-induced DNA damage-predispose individuals to xeroderma pigmentosum variant (XPV) and result in a high incidence of skin cancers. We designed, developed and assessed several complementary molecular approaches to detect a genetically inherited deletion within DNA polymerase eta. RNA was reverse transcribed from XPV fibroblasts and from normal human cells, and standard polymerase chain reaction (PCR) was conducted on the cDNA targeting a region with a 13 base pair deletion within the polymerase eta gene. PCR products were subjected to restriction fragment length polymorphism (RFLP) analysis and cycle DNA sequencing. The deletion was found to eliminate a BsrGI restriction site and affected the number of resultant fragments visualized after gel electrophoresis. Cycle sequencing of polymerase eta-specific amplicons from XPV and normal cells provided a second approach for detecting the mutation. Additionally, the use of a fluorescent nucleic acid dye-EvaGreen-in real-time PCR and melt curve analysis distinguished normal and XPV patient-derived amplicons as well as heteroduplexes that represent heterozygotic carriers without the need for high resolution melt analysis-compatible software. Our approaches are easily adaptable by diagnostic laboratories that screen for or verify genetically inherited disorders and identify carriers of a defective gene.

21499297|t|C10ORF97 is a novel tumor-suppressor gene of non-small-cell lung cancer and a functional variant of this gene increases the risk of non-small-cell lung cancer.
21499297|a|In an earlier study we showed that C10ORF97 (chromosome-10, open reading frame-97) was expressed in almost all of the tissues and cell lines tested, and that it inhibited the growth of seven tumor cell lines, including two lung carcinoma cell lines (A549 and PG). Here, we show that C10ORF97 is downregulated in non-small-cell lung cancer (NSCLC) tissue compared with normal lung tissue. Overexpression of C10ORF97 significantly suppressed human lung carcinoma A549 cell growth (proliferation and anchorage-independent growth in soft agar) and motility (migration and adhesion). This tumor-suppressive function of C10ORF97 was also verified in vivo. We further found that C10ORF97 caused G(1) arrest of A549 cells and modulated the expression level of several cell-cycle regulators (such as CDK2, cyclin-E and p27). These effects of C10ORF97 were mediated by physical association between C10ORF97 and Jun-activating domain-binding protein-1 (JAB1), and blocking of JAB1-mediated translocation of p27 from the nucleus to the cytoplasm. Together, these results indicated that C10ORF97 functions as a novel tumor suppressor by modulating several key G(1)/S-regulatory proteins by interacting with JAB1. These findings led us to hypothesize that a single-nucleotide polymorphism (SNP) in the C10ORF97 gene that affects its expression might be associated with susceptibility to NSCLC. SNP216 C>T (rs2297882) in the C10ORF97 Kozak sequence was identified, and allele T of SNP216 suppressed C10ORF97 expression in vitro and in vivo. Furthermore, the TT genotype of SNP216 was associated with an increased risk of NSCLC (adjusted odds ratio=1.73 (95% confidence interval: 1.33-2.25), P=4.6   10(-5)). These data indicated that C10ORF97 is a tumor suppressor of NSCLC progression and C10ORF97-SNP216 may serve as a predictor of NSCLC.
21499297	1547	1550	C>T	DNAMutation	|C||T
21499297	1552	1561	rs2297882	SNP	rs2297882

21695597|t|MHC region and risk of systemic lupus erythematosus in African American women.
21695597|a|The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case-control study (380 cases, 765 age-matched controls) nested within the prospective Black Women's Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6   10(-5)) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2   10(-4)), rs2071349 (OR = 1.53, p = 1.0   10(-3)), and rs2844580 (OR = 1.43, p = 1.3   10(-3)), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.
21695597	891	900	rs9271366	SNP	rs9271366
21695597	1025	1033	rs204890	SNP	rs204890
21695597	1065	1074	rs2071349	SNP	rs2071349
21695597	1110	1119	rs2844580	SNP	rs2844580
21695597	1196	1205	rs9271366	SNP	rs9271366
21695597	1576	1585	rs9271366	SNP	rs9271366

21629979|t|Molecular and clinical analysis of glioblastoma with an oligodendroglial component (GBMO).
21629979|a|The genetic and clinical features of glioblastoma with an oligodendroglial component (GBMO), pathologically defined as anaplastic oligo-astrocytoma with necrosis, remain unclear. We investigated the correlation between genetic alterations and clinical outcomes in 19 GBMO patients we have encountered since 1997. Using single nucleotide polymorphism oligonucleotide genomic (SNP) microarrays, we analyzed gene amplification, loss of heterozygosity (LOH), and homozygous deletions in their whole genome. We also analyzed their overall survival (OS). Pathological studies revealed the presence of calcification in 11 and of a cyst in 9 of the 19 patients. Whole-genome analysis using SNP microarrays revealed LOH of chromosome 10 in 11, EGFR amplification in 8, 9p21 (INK4 locus) deletion in 12, PDGFR amplification in 2, and LOH of 1p19q in 2 patients. Median OS was 14  months (average 22.8  months). The pattern of genetic alterations was similar in GBMO and glioblastoma multiforme (GBM) patients, and the clinical outcomes were similar in GBMO and GBM patients.

22048266|t|Exploratory investigation on functional significance of ETS2 and SIM2 genes in Down syndrome.
22048266|a|Trisomy of the 21{st} chromosome leads to an over dosage of several regulatory genes in Down syndrome (DS). Though allelic and genotypic combinations formed between genes are interesting, till date, this particular area has never been explored in DS. In the present investigation four SNPs in two transcription factors, Single minded 2 (SIM2) and V-ets erythroblastosis virus E26 oncogene homolog2 (ETS2), located in the 21{st} chromosome were genotyped to understand their role in DS. Genomic DNA of eastern Indian probands with DS (N=132), their parents (N=209) and ethnically matched controls (N=149) was subjected to PCR-based analyses of functionally important SNPs followed by statistical analyses. ETS2 rs461155 showed high heterozygosity in DS. Significantly lower frequency of SIM2 C-G haplotype (rs2073601-rs2073416) was noticed in individuals with DS (P value =0.01669) and their fathers (P value=0.01185). Significantly lower frequency of the A-C-C-G with higher frequency of A-C-A-G haplotypes was also noticed in subjects with DS (P value =0.02089 and 0.00588 respectively). Data obtained indicate that the rs2073601 'A' allele, responsible for nonsynonymous substitution of leucine to methionine, may have some role in DS in this population.
22048266	804	812	rs461155	SNP	rs461155
22048266	900	909	rs2073601	SNP	rs2073601
22048266	910	919	rs2073416	SNP	rs2073416
22048266	1215	1224	rs2073601	SNP	rs2073601

22028770|t|APOE genotype-function relationship: evidence of -491 A/T promoter polymorphism modifying transcription control but not type 2 diabetes risk.
22028770|a|BACKGROUND: The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE -491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The -491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (-1017 to +406). Using the -501 to -481 nucleotide sequence of the APOE promoter as a 'bait' to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not -491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs -491A/T, -219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. CONCLUSIONS/SIGNIFICANCE: At molecular level, polymorphism -491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese.
22028770	49	57	-491 A/T	DNAMutation	c|A|-491|T
22028770	745	752	-491A/T	DNAMutation	c|A|-491|T
22028770	754	762	rs449647	SNP	rs449647
22028770	857	868	-491 A to T	DNAMutation	c|A|-491|T
22028770	1553	1560	-491A/T	DNAMutation	c|A|-491|T
22028770	1748	1755	-491A/T	DNAMutation	c|A|-491|T
22028770	1757	1764	-219G/T	DNAMutation	c|G|-219|T
22028770	1766	1774	rs405509	SNP	rs405509
22028770	1781	1788	+113G/C	DNAMutation	c|G|+113|C
22028770	1790	1798	rs440446	SNP	rs440446
22028770	2011	2018	-491A/T	DNAMutation	c|A|-491|T

21771880|t|Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.
21771880|a|Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 (   14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children.

21790735|t|A large heterozygous deletion including the entire C1 inhibitor gene in a sporadic case of hereditary angio-oedema.
21790735|a|C1 inhibitor (C1-INH) deficiency [hereditary or acquired angio-oedema (HAE or AAE)] is characterized by recurring episodes of subcutaneous or submucosal oedema. Many different mutations in the C1-INH gene have been identified as a cause of HAE. We investigated the molecular basis of the disease in a Japanese woman with sporadic HAE. Direct sequencing of genomic DNA revealed no point mutation in the C1-INH gene. Quantitative real-time PCR showed that the copy number of the C1-INH gene in the patient was half that of a healthy control. Furthermore, we identified a 650-kbp deletion on the chromosome, which included the C1-INH gene. We evaluated the correlation between the patient's attacks and her coagulation activity. The levels of D-dimer were high during the angio-oedema attacks, and often exceeded the normal range even during remission, thus the level of D-dimer reflected the activity of HAE in this patient.

21506149|t|Phenotype of the 202 adenine deletion in the parkin gene: 40 years of follow-up.
21506149|a|BACKGROUND: We describe the four decades follow-up of 14 parkin patients belonging to two large eight-generation-long in-bred Muslim-Arab kindreds. RESULTS: All patients had a single base-pair of adenine deletion at nucleotide 202 of exon 2 (202A) of the parkin gene (all homozygous, one heterozygous). Parkinson's disease onset age was 17-68 years. Special features were intractable axial symptoms (low back pain, scoliosis, camptocormia, antecollis), postural tremor, and preserved cognition. CONCLUSIONS: The 202A deletion of the parkin gene causes early-onset Parkinson's disease with marked levodopa/STN-DBS-resistant axial features. Postural tremor and preserved cognition, even after 40 years of disease, were also evident.

21904390|t|Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients.
21904390|a|PURPOSE: Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. PATIENTS AND METHODS: Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. RESULTS: By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T>C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6gene and DKFZ p686k1684gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. CONCLUSION: Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6gene.
21904390	1245	1255	c.357-3C>G	DNAMutation	c|C|357-3|G
21904390	1257	1268	p.Ser119fsX	ProteinMutation	p|S|119||FSX
21904390	1345	1353	c.643T>C	DNAMutation	c|T|643|C
21904390	1355	1362	p.S216P	ProteinMutation	p|S|216|P
21904390	1434	1441	p.S216P	ProteinMutation	p|S|216|P

21496008|t|Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene.
21496008|a|ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation.
21496008	524	537	c.304ins(GCG)	DNAMutation	c|INS|304|GCG
21496008	563	575	c.429_452dup	DNAMutation	c|DUP|429_452|
21496008	577	584	dup24bp	DNAMutation	|DUP||24
21496008	971	978	dup24bp	DNAMutation	|DUP||24
21496008	1016	1023	dup24bp	DNAMutation	|DUP||24
21496008	1045	1052	dup27bp	DNAMutation	|DUP||27
21496008	1054	1061	dup33bp	DNAMutation	|DUP||33
21496008	1147	1156	c.1074G>T	DNAMutation	c|G|1074|T

21717135|t|Variation in genotype and higher virulence of a strain of Sporothrix schenckii causing disseminated cutaneous sporotrichosis.
21717135|a|Sporotrichosis is usually a localized, lymphocutaneous disease, but its disseminated type was rarely reported. The main objective of this study was to identify specific DNA sequence variation and virulence of a strain of Sporothrix schenckii isolated from the lesion of disseminated cutaneous sporotrichosis. We confirmed this strain to be S. schenckii by(  ) tubulin and chitin synthase gene sequence analysis in addition to the routine mycological and partial ITS and NTS sequencing. We found a 10-bp deletion in the ribosomal NTS region of this strain, in reference to the sequence of control strains isolated from fixed cutaneous sporotrichosis. After inoculated into immunosuppressed mice, this strain caused more extensive system involvement and showed stronger virulence than the control strain isolated from a fixed cutaneous sporotrichosis. Our study thus suggests that different clinical manifestation of sporotrichosis may be associated with variation in genotype and virulence of the strain, independent of effects due to the immune status of the host.

21976953|t|Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome.
21976953|a|PURPOSE: To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS). METHODS: Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation. RESULTS: A novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain. CONCLUSIONS: We indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome.
21976953	1018	1027	c.3703T>C	DNAMutation	c|T|3703|C
21976953	1154	1162	p.S1235P	ProteinMutation	p|S|1235|P
21976953	1540	1548	p.S1235P	ProteinMutation	p|S|1235|P

21546516|t|The 57 kb deletion in cystinosis patients extends into TRPV1 causing dysregulation of transcription in peripheral blood mononuclear cells.
21546516|a|BACKGROUND: Cystinosis is an autosomal recessive disease characterised by the abnormal accumulation of lysosomal cystine. Mutations in the cystinosin gene (CTNS) represent known causes for the disease. The major cystinosis mutation is a 57 kb deletion on human chromosome 17p13 that removes the majority of CTNS and the entire adjacent gene, CARKL/SHPK. OBJECTIVES: In order to identify other genes that may influence the cystinosis pathobiological pathway, peripheral blood mononuclear cells (PBMC) were collected from cystinosis family members, and DNA and RNA extracted. RESULTS: Using whole genome transcriptional profiling, transient receptor potential vanilloid 1 (TRPV1) was found to be differentially expressed in association with cystinosis. This was verified using TaqMan qRT-PCR. There was a 72% reduction in PBMC TRPV1 mRNA levels in cystinosis individuals homozygous for the 57 kb deletion (n=6) compared to unaffected individuals without the deletion (n=6) (p=0.002). TRPV1 is a sensory receptor located on chromosome 17p13, adjacent to CARKL/SHPK. It was ascertained that the 57 kb deletion extends from exon 10 of CTNS, upstream through CARKL/SHPK, to intron 2 of TRPV1, thus deleting the first two non-coding exons. CONCLUSION: This is the first study to report that the 57 kb deletion extends into the TRPV1 gene causing dysregulation of transcription in PBMC isolated from cystinosis patients.

21799811|t|Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis.
21799811|a|BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies. METHODOLOGY/PRINCIPAL FINDINGS: We undertook genotyping on a total of 837 individuals including well characterized infertile (N=522) and confirmed fertile (N=315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included 'Pubmed', 'Ovid' and 'Google Scholar'. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p=0.0025) and genotypes (CT+TT) (p=0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p=0.000), 1.310 (p=0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility. CONCLUSIONS/SIGNIFICANCE: 677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.
21799811	22	29	677 C>T	DNAMutation	|C|677|T
21799811	360	366	677C>T	DNAMutation	|C|677|T
21799811	938	944	677C>T	DNAMutation	|C|677|T
21799811	1639	1645	677C>T	DNAMutation	|C|677|T
21799811	1708	1714	677C>T	DNAMutation	|C|677|T

21976404|t|Angiotensin-converting enzyme (ACE) serum levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus.
21976404|a|OBJECTIVES: To investigate the association of angiotensin-converting enzyme (ACE) gene polymorphism and serum ACE level among Egyptian SLE patients and its relation to disease activity parameters. SUBJECTS AND METHODS: We enrolled 50 Egyptian female systemic lupus erythematosus (SLE) patients and 29 healthy controls. Measurement of serum ACE level was done using ELISA, and the ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. RESULTS: A significant difference was found in ACE genotypes between SLE patients and controls (  (2   )=   7.84, p   =   0.02). The frequency of ACE DD versus (DI and II) genotypes was significantly higher in SLE patients compared with controls (  (2   )=   5.57, p = 0.018 and OR for risk of SLE was 3.1 with 95% confidence interval: 1.198.06). Mean serum ACE level was significantly higher in the SLE group compared with controls (p   =   0.006). Subjects with DD genotype had a significantly higher mean level than those with DI (p   =   0.015) and II genotypes (p   =   0.02). Lupus nephritis patients had a significantly higher frequency of DD versus DI and II genotypes compared with lupus patients without nephritis (Fisher's exact test, p   =   0.025) and controls (   (2) =8.74, p   =   0.003). SLE patients with vasculopathy had a significantly higher frequency of DD versus DI/II genotypes compared with SLE patients without vasculopathy (Fisher's exact test, p   =   0.04) and controls (  (2   )=   9.84 and p   =   0.002). Mean serum ACE level was significantly higher in the lupus nephritis and SLE patients with vasculopathy compared with controls (p   =   0.008, p   =   0.001, respectively). Significant positive correlations were found between serum ACE level and serum creatinine and 24   h proteinuria (p   =   0.03, 0.009, respectively). SLE patients with DD genotype had a statistically significant higher mean SLEDAI score than those with (DI/II) genotypes (p   =   0.02). Significant positive correlation was found between serum ACE levels and SLEDAI scores (p   =   0.04). CONCLUSION: ACE genotype and subsequently serum ACE level could be associated with the disease activity of Egyptian SLE patients; in addition, ACE deletion polymorphism might be used as one of the predictive factors for the activity of SLE. Further studies on a larger number of patients should be done to determine the exact prevalence of ACE gene polymorphism among Egyptian SLE patients.

21879313|t|Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C.
21879313|a|The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1   10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4   10(-3)) and LDL cholesterol (P = 4.2   10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype.
21879313	9	18	rs8099917	SNP	rs8099917
21879313	1047	1056	rs8099917	SNP	rs8099917
21879313	1425	1434	rs8099917	SNP	rs8099917
21879313	1905	1914	rs8099917	SNP	rs8099917

20854438|t|SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda.
20854438|a|BACKGROUND: Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1). SLURP-1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T-cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis. OBJECTIVES: To investigate the association of the SLURP1 gene mutation with T-cell activation in a Taiwanese family with MDM. To test that SLURP-1 is essential for T-cell activation. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 (G86R) in the SLURP-1 protein. PBMCs from homozygotes and wild-type controls were stimulated with anti-CD3/anti-CD28 antibodies and the level of T-cell activation was determined by the stimulation index. RESULTS: PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0  5 ug mL(-1) recombinant human SLURP-1 protein. CONCLUSIONS: Patients with MDM with the homozygous SLURP-1 G86R mutation may have an impaired T-cell activation. The presence of wild-type SLURP-1 is essential for normal T-cell activation.
20854438	1233	1237	G86R	ProteinMutation	p|G|86|R
20854438	1496	1500	G86R	ProteinMutation	p|G|86|R
20854438	1689	1693	G86R	ProteinMutation	p|G|86|R

20728296|t|Interstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma.
20728296|a|A patient with a large deletion of the distal part of the long arm of chromosome 13 showed severe psychomotor retardation, a characteristic face, nystagmus, retinopathy, cystic kidney disease, and brain malformation with molar tooth sign and cerebellar vermis hypoplasia, a phenotype typical of Arima syndrome. This patient also had bilateral retinoblastoma. Fluorescent in situ hybridization and single-nucleotide-polymorphism genotyping microarray demonstrated an interstitial deletion of 54 Mbp, ranging from 13q14.13 to 13q32.3 and involving the RB1 gene. This patient is the first case of Arima syndrome, or a Joubert syndrome-related disorder, that showed linkage to chromosome 13q.

20887110|t|Impact of 5,10-methylenetetrahydrofolate reductase gene polymorphism on neural tube defects.
20887110|a|OBJECT: Neural tube defects (NTDs) are among the most common congenital malformations worldwide. Their etiology and exact mechanisms of development are incompletely understood. Many enzymes involved in folate metabolism and the genes encoding these enzymes have been studied as candidates in their etiology. A mutation in the methylenetetrahydrofolate reductase (MTHFR) gene--a C-->T transition at nucleotide 677--is one among them. The mutation results in substitution of alanine by valine at a functionally important site in the enzyme. It has been shown to be a risk factor for development of NTDs in certain populations. The present study was conducted to evaluate the role of MTHFR 677 C-->T mutation as a risk factor for NTD in the South Indian population and to determine the relative importance of the genotypes in the affected child and its mother. METHODS: Blood samples were collected from the test and the control groups. The test group consisted of children with NTDs and their mothers, while the control group consisted of apparently healthy controls. MTHFR C677T polymorphism in the 3 groups was determined by polymerase chain reaction and restriction fragment length polymorphism studies. Comparison of polymorphism in the 3 groups was using the chi-square test. RESULTS: There was a significant difference in the prevalence of MTHFR 677 C-->T mutation among the 3 groups (p = 0.002). The risk conferred by the TT genotype in the child was statistically significant (OR 12.625, 95% CI 1.430-111.465). In the mothers, however, although there was an increased prevalence of the mutation compared with the control individuals, the difference was not statistically significant (p = 0.152). CONCLUSIONS: The MTHFR 677TT genotype is considered to be a definite risk factor for development of NTDs. It is the TT genotype status of the developing embryo, rather than the TT genotype status of its mother, that is the critical genetic determinant of MTHFR-related NTD risk.
20887110	471	505	C-->T transition at nucleotide 677	DNAMutation	|C|677|T
20887110	780	789	677 C-->T	DNAMutation	|C|677|T
20887110	1165	1170	C677T	DNAMutation	|C|677|T
20887110	1443	1452	677 C-->T	DNAMutation	|C|677|T

20602574|t|Bikunin and a1-microglobulin/bikunin precursor (AMBP) gene mutational screening in patients with kidney stones: a case-control study.
20602574|a|OBJECTIVE: Bikunin is an inhibitor of kidney stone formation synthesized in the liver together with a(1)-microglobulin from the a(1)-microglobulin/bikunin precursor (AMBP) gene. The aim of this study was to investigate the possible association between bikunin/AMBP gene polymorphisms and urinary stone formation. MATERIAL AND METHODS: To analyse the DNA, blood samples were taken from 75 kidney stone formers who had a familial stone history, 35 sporadic stone formers and 101 healthy individuals. Four exons of bikunin gene and five parts of the promoter region of the AMBP gene were screened using single-strand conformation polymorphism and nucleotide sequence analysis. RESULTS: The Init-2 region of the promoter of AMBP gene had polymorphisms at positions -218 and -189 nt giving three different genotypes having 1,3, 2,4 and 1,2,3,4 alleles with frequencies of 17.06%, 60.19% and 22.75%, respectively, in all groups. Therefore, the Init-2 region appears to be polymorphic. As a result, the 1,3 allele has -218G and -189T complying with the reference database sequence, the 2,4 allele has -218G and T-189C substitution and the allele 1,2,3,4 genotype has substitutions at positions G-218C and T-189C. CONCLUSIONS: There were no significant differences in allele distribution between patients and controls. These common alleles exist in the Turkish population independent of stone formation. These results are the first to demonstrate the existence of bikunin and AMBP promoter polymorphism. Although the Init-2 region of the AMBP gene is the binding site for various transcription factors, the results showed no association between these observed genotypes and stone-forming phenotypes.
20602574	1238	1244	T-189C	DNAMutation	c|T|-189|C
20602574	1321	1327	G-218C	DNAMutation	c|G|-218|C
20602574	1332	1338	T-189C	DNAMutation	c|T|-189|C

21080147|t|Novel CRELD1 gene mutations in patients with atrioventricular septal defect.
21080147|a|BACKGROUND: Atrioventricular septal defects (AVSDs) occur as clinical defects of several different syndromes, as autosomal dominant defects, and as sporadically occurring malformations. Consequently, there is genetic heterogeneity, but until recently, little is known about the genes involving in the pathogenesis of AVSD. CRELD1 gene, a novel cell adhesion molecule, is a candidate gene for AVSD. METHODS: This study included 133 patients with AVSD and 200 healthy controls. Peripheral blood samples were collected and genomic DNA was extracted from the leukocytes. CRELD1 was amplified by polymerase chain reaction (PCR) with specific primers. The sequences of PCR products were compared between the patients and controls. RESULTS: In a patient, a C-to-G transition was identified at nucleotide 857 in exon 8 that resulted in a substitution of alanine for proline at amino acid 286 in the first calcium-binding EGF domain. This patient had an isolated partial AVSD and the mutation was inherited from her mother. Another mutation was detected in a patient with a partial AVSD and evidence of Down syndrome. The heterozygous c.973G>A transition in exon 9 resulted in a substitution of lysine for glutamic acid at amino acid 325 (E325K) in the second calcium-binding EGF domain. CONCLUSIONS: Two novel CRELD1 mutations were identified in the calcium-binding EGF domain in patients with AVSD. CRELD1 is likely to be an AVSD-susceptibility gene and CRELD1 mutations may increase the risk of developing a heart defect rather than being a direct causative mutation.
21080147	1203	1211	c.973G>A	DNAMutation	c|G|973|A
21080147	1307	1312	E325K	ProteinMutation	p|E|325|K

20708777|t|Association of DNA polymorphisms within the CYP11B2/CYP11B1 locus and postoperative hypertension risk in the patients with aldosterone-producing adenomas.
20708777|a|OBJECTIVES: Hypertension often persists after adrenalectomy for primary aldosteronism. Traditional factors associated with postoperative hypertension were evaluated, but whether genetic determinants were involved remains poorly understood. The aim of this study was to investigate the association of DNA polymorphisms within steroid synthesis genes (CYP11B2, CYP11B1) and the postoperative resolution of hypertension in Chinese patients undergoing adrenalectomy for aldosterone-producing adenomas (APA). METHODS: Ninety-three patients with APA were assessed for postoperative resolution of hypertension. All patients were genotyped for rs1799998 (C-344 T), intron 2 conversion, rs4539 (A2718G) within CYP11B2 and rs6410 (G22 5A), rs6387 (A2803G) within CYP11B1. The associations between CYPB11B2/CYP11B1 polymorphisms and persistent postoperative hypertension were assessed by multivariate analysis. RESULTS: CYP11B2-CYP11B1 haplotype was associated with persistent postoperative hypertension in Chinese patients undergoing adrenalectomy with APA (P = .006). Specifically, the rs4539 (AA) polymorphism was associated with persistent postoperative hypertension (P = .002). Multivariate logistic regression revealed the common haplotypes H1 (AGACT), H2 (AGAWT), and H3 (AGAWC) were associated with the persistent postoperative hypertension (P = .01, 0.03, 0.005 after Bonferroni correction). Additional predictors of persistent postoperative hypertension included duration of hypertension (P <.0005), family history of hypertension (P = .001), and elevated systolic blood pressure (P = .015). CONCLUSIONS: The rs4539 (AA), H1, H2, and H3 are genetic predictors for postoperative persistence of hypertension for Chinese patients treated by adrenalectomy with APA. DNA polymorphisms at CYP11B2/B1 locus may confer susceptibility to postoperative hypertension of patients with APA.
20708777	791	800	rs1799998	SNP	rs1799998
20708777	802	809	C-344 T	DNAMutation	c|C|-344|T
20708777	833	839	rs4539	SNP	rs4539
20708777	841	847	A2718G	DNAMutation	c|A|2718|G
20708777	868	874	rs6410	SNP	rs6410
20708777	876	882	G22 5A	DNAMutation	c|G|225|A
20708777	885	891	rs6387	SNP	rs6387
20708777	893	899	A2803G	DNAMutation	c|A|2803|G
20708777	1232	1238	rs4539	SNP	rs4539
20708777	1763	1769	rs4539	SNP	rs4539

21059483|t|The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population.
21059483|a|Classic galactosemia is an autosomal recessive disorder of galactose metabolism manifesting in the first weeks of life following exposure to a milk-based diet. Despite the benefit of avoidance of lactose, many patients suffer from long-term complications including neurological deficits and ovarian failure. To date, over 230 mutations have been described in the GALT gene resulting in galactosemia. Recently, an unusual mutation was characterized causing a 5.5 kb deletion, with a relatively high carrier rate in subjects of Ashkenazi Jewish (AJ) descent. The aim of this study was to estimate the carrier frequency of this mutation in the AJ population in Israel. For this purpose we developed a high-throughput methodology to genotype both normal and deleted alleles using a chip-based matrix-assisted laser desorption-time-of-flight (MALDI-TOF) mass spectrometer and Multiplex PCR. DNA samples of 760 anonymous AJ subjects were submitted for analysis, subsequently detecting six individuals heterozygous for the GALT deletion mutation, giving a carrier frequency of 1 in 127 (0.79%). Based on these results, we suggest that the method described here provides a basis for genetic screening and prenatal counseling and can potentially reduce the morbidity and mortality associated with delayed diagnosis of galactosemia in this patient population.

21103668|t|Characterisation of two novel large F8 deletions in patients with severe haemophilia A and factor VIII inhibitors.
21103668|a|Large deletions are found in approximately 5% of patients with severe haemophilia A, but only a few deletion breakpoints have been characterised precisely so far. In this study we characterised the deletion breakpoints of two patients with severe haemophilia A, large deletions and factor VIII (FVIII) inhibitors, and subsequently established deletion-specific assays for the identification of carriers. Patient 1 had a deletion of 37,410 bp comprising exon 1 and the F8 promoter region, and a 5 bp homology (GGGCC) is present at the chromosomal fusion site. In patient 2, a deletion of 22,230 bp including parts of intron 25, exon 26 and 3'-UTR was identified. No homologous repetitive elements were found at the breakpoints. However, both breakpoints were located within long terminal repeats of endogenous retroviruses and the DNA motif TTTAAA - known to be able to bend DNA molecules - was identified at the centromeric breakpoint. By deletion-specific PCR experiments we were able to identify a heterozygous state in mother 2 (carrier) while mother 1 presented only with wild-type alleles (non-carrier). Both deletions are most likely created by DNA double strand breaks and subsequent DNA repair by the non-homologous end joining DNA repair pathway (NHEJ). The exact identification of the deletion breakpoints provides a reliable diagnostic tool for carrier identification in affected families by means of a deletion-specific PCR.

20682662|t|Lack of association of C-C chemokine receptor 5 /\32 deletion status with rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, and disease severity.
20682662|a|OBJECTIVE: C-C chemokine receptor 5 (CCR5) plays an important role in inflammation. A 32 base-pair (/\32) deletion in the CCR5 gene leads to a nonfunctional receptor. This deletion has been reported to have a protective effect on the development and progression of several autoimmune diseases. We investigated whether the /\32 deletion is associated with disease susceptibility in a population of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and lupus nephritis (LN); and whether it is associated with disease severity. METHODS: DNA samples from 405 RA patients, 97 SLE patients, 113 LN patients, and 431 healthy controls were genotyped for the CCR5 /\32 deletion. Differences in genotype frequencies were tested between patients and controls. Association of genotypes with disease severity was analyzed. RESULTS: Genotype frequencies of each group were in Hardy-Weinberg equilibrium. The genotype frequencies of patients did not differ significantly from controls (CCR5//\32, /\32//\32: RA 18.3% and 1.2%, respectively; SLE 17.5% and 2.1%; LN 13.3% and 1.8%; controls 20.0% and 2.8%). However, there was a trend for lower /\32 deletion allele frequency in LN patients compared to controls (p = 0.08). There was no significant association between the CCR5 status and disease severity in RA, SLE, or LN. CONCLUSION: Although an association with LN cannot be excluded, the CCR5 /\32 deletion does not seem to be a disease susceptibility genotype for RA, SLE, or LN. No significant effect of the /\32 deletion on disease severity was demonstrated.

20806042|t|A novel mutation in GJA8 causing congenital cataract-microcornea syndrome in a Chinese pedigree.
20806042|a|PURPOSE: To identify the underlying genetic defect in a four-generation family of Chinese origin with autosomal dominant congenital cataract-microcornea syndrome (CCMC). METHODS: All individuals in the study underwent a full clinical examination and the details of history were collected . Genomic DNA extracted from peripheral blood was amplified by polymerase chain reaction (PCR) method and the exons of all candidate genes were sequenced. RESULTS: Direct sequencing of the encoding regions of the candidate genes revealed a heterozygous mutation c.592C-->T in exon 2 of the gap junction protein, alpha 8 (GJA8) gene. This mutation was responsible for the familial disorder through the substitution of a highly conserved arginine to tryptophan at codon 198 (p.R198W). This change co-segregated with all affected members of the family, but was not detected either in the non-carrier relatives or in the 100 normal controls. CONCLUSIONS: This report is the first to relate p.R198W mutation in GJA8 with CCMC. The result expands the mutation spectrum of GJA8 in associated with congenital cataract and microcornea, and implies that this gene has direct involvement with the development of the lens as well as the other anterior segment of the eye.
20806042	647	657	c.592C-->T	DNAMutation	c|C|592|T
20806042	858	865	p.R198W	ProteinMutation	p|R|198|W
20806042	1071	1078	p.R198W	ProteinMutation	p|R|198|W

21159032|t|Alpha2B-adrenergic receptor insertion/deletion polymorphism in women with spontaneous recurrent abortions.
21159032|a|AIM: The aim of our study was to investigate the relationship between the alpha2B-adrenoreceptor insertion/deletion (I/D) polymorphism and recurrent spontaneous abortions (RSA). METHODS: Genotyping was performed in 48 women with a history of at least three consecutive spontaneous abortions and 96 women with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction and PCR were used for the research of DD, ID and II genotype characters. RESULTS: The distribution of DD, ID and II genotypes of the alpha2B-adrenoreceptor gene was 2 (4.2%), 19 (39.6%) and 27 (56.2%) in the study group and 6 (6.5%), 28 (30.4%) and 58 (63%) in the control group, respectively. There was no significant difference between the groups. The presence of the D allele was not associated with RSA (P = 0.78, odds ratio = 0.88, 95% CI = 0.47-1.65). CONCLUSION: Our data fall short of showing any association between the presence of the alpha2B D allele and the occurrence of spontaneous abortions in the examined population.

20949073|t|Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier.
20949073|a|Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.
20949073	575	580	E831X	ProteinMutation	p|E|831|X
20949073	591	598	2623G>T	DNAMutation	|G|2623|T

20651814|t|Lack of association between ADRA2B-4825 gene insertion/deletion polymorphism and migraine in Chinese Han population.
20651814|a|OBJECTIVE: The present study aimed to estimate the association between susceptibility to migraine and the 12-nucleotide insertion/deletion (indel) polymorphism in promoter region of alpha(2B)-adrenergic receptor gene (ADRA2B). METHODS: A case-control study was carried out in Chinese Han population, including 368 cases of migraine and 517 controls. Genomic DNA was extracted from blood samples, and DNA fragments containing the site of polymorphism were amplified by PCR. Data were adjusted for sex, age, migraine history and family history, and analyzed using a logistic regression model. RESULTS: There was no association between indel polymorphism and migraine, at either the allele or the genotype level. CONCLUSION: These findings do not support a functional significance of ADRA2B indel polymorphism at position -4825 relative to the start codon in the far upstream region of the promoter in the present migraine subjects.

20534762|t|Two novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening.
20534762|a|CONTEXT: Patients with TSH-beta subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. OBJECTIVE: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-beta subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. RESULTS: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-beta subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. CONCLUSIONS: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.
20534762	1066	1073	313delT	DNAMutation	c|DEL|313|T
20534762	1075	1086	C105Vfs114X	ProteinMutation	p|C|105|V|FSX|114
20534762	1209	1213	C88Y	ProteinMutation	p|C|88|Y
20534762	1383	1387	C88Y	ProteinMutation	p|C|88|Y
20534762	1519	1523	C88Y	ProteinMutation	p|C|88|Y

20529581|t|A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient.
20529581|a|BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. METHODS: CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. RESULTS: CD18 expression level on this patient's leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A > T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. CONCLUSION: This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region (HCR) of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.
20529581	1150	1160	c.899A > T	DNAMutation	c|A|899|T
20529581	1421	1432	Asp 300 Val	ProteinMutation	p|D|300|V

20523265|t|Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population.
20523265|a|PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population. METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis. RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen. CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD.
20523265	906	915	rs3753394	SNP	rs3753394
20523265	930	938	rs800292	SNP	rs800292
20523265	953	962	rs1061170	SNP	rs1061170
20523265	982	991	rs1329428	SNP	rs1329428
20523265	1298	1307	rs2274700	SNP	rs2274700
20523265	1312	1321	rs1410996	SNP	rs1410996
20523265	1780	1789	rs3753394	SNP	rs3753394
20523265	1804	1812	rs800292	SNP	rs800292
20523265	1827	1836	rs1061170	SNP	rs1061170
20523265	1856	1865	rs1329428	SNP	rs1329428
20523265	1888	1897	rs7535263	SNP	rs7535263
20523265	1899	1908	rs1410996	SNP	rs1410996
20523265	1913	1922	rs2274700	SNP	rs2274700

20352162|t|4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries.
20352162|a|We assessed the association between common variation at the SERPINE1 (PAI1) locus and myocardial infarction (MI). Haplotype-tagging polymorphisms, including the 4G/5G deletion/insertion polymorphism and seven single nucleotide polymorphisms, were analysed in a German sample containing 3,657 cases with MI and 1,211 controls. The association between the 4G/5G polymorphism and MI was examined in a meta-analysis of data extracted from 32 studies (13,267 cases/14,716 controls). In addition, the relation between the 4G/5G polymorphism and coronary diseases, comprising MI, coronary artery disease, coronary heart disease, or the acute coronary syndrome, was assessed in a combined analysis enclosing 43 studies (17,278 cases/18,039 controls). None of the tagging polymorphisms was associated with MI in the present sample (p <or= 0.34). The adjusted odds ratio (OR) for 4G allele carriers was 1.02 (95% confidence interval [CI] 0.87-1.19) compared to the 5G5G genotype. None of 13 common (frequency >1.0%) 8-marker haplotypes was related to the risk of MI. In a meta-analysis specifically addressing the association with MI, no elevated risk was found in the carriers of the 4G allele (OR 1.07, 95% CI 0.99-1.16; p = 0.11). A more general combined analysis of coronary diseases showed a marginally increased risk in 4G allele carriers (OR 1.08, 95% CI 1.00-1.16; p = 0.044). In essence, tagging polymorphisms, including the 4G/5G polymorphism, and common haplotypes of the SERPINE1 gene region were not associated with MI in a German sample, and no compelling evidence was obtained for a relationship of the 4G/5G polymorphism to MI and coronary atherosclerosis in a meta-analysis.

20202300|t|Recent nosocomial transmission and genotypes of multidrug-resistant Mycobacterium tuberculosis.
20202300|a|SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a serious health problem in Eastern European countries, including Latvia. OBJECTIVE: To investigate the proportion of tuberculosis, including MDR-TB cases, attributable to recent transmission and risk factors associated with clustering. DESIGN: Retrospective nested case-control study. The data set incorporated a wide spectrum of social features, as well as genotypes of Mycobacterium tuberculosis isolates determined by insertion sequence 6110 restriction fragment length polymorphism analysis of PvuII cleaved genomic DNA and spoligotyping. RESULTS: In comparison with non-clustered M. tuberculosis, the Beijing genotype (OR 12.15) and multidrug resistance (OR 5.61, P < 0.01) were associated with clustering. In comparison with clustered drug-susceptible M. tuberculosis, clustering of MDR M. tuberculosis was associated with Beijing genotype (OR 41.67), previous hospitalisation (OR 18.33) and previous TB treatment (OR 17.68, P < 0.05). Direct epidemiological links in hospitals were found for almost one third (32%) of MDR Beijing cases. CONCLUSIONS: MDR cases were more likely to be found in clusters than drug-susceptible cases (74.0% vs. 33.6%). Recent nosocomial transmission of MDR-TB is an important risk factor for the spread of multiresistance, and is associated with the Beijing genotype. Special attention should be paid to infection control measures in hospitals and ambulatory treatment should be enforced.

20126413|t|U87MG decoded: the genomic sequence of a cytogenetically aberrant human cancer cell line.
20126413|a|U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30x genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (>100 bp), 191,743 small (<21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date.

20113448|t|Development and validation of a SYBR Green I-based real-time polymerase chain reaction method for detection of haptoglobin gene deletion in clinical materials.
20113448|a|BACKGROUND: Anhaptoglobinemic patients run the risk of severe anaphylactic transfusion reaction because they produce serum haptoglobin (Hp) antibodies. Being homozygous for the Hp gene deletion (HP(del)) is the only known cause of congenital anhaptoglobinemia, and clinical diagnosis of HP(del) before transfusion is important to prevent anaphylactic shock. We recently developed a 5'-nuclease (TaqMan) real-time polymerase chain reaction (PCR) method. STUDY DESIGN AND METHODS: A SYBR Green I-based duplex real-time PCR assay using two forward primers and a common reverse primer followed by melting curve analysis was developed to determine HP(del) zygosity in a single tube. In addition, to obviate initial DNA extraction, we examined serially diluted blood samples as PCR templates. RESULTS: Allelic discrimination of HP(del) yielded optimal results at blood sample dilutions of 1:64 to 1:1024. The results from 2231 blood samples were fully concordant with those obtained by the TaqMan-based real-time PCR method. CONCLUSION: The detection rate of the HP(del) allele by the SYBR Green I-based method is comparable with that using the TaqMan-based method. This method is readily applicable due to its low initial cost and analyzability using economical real-time PCR machines and is suitable for high-throughput analysis as an alternative method for allelic discrimination of HP(del).

20017074|t|Investigation of SERPINE1 genetic polymorphism in Macedonian patients with occlusive artery disease and deep vein thrombosis.
20017074|a|BACKGROUND: Raised SERPINE1 plasma levels are related to a 1-bp guanine deletion/insertion (4G5G) polymorphism in the promoter of the SERPINE1 (plasminogen activator inhibitor 1 - PAI1) gene. Evidence suggested that the plasma levels of SERPINE1 modulate the risk of coronary artery disease; furthermore, that the 4G5G polymorphism affects the expression of the SERPINE1 gene. AIM: To analyse association of SERPINE1 polymorphism with occlusive artery disease (OAD) and deep venous thrombosis (DVT) in Macedonians in order to investigate its role as a part of candidate genes in different vascular diseases in Macedonians. METHODS: Investigated groups consisted of 82 healthy patients, 75 with OAD, and 66 with DVT. Blood samples were collected after written informed consent was obtained, and DNA was isolated from peripheral blood leukocytes. Identification of SERPINE1 polymorphism was done with CVD StripAssay (ViennaLab, Labordiagnostica GmbH, Austria). The population genetics analysis package, PyPop, was used for analysis of the SERPINE1 data. Pearson's P-values, crude odds ratio and Wald's 95% CI were calculated with Bonferroni corrected p value. RESULTS: The frequency of 4G allele for SERPINE1 was 0.538 for DVT, 0.555 for healthy participants, and 0.607 for OAD. The frequency of 5G allele for SERPINE1 was the smallest in patients with OAD (0.393) and was higher in healthy participants (0.445), and patients with DVT (0.462). Test of neutrality (Fnd) showed negative value, but was significantly different from 0 for SERPINE1 in healthy participants (p of F = 0.041) and in patients with DVT (p of F = 0.030). SERPINE1 genotypes in healthy participants and patients with OAD were not in Hardy Weinberg proportions (p = 0.019 and 0.001, respectively). No association between SERPINE1 polymorphisms and OAD or DVT was found. CONCLUSION: There is no significant relationship between SERPINE1 polymorphisms and occlusive artery disease or deep venous thrombosis in Macedonian population.

20005218|t|A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population.
20005218|a|BACKGROUND: Mice with defects in the Klotho gene exhibit multiple aging phenotypes including arteriosclerosis. We hypothesised that the G-395A polymorphism in the promoter region of the human Klotho gene may contribute to the prevalence of Essential Hypertension (EH). METHODS: We investigate whether the G-395A polymorphism of Klotho is associated with EH in a population consisting of 215 patients with EH and 220 non-hypertensive subjects. We also tested whether a G/A substitution at the G-395A site affected the transcription level in vitro through the dual-luciferase reporter assay. RESULTS: Differences in the genotype distributions of the G-395A polymorphism between the EH and non-hypertension groups are statistically significant (P=0.032). There are differential effects of age, gender and smoking status on the association of the G-395A polymorphism with EH; the G-395A polymorphism is significantly associated with EH in subjects over 60years old, in females and in nonsmokers. A multiple logistic regression analysis indicated that the odds ratio for EH in the -395A allele carriers as compared with the control group was 0.593 (P=0.024) after adjusting for current traditional risk factors. The dual-luciferase reporter assay revealed that the -395A carrier of a 498-bp DNA fragment (containing the G-395A site) upstream of the Klotho gene has higher relative luciferase activity than the -395G carrier. CONCLUSIONS: The G-395A polymorphism of the human Klotho gene is associated with EH and may be a potential regulatory site.
20005218	302	308	G-395A	DNAMutation	c|G|-395|A
20005218	471	477	G-395A	DNAMutation	c|G|-395|A
20005218	634	637	G/A	DNAMutation	|G||A
20005218	658	664	G-395A	DNAMutation	c|G|-395|A
20005218	814	820	G-395A	DNAMutation	c|G|-395|A
20005218	1009	1015	G-395A	DNAMutation	c|G|-395|A
20005218	1042	1048	G-395A	DNAMutation	c|G|-395|A
20005218	1481	1487	G-395A	DNAMutation	c|G|-395|A
20005218	1603	1609	G-395A	DNAMutation	c|G|-395|A

19897031|t|An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males.
19897031|a|The interferon regulatory factor (IRF) family of DNA-binding proteins regulates expression of interferon-inducible genes with roles in the immune response and carcinogenesis. IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of c-REL (NF-kappaB) hyperactivation. IRF4 polymorphisms are associated with susceptibility to chronic lymphoid leukemia (CLL) and non-Hodgkin lymphoma (NHL). We examined 13 IRF4 SNPs in 114 cases of childhood acute lymphoblastic leukemia (ALL) and 388 newborn controls from Wales (U.K.) using TaqMan assays. IRF4 intron 4 SNP rs12203592 showed a male-specific risk association (OR=4.4, 95% CI=1.5 to 12.6, P=0.007). Functional consequences of the C>T substitution at this SNP were assessed by cell-based reporter assays using three different cell lines. We found a repressive effect of the rs12203592 wildtype allele C on IRF4 promoter activity (P<0.001) but no repression by the variant allele in any cell line tested. Thus, homozygosity for the rs12203592 variant allele would result in increased IRF4 expression. This increase would be compounded by high levels of NF-kappaB activity in males due to the absence of estrogen. IRF4 differs from other IRFs in its anti-interferon activity which interferes with immune surveillance. We propose that a detailed study of IRF4 can provide information on the mechanism of the sex effect and the role of immune surveillance in childhood ALL development.
19897031	775	785	rs12203592	SNP	rs12203592
19897031	896	899	C>T	DNAMutation	|C||T
19897031	1039	1049	rs12203592	SNP	rs12203592
19897031	1196	1206	rs12203592	SNP	rs12203592

19766614|t|A novel insertion mutation in the SEDL gene results in X-linked spondyloepiphyseal dysplasia tarda in a large Chinese pedigree.
19766614|a|BACKGROUND: Spondyloepiphyseal dysplasia tarda (SEDT) is an X-chromosome linked primary skeletal dysplasia characterized by a disproportionate short-trunked short stature, dysplasia of the large joints and flattened thoracic and lumber vertebral bodies. The objective of this study is to describe a large Chinese SEDT family with a milder phenotype and describe the molecular and clinical findings. METHODS: Eight affected males of the family were diagnosed with SEDT according to their clinical and radiological features. Direct DNA sequencing of the SEDL gene was performed. RT-PCR experiments on total RNA from blood lymphocytes were performed to confirm the defect on the SEDL gene. A short summary of all currently known SEDL gene mutations is presented. RESULTS: DNA sequencing revealed that all the affected males carried an insertion mutation (c.370-371insA) unreported previously, predicted to result in frameshifts and generate a premature stop codon (p.S124fsX127). The identical mutation was also observed in a 10-year old presymptomatic boy of the family. Eight female carriers had the typical sequencing chromatograms of heterozygotes. CONCLUSIONS: Identification of the novel insertion mutation (c.370-371insA) in this SEDT family enables carrier detection and presymptomatic/prenatal diagnosis, but also the detailed molecular and clinical features will be useful for extending the evidence for genetic and phenotypic heterogeneity in SEDT.
19766614	980	993	c.370-371insA	DNAMutation	c|INS|370_371|A
19766614	1090	1102	p.S124fsX127	ProteinMutation	p|S|124||FSX|127
19766614	1339	1352	c.370-371insA	DNAMutation	c|INS|370_371|A

19730022|t|Congestive heart failure with rhabdomyolysis and acute renal failure in a manifesting female carrier of Duchenne muscular dystrophy with duplication of dystrophin gene.
19730022|a|We report a 69-year-old woman who presented with dyspnea, orthopnea, and acute renal failure. She also had proximal muscle weakness suggestive of muscle disease. Her symptoms were alleviated by induced dieresis, although there was high-serum creatine kinase. Investigations for any possible etiologies of rhabdomyolysis were all negative. An X-linked recessive muscle disease was highly suspicious in view of the fact that both of her sons had suffered from muscle disease and died of respiratory failure at the ages of 22 and 29, respectively. Her muscle biopsy showed mosaic pattern with dystrophin antibody against amino-terminal, carboxy-terminal, and rod domain. Her DNA study revealed heterozygous duplication at exon 1 to 6 of the dystrophin gene as well. Therefore, she is a manifesting carrier of dystrophinopathy who was first diagnosed in late adulthood with congestive heart failure, acute episode of spontaneous rhabdomyolysis, and acute renal failure.

19681861|t|Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort.
19681861|a|BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a severe genetic skin blistering disorder caused by mutations in the gene COL7A1, encoding collagen VII. Recently, the MMP1 promoter single nucleotide polymorphism (SNP) rs1799750, designated as 1G 2G, was shown to be involved in modulation of disease severity in patients with recessive DEB (RDEB), and was proposed as a genetic modifier. OBJECTIVES: To identify the molecular basis of DEB in 103 individuals and to replicate the results of the MMP1 promoter SNP analysis in an independent patient group, as verification is necessary in such a rare and heterogeneous disorder. METHODS: To determine the molecular basis of the disease, we performed COL7A1 mutation screening, reverse transcription-polymerase chain reaction (PCR) and real-time quantitative PCR. The status of the MMP1 SNP was analysed by PCR and restriction enzyme digestion and verified by sequencing. RESULTS: We disclosed 42 novel COL7A1 mutations, including the first large genomic deletion of 4 kb affecting only the COL7A1 gene, and three apparently silent mutations affecting splicing. Even though the frequency of the high-risk allele was increased in patients with RDEB, no statistically significant correlation between disease severity and genotype could be made. Also, no correlation was observed with development of squamous cell carcinoma, a severe complication of DEB. CONCLUSIONS: Taken together, the results suggest that the MMP1 SNP is not the sole disease modifier in different forms of DEB, and other genetic and environmental factors contribute to the clinical phenotype.
19681861	431	440	rs1799750	SNP	rs1799750

19559455|t|A combination of defective DNA and protective host factors are found in a set of HIV-1 ancestral LTNPs.
19559455|a|We studied viral evolution in three HIV-1 ancestral patients from a group of LTNPs; although some minor sequences showing viral evolution were detected in all patients, the extremely low viral evolution of their viruses was shown by the phylogenetic analysis of the env sequences. Complete nucleotide sequencing of viral DNA showed the major presence of deletions. In two patients, deletions of 1088 and 228 nucleotides mapped to 5' LTR-gag region; in the other, a 247 nucleotide deletion was positioned in pol gene up to the vif ORF. These deleted genomes became dominant during follow up. Patient's viruses displayed 13 common mutations in conserved residues, from the 5' LTR to the nef gene. These mutations provided evidence of a common origin. Regarding host characteristics, one patient had HLA B2705/B5801; another B1402/B5701; whereas a third showed B3901/B4402 and was Delta32-CCR5 heterozygous. These HIV controllers presented a combination of deleted viral genomes and host protective factors.
19559455	982	989	Delta32	DNAMutation	|DEL||32

19542096|t|Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.
19542096|a|Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies.

19477219|t|Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array.
19477219|a|OBJECTIVE: Mantle cell lymphoma (MCL) is a lymphoma characterized by aberrant activation of CCND1/cyclin D1 followed by sequential genetic abnormalities. Genomic abnormalities in MCL have been extensively examined by classical cytogenetics and microarray-based comparative genomic hybridization techniques, pointing out a number of alterations in genomic regions that correlate with the neoplastic phenotype and survival. Recently, single nucleotide polymorphism genomic microarrays (SNP-chip) have been developed and used for analysis of cancer genomics. This technique allows detection of genomic changes with higher resolution, including loss of heterozygosity without changes of gene dosage, so-called acquired uniparental disomy (aUPD). MATERIALS AND METHODS: We have examined 33 samples of MCL (28 primary MCL and 5 cell lines) using the 250,000 SNP-chip from Affymetrix. RESULTS: Known alterations were confirmed by SNP arrays, including deletion of INK4A/ARF, duplication/amplification of MYC, deletion of ATM, and deletion of TP53. We also identified a duplication/amplification that occurred at 13q involving oncogenic microRNA, miR17-92. We found other genomic abnormalities, including duplication/amplification of cyclin D1, del(1p), del(6q), dup(3q) and dup(18q). Our SNP-chip analysis detected these abnormalities at high resolution, allowing us to narrow the size of the commonly deleted regions, including 1p and 6q. Our SNP-chip analysis detected a number of aUPD sites, including whole chromosome 9 aUPD and 9p aUPD. We also found an MCL case with 19p, leading to homozygous deletion of TNFSF genes. CONCLUSION: SNP-chip analysis detected in MCL very small genomic gains/losses, as well as aUPDs, which could not be detected by more conventional methods.

19444361|t|COL3A1 2209G>A is a predictor of pelvic organ prolapse.
19444361|a|INTRODUCTION AND HYPOTHESIS: A familial tendency has been demonstrated in the etiology of pelvic organ prolapse (POP), but the specific genetic defects have not been identified. Type III collagen is an important factor in the repair of connective tissue, and gene polymorphisms may impair the tensile strength. We hypothesized that polymorphisms in the alpha I chain of the type III collagen protein-encoding gene (COL3A1) pose women at risk for POP. METHODS: In this case-control study, the prevalence of type III collagen polymorphisms was compared in women with and without signs and symptoms of POP. RESULTS: Two hundred and two POP patients and 102 normal parous controls were included. A homozygous single-nucleotide substitution in the coding region of type III collagen (COL3A1 2209G>A, rs1800255) was identified in 27 (13%) POP patients and three (3%) controls (odds ratio, 5.0; 95% confidence interval, 1.4-17.1). CONCLUSIONS: The probability of POP was higher in women with COL3A1 2209G>A. This polymorphism showed to be a relevant risk factor for POP.
19444361	7	14	2209G>A	DNAMutation	r|g|2209|a
19444361	842	849	2209G>A	DNAMutation	r|g|2209|a
19444361	851	860	rs1800255	SNP	rs1800255
19444361	1048	1055	2209G>A	DNAMutation	r|g|2209|a

19429807|t|A novel ATP7A gross deletion mutation in a Korean patient with Menkes disease.
19429807|a|Menkes disease (MD, MIM 309400) is a fatal X-linked recessive disorder that is caused by mutations in the gene encoding ATP7A, a copper-transporting, P-type ATPase. Patients with MD are characterized by progressive hypotonia, seizures, failure to thrive, and death in early childhood. Two Korean patients were diagnosed with Menkes disease by clinical and biochemical findings. We found one missense mutation and one gross deletion in the ATP7A gene in the patients. The missense mutation in Patient 1, c.3943G>A (p.G1315R) in exon 20, was identified in a previous report. Patient 2 had a gross deletion of c.1544-?_2916+?, which was a novel mutation. The patients' mothers were shown to be carriers of the respective mutations. Prenatal DNA diagnosis in the family of Patient 2 was successfully performed, showing a male fetus with the wild-type genotype. The gross deletion is the first mutation to be identified in the ATP7A gene in Korean MD patients. We expect that our findings will be helpful in understanding the wide range of genetic variation in ATP7A in Korean MD patients.
19429807	582	591	c.3943G>A	DNAMutation	c|G|3943|A
19429807	593	601	p.G1315R	ProteinMutation	p|G|1315|R
19429807	686	701	c.1544-?_2916+?	DNAMutation	c|DEL|1544-?_2916+?|

19394258|t|The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome.
19394258|a|Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.
19394258	420	431	c.444-62C>A	DNAMutation	c|C|444-62|A

19365571|t|Macular corneal dystrophy in a Chinese family related with novel mutations of CHST6.
19365571|a|PURPOSE: To identify mutations in the carbohydrate sulfotransferase gene (CHST6) for a Chinese family with macular corneal dystrophy (MCD) and to investigate the histopathological changes in the affected cornea. METHODS: A corneal button of the proband was obtained by penetrating keratoplasty. The half button and ultrathin sections from the other half button were examined with special stains under a light microscope (LM) and an electron microscope (EM) separately. Genomic DNA was extracted from peripheral blood of 11 family members, and the coding region of CHST6 was amplified by the polymerase chain reaction (PCR) method. The PCR products were analyzed by direct sequencing and restriction enzyme digestion. RESULTS: The positive reaction to colloidal iron stain (extracellular blue accumulations in the stroma) was detected under light microscopy. Transmission electron microscopy revealed the enlargement of smooth endoplasmic reticulum and the presence of intracytoplasmic vacuoles. The compound heterozygous mutations, c.892C>T and c.1072T>C, were identified in exon 3 of CHST6 in three patients. The two transversions resulted in the substitution of a stop codon for glutamine at codon 298 (p.Q298X) and a missense mutation at codon 358, tyrosine to histidine (p.Y358H). The six unaffected family individuals carried alternative heterozygous mutations. These two mutations were not detected in any of the 100 control subjects. CONCLUSIONS: Those novel compound heterozygous mutations were thought to contribute to the loss of CHST6 function, which induced the abnormal metabolism of keratan sulfate (KS) that deposited in the corneal stroma. It could be proved by the observation of a positive stain reaction and the enlarged collagen fibers as well as hyperplastic fibroblasts under microscopes.
19365571	1117	1125	c.892C>T	DNAMutation	c|C|892|T
19365571	1130	1139	c.1072T>C	DNAMutation	c|T|1072|C
19365571	1290	1297	p.Q298X	ProteinMutation	p|Q|298|X
19365571	1360	1367	p.Y358H	ProteinMutation	p|Y|358|H

19298002|t|Genetic polymorphism in chemokine CCL22 and susceptibility to Helicobacter pylori infection-related gastric carcinoma.
19298002|a|BACKGROUND: Gastric carcinoma is widely considered to be related to Helicobacter pylori infection, and the chemokine (C-C motif) ligand 22 (CCL22) plays an important role in suppressing immune responses against H. pylori and tumor cells. In this study, the authors examined the association between single nucleotide polymorphisms (SNPs) in the CCL22 gene and the risk of gastric carcinoma. METHODS: Information on SNPs in the CCL22 coding region was obtained from the HapMap Project database. Genotypes were determined in a case-control cohort that consisted of 1001 patients with gastric carcinoma and 1066 controls, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed by using a logistic regression model. Serum H. pylori antibody levels were measured by using an enzyme-linked immunosorbent assay. RESULTS: The 16C-->A SNP (reference SNP no. 4359426) in exon 1 of the CCL22 gene, which causes a 2 aspartate (2Asp) to 2 alanine (2Ala) substitution in the CCL22 protein, was associated with a significantly increased risk of gastric carcinoma. Individuals who were homozygous for the Ala/Ala genotype had an OR of 2.27 (95% CI, 1.28-4.02) compared with individuals who had the Asp/Asp genotype. Stratification analysis indicated that the association was more pronounced among men (OR, 2.64; 95% CI, 1.29-5.41) and among younger individuals (OR, 2.85; 95% CI, 1.36-5.96) compared with women and older individuals. Moreover, a multiplicative joint effect between the CCL22 SNP and H. pylori infection that intensified the risk was observed (OR for the presence of both Ala/Ala genotype and H. pylori infection, 18.37; 95% CI, 2.30-146.67). CONCLUSIONS: The results from this study suggested that the CCL22 polymorphism is associated with an increase risk of developing H. pylori infection-related gastric carcinoma.
19298002	956	963	16C-->A	DNAMutation	|C|16|A
19298002	969	994	reference SNP no. 4359426	SNP	rs4359426

19132389|t|Impact of pepsinogen C polymorphism on individual susceptibility to gastric cancer and its precancerous conditions in a Northeast Chinese population.
19132389|a|PURPOSE: Human pepsinogen C (PGC) is an aspartic protease produced specifically by the gastric mucosa, and is considered as a mature marker of gastric epithelium. This study examined the contributions of PGC polymorphisms and the Helicobacter pylori (H. pylori) infection to the risk of gastric cancer (GC), and its precancerous conditions in a Northeast Chinese population. METHODS: The PGC insertion/deletion polymorphism was evaluated by polymerase chain reaction analysis, followed by direct DNA sequencing in 564 cases of GC, atrophic gastritis (AG), gastric ulcer (GU) and superficial gastritis (as control). All cases were frequency-matched 1:1 by gender and age (+/-5). H. pylori infection was identified by serum anti-H. pylori IgG measurement through enzyme-linked immunosorbent assay. RESULTS: Patients with a homozygous PGC allele 1 genotype had a significant risk of AG [adjusted odds ratio (OR) 3.11; 95% confidence interval (CI) 1.44-6.71] or of GC (OR 3.00; 95% CI 1.38-6.51), and a significantly elevated risk of intestinal metaplasia (OR 1.90, 95% CI 1.11-3.27). PGC polymorphism with H. pylori infection increased risk of GU (OR 8.69; 95% CI 1.01-74.69), and AG (OR 11.12; 95% CI 1.37-90.84) or GC (OR 10.61; 95% CI 1.28-87.79) in a super-multiplicative manner. The S value was 5.40, 6.48 and 4.34; and the AP value was 72.09, 7.00 and 69.69%, respectively. CONCLUSIONS: The PGC gene polymorphism increases an individual's susceptibility to GC and its precancerous conditions. Moreover, the PGC gene polymorphism shows a positive link to H. pylori infection in the development of GC.

19129715|t|Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins.
19129715|a|BACKGROUND/AIMS: To date, four mutations in the IGFALS gene have been reported. We now describe two children of different ethnic background with total acid-labile subunit (ALS) and severe circulating IGF-I/IGFBP-3 deficiencies resulting from three novel mutations in the IGFALS gene. PATIENTS/METHODS: Serum and DNA of patients were analyzed. RESULTS: Case 1 is a 12-year-old boy of Mayan origin. Case 2 is a 5-year-old girl of Jewish/Eastern European (Polish, Russian, Austrian-Hungarian)/Icelandic/European (French, English) ancestry. The reported cases had moderate short stature (-2.91 and -2.14 SDS, respectively), nondetectable serum ALS and extremely low serum concentrations of IGF-I and IGFBP-3. Case 1 harbored a novel homozygous 1308_1316 dup9 mutation in a highly conserved leucine-rich repeat (LRR) 17 motif of exon 2, representing an in-frame insertion of 3 amino acids, LEL. Case 2 harbored a novel heterozygous C60S/L244F mutation in exon 2, located within a highly conserved LRR 1 and LRR 9, respectively. CONCLUSIONS: The identification of additional novel IGFALS mutations, resulting in severe IGF-I/IGFBP-3 and ALS deficiencies, supports IGFALS as a candidate gene of the GH/IGF system, implicated in the pathogenesis of primary IGF deficiency, and represents an important part of its differential diagnosis.
19129715	886	900	1308_1316 dup9	DNAMutation	|DUP|1308_1316|9
19129715	1073	1077	C60S	ProteinMutation	p|C|60|S
19129715	1078	1083	L244F	ProteinMutation	p|L|244|F

19110214|t|A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.
19110214|a|Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.
19110214	922	935	c.6799G --> A	DNAMutation	c|G|6799|A
19110214	953	961	p.D2267N	ProteinMutation	p|D|2267|N

19101703|t|Study of a Taiwanese family with oculopharyngeal muscular dystrophy.
19101703|a|BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. OPMD is caused by a short trinucleotide repeat expansion encoding an expanded polyalanine tract in the polyadenylate binding-protein nuclear 1 (PABPN1) gene. We identified and characterized a PABPN1 mutation in a Taiwanese family with OPMD. METHODS: The phenotypic and genotypic characteristics of all subjects were evaluated in a Taiwanese OPMD family. Genetic alterations in the PABPN1 gene were identified using PCR and DNA sequencing. RESULTS: Ten subjects with OPMD (6 symptomatic and 4 asymptomatic) within the Taiwanese family carried a novel mutation in the PABPN1 gene. The normal (GCG)6(GCA)3GCG sequence was replaced by (GCG)6(GCA)(GCG)4(GCA)3GCG due to an insertion of (GCG)4GCA into the normal allele in the Taiwanese OPMD subjects. CONCLUSIONS: In contrast to a single GCG expansion in most of OPMD patients in the literature, an insertion of (GCG)4GCA in the PABPN1 gene was found in the Taiwanese OPMD subjects. The identification of this mutation appears to support the molecular mechanism of unequal cross-over of two PABPN1 alleles.

19082493|t|Combination of polymorphisms within 5' and 3' untranslated regions of thymidylate synthase gene modulates survival in 5 fluorouracil-treated colorectal cancer patients.
19082493|a|In the present study we explored the effect of three polymorphisms of the TS gene on overall and progression- free survival of colorectal cancer (CRC) patients subjected to 5FU chemotherapy. A 28 bp variable number of tandem repeats (VNTR), a G/C single nucleotide polymorphism (SNP), and a deletion of 6 bp at position 1494 were studied. The possible combined effect of these DNA polymorphisms on the clinical outcome of patients was also evaluated. A retrospective study was carried out on paraffin-embedded sections from 113 patients diagnosed of advanced CRC. TS genotyping methods were polymerase chain reaction (PCR) for VNTR and PCR, followed by restriction length fragment polymorphism (PCR-RFLP) for SNP and ins/del 6 bp. To study the combined effect of TS polymorphisms, four categories were defined accordingly to the level of expression attributed to SNP and ins/del 6 bp genotypes: C_allele 6-, C_6+/6+, G_allele6- and G_6+/6+. VNTR and ins/del 6 bp genotypes varied with tumour anatomical site: 2R/2R genotype was rare in left-sided tumours (7.0% vs. 26.3% of right-sided and 24.1% of rectal cancers; P<0.01), where the variant allele 6- was very frequent (69.0%). Instead, most patients with right-sided tumours were wild-type homozygous 6+/6+ (63.9%) (P<0.01). Heterozygous 6+/6- genotype was more frequent among tumours classified as C (50.0%) and D (76.5%) Dukes stages (P=0.05). None of the studied polymorphisms alone affected overall or progression-free survival (PFS). C_6+/6+ and G_6+/6+ combined genotypes were respectively associated to the best and worst PFS (P=0.03 when compared with each other), while combinations carrying the allele 6- determined an intermediate evolution that might be indicative of a variable response to chemotherapy. The rate of Dukes B stage tumours was unexpectedly high (59.1%) among patients with the unfavourable G_6+/6+ combination. In our study the combination of high TS expression genotypes G_6+/6+ identifies a group of high risk within CRC patients treated with 5FU.
19082493	412	415	G/C	DNAMutation	|G||C
19082493	886	898	ins/del 6 bp	DNAMutation	|INDEL||6
19082493	1040	1052	ins/del 6 bp	DNAMutation	|INDEL||6
19082493	1119	1131	ins/del 6 bp	DNAMutation	|INDEL||6

19047089|t|Genome-wide loss of heterozygosity and uniparental disomy in BRCA1/2-associated ovarian carcinomas.
19047089|a|PURPOSE: The importance of the BRCA gene products in maintaining genomic stability led us to hypothesize that BRCA-associated and sporadic ovarian cancers would have distinctive genetic profiles despite similarities in histologic appearance. EXPERIMENTAL DESIGN: A whole-genome copy number analysis of fresh, frozen, papillary serous ovarian cancer DNA was done using the Affymetrix 50K Xba Mapping Array using each patient's normal genomic DNA as the matched control. Loss of heterozygosity and copy number abnormalities were summarized to define regions of amplification, deletion, or uniparental disomy (UPD), defined as loss of one allele and duplication of the remaining allele. Genomic abnormalities were compared between BRCA-associated and sporadic tumors. RESULTS: We compared 6 BRCA-associated with 14 sporadic papillary serous ovarian carcinomas. Genetic instability, measured by percentage of genome altered, was more pronounced in BRCA-associated tumors (median, 86.6%; range, 54-100%) than sporadic tumors (median, 43.6%; range, 2-83%; P = 0.009). We used frequency plots to show the proportion of cases affected by each type abnormality at each genomic region. BRCA-associated tumors showed genome-wide loss of heterozygosity primarily due to the occurrence of UPD rather than deletion. UPD was found in 100% of the BRCA-associated and 50% of the sporadic tumors profiled. CONCLUSIONS: This study reports on a previously underappreciated genetic phenomenon of UPD, which occurs frequently in ovarian cancer DNA. We observed distinct genetic patterns between BRCA-associated and sporadic ovarian cancers, suggesting that these papillary serous tumors arise from different molecular pathways.

19037252|t|Mutations in phospholipase C epsilon 1 are not sufficient to cause diffuse mesangial sclerosis.
19037252|a|Diffuse mesangial sclerosis occurs as an isolated abnormality or as a part of a syndrome. Recently, mutations in phospholipase C epsilon 1 (PLCE1) were found to cause a nonsyndromic, autosomal recessive form of this disease. Here we describe three children from one consanguineous kindred of Pakistani origin with diffuse mesangial sclerosis who presented with congenital or infantile nephrotic syndrome. Homozygous mutations in PLCE1 (also known as KIAA1516, PLCE, or NPHS3) were identified following genome-wide mapping of single-nucleotide polymorphisms. All affected children were homozygous for a four-basepair deletion in exon 3, which created a premature translational stop codon. Analysis of the asymptomatic father of two of the children revealed that he was also homozygous for the same mutation. We conclude this nonpenetrance may be due to compensatory mutations at a second locus and that mutation within PLCE1 is not always sufficient to cause diffuse mesangial sclerosis.

19012332|t|Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome.
19012332|a|We present a girl who developed adrenocortical adenoma at the age of 1 year and osteosarcoma at the age of 5 years. There was no history of cancer in her parents and their relatives. However, both tumors were typical for the Li-Fraumeni syndrome (LFS), and the patient met criteria for germline TP53 mutation testing. A mutation in codon 282 (Arg282Trp) was identified in her blood lymphocyte genomic DNA. The substitution was found in neither of her parents, which indicated a possibility of a de novo mutation. Unexpectedly, sequencing of the DNA of the patient repeatedly showed allelic imbalance in favor of the normal allele. This observation prompted us to investigate the putative somatic mosaicism in the patient consisting of normal cells and cells heterozygous for the mutation. The imbalance was also examined in two other non-invasively sampled tissues, buccal cells, and cells from the urine sediment, and sequencing was confirmed with two other independent methods. While the findings in blood and the urine sediment were similar, in buccal cells both alleles were present in equal amounts. The allele ratio in lymphocytes was consistent with a mosaic where about 2/3 of cells carried two normal alleles and only 1/3 was heterozygous for the mutation. Despite the mosaicism the girl developed two early childhood tumors of mesodermal origin, and her phenotype was thus not milder than that of other germline TP53 mutation carriers. To our knowledge this is the first description of somatic mosaicism for a de novo TP53 mutation in LFS.
19012332	415	424	Arg282Trp	ProteinMutation	p|R|282|W

18838613|t|A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups.
18838613|a|Inactivation of the tumor suppressor gene, CDKN2A, can occur by deletion, methylation, or mutation. We assessed the principal mode of inactivation in childhood acute lymphoblastic leukemia (ALL) and frequency in biologically relevant subgroups. Mutation or methylation was rare, whereas genomic deletion occurred in 21% of B-cell precursor ALL and 50% of T-ALL patients. Single nucleotide polymorphism arrays revealed copy number neutral (CNN) loss of heterozygosity (LOH) in 8% of patients. Array-based comparative genomic hybridization demonstrated that the mean size of deletions was 14.8 Mb and biallelic deletions composed a large and small deletion (mean sizes, 23.3 Mb and 1.4 Mb). Among 86 patients, only 2 small deletions were below the resolution of detection by fluorescence in situ hybridization. Patients with high hyperdiploidy, ETV6-RUNX1, or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%), whereas patients with t(9;22), t(1;19), TLX3, or TLX1 rearrangements had higher frequencies (61%, 42%, 78%, and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region.

18827003|t|A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression.
18827003|a|CONTEXT: Interindividual variations in glucocorticoid sensitivity have been associated with manifestations of cortisol excess or deficiency and may be partly explained by polymorphisms in the human glucocorticoid receptor (hGR) gene. We studied a 43-yr-old female, who presented with manifestations consistent with tissue-selective glucocorticoid hypersensitivity. We detected a novel, single, heterozygous nucleotide (G --> C) substitution at position 1201 (exon 2) of the hGR gene, which resulted in aspartic acid to histidine substitution at amino acid position 401 in the amino-terminal domain of the hGRalpha. We investigated the molecular mechanisms of action of the natural mutant receptor hGRalphaD401H. METHODS-RESULTS: Compared with the wild-type hGRalpha, the mutant receptor hGRalphaD401H demonstrated a 2.4-fold increase in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone but had similar affinity for the ligand (dissociation constant = 6.2 +/- 0.6 vs. 6.1 +/- 0.6 nm) and time to nuclear translocation (14.75 +/- 0.25 vs. 14.25 +/- 1.13 min). The mutant receptor hGRalphaD401H did not exert a dominant positive or negative effect upon the wild-type receptor, it preserved its ability to bind to glucocorticoid response elements, and displayed a normal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. CONCLUSIONS: The mutant receptor hGRalphaD401H enhances the transcriptional activity of glucocorticoid-responsive genes. The presence of the D401H mutation may predispose subjects to obesity, hypertension, and other manifestations of the metabolic syndrome.
18827003	558	597	(G --> C) substitution at position 1201	DNAMutation	c|G|1201|C
18827003	845	850	D401H	ProteinMutation	p|D|401|H
18827003	935	940	D401H	ProteinMutation	p|D|401|H
18827003	1299	1304	D401H	ProteinMutation	p|D|401|H
18827003	1601	1606	D401H	ProteinMutation	p|D|401|H
18827003	1701	1706	D401H	ProteinMutation	p|D|401|H

18813858|t|Novel mutations in the IRF6 gene in Brazilian families with Van der Woude syndrome.
18813858|a|Van der Woude Syndrome (VWS) is an autosomal craniofacial disorder characterized by lower lip pits and cleft lip and/or palate. Mutations in the interferon regulatory factor 6 (IRF6) gene have been identified in patients with VWS. To identify novel IRF6 mutations in patients affected by VWS, we screened 2 Brazilian families, sequencing the entire IRF6-coding region and flanking intronic boundaries. Two novel heterozygous mutations were identified: a frame shift mutation with deletion of G at the nucleotide position 520 in the exon 6 (520delG), and a missense single nucleotide substitution from T to A at nucleotide position 1135 in exon 8 (T1135A). By using restriction enzyme analysis, we were able to demonstrate the lack of similar mutations in unrelated healthy individuals and non-syndromic cleft lip and palate patients. Our results further confirmed that haploinsufficiency of the IRF6 gene results in VWS.
18813858	624	631	520delG	DNAMutation	|DEL|520|G
18813858	731	737	T1135A	DNAMutation	|T|1135|A

18806880|t|Genetics of Meesmann corneal dystrophy: a novel mutation in the keratin 3 gene in an asymptomatic family suggests genotype-phenotype correlation.
18806880|a|PURPOSE: Juvenile epithelial corneal dystrophy of Meesmann (MCD, OMIM 122100) is a dominantly inherited disorder characterized by fragility of the anterior corneal epithelium and intraepithelial microcyst formation. Although the disease is generally mild and affected individuals are often asymptomatic, some suffer from recurrent erosions leading to lacrimation, photophobia, and deterioration in visual acuity. MCD is caused by mutations in keratin 3 (KRT3) or keratin 12 (KRT12) genes, which encode cornea-specific cytoskeletal proteins. Seventeen mutations in KRT12 and two in KRT3 have been described so far. The purpose of this study was to investigate the genetic background of MCD in a Polish family. METHODS: We report on a three-generation family with MCD. Epithelial lesions characteristic for MCD were visualized with slit-lamp examination and confirmed by in vivo confocal microscopy. Using genomic DNA as a template, all coding regions of KRT3 and KRT12 were amplified and sequenced. Presence of the mutation was verified with restriction endonuclease digestion. RESULTS: In the proband, direct sequencing of the polymerase chain reaction (PCR) product from amplified coding regions of KRT3 and KRT12 revealed a novel 1493A>T heterozygous missense mutation in exon 7 of KRT3, which predicts the substitution of glutamic acid for valine at codon 498 (E498V). Using PCR-Restriction Fragment Length Polymorphism (RFLP) analysis, the mutation was demonstrated to segregate with the disease (four affected members, three non-affected) and to be absent in 100 controls from the Polish population, indicating that it is not a common polymorphism. CONCLUSIONS: Location of the E498V mutation emphasizes the functional relevance of the highly conserved boundary motifs at the COOH-terminus of the alpha-helical rod domain in keratin 3 (K3).
18806880	1378	1385	1493A>T	DNAMutation	c|A|1493|T
18806880	1510	1515	E498V	ProteinMutation	p|E|498|V
18806880	1829	1834	E498V	ProteinMutation	p|E|498|V

18779591|t|Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors.
18779591|a|There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile(146)-->Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlR(I146L)), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlR(I146L) in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future.
18779591	806	820	Ile(146)-->Leu	ProteinMutation	p|I|146|L
18779591	963	968	I146L	ProteinMutation	p|I|146|L
18779591	1354	1359	I146L	ProteinMutation	p|I|146|L

18704161|t|Genetic variation in an individual human exome.
18704161|a|There is much interest in characterizing the variation in a human individual, because this may elucidate what contributes significantly to a person's phenotype, thereby enabling personalized genomics. We focus here on the variants in a person's 'exome,' which is the set of exons in a genome, because the exome is believed to harbor much of the functional variation. We provide an analysis of the approximately 12,500 variants that affect the protein coding portion of an individual's genome. We identified approximately 10,400 nonsynonymous single nucleotide polymorphisms (nsSNPs) in this individual, of which approximately 15-20% are rare in the human population. We predict approximately 1,500 nsSNPs affect protein function and these tend be heterozygous, rare, or novel. Of the approximately 700 coding indels, approximately half tend to have lengths that are a multiple of three, which causes insertions/deletions of amino acids in the corresponding protein, rather than introducing frameshifts. Coding indels also occur frequently at the termini of genes, so even if an indel causes a frameshift, an alternative start or stop site in the gene can still be used to make a functional protein. In summary, we reduced the set of approximately 12,500 nonsilent coding variants by approximately 8-fold to a set of variants that are most likely to have major effects on their proteins' functions. This is our first glimpse of an individual's exome and a snapshot of the current state of personalized genomics. The majority of coding variants in this individual are common and appear to be functionally neutral. Our results also indicate that some variants can be used to improve the current NCBI human reference genome. As more genomes are sequenced, many rare variants and non-SNP variants will be discovered. We present an approach to analyze the coding variation in humans by proposing multiple bioinformatic methods to hone in on possible functional variation.

18398821|t|Genome-wide analysis identifies 16q deletion associated with survival, molecular subtypes, mRNA expression, and germline haplotypes in breast cancer patients.
18398821|a|Breast carcinomas are characterized by DNA copy number alterations (CNAs) with biological and clinical significance. This explorative study integrated CNA, expression, and germline genotype data of 112 early-stage breast cancer patients. Recurrent CNAs differed substantially between tumor subtypes classified according to expression pattern. Deletion of 16q was overrepresented in Luminal A, and a predictor of good prognosis, both overall and for the nonluminal A subgroups. The deleted region most significantly associated with survival mapped to 16q22.2, harboring the genes TXNL4B and DXH38, whose expression was strongly correlated with the deletion. The area most frequently deleted resided on 16q23.1, 3.5 MB downstream of the area most significantly associated with survival, and included the tumor suppressor gene ADAMTS18 and the cell recognition gene CNTNAP4. Whole-genome association analysis identified germline single nucleotide polymorphisms (SNPs) and their corresponding haplotypes, residing on several different chromosomes, to be associated with deletion of 16q. The genes where these SNPs reside encode proteins involved in the extracellular matrix (CHST3 and SPOCK2), in regulation of the cell cycle (JMY, PTPRN2, and Cwf19L2) and chromosome stability (KPNB1).

18385169|t|TNFA -308G>A in two international population-based cohorts and risk of asthma.
18385169|a|Genetic association studies have related the tumour necrosis factor-alpha gene (TNFA) guanine to adenine substitution of nucleotide -308 (-308G>A) polymorphism to increased risk of asthma, but results are inconsistent. The aim of the present study was to test whether two single-nucleotide polymorphisms, of TNFA and of the lymphotoxin-alpha gene (LTA), are associated with asthma, bronchial hyperresponsiveness and atopy in adults, by combining the results of two large population-based multicentric studies and conducting a meta-analysis of previously published studies. The European Community Respiratory Health Survey (ECRHS) and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) used comparable protocols, including questionnaires for respiratory symptoms and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped at TNFA -308 and LTA 252. Logistic regression employing fixed and random effects models and nonparametric techniques were used. The prevalence of asthma was 6%. The TNFA -308G>A polymorphism was associated with increased asthma prevalence and with bronchial hyperresponsiveness. No consistent association was found for atopy. The LTA 252A>G polymorphism was not associated with any of the outcomes. A meta-analysis of 17 studies showed an increased asthma risk for the TNFA -308 adenine allele. The tumour necrosis factor-alpha gene nucleotide -308 polymorphism is associated with a moderately increased risk of asthma and bronchial hyperresponsiveness, but not with atopy. These results are supported by a meta-analysis of previously published studies.
18385169	5	12	-308G>A	DNAMutation	c|G|-308|A
18385169	217	224	-308G>A	DNAMutation	c|G|-308|A
18385169	1138	1145	-308G>A	DNAMutation	c|G|-308|A
18385169	1302	1308	252A>G	DNAMutation	c|A|252|G

18272172|t|A splice site mutation in hERG leads to cryptic splicing in human long QT syndrome.
18272172|a|Mutations in the human ether-a-go-go-related gene (hERG) cause type 2 long QT syndrome. In this study, we investigated the pathogenic mechanism of the hERG splice site mutation 2398+1G>C and the genotype-phenotype relationship of mutation carriers in three unrelated kindreds with long QT syndrome. The effect of 2398+1G>C on mRNA splicing was studied by analysis of RNA isolated from lymphocytes of index patients and using minigenes expressed in HEK293 cells and neonatal rat ventricular myocytes. RT-PCR analysis revealed that the 2398+1G>C mutation disrupted the normal splicing and activated a cryptic splice donor site in intron 9, leading to the inclusion of 54 nt of the intron 9 sequence in hERG mRNA. The cryptic splicing resulted in an in-frame insertion of 18 amino acids in the middle of the cyclic nucleotide binding domain. In patch clamp experiments the splice mutant did not generate hERG current. Western blot and immunostaining studies showed that the mutant expressed an immature form of hERG protein that failed to reach the plasma membrane. Coexpression of the mutant and wild-type channels led to a dominant negative suppression of wild-type channel function by intracellular retention of heteromeric channels. Our results demonstrate that 2398+1G>C activates a cryptic site and generates a full-length hERG protein with an insertion of 18 amino acids, which leads to a trafficking defect of the mutant channel.
18272172	261	270	2398+1G>C	DNAMutation	c|G|2398+1|C
18272172	397	406	2398+1G>C	DNAMutation	c|G|2398+1|C
18272172	618	627	2398+1G>C	DNAMutation	c|G|2398+1|C
18272172	1347	1356	2398+1G>C	DNAMutation	c|G|2398+1|C

18270997|t|Catechol-O-methyltransferase (COMT) gene variants: possible association of the Val158Met variant with opiate addiction in Hispanic women.
18270997|a|Catechol-O-methyltransferase (COMT) catalyzes the breakdown of catechol neurotransmitters, including dopamine, which plays a prominent role in drug reward. A common single nucleotide polymorphism (SNP), G472A, codes for a Val158Met substitution and results in a fourfold down regulation of enzyme activity. We sequenced exon IV of COMT gene in search for novel polymorphisms and then genotyped four out of five identified by direct sequencing, using TaqMan assay on 266 opioid-dependent and 173 control subjects. Genotype frequencies of the G472A SNP varied significantly (P = 0.029) among the three main ethnic/cultural groups (Caucasians, Hispanics, and African Americans). Using a genotype test, we found a trend to point-wise association (P = 0.053) of the G472A SNP in Hispanic subjects with opiate addiction. Further analysis of G472A genotypes in Hispanic subjects with data stratified by gender identified a point-wise significant (P = 0.049) association of G/A and A/A genotypes with opiate addiction in women, but not men. These point-wise significant results are not significant experiment-wise (at P < 0.05) after correction for multiple testing. No significant association was found with haplotypes of the three most common SNPs. Linkage disequilibrium patterns were similar for the three ethnic/cultural groups.
18270997	79	88	Val158Met	ProteinMutation	p|V|158|M
18270997	341	346	G472A	DNAMutation	c|G|472|A
18270997	360	369	Val158Met	ProteinMutation	p|V|158|M
18270997	679	684	G472A	DNAMutation	c|G|472|A
18270997	899	904	G472A	DNAMutation	c|G|472|A
18270997	973	978	G472A	DNAMutation	c|G|472|A

18266724|t|Histamine-N-methyl transferase polymorphism and risk for migraine.
18266724|a|BACKGROUND/OBJECTIVES: Histamine has been implicated in the pathogenesis of migraine. In the CNS, histamine is almost exclusively metabolized by the polymorphic enzyme histamine N-methyltransferase (HNMT). The HNMT gene (chromosome 2q22.1), shows diverse single nucleotide polymorphisms. One of these, located in exon 4 C314T, causes the amino acid substitution Thr105Ile, related to decreased enzyme activity. The aim of this study was to investigate the possible association between HNMT polymorphism and the risk for migraine. METHODS: We studied the frequency of the HNMT genotypes and allelic variantes in 197 patients with migraine and 245 healthy controls using a PCR-RLFP method. RESULTS: The frequencies of the HNMT genotypes and allelic variants did not differ significantly between migraine patients and controls, and were unrelated with the age of onset of migraine attacks, gender, personal history of allergic diseases, family history of migraine, or presence of aura. CONCLUSION: The results of the present study suggest that HNMT polymorphism in not related with the risk for migraine.
18266724	387	392	C314T	DNAMutation	c|C|314|T
18266724	429	438	Thr105Ile	ProteinMutation	p|T|105|I

18164595|t|Mutations in the hairless gene underlie APL in three families of Pakistani origin.
18164595|a|BACKGROUND: Atrichia with papular lesions (APL) (OMIM#209500) is a rare autosomal recessively inherited form of irreversible alopecia characterized by papular lesions of keratin-filled cysts on various regions of the body. Males and females are equally affected and present with a distinct pattern of total hair loss on scalp, axilla and body. It begins shortly after birth with the development of hair loss, and patients are normally devoid of eyelashes and eyebrows. Mutations in the hairless (HR) gene have been previously shown to be responsible for APL. OBJECTIVE: In this study, we studied the molecular basis of APL in three unrelated families of Pakistani origin. METHOD: Molecular analysis of the HR genes was performed on genomic DNA from probands and family members. RESULTS: DNA sequencing of the HR gene in family A revealed a novel homozygous 2bp deletion in exon 6 leading to a frameshift and a downstream premature termination codon in exon 8 (1782-83delAG). In family B, we identified a novel homozygous deletion of a G nucleotide at the exon 15-intron 15 boundary, termed 3097delG. Family C carries a previously reported missense mutation consisting of an A-to-G transition at nucleotide 276 resulting in the mutation N970S in exon 14. CONCLUSION: Two mutations identified in this study are novel mutations in the HR gene and extend the body of evidence implicating the hairless gene family in the pathogenesis of human skin disorders. The one previously reported mutation suggests it may represent a recurrent mutation, or alternatively, an allele that is widely dispersed around the world.
18164595	1043	1055	1782-83delAG	DNAMutation	|DEL|1782_1783|AG
18164595	1173	1181	3097delG	DNAMutation	|DEL|3097|G
18164595	1319	1324	N970S	ProteinMutation	p|N|970|S

18046082|t|Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy.
18046082|a|BACKGROUND/AIMS: Lipoprotein glomerulopathy (LPG) is a rare disease characterized by thrombus-like substances in markedly dilated glomerular capillaries and elevated plasma levels of apolipoprotein E (apoE). Previous studies have shown that genetic disorders of apoE may contribute to the pathogenesis of LPG, but LPG may not be caused by apoE gene mutations in Chinese patients. This study investigated the association of a new variant of apoE with LPG in a Chinese family. METHODS: The apoE gene in a family with 4 LPG patients was sequenced. The polymerase chain reaction product of coding region of apoE exon 4 was cloned into pMD 18-T vector and then sequenced. RESULTS: A novel point mutation in exon 4 of the apoE gene was identified in all 4 LPG patients and 1 asymptomatic family member. Sequence analysis confirmed a nucleotide G to C point mutation in exon 4 (base 308) of the apoE gene in all patients and the asymptomatic family member. This missense mutation denotes amino acid substitution of the proline residue for arginine residue at position 150 of apoE. Those patients were all heterozygotes with apoE Guangzhou. One of 2 grandsons was a heterozygous carrier of apoE Guangzhou, although he did not have proteinuria. CONCLUSION: The results of this study suggest that apoE (arginine 150 proline) is a novel apoE variant that etiologically related to LPG. This variant (apoE Guangzhou) may cause a marked molecular conformational change of the apoE and thus impair its binding ability to lipids.
18046082	46	66	arginine 150 proline	ProteinMutation	p|R|150|P
18046082	1420	1440	arginine 150 proline	ProteinMutation	p|R|150|P

18036257|t|Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype.
18036257|a|BACKGROUND: Osteoporosis is defined as the loss of bone mineral density that leads to bone fragility with aging. Population-based case-control studies have identified polymorphisms in many candidate genes that have been associated with bone mass maintenance or osteoporotic fracture. To investigate single nucleotide polymorphisms (SNPs) that are associated with osteoporosis, we examined the genetic variation among Koreans by analyzing 81 genes according to their function in bone formation and resorption during bone remodeling. METHODS: We resequenced all the exons, splice junctions and promoter regions of candidate osteoporosis genes using 24 unrelated Korean individuals. Using the common SNPs from our study and the HapMap database, a statistical analysis of deviation in heterozygosity depicted. RESULTS: We identified 942 variants, including 888 SNPs, 43 insertion/deletion polymorphisms, and 11 microsatellite markers. Of the SNPs, 557 (63%) had been previously identified and 331 (37%) were newly discovered in the Korean population. When compared SNPs in the Korean population with those in HapMap database, 1% (or less) of SNPs in the Japanese and Chinese subpopulations and 20% of those in Caucasian and African subpopulations were significantly differentiated from the Hardy-Weinberg expectations. In addition, an analysis of the genetic diversity showed that there were no significant differences among Korean, Han Chinese and Japanese populations, but African and Caucasian populations were significantly differentiated in selected genes. Nevertheless, in the detailed analysis of genetic properties, the LD and Haplotype block patterns among the five sub-populations were substantially different from one another. CONCLUSION: Through the resequencing of 81 osteoporosis candidate genes, 118 unknown SNPs with a minor allele frequency (MAF) > 0.05 were discovered in the Korean population. In addition, using the common SNPs between our study and HapMap, an analysis of genetic diversity and deviation in heterozygosity was performed and the polymorphisms of the above genes among the five populations were substantially differentiated from one another. Further studies of osteoporosis could utilize the polymorphisms identified in our data since they may have important implications for the selection of highly informative SNPs for future association studies.

17962469|t|Novel TULP1 mutation causing leber congenital amaurosis or early onset retinal degeneration.
17962469|a|PURPOSE: To report a large, consanguineous Algerian family affected with Leber congenital amaurosis (LCA) or early-onset retinal degeneration (EORD). METHODS: All accessible family members underwent a complete ophthalmic examination, and blood was obtained for DNA extraction. Homozygosity mapping was performed with markers flanking 12 loci associated with LCA. The 15 exons of TULP1 were sequenced. RESULTS: Seven of 30 examined family members were affected, including five with EORD and two with LCA. All patients had nystagmus, hemeralopia, mild myopia, and low visual acuity without photophobia. Fundus features were variable among EORD patients: typical spicular retinitis pigmentosa or clumped pigmented retinopathy with age-dependent macular involvement. A salt-and-pepper retinopathy with midperipheral retinal pigment epithelium (RPE) atrophy was present in the older patients with LCA, whereas the retina appeared virtually normal in the younger ones. Both scotopic and photopic electroretinograms were nondetectable. Fundus imaging revealed a perifoveal ring of increased fundus autofluorescence (FAF) in the proband, and optical coherence tomography disclosed a thinned retina, mainly due to photoreceptor loss. Linkage analysis identified a region of homozygosity on chromosome 6, region p21.3, and mutation screening revealed a novel 6-base in-frame duplication, in the TULP1 gene. CONCLUSIONS: Mutation in the TULP1 gene is a rare cause of LCA/EORD, with only 14 mutations reported so far. The observed intrafamilial phenotypic variability could be attributed to disease progression or possibly modifier alleles. This study provides the first description of FAF and quantitative reflectivity profiles in TULP1-related retinopathy.

17951029|t|Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene.
17951029|a|BACKGROUND: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development. OBJECTIVES: To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata. METHODS: Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene. RESULTS: DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes. CONCLUSION: Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis.
17951029	64	71	p.E300X	ProteinMutation	p|E|300|X
17951029	1058	1094	G>T substitution at nucleotide c.898	DNAMutation	c|G|898|T
17951029	1232	1239	p.E300X	ProteinMutation	p|E|300|X

17868390|t|A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family.
17868390|a|We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.
17868390	24	34	IVS8+4 A>G	DNAMutation	c|A|IVS8+4|G
17868390	659	669	IVS8+4 A>G	DNAMutation	c|A|IVS8+4|G
17868390	998	1008	IVS8+4 A>G	DNAMutation	c|A|IVS8+4|G

17635946|t|A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance.
17635946|a|BACKGROUND: Generalized glucocorticoid resistance is a rare condition characterized by partial, end-organ insensitivity to glucocorticoids, compensatory elevations in adrenocorticotropic hormone and cortisol secretion, and increased production of adrenal steroids with androgenic and/or mineralocorticoid activity. We have identified a new case of glucocorticoid resistance caused by a novel mutation of the human glucocorticoid receptor (hGR) gene and studied the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. METHODS AND RESULTS: We identified a novel, single, heterozygous nucleotide (T --> C) substitution at position 2209 (exon 9alpha) of the hGR gene, which resulted in phenylalanine (F) to leucine (L) substitution at amino acid position 737 within helix 11 of the ligand-binding domain of the protein. Compared with the wild-type receptor, the mutant receptor hGRalphaF737L demonstrated a significant ligand-exposure time-dependent decrease in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone and displayed a 2-fold reduction in the affinity for ligand, a 12-fold delay in nuclear translocation, and an abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. The mutant receptor preserved its ability to bind to DNA and exerted a dominant-negative effect on the wild-type hGRalpha only after a short duration of exposure to the ligand. CONCLUSIONS: The mutant receptor hGRalphaF737L causes generalized glucocorticoid resistance because of decreased affinity for the ligand, marked delay in nuclear translocation, and/or abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. These findings confirm the importance of the C terminus of the ligand-binding domain of the receptor in conferring transactivational activity.
17635946	793	832	(T --> C) substitution at position 2209	DNAMutation	c|T|2209|C
17635946	1082	1087	F737L	ProteinMutation	p|F|737|L
17635946	1697	1702	F737L	ProteinMutation	p|F|737|L

17634480|t|Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer.
17634480|a|PURPOSE: The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer. PATIENTS AND METHODS: We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer. RESULTS: Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes. CONCLUSION: These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.
17634480	797	805	rs713041	SNP	rs713041
17634480	810	818	rs757229	SNP	rs757229
17634480	1010	1018	rs713041	SNP	rs713041

17628794|t|Manganese superoxide dismutase (Mn-SOD) gene polymorphisms in urolithiasis.
17628794|a|Polymorphism in manganese superoxide dismutase gene (Mn-SOD) is a new approach to identify its probable association with urolithiasis. Oxidative stress may be involved in the development of stone formation in the renal system. MnSOD is one of the primary enzymes that directly scavenges potential harmful oxidizing species. A valine (Val) to alanine (Ala) substitution at amino acid 16, occurring in the mitochondrial targeting sequence of the MnSOD gene, has been associated with an increase in urolithiasis risk. This study was conducted to investigate the association of MnSOD gene polymorphism with the risk of urolithiasis. We investigated the MnSOD in 66 stone-forming adults and 72 healthy volunteers. DNA was isolated from peripheral blood and genotyping was performed with PCR-based methods. Then PCR products were cut by BsaW1. Products were run on 3% agarose gel, 246 bp regions were 1-Ala-9, 164 and 82 bp products were determined as 2 Val-9. Chi-square test was used for comparison between patients and controls. In the control group the homozygote Ala allele was significantly higher than in the patient group (P < 0.01). The distribution of Ala/Val and homozygote Val alleles in the patient group was significantly higher than in the control group (P < 0.05). MnSOD genotype determination may provide a tool to identify individuals who are at risk of urolithiasis. This experiment also provides data about antioxidant status and stone formation.

17615540|t|A novel "pearl box" cataract associated with a mutation in the connexin 46 (GJA3) gene.
17615540|a|PURPOSE: To undertake mutation screening in the connexin 46 (GJA3) gene in seven congenital cataract families of Indian origin. METHODS: Seven Indian families with congenital cataract were analyzed by detailed family history and clinical evaluation. Each family had two to five affected members. Mutation screening was carried out in the candidate gene, connexin 46 (GJA3), using bidirectional sequencing of amplified products. Segregation of the observed change with the disease phenotype was further tested by restriction fragment length polymorphism (RFLP). RESULTS: Sequencing of the coding region of GJA3 showed the presence of a novel, heterozygous C260T change in one family (CC-472) who had two affected members. The cataract phenotype gave the appearance like a "pearl box" in these two affected individuals of this family. The observed C260T substitution created a novel restriction enzyme site for NlaIII and resulted in substitution of highly conserved threonine at position 87 by methionine (T87M). NlaIII restriction digestion analysis revealed this nucleotide change was not in unaffected members of this family or in 100 unrelated control subjects (200 chromosomes) with the same ethnic background. CONCLUSIONS: This is a novel mutation identified in the second transmembrane domain of the connexin 46. These findings thus expand the mutation spectrum of the GJA3 in association with congenital cataract.
17615540	743	748	C260T	DNAMutation	c|C|260|T
17615540	934	939	C260T	DNAMutation	c|C|260|T
17615540	1093	1097	T87M	ProteinMutation	p|T|87|M

17595233|t|Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease.
17595233|a|BACKGROUND AND AIMS: A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD). Materials and METHODS: A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6. RESULTS: When compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively. CONCLUSION: Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD.
17595233	2271	2276	D299G	ProteinMutation	p|D|299|G
17595233	2286	2291	P631H	ProteinMutation	p|P|631|H

17495183|t|Tenomodulin is associated with obesity and diabetes risk: the Finnish diabetes prevention study.
17495183|a|We recently showed that long-term weight reduction changes the gene expression profile of adipose tissue in overweight individuals with impaired glucose tolerance (IGT). One of the responding genes was X-chromosomal tenomodulin (TNMD), a putative angiogenesis inhibitor. Our aim was to study the associations of individual single nucleotide polymorphisms and haplotypes with adiposity, glucose metabolism, and the risk of type 2 diabetes (T2D). Seven single nucleotide polymorphisms from two different haploblocks were genotyped from 507 participants of the Finnish Diabetes Prevention Study (DPS). Sex-specific genotype effects were observed. Three markers of haploblock 1 were associated with features of adiposity in women (rs5966709, rs4828037) and men (rs11798018). Markers rs2073163 and rs1155794 from haploblock 2 were associated with 2-hour plasma glucose levels in men during the 3-year follow-up. The same two markers together with rs2073162 associated with the conversion of IGT to T2D in men. The risk of developing T2D was approximately 2-fold in individuals with genotypes associated with higher 2-hour plasma glucose levels; the hazard ratios were 2.192 (p = 0.025) for rs2073162-A, 2.191 (p = 0.027) for rs2073163-C, and 1.998 (p = 0.054) for rs1155974-T. These results suggest that TNMD polymorphisms are associated with adiposity and also with glucose metabolism and conversion from IGT to T2D in men.
17495183	824	833	rs5966709	SNP	rs5966709
17495183	835	844	rs4828037	SNP	rs4828037
17495183	855	865	rs11798018	SNP	rs11798018
17495183	876	885	rs2073163	SNP	rs2073163
17495183	890	899	rs1155794	SNP	rs1155794
17495183	1039	1048	rs2073162	SNP	rs2073162
17495183	1282	1291	rs2073162	SNP	rs2073162
17495183	1317	1326	rs2073163	SNP	rs2073163
17495183	1356	1365	rs1155974	SNP	rs1155974

17437275|t|Novel mutations in the ZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy.
17437275|a|We describe the search for mutations in six unrelated Czech and four unrelated British families with posterior polymorphous corneal dystrophy (PPCD); a relatively rare eye disorder. Coding exons and intron/exon boundaries of all three genes (VSX1, COL8A2, and ZEB1/TCF8) previously reported to be implicated in the pathogenesis of this disorder were screened by DNA sequencing. Four novel pathogenic mutations were identified in four families; two deletions, one nonsense, and one duplication within exon 7 in the ZEB1 gene located at 10p11.2. We also genotyped the Czech patients to test for a founder haplotype and lack of disease segregation with the 20p11.2 locus we previously described. Although a systematic clinical examination was not performed, our investigation does not support an association between ZEB1 changes and self reported non-ocular anomalies. In the remaining six families no disease causing mutations were identified thereby indicating that as yet unidentified gene(s) are likely to be responsible for PPCD.

17426470|t|3' Mutation of the APC gene and family history of FAP in a patient with apparently sporadic desmoid tumors.
17426470|a|Desmoid tumors may occur sporadically or as part of the extraintestinal manifestations of familial adenomatous polyposis. Different phenotypes have been described and some genotype-phenotype correlations have been raised, associated with different sites of germline mutations in the adenomatous polyposis coli (APC) gene. We report on a 42-year-old woman ascertained for a large desmoid tumor of the anterior chest wall with pleural involvement, which persistently recurred despite a decade of treatment including hormone therapy, chemotherapy, and surgery. Spontaneous disappearance of the tumor was later noted after 1 year without any treatment and confirmed after 4 years of regular follow-up. Repeated colonoscopies were normal in the proband and DNA sequencing showed a frameshift mutation due to a single adenosine deletion at position 5772 (codon 1924). This mutation, located in the exon 15 at the 3' end of the APC gene, leads to an unusual and late onset phenotype. The pedigree revealed other isolated or familial adenomatous polyposis-associated cases of desmoid tumors. This family report shows that a molecular analysis of the APC gene should be performed in familial desmoid tumors for accurate genetic counseling and follow-up.

17372760|t|Atypical Rothmund-Thomson syndrome in a patient with compound heterozygous mutations in RECQL4 gene and phenotypic features in RECQL4 syndromes.
17372760|a|We describe the natural history of the RTSII phenotype in a 7-year-old boy who developed intrauterine and postnatal growth retardation, failure to thrive and persisting diarrhoea. The growth hormone stimulation test identified an isolated growth hormone deficiency. Since infancy, the patient manifested skin lesions characterized by a very mild poikilodermic-like appearance on the cheeks only, widespread caf  -au-lait spots and the absence of eyebrows and eyelashes. There was no cataract. Orthopaedic and radiologic work-up identified the absence of thumb anomaly and radial head luxation and patellar hypoplasia. Neurologic, cognitive milestones and intelligence were normal. The cytogenetic work-up did not show any anomaly. Based on this clinical presentation, we carried out a sequencing analysis of the RECQL4 gene, which is responsible for Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes and found a splice site mutation (IVS10-1G>A) and a nucleotide substitution in exon 12 (L638P). The mother was identified as a carrier for the substitution in exon 12 and the father for the splice site mutation, respectively. An analysis of the transcripts focused on the RECQL4 helicase domain: in the proband only those generated from the maternal L638 allele were present. This case report emphasizes the clinical overlap between RAPADILINO and Rothmund-Thomson syndromes within a continuum phenotypic spectrum. The distinctive set of clinical signs displayed by the patient may be accounted for by his unique combination of two different RECQL4 mutations. The molecular findings provide information that enhances our comprehension of genotype-phenotype correlations in RECQL4 diseases, enables a more precise genetic counseling to the parents and facilitates a more appropriate long-term follow-up to the affected child.
17372760	1086	1096	IVS10-1G>A	DNAMutation	c|G|IVS10-1|A
17372760	1140	1145	L638P	ProteinMutation	p|L|638|P

17327916|t|Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays.
17327916|a|BACKGROUND: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array. FINDINGS: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. CONCLUSIONS: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy.

17311329|t|Epstein Barr virus genotypes and LMP-1 variants in HIV-infected patients.
17311329|a|Two Epstein Barr virus (EBV) genotypes: EBV-1 and EBV-2 have been described. A 30-bp deletion in latent membrane protein-1 gene (del-LMP-1) has been identified in various pathologies. The aim of this study was to determine EBV genotypes and 30-bp deletion frequency in HIV-infected patients from Argentina. The study was performed on 258 individuals: Cases: 144 HIV-infected patients that included: (a) 7 AIDS patients with primary central nervous system lymphoma (PCNSL), (b) 62 AIDS patients, and (c) 75 asymptomatic HIV-infected patients. Controls: 114 HIV-negative individuals. EBV genotypes and variants in LMP-1 gene were detected by polymerase chain reaction (PCR)-Southern blot on DNA extracted from peripheral blood mononuclear cells and brain biopsies. In PCNSL, the presence of EBV was confirmed by EBER RNA in situ hybridization, and DNA sequencing of 3' end LMP-l gene of PCR products was performed. In HIV-infected patients, EBV-1 was detected in 48.6%, EBV-2 in 18.8%, and co-infection with both genotypes in 32.6%. In control group, EBV-1 was present in 74.3%, EBV-2 in 12.4%, and co-infection in 13.3%. Del-LMP-1 was found in 44.4% of HIV-infected patients samples (20.7% alone and 23.7% co-infection with non-deleted form) while it was found in 25.3% (6.3% alone and 19% with co-infection) in HIV-negative individuals. In HIV-infected patients EBV-2, co-infection and 30-bp deletion are more prevalent than in control group. In all, PCNSL brain biopsies samples, del-LMP-1 always was detected with EBV-2, but more cases would have to be included to draw definitive conclusions.

17286451|t|Retinoblastoma in India : microsatellite analysis and its application in genetic counseling.
17286451|a|OBJECTIVES: This study was conducted with two objectives. The first was to estimate the frequency of loss of heterozygosity (LOH) of the RB1 gene as a mechanism in disease causation in tumors of patients from India. The second objective was to employ RB1 molecular deletion and microsatellite-based linkage analysis as laboratory tools, while counseling families with a history of retinoblastoma (RB). METHODS: DNA was extracted from peripheral blood and tumors of 54 RB patients and their relatives. Eight fluorescent microsatellite markers, both intragenic and flanking the RB1 gene, were used. After PCR amplification, samples were run on an ABI PRISM 310 genetic analyzer for LOH, deletion detection, and haplotype generation. RESULTS: LOH was found in conjunction with tumor formation in 72.9% of RB patients (39/54 patients; p=0.001; 95% CI 0.6028, 0.8417); however, we could not associate various other clinical parameters of RB patients with the presence or absence of RB1 LOH. Seven germline deletions (13% of RB patients) were identified, and the maternal allele was more frequently lost (p=0.01). A disease co-segregating haplotype was detected in two hereditary autosomal dominant cases. CONCLUSION: LOH of the RB1 gene could play an important role in tumor formation. Large deletions involving RB1 were observed, and a disease co-segregating haplotype was used for indirect genetic testing. This is the first report from India where molecular testing has been applied for RB families in conjunction with genetic counseling. In tertiary ophthalmic practice in India, there is an emerging trend towards the application of genetical knowledge in clinical practice.

17221831|t|The G51S purine nucleoside phosphorylase polymorphism is associated with cognitive decline in Alzheimer's disease patients.
17221831|a|Alzheimer's disease (AD) is a polygenic and multifactorial complex disease, whose etiopathology is still unclear, however several genetic factors have shown to increase the risk of developing the disease. Purine nucleotides and nucleosides play an important role in the brain. Besides their role in neurotransmission and neuromodulation, they are involved in trophic factor release, apoptosis, and inflammatory responses. These mediators may also have a pivotal role in the control of neurodegenerative processes associated with AD. In this report the distribution of the exonic G/A single nucleotide polymorphism (SNP) in purine nucleoside phosphorylase (PNP) gene, resulting in the amino acid substitution serine to glycine at position 51 (G51S), was investigated in a large population of AD patients (n=321) and non-demented control (n=208). The PNP polymorphism distribution was not different between patients and controls. The polymorphism distribution was also analyzed in AD patients stratified according to differential progressive rate of cognitive decline during a 2-year follow-up. An increased representation of the PNP AA genotype was observed in AD patients with fast cognitive deterioration in comparison with that from patients with slow deterioration rate. Our findings suggest that the G51S PNP polymorphism is associated with a faster rate of cognitive decline in AD patients, highlighting the important role of purine metabolism in the progression of this neurodegenerative disorder.
17221831	4	8	G51S	ProteinMutation	p|G|51|S
17221831	703	706	G/A	DNAMutation	|G||A
17221831	866	870	G51S	ProteinMutation	p|G|51|S
17221831	1428	1432	G51S	ProteinMutation	p|G|51|S

17185385|t|Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia.
17185385|a|Unusual forms of amyotrophic lateral sclerosis (ALS-G), Parkinsonism dementia complex (PDC-G) and Guam dementia (GD) are found in Chamorros, the indigenous people of Guam. Neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathologic feature of these closely related disorders. To determine if variation in the gene that encodes microtubule-associated protein tau gene (MAPT) contributes to risk for these disorders, we genotyped nine single nucleotide polymorphism (SNP) sites and one insertion/deletion in the 5' end of MAPT in 54 ALS-G, 135 PDC-G, 153 GD and 258 control subjects, all of whom are Chamorros. Variation at three SNPs (sites 2, 6 and 9) influenced risk for ALS-G, PDC-G and GD. SNP2 acts through a dominant mechanism and is independent of the risk conferred by SNPs 6 and 9, the latter two acting by a recessive mechanism. Persons with the high-risk SNP6 and SNP9 AC/AC diplotype had an increased risk of 3-fold [95% confidence interval (CI)=1.10-8.25] for GD, 4-fold (95% CI=1.40-11.64) for PDC-G and 6-fold (95% CI=1.44-32.14) for ALS-G, compared to persons with other diplotypes after adjusting for SNP2. Carriers of the SNP2 G allele had an increased risk of 1.6-fold (95% CI=1.00-2.62) for GD, 2-fold (95% CI=1.28-3.66) for PDC-G, and 1.5-fold (95% CI=0.74-3.00) for ALS-G, compared to non-carriers after adjusting for SNPs 6 and 9. Others have shown that SNP6 is also associated with risk for progressive supranuclear palsy. These two independent cis-acting sites presumably influence risk for Guam neuro-degenerative disorders by regulating MAPT expression.

17177139|t|A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome.
17177139|a|Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.
17177139	18	23	E333D	ProteinMutation	p|E|333|D
17177139	497	502	E333D	ProteinMutation	p|E|333|D
17177139	1107	1114	1284A>C	DNAMutation	|A|1284|C
17177139	1198	1203	E333D	ProteinMutation	p|E|333|D
17177139	1295	1300	E333D	ProteinMutation	p|E|333|D
17177139	1509	1514	E333D	ProteinMutation	p|E|333|D
17177139	1931	1936	E333D	ProteinMutation	p|E|333|D

17065479|t|Homozygous deletion related to Alu repeats in RLBP1 causes retinitis punctata albescens.
17065479|a|PURPOSE: Retinitis punctata albescens (RPA) is an infrequently occurring form of autosomal recessive (and rarely dominant) retinal dystrophy featuring early-onset severe night blindness and tiny, dotlike, white deposits in the fundus. RPA is associated mostly with mutations in RLBP1 and occasionally in RHO, RDS, and RDH5. In this study, mutations were sought in RLBP1, which encodes the retinol binding protein CRALBP in patients with typical RPA. METHODS: Clinical investigation included funduscopy, visual field testing, electroretinogram recording, and adaptometry. The 7 coding exons (3-9) of RLBP1 and the 15th (last) exon of ABDH2 were PCR amplified and sequenced. Long-distance PCR and cloning of genomic DNA were performed to characterize the deletion. RESULTS: The study involved a 24-year-old Moroccan patient with typical RPA, born of first-cousin parents. He carried a 7.36-kb homozygous deletion encompassing the last 3 exons of RLBP1 (7, 8, and 9) and part of the intergenic region between RLBP1 and ABHD2, which lies downstream of RLBP1. This deletion abolishes the retinal binding site of CRALBP. The telomeric breakpoint of the deletion (in RLBP1 intron 6) is embedded in an Alu element, whereas the centromeric breakpoint (in the intergenic region) lies between two Alu elements placed in the opposite orientation. CONCLUSIONS: Because of the high density of Alu elements in RLBP1, a systematic search should be made for deletions in this gene when one or both alleles lack point mutations, in the case of RPA or flecked retinal dystrophy.

17065190|t|Monocyte chemotactic protein-1 single nucleotide polymorphisms do not confer susceptibility for the development of adult onset polymyositis/dermatomyositis in UK Caucasians.
17065190|a|OBJECTIVES: Polymyositis (PM) and dermatomyositis (DM) form part of the idiopathic inflammatory myopathies (IIMs). The chemokine monocyte chemotactic protein-1 (MCP-1) is expressed at sites of the T cell inflammatory response in the IIMs. We thus investigate whether genetic markers in the MCP-1 gene confer disease susceptibility for the development of PM and DM. METHODS: DNA samples were analysed from a group of 195 UK Caucasian IIM patients, comprising 103 PM and 92 DM. Their results were compared with those of 162 ethnically matched controls. The polymorphic positions of three single nucleotide polymorphisms (SNPs) and one insertion-deletion sequence within regions coding for MCP-1 were tested. The SNPs examined were located in intron 1 (rs2857657, C/G), exon 2 (rs4586, A/G) and the 3 ' untranslated region (rs13900, C/T). The insertion-deletion sequence was located in intron 1 (rs3917887, AGCTCCTCCTTCTC/-). Each SNP was tested for Hardy-Weinberg equilibrium and allelic/genotypic associations. Haplotype frequencies were estimated using the Expectation/Maximization algorithm. RESULTS: There was strong linkage disequilibrium present between three out of these four markers. The majority of controls were in Hardy Weinberg equilibrium. No allelic, genotypic or haplotypic associations were detected when comparing PM or DM cases to controls, or when PM and DM were compared with each other. CONCLUSIONS: Genetic markers in the MCP-1 gene do not demonstrate significant genetic associations with the IIMs, and do not discriminate PM from DM in a UK Caucasian population.
17065190	924	933	rs2857657	SNP	rs2857657
17065190	935	938	C/G	DNAMutation	|C||G
17065190	949	955	rs4586	SNP	rs4586
17065190	957	960	A/G	DNAMutation	|A||G
17065190	995	1002	rs13900	SNP	rs13900
17065190	1004	1007	C/T	DNAMutation	|C||T
17065190	1067	1076	rs3917887	SNP	rs3917887
17065190	1078	1094	AGCTCCTCCTTCTC/-	DNAMutation	|DEL||AGCTCCTCCTTCTC

17003923|t|Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population.
17003923|a|Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced by a multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to give a detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, beta-fibrinogen -455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1-675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy-Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors.
17003923	1104	1111	1691G>A	DNAMutation	c|G|1691|A
17003923	1140	1147	4070A>G	DNAMutation	c|A|4070|G
17003923	1185	1194	Arg353Gln	ProteinMutation	p|R|353|Q
17003923	1208	1216	Val34Leu	ProteinMutation	p|V|34|L
17003923	1234	1241	-455G>A	DNAMutation	c|G|-455|A
17003923	1255	1263	20210G>A	DNAMutation	c|G|20210|A
17003923	1322	1328	536C>T	DNAMutation	c|C|536|T
17003923	1345	1351	127G>A	DNAMutation	c|G|127|A
17003923	1467	1474	1601G>A	DNAMutation	c|G|1601|A
17003923	1746	1752	807C>T	DNAMutation	c|C|807|T
17003923	1790	1796	677C>T	DNAMutation	c|C|677|T
17003923	1849	1855	807C>T	DNAMutation	c|C|807|T

17002658|t|Severe prothrombin deficiency caused by prothrombin-Edmonton (R-4Q) combined with a previously undetected deletion.
17002658|a|BACKGROUND: During infancy, a male patient experienced several life-threatening bleeding episodes. Standard coagulation tests revealed that the patient's plasma prothrombin activity was 8%, while his father's and mother's levels were 74% and 62%, respectively. OBJECTIVES: A molecular genetic approach was used to determine the molecular basis of prothrombin deficiency within the family. PATIENT/METHODS: Prothrombin genomic DNA fragments were amplified by using the polymerase chain reaction (PCR). In addition, liver cDNA fragments were amplified from the patient by using reverse transcription (RT) and PCR. The nucleotide sequences of the DNA fragments were determined. RESULTS: A novel, heterozygous point mutation (g.1755 G > A, named prothrombin-Edmonton) was detected in the patient and his mother, resulting in the mutation of Arg-4 in the prothrombin propeptide to Gln (R-4Q). RT-PCR analysis of the patient's liver sample demonstrated the presence of two mRNA transcripts that differed by the presence or absence of exon 11. Real-time PCR analysis on genomic DNA and cDNA confirmed a deletion (g.10435_10809del) in the paternal allele. CONCLUSIONS: The patient has a maternally-inherited point mutation (R-4Q) and a paternally-inherited deletion. By analogy with the previously reported factor IX San Dimas, the R-4Q mutation probably causes under-carboxylation of prothrombin and poor cleavage of the propeptide in the hepatocyte. The deletion probably results in a polypeptide that lacks 50 amino acids from the protease domain; this is likely to impair folding, secretion, stability and/or activity of the truncated prothrombin. The two mutations combine to give the prothrombin deficiency observed in the patient.
17002658	62	66	R-4Q	ProteinMutation	p|R|-4|Q
17002658	838	850	g.1755 G > A	DNAMutation	g|G|1755|A
17002658	997	1001	R-4Q	ProteinMutation	p|R|-4|Q
17002658	1222	1238	g.10435_10809del	DNAMutation	g|DEL|10435_10809|
17002658	1332	1336	R-4Q	ProteinMutation	p|R|-4|Q
17002658	1440	1444	R-4Q	ProteinMutation	p|R|-4|Q

16989765|t|A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy.
16989765|a|PURPOSE: To describe the phenotype and genotype of a family with suspected Sorsby fundus dystrophy (SFD). DESIGN: Case reports and results of deoxyribonucleic acid (DNA) analysis. METHODS: Clinical features were determined by complete ophthalmologic examination or by review of medical records. Mutational analysis of the tissue inhibitor of metalloproteinase (TIMP)3 gene was performed by DNA resequencing. Biochemical properties of the mutant TIMP3 protein were studied, and phylogenetic and molecular modeling analyses of TIMP proteins were performed. RESULTS: Fundi of four affected family members demonstrated active or regressed bilateral choroidal neovascularization, whereas another affected individual displayed severe diffuse pigmentary degeneration associated with nyctalopia characteristic of SFD. Onset of disease occurred in the fifth to seventh decades of life. A heterozygous His158Arg mutation was found in seven affected family members and was absent from an unaffected member and 98 unrelated controls. Bioinformatic analyses indicate that histidine 158 is an evolutionarily conserved residue in most vertebrate TIMP homologs and predict that substitution by arginine disrupts TIMP3 function. The mutant protein appears to be expressed by fibroblasts from an affected family member. Molecular modeling suggests that TIMP3 residue 158 may be part of a protein-protein interaction interface. CONCLUSION: A novel mutation in TIMP3 causes a late-onset form of SFD in this family. His158Arg is the first reported TIMP3 SFD coding sequence mutation that does not create an unpaired cysteine. Further study of this unusual mutation may provide insight into the mechanism of SFD pathogenesis.
16989765	8	17	His158Arg	ProteinMutation	p|H|158|R
16989765	981	990	His158Arg	ProteinMutation	p|H|158|R
16989765	1584	1593	His158Arg	ProteinMutation	p|H|158|R

16953235|t|Analysis of a missense variant of the human N-formyl peptide receptor that is associated with agonist-independent beta-arrestin association and indices of inflammation.
16953235|a|Formyl-Met-Leu-Phe (fMLP) is a potent chemoattractant molecule released from both bacteria and damaged mitochondria that activates fMLP receptors (FPR) leading to neutrophil chemotaxis, degranulation and superoxide production. A common missense single nucleotide polymorphism in the human FPR1 gene at nucleotide c.32C>T results in the amino-acid substitution, p.I11T, in the FPR1 extracellular amino-terminus. The minor (c.32T) allele frequencies were 0.25, 0.27, 0.25, 0.15 and 0.14 in healthy Caucasian, African, East Indian, Chinese and Native Canadian individuals, respectively. In subjects homozygous for the p.T11 allele, we find elevated serum concentrations of C-reactive protein, increased absolute counts of blood leukocytes and neutrophils, and erythrocyte sedimentation rates. When expressed in HEK 293 and RBL-2H3 cells a substantial proportion of FPR1 p.I11T variant is retained intracellularly and agonist-independent internalization of the FPR1 p.I11T variant, but not the wild-type FPR1, is constitutively associated with beta-arrestin2-GFP in vesicles. Moreover, basal N-acetyl-D-glucosaminidase release is increased in primary neutrophils isolated from subjects either heterozygous or homozygous for the FPR1 p.T11 allele. Taken together, the data suggest an increased receptor activity and phenotypic expression of increased inflammatory indices in subjects with the p.T11 allele.
16953235	482	489	c.32C>T	DNAMutation	c|C|32|T
16953235	530	536	p.I11T	ProteinMutation	p|I|11|T
16953235	1036	1042	p.I11T	ProteinMutation	p|I|11|T
16953235	1131	1137	p.I11T	ProteinMutation	p|I|11|T

16911351|t|Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients.
16911351|a|OBJECTIVES: Dystonia is a common movement disorder. The purpose of this study is to examine the relative distribution of the primary dystonia subtypes and identify mutation (s) in the DYT1 gene in Indian patients. MATERIALS AND METHODS: Primary dystonia patients (n = 178) and controls (n = 63), lacking any symptoms of the disease, were recruited for the study from eastern India. The nucleotide variants in the DYT1 gene were identified by carrying out polymerase chain reaction, single stranded conformation polymorphism, and DNA sequencing. RESULTS: Unlike other reports, pain and/or tremor was more common in our sporadic patients than in familial cases. Three reported and two novel changes were identified in this gene. The homozygous genotype (G,G) for a missense variant (c.646G > C; Asp216His) was significantly over-represented in the patients compared with controls (P < 0.05). However, the commonly reported 3 bp deletion (904-906delGAG) was not detected. CONCLUSION: Our results suggest that the DYT1 gene might have a limited role in causation of dystonia in the Indian population.
16911351	872	882	c.646G > C	DNAMutation	c|G|646|C
16911351	884	893	Asp216His	ProteinMutation	p|D|216|H
16911351	1027	1040	904-906delGAG	DNAMutation	c|DEL|904_906|GAG

16840830|t|Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1.
16840830|a|Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.
16840830	1035	1044	AAG-->GAG	DNAMutation	|AAG||GAG
16840830	1225	1234	GAC-->TAT	DNAMutation	|GAC||TAT

16838170|t|Single nucleotide polymorphisms of the HNF4alpha gene are associated with the conversion to type 2 diabetes mellitus: the STOP-NIDDM trial.
16838170|a|Hepatocyte nuclear factor 4alpha (HNF4alpha) is a transcription factor, which is necessary for normal function of human liver and pancreatic islets. We investigated whether single nucleotide polymorphisms (SNPs) of HNF4A, encoding HNF4alpha, influenced the conversion from impaired glucose tolerance (IGT) to type 2 diabetes mellitus in subjects of the STOP-NIDDM trial. This trial aimed at evaluating the effect of acarbose compared to placebo in the prevention of type 2 diabetes mellitus. Eight SNPs covering the intragenic and alternate P2 promoter regions of HNF4A were genotyped in study samples using the TaqMan Allelic Discrimination Assays. Three SNPs in the P2 promoter region (rs4810424, rs1884614, and rs2144908) were in almost complete association (D'>0.97, r (2)>0.95) and, therefore, only rs4810424 was included in further analyses. Female carriers of the less frequent C allele of rs4810424 had a 1.7-fold elevated risk [95% confidence interval (CI) 1.09-2.66; P=0.020] for the conversion to diabetes compared to women with the common genotype after the adjustment for age, treatment group (placebo or acarbose), smoking, weight at baseline, and weight change. No association was found in men. Haplotype analysis based on three SNPs (rs4810424, rs2071197, and rs3818247) representing the linkage disequilibrium blocks in our study population indicated that the conversion to type 2 diabetes mellitus was dependent on the number of risk alleles in different haplotypes in women. Our results suggest that SNPs of HNF4A and their haplotypes predispose to type 2 diabetes mellitus in female subjects of the STOP-NIDDM study population.
16838170	828	837	rs4810424	SNP	rs4810424
16838170	839	848	rs1884614	SNP	rs1884614
16838170	854	863	rs2144908	SNP	rs2144908
16838170	944	953	rs4810424	SNP	rs4810424
16838170	1037	1046	rs4810424	SNP	rs4810424
16838170	1390	1399	rs4810424	SNP	rs4810424
16838170	1401	1410	rs2071197	SNP	rs2071197
16838170	1416	1425	rs3818247	SNP	rs3818247

16796766|t|Genomic characterization of five deletions in the LDL receptor gene in Danish Familial Hypercholesterolemic subjects.
16796766|a|BACKGROUND: Familial Hypercholesterolemia is a common autosomal dominantly inherited disease that is most frequently caused by mutations in the gene encoding the receptor for low density lipoproteins (LDLR). Deletions and other major structural rearrangements of the LDLR gene account for approximately 5% of the mutations in many populations. METHODS: Five genomic deletions in the LDLR gene were characterized by amplification of mutated alleles and sequencing to identify genomic breakpoints. A diagnostic assay based on duplex PCR for the exon 7-8 deletion was developed to discriminate between heterozygotes and normals, and bioinformatic analyses were used to identify interspersed repeats flanking the deletions. RESULTS: In one case 15 bp had been inserted at the site of the deleted DNA, and, in all five cases, Alu elements flanked the sites where deletions had occurred. An assay developed to discriminate the wildtype and the deletion allele in a simple duplex PCR detected three FH patients as heterozygotes, and two individuals with normal lipid values were detected as normal homozygotes. CONCLUSION: The identification of the breakpoints should make it possible to develop specific tests for these mutations, and the data provide further evidence for the role of Alu repeats in intragenic deletions.

16781314|t|Ectodermal dysplasia-skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1.
16781314|a|We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development.
16781314	87	94	888delC	DNAMutation	|DEL|888|C

16723031|t|Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis.
16723031|a|BACKGROUND: Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS) is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and a 6-bp deletion/insertion in the TYMS 3'-untranslated region (TS 3'-UTR)] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk. METHODS: To test the hypothesis that polymorphisms of the TYMS gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population. RESULTS: We found that the distribution of TS3'-UTR (1494del6) genotype frequencies were significantly different between the cases and controls (P = 0.026). Compared with the TS3'-UTR del6/del6 wild-type genotype, a significantly reduced risk was associated with the ins6/ins6 homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35-0.97) but not the del6/ins6 genotype (OR = 1.09, 95% CI = 0.82-1.46). Furthermore, breast cancer risks associated with the TS3'-UTR del6/del6 genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the TSER polymorphism and breast cancer risks. CONCLUSION: These findings suggest that the TS3'-UTR del6 polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the variants are warranted to confirm our findings.
16723031	1198	1206	1494del6	DNAMutation	g|DEL|1494|6

16614502|t|Insertion/deletion polymorphism of angiotensin converting enzyme gene in Kawasaki disease.
16614502|a|Polymorphism of angiotensin converting enzyme (ACE) gene is reported to be associated with ischemic heart disease, hypertrophic cardiomyopathy, and idiopathic dilated cardiomyopathy. In this study, we investigated the relationship between Kawasaki disease and insertion/deletion polymorphism of ACE gene. Fifty five Kawasaki disease patients and 43 healthy children were enrolled. ACE genotype was evaluated from each of the subjects' DNA fragments through polymerase chain reaction (PCR). Frequencies of ACE genotypes (DD, ID, II) were 12.7%, 60.0%, 27.3% in Kawasaki group, and 41.9%, 30.2%, 27.9% in control group respectively, indicating low rate of DD and high rate of ID genotype among Kawasaki patients (p<0.01). Comparing allelic (I, D) frequencies, I allele was more prevalent in Kawasaki group than in control group (57.3% vs. 43.0%, p<0.05). In Kawasaki group, both genotype and allelic frequencies were not statistically different between those with coronary dilatations and those without. ACE gene I/D polymorphism is thought to be associated with Kawasaki disease but not with the development of coronary dilatations.

16575011|t|Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment.
16575011|a|PURPOSE: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. PATIENTS AND METHODS: One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. RESULTS: Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. CONCLUSION: Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.
16575011	27	35	1494del6	DNAMutation	|DEL|1494|6
16575011	581	586	G > C	DNAMutation	|G||C
16575011	632	640	1494del6	DNAMutation	|DEL|1494|6
16575011	1214	1219	G > C	DNAMutation	|G||C
16575011	1280	1288	1494del6	DNAMutation	|DEL|1494|6
16575011	1895	1903	1494del6	DNAMutation	|DEL|1494|6

16506214|t|Genetic variation in the COX-2 gene and the association with prostate cancer risk.
16506214|a|COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Accumulating evidence from epidemiologic studies, chemical carcinogen-induced rodent models and clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed in prostate cancer tissue. We examined whether sequence variants in the COX-2 gene are associated with prostate cancer risk. We analyzed a large population-based case-control study, cancer prostate in Sweden (CAPS) consisting of 1,378 cases and 782 controls. We evaluated 16 single nucleotide polymorphisms (SNPs) spanning the entire COX-2 gene in 94 subjects of the control group. Five SNPs had a minor allele frequency of more than 5% in our study population and these were genotyped in all case patients and control subjects and gene-specific haplotypes were constructed. A statistically significant difference in allele frequency between cases and controls was observed for 2 of the SNPs (+3100 T/G and +8365 C/T), with an odds ratio of 0.78 (95% CI=0.64-0.96) and 0.65 (95% CI=0.45-0.94) respectively. In the haplotype analysis, 1 haplotype carrying the variant allele from both +3100 T/G and +8365 C/T, with a population frequency of 3%, was also significantly associated with decreased risk of prostate cancer (p=0.036, global simulated p-value=0.046). This study supports the hypothesis that inflammation is involved in prostate carcinogenesis and that sequence variation within the COX-2 gene influence the risk of prostate cancer.
16506214	1163	1172	+3100 T/G	DNAMutation	c|T|+3100|G
16506214	1177	1186	+8365 C/T	DNAMutation	c|C|+8365|T
16506214	1354	1363	+3100 T/G	DNAMutation	c|T|+3100|G
16506214	1368	1377	+8365 C/T	DNAMutation	c|C|+8365|T

16419642|t|A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes.
16419642|a|A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.
16419642	27	32	F826Y	ProteinMutation	p|F|826|Y
16419642	187	192	S810L	ProteinMutation	p|S|810|L
16419642	611	616	S810L	ProteinMutation	p|S|810|L
16419642	671	676	S810L	ProteinMutation	p|S|810|L
16419642	734	739	S810L	ProteinMutation	p|S|810|L
16419642	872	877	F826Y	ProteinMutation	p|F|826|Y
16419642	1010	1015	L809L	ProteinMutation	p|L|809|L
16419642	1022	1027	F826Y	ProteinMutation	p|F|826|Y
16419642	1123	1128	F826Y	ProteinMutation	p|F|826|Y
16419642	1315	1320	F826Y	ProteinMutation	p|F|826|Y
16419642	1628	1633	F826Y	ProteinMutation	p|F|826|Y

16410744|t|Genetic alterations in primary glioblastomas in Japan.
16410744|a|Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.
16410744	1499	1516	codon 787 CAG/CAA	DNAMutation	|CAG|CODON787|CAA

16402033|t|Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia.
16402033|a|In this paper, we present whole-organ histologic and genetic mapping studies using hypervariable DNA markers on chromosome 13 and then integrate the recombination- and single-nucleotide polymorphic sites (SNPs)-based deletion maps with the annotated genome sequence. Using bladders resected from patients with invasive urothelial carcinoma, we studied allelic patterns of 40 microsatellite markers mapping to all regions of chromosome 13 and 79 SNPs located within the 13q14 region containing the RB1 gene. A whole-organ histologic and genetic mapping strategy was used to identify the evolution of allelic losses on chromosome 13 during the progression of bladder neoplasia. Markers mapping to chromosomal regions involved in clonal expansion of preneoplastic intraurothelial lesions were subsequently tested in 25 tumors and 21 voided urine samples of patients with bladder cancer. Four clusters of allelic losses mapping to distinct regions of chromosome 13 were identified. Markers mapping to the 13q14 region that is flanked by D13S263 and D13S276, which contains the RB1 gene, showed allelic losses associated with early clonal expansion of intraurothelial neoplasia. Such losses could be identified in approximately 32% bladder tumor tissue samples and 38% of voided urines from patients with bladder cancer. The integration of distribution patterns of clonal allelic losses revealed by the microsatellite markers with those obtained by genotyping of SNPs disclosed that the loss within an approximately 4-Mb segment centered around RB1 may represent an incipient event in bladder neoplasia. However, the inactivation of RB1 occurred later and was associated with the onset of severe dysplasia/carcinoma in situ. Our studies provide evidence for the presence of critical alternative candidate genes mapping to the 13q14 region that are involved in clonal expansion of neoplasia within the bladder antecedent to the inactivation of the RB1 gene.

16322765|t|Allele-specific amplification in cancer revealed by SNP array analysis.
16322765|a|Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ.

16311014|t|Tag/anti-tag liquid-phase primer extension array: a flexible and versatile genotyping platform.
16311014|a|This study demonstrates an array-based platform to genotype simultaneously single nucleotide polymorphisms (SNPs) and some short insertions/deletions (indels) by the integration of the universal tag/anti-tag (TAT) system, liquid-phase primer extension (LIPEX), and a novel two-color detection strategy on an array format (TATLIPEXA). The TAT system permits a universal chip to be used for many applications, and the LIPEX simplifies the sample preparation but improves the sensitivity significantly. More importantly, all SNPs and some short indels can be interrogated in a single reaction with only two fluorescent ddNTPs. The concept of TATLIPEXA is demonstrated for nine SNPs (eight point mutations and one single-base insertion), and genotypes obtained show a remarkable concordance rate of 100% with both DNA sequencing and restriction fragment length polymorphism. Moreover, TATLIPEXA is able to provide quantitative information on allele frequency in pooled DNA samples, which could serve as a rapid screening tool for SNPs associated with diseases.

16288199|t|The promoter of inducible nitric oxide synthase implicated in glaucoma based on genetic analysis and nuclear factor binding.
16288199|a|PURPOSE: Nitric oxide has many beneficial functions in the human body at the right amounts, but it can also be hazardous if it is produced in amounts more than needed and has therefore been studied in relation to several neurological and non-neurological disorders. In vitro and in vivo studies demonstrate a connection between the inducible form of Nitric Oxide Synthase, iNOS, and the neuropathological disorder glaucoma, one of the major causes of blindness in the world. In this study, we sought to establish the genetic association between iNOS and primary open angle glaucoma, POAG, and to find the functional element(s) connected with the pathogenesis of the disease. METHODS: Two microsatellites, 1 insertion/deletion, and 8 single nucleotide polymorphisms (SNPs) in the regulatory region of iNOS were genotyped in 200 POAG patients and 200 age-matched controls. Also, the CCTTT-microsatellite was examined for its protein-binding capability in an electrophoretic mobility shift assay, EMSA. RESULTS: There was a significant difference in allele distribution of the CCTTT-microsatellite, between patients and controls. (CCTTT)14, which has been reported to have a higher activity in a reporter-construct, was significantly more abundant in POAG patients, while (CCTTT)10 and (CCTTT)13 were less common. In EMSA, the (CCTTT)14 allele exhibited specific binding of nuclear proteins. CONCLUSIONS: These results, together with other studies on this gene and the CCTTT-microsatellite, establish, for the first time, a genetic association of iNOS with POAG and suggest a regulatory function for the microsatellite.

16288197|t|Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree.
16288197|a|PURPOSE: Congenital microcoria is a rare autosomal dominant developmental disorder of the iris associated with myopia and juvenile open angle glaucoma. Linkage to the chromosomal locus 13q31-q32 has previously been reported in a large French family. In the current study, a three generation Asian Indian family with 15 congenital microcoria (pupils with a diameter <2 mm) affected members was studied for linkage to candidate microsatellite markers at the 13q31-q32 locus. METHODS: Twenty-four members of the family were clinically examined and genomic DNA was extracted. Microsatellite markers at 13q31-q32 were PCR amplified and run on an ABI Prism 310 genetic analyzer and genotyped with the GeneScan analysis. Two point and multipoint linkage analyses were performed using the MLINK and SUPERLINK programs. RESULTS: Peak two point LOD scores of 3.5, 4.7, and 5.3 were found co-incident with consecutive markers D13S154, DCT, and D13S1280. Multipoint analysis revealed a 4 cM region encompassing D13S1300 to D13S1280 where the LOD remains just over 6.0 Thus we confirm localization of the congenital microcoria locus to chromosomal locus 13q31-q32. In addition, eight individuals who had both microcoria and glaucoma were screened for glaucoma genes: myocilin (MYOC), optineurin (OPTN) and CYP1B1. Using direct sequencing a point mutation (144 G>A) resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five of the eight glaucoma patients, but not in unaffected family members and 100 unrelated controls. CONCLUSIONS: We have confirmed the localization of the congenital microcoria locus (MCOR) to 13q31-q32 in a large Asian Indian family and conclude that current information suggests this is a single locus disorder and genetically homogeneous. When combined with the initial linkage paper our haplotype and linkage data map the MCOR locus to a 6-7 cM region between D13S265 and D13S1280. The DCT locus, a member of the tyrosinase family involved in pigmentation, maps within this region. Data presented here supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma, although this observation is complicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), a mutation known to be associated with glaucoma in India. Fine mapping and candidate gene analysis continues with the hope that characterizing the micocoria gene will lead to a better understanding of microcoria and glaucoma causation. The relationship between microcoria, glaucoma, and the MYOC Q48H mutation in this family is discussed.
16288197	1433	1440	144 G>A	DNAMutation	c|G|144|A
16288197	1457	1461	Q48H	ProteinMutation	p|Q|48|H
16288197	2294	2298	Q48H	ProteinMutation	p|Q|48|H
16288197	2611	2615	Q48H	ProteinMutation	p|Q|48|H

16277682|t|Segregation of a M404V mutation of the p62/sequestosome 1 (p62/SQSTM1) gene with polyostotic Paget's disease of bone in an Italian family.
16277682|a|Mutations of the p62/Sequestosome 1 gene (p62/SQSTM1) account for both sporadic and familial forms of Paget's disease of bone (PDB). We originally described a methionine-->valine substitution at codon 404 (M404V) of exon 8, in the ubiquitin protein-binding domain of p62/SQSTM1 gene in an Italian PDB patient. The collection of data from the patient's pedigree provided evidence for a familial form of PDB. Extension of the genetic analysis to other relatives in this family demonstrated segregation of the M404V mutation with the polyostotic PDB phenotype and provided the identification of six asymptomatic gene carriers. DNA for mutational analysis of the exon 8 coding sequence was obtained from 22 subjects, 4 PDB patients and 18 clinically unaffected members. Of the five clinically ascertained affected members of the family, four possessed the M404V mutation and exhibited the polyostotic form of PDB, except one patient with a single X-ray-assessed skeletal localization and one with a polyostotic disease who had died several years before the DNA analysis. By both reconstitution and mutational analysis of the pedigree, six unaffected subjects were shown to bear the M404V mutation, representing potential asymptomatic gene carriers whose circulating levels of alkaline phosphatase were recently assessed as still within the normal range. Taken together, these results support a genotype-phenotype correlation between the M404V mutation in the p62/SQSTM1 gene and a polyostotic form of PDB in this family. The high penetrance of the PDB trait in this family together with the study of the asymptomatic gene carriers will allow us to confirm the proposed genotype-phenotype correlation and to evaluate the potential use of mutational analysis of the p62/SQSTM1 gene in the early detection of relatives at risk for PDB.
16277682	17	22	M404V	ProteinMutation	p|M|404|V
16277682	298	343	methionine-->valine substitution at codon 404	ProteinMutation	p|M|404|V
16277682	345	350	M404V	ProteinMutation	p|M|404|V
16277682	646	651	M404V	ProteinMutation	p|M|404|V
16277682	991	996	M404V	ProteinMutation	p|M|404|V
16277682	1317	1322	M404V	ProteinMutation	p|M|404|V
16277682	1572	1577	M404V	ProteinMutation	p|M|404|V

16216473|t|HPRTSardinia: a new point mutation causing HPRT deficiency without Lesch-Nyhan disease.
16216473|a|Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency always causing hyperuricemia presents various degrees of neurological manifestations, the most severe which is Lesch-Nyhan syndrome. The HPRT gene is situated in the region Xq26-q27.2 and consists of 9 exons. At least 300 different mutations at different sites in the HPRT coding region from exon 1 to exon 9 have been identified. A new mutation in the HPRT gene has been determined in one patient with complete deficiency of erythrocyte activity, with hyperuricemia and gout but without Lesch-Nyhan disease. Analysis of cultured fibroblasts revealed minimal residual HPRT activity mainly when guanine was the substrate. Genomic DNA sequencing demonstrated patient's mother heterozygosity for the mutation and no mutation in her brother. The mutation consists in a C-->T transversion at cDNA base 463 (C463T) in exon 6, resulting in proline to serine substitution at codon 155 (P155S). This mutation had not been reported previously and has been designated HPRT(Sardinia). The mutation identified in this patient allows some expression of functional enzyme in nucleated cells such as fibroblasts, indicating that such cell type may add further information to conventional blood analysis. A multicentre survey gathering patients with variant neurological forms could contribute to understand the pathophysiology of the neurobehavioral symptoms of HPRT deficiency.
16216473	918	953	C-->T transversion at cDNA base 463	DNAMutation	c|C|463|T
16216473	955	960	C463T	DNAMutation	c|C|463|T
16216473	1031	1036	P155S	ProteinMutation	p|P|155|S

16167150|t|Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians.
16167150|a|AIMS/HYPOTHESIS: Uncoupling protein-2 (UCP2) is thought to play a role in insulin secretion and the development of obesity. In this study, we investigated the effects of genetic variation in UCP2 on type 2 diabetes and obesity, as well as on metabolic phenotypes related to these diseases, in Pima Indians. METHODS: The coding and untranslated regions of UCP2, and approximately 1 kb of the 5' upstream region, were sequenced in DNA samples taken from 83 extremely obese Pima Indians who were not first-degree relatives. RESULTS: Five variants were identified: (1) a -866G/A in the 5' upstream region; (2) a G/A in exon 2; (3) a C/T resulting in an Ala55Val substitution in exon 4; and (4, 5) two insertion/deletions (ins/del; 45-bp and 3-bp) in the 3' untranslated region. Among the 83 subjects whose DNA was sequenced, the -866G/A was in complete genotypic concordance with the Ala55Val and the 3-bp ins/del polymorphism. The G/A polymorphism in exon 2 was extremely rare. To capture the common variation in this gene for association analyses, the -866G/A variant (as a representative of Ala55Val and the 3-bp ins/del polymorphism) and the 45-bp ins/del were also genotyped for 864 full-blooded Pima Indians. Neither of these variants was associated with type 2 diabetes or body mass index. However, in a subgroup of 185 subjects who had undergone detailed metabolic measurements, these variants were associated with 24-h energy expenditure as measured in a human metabolic chamber (p=0.007 for the 45-bp ins/del and p=0.03 for the -866G/A after adjusting for age, sex, family membership, fat-free mass and fat mass). CONCLUSIONS/INTERPRETATION: Our data indicate that variation in UCP2 may play a role in energy metabolism, but this gene does not contribute significantly to the aetiology of type 2 diabetes and/or obesity in Pima Indians.
16167150	670	677	-866G/A	DNAMutation	c|G|-866|A
16167150	711	714	G/A	DNAMutation	|G||A
16167150	732	735	C/T	DNAMutation	|C||T
16167150	752	760	Ala55Val	ProteinMutation	p|A|55|V
16167150	928	935	-866G/A	DNAMutation	c|G|-866|A
16167150	983	991	Ala55Val	ProteinMutation	p|A|55|V
16167150	1031	1034	G/A	DNAMutation	|G||A
16167150	1153	1160	-866G/A	DNAMutation	c|G|-866|A
16167150	1193	1201	Ala55Val	ProteinMutation	p|A|55|V
16167150	1637	1644	-866G/A	DNAMutation	c|G|-866|A

16159638|t|Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33.
16159638|a|BACKGROUND: The T-cell immunoglobulin domain and mucin domain (TIM) gene family and the gene for IL-2-inducible T-cell kinase (ITK), located in chromosome 5 q 33 and potentially involved in the T-cell proliferation and differentiation, are good candidate genes for allergic diseases. OBJECTIVE: We assessed the role of polymorphisms in the TIM family genes and ITK in atopy, eczema, and asthma. METHODS: Twenty-one polymorphisms in the TIM-ITK gene cluster were genotyped in 564 children enrolled in the Tucson Children's Respiratory Study. Skin prick tests to common allergens were performed at age 6.1 years (n=508), age 10.8 years (n=539), and age 16.6 years (n=424). Asthma and eczema were assessed by questionnaire at these 3 points. Averaged relative risks were estimated. RESULTS: One 15-bp insertion/deletion in exon 4 of TIM 1 was significantly related to atopy and eczema (relative risk associated with carrying at least 1 rare allele=1.24 [1.07--1.45], P=.005; and 1.43 [1.01--2.01], P=.004, respectively). The 3 tested single nucleotide polymorphisms (SNPs) in TIM 3 were significantly related to atopy and eczema. One of them, at position +4259 calculated from the translation start site, predicts a putative change in the amino acid sequence of the protein, and was the most strongly related to atopy (relative risk=1.28 [1.12--1.47]; P=.0003). SNPs in the 5' genomic region in ITK, which show moderate linkage disequilibrium with those in TIM 3, had an independent effect on atopy. None of the polymorphisms studied was related to asthma. CONCLUSION: Our findings support a potential role for SNPs in TIM 1, TIM 3, and ITK, independent of each other, in allergic diseases.

16152606|t|Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies.
16152606|a|Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence.
16152606	30	37	657del5	DNAMutation	c|DEL|657|5
16152606	427	434	657del5	DNAMutation	c|DEL|657|5
16152606	588	594	643C>T	DNAMutation	c|C|643|T
16152606	596	601	R215W	ProteinMutation	p|R|215|W
16152606	892	899	657del5	DNAMutation	c|DEL|657|5
16152606	1096	1101	R215W	ProteinMutation	p|R|215|W
16152606	1168	1175	657del5	DNAMutation	c|DEL|657|5
16152606	1429	1436	657del5	DNAMutation	c|DEL|657|5

16130093|t|Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy.
16130093|a|In this study, we characterized five Ullrich scleroatonic muscular dystrophy patients (two Italians, one Belgian, and two Turks) with a clinical phenotype showing different degrees of severity, all carrying mutations localized in COL6A1. We sequenced the three entire COL6 complementary DNA. Three of five patients have recessive mutations: two patients (P1and P3) have homozygous single-nucleotide deletions, one in exon 9 and one in exon 22; one patient (P2) has a homozygous single-nucleotide substitution leading to a premature termination codon in exon 31. The nonsense mutation of P2 also causes a partial skipping of exon 31 with the formation of a premature termination codon in exon 32 in 15% of the total COL6A1 messenger RNA. The remaining two patients carry a heterozygous glycine substitution in exons 9 and 10 inside the triple-helix region; both are dominant mutations because the missense mutations are absent in the DNA of their respective parents. As for the three homozygous recessive mutations, the apparently healthy consanguineous parents all carry a heterozygous mutated allele. Here, for the first time, we report a genotype-phenotype correlation demonstrating that heterozygous glycine substitutions in the triple-helix domain of COL6A1 are dominant and responsible for a milder Ullrich scleroatonic muscular dystrophy phenotype, and that recessive mutations in COL6A1 correlate with more severe clinical and biochemical Ullrich scleroatonic muscular dystrophy phenotypes.

16120104|t|A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference.
16120104|a|The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C-1228T), one in exon 2 in the 5'-untranslated region (5'-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n=35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value=0.031, odds ratio=5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS.
16120104	478	485	C-1228T	DNAMutation	c|C|-1228|T
16120104	542	547	C111G	DNAMutation	c|C|111|G
16120104	577	583	G3853A	DNAMutation	c|G|3853|A
16120104	1382	1387	C111G	DNAMutation	c|C|111|G

16046395|t|Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G.
16046395|a|As a primary target for opioid drugs and peptides, the mu opioid receptor (OPRM1) plays a key role in pain perception and addiction. Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10-32%, and uncertain functions. We have measured allele-specific mRNA expression of OPRM1 in human autopsy brain tissues, using A118G as a marker. In 8 heterozygous samples measured, the A118 mRNA allele was 1.5-2.5-fold more abundant than the G118 allele. Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay. After transfection and inhibition of transcription with actinomycin D, analysis of mRNA turnover failed to reveal differences in mRNA stability between A118 and G118 alleles, indicating a defect in transcription or mRNA maturation. These results indicate that OPRM1-G118 is a functional variant with deleterious effects on both mRNA and protein yield. Clarifying the functional relevance of polymorphisms associated with susceptibility to a complex disorder such as drug addiction provides a foundation for clinical association studies.
16046395	83	88	A118G	DNAMutation	c|A|118|G
16046395	356	361	A118G	DNAMutation	c|A|118|G
16046395	377	381	N40D	ProteinMutation	p|N|40|D
16046395	553	558	A118G	DNAMutation	c|A|118|G

16005363|t|Identification of a novel WFS1 mutation (AFF344-345ins) in Japanese patients with Wolfram syndrome.
16005363|a|Wolfram syndrome (WFS) is an autosomal recessive disorder characterized by early onset diabetes mellitus, progressive optic atrophy, sensorineural deafness and diabetes insipidus. Affected individuals may also have renal tract abnormalities as well as neurogical and psychiatric syndromes. WFS1 encoding a transmembrane protein was identified as the gene responsible for WFS. We report herein a Japanese family, of which two members had this syndrome. In the WFS1 gene of these patients, we identified a novel mutation, a nine nucleotide insertion (AFF344-345ins). In addition, one of these patients had preclinical hypopituitarism, which is an unusual feature of WFS. As only the two family members homozygous for the mutation showed WFS, these data support the notion that this mutation is the cause of WFS.
16005363	41	54	AFF344-345ins	ProteinMutation	p|INS|344_345|AFF
16005363	649	662	AFF344-345ins	ProteinMutation	p|INS|344_345|AFF

15937959|t|Loss of heterozygosity and transcriptome analyses of a 1.2 Mb candidate ovarian cancer tumor suppressor locus region at 17q25.1-q25.2.
15937959|a|Loss of heterozygosity (LOH) analysis was performed in epithelial ovarian cancers (EOC) to further characterize a previously identified candidate tumor suppressor gene (TSG) region encompassing D17S801 at chromosomal region 17q25.1. LOH of at least one informative marker was observed for 100 (71%) of 140 malignant EOC samples in an analysis of 6 polymorphic markers (cen-D17S1839-D17S785-D17S1817-D17S801-D17S751-D17S722-tel). The combined LOH analysis revealed a 453 kilobase (Kb) minimal region of deletion (MRD) bounded by D17S1817 and D17S751. Human and mouse genome assemblies were used to resolve marker inconsistencies in the D17S1839-D17S722 interval and identify candidates. The region contains 32 known and strongly predicted genes, 9 of which overlap the MRD. The reference genomic sequences share nearly identical gene structures and the organization of the region is highly collinear. Although, the region does not show any large internal duplications, a 1.5 Kb inverted duplicated sequence of 87% nucleotide identity was observed in a 13 Kb region surrounding D17S801. Transcriptome analysis by Affymetrix GeneChip and reverse transcription (RT)-polymerase chain reaction (PCR) methods of 3 well characterized EOC cell lines and primary cultures of normal ovarian surface epithelial (NOSE) cells was performed with 32 candidates spanning D17S1839-D17S722 interval. RT-PCR analysis of 8 known or strongly predicted genes residing in the MRD in 10 EOC samples, that exhibited LOH of the MRD, identified FLJ22341 as a strong candidate TSG. The proximal repeat sequence of D17S801 occurs 8 Kb upstream of the putative promoter region of FLJ22341. RT-PCR analysis of the EOC samples and cell lines identified DKFZP434P0316 that maps proximal to the MRD, as a candidate. While Affymetrix technology was useful for initially eliminating less promising candidates, subsequent RT-PCR analysis of well-characterized EOC samples was essential to prioritize TSG candidates for further study.

15770126|t|Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6.
15770126|a|Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition.

15768551|t|Hb zoeterwoude [beta23(B5)Val-->Ala)]: a new beta-globin variant found in association with erythrocytosis.
15768551|a|We describe the characterization of a new hemoglobin (Hb) variant found in a 77-year-old Dutch woman, suspected of hypoxia-mediated erythrocytosis. The typical blood parameters (Hb 17.3 g/dL; PCV 0.525 L/L; RBC 5.82 x 10(12)/L) could not be explained by any of the pathological or physiological conditions causing erythrocytosis. The patient was preventively phlebotomized because of intermittent claudication and erythrocytosis. At the hematological and biochemical levels, no anemia or hemolysis were present and no abnormal Hb fractions were detectable on alkaline electrophoresis or high performance liquid chromatography (HPLC). Molecular analysis revealed intact alpha-globin genes and a heterozygosity for a GTT-->GCT transition at codon 23 of the beta-globin gene, causing a Val-->Ala amino acid substitution. The P50 measured in full blood indicated that this mutant has an elevated oxygen affinity. This is the fourth single nucleotide substitution at codon 23 of the beta gene and the second associated with erythrocytosis. Because the family was not available for investigation no information was obtained as to whether the mutation represents a de novo event or was inherited, and might be a more common cause of erythrocytosis in Dutch patients. Considering the relatively high frequency of beta-thalassemia (thal) in the large allochthonous population in The Netherlands, combinations of Hb Zoeterwoude and beta-thal traits may lead to hemizygosity, with severe hypoxia and erythrocytosis from a few months after birth.
15768551	26	35	Val-->Ala	ProteinMutation	p|V||A
15768551	822	854	GTT-->GCT transition at codon 23	DNAMutation	|GTT|CODON23|GCT
15768551	890	899	Val-->Ala	ProteinMutation	p|V||A

15732660|t|[Angiotensin converting enzyme gene polymorphisms and coronary risk in a Portuguese population].
15732660|a|BACKGROUND: A family history of coronary heart disease (CHD) is a strong risk marker for the disease, independently of classical risk factors. It could be decoded by recognizing the polymorphisms associated with increased risk. Renin-angiotensin system genes are candidate genes in CHD and the deletion allele of the angiotensin converting enzyme (ACE) has been reported as deleterious. However, there is disagreement as to the role of the insertion/deletion polymorphism of the ACE gene in coronary risk. AIM: To evaluate whether ACE gene polymorphisms constitute a CHD risk factor. METHODS: We conducted a population-based case-control study of 301 subjects with a history of myocardial infarction or angiographic evidence of coronary heart disease and 510 age- and gender-matched controls, without CHD, living in a region with high CHD mortality rates. Blood samples were taken, DNA extracted and genotypes determined by the polymerase chain reaction (PCR). Amplification products were identified by agarose gel electrophoresis. STATISTICAL ANALYSIS: The Data were evaluated by SPSS for Windows, using the Student's t test, the chi-square test, odds ratios and 95% confidence intervals. RESULTS: The prevalence of the DD, ID and II genotype was 41.2%, 46.3%, 12.5% in the cases and 28.1%, 55.2% and 16.7% in the control group. The frequency of the DD genotype was significantly higher in the cases than in the controls (41.2% vs. 28.1%, odds ratio 1.79, 95% CI 1.31 to 2.4, p < 0.0001). By contrast, the ID and II genotypes' prevalence was higher in the control group (55.2% vs. 46.3%, p = 0.002 and 16.7 vs. 12.5%, p = NS, respectively) compared to the case group. CONCLUSIONS: This study clearly shows that the ACE DD polymorphism is strongly linked to CHD, and if our data are confirmed in a larger population sample, more aggressive vascular prevention could be justified in patients carrying the DD genotype.

15680411|t|DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers.
15680411|a|Polymorphic variation in DNA repair genes was examined in a group of retired workers from the British Nuclear Fuels plc facility at Sellafield in relation to previously determined translocation frequencies in peripheral blood lymphocytes. Variation at seven polymorphisms in four genes involved in the base excision repair (XRCC1 R194W, R399Q and a [AC]n microsatellite in the 3' UTR) and double strand break repair (XRCC3 T241M and a [AC]n microsatellite in intron 3 of XRCC3, XRCC4 I134T, and a GACTAn microsatellite located 120 kb 5' of XRCC5) pathways was determined for 291 retired radiation workers who had received cumulative occupational external radiation doses of between 0 and 1873 mSv. When the interaction between radiation dose and each DNA repair gene polymorphism was examined in relation to translocation frequency there was no evidence for any of the polymorphisms studied influencing the response to occupational exposure. A positive interaction observed between genotype (individuals with at least one allele > or =20 repeat units) at a microsatellite locus in the XRCC3 gene and smoking status should be interpreted cautiously because interactions were investigated for seven polymorphisms and two exposures. Nonetheless, further research is warranted to examine whether this DNA repair gene variant might be associated with a sub-optimal repair response to smoking-induced DNA damage and hence an increased frequency of translocations.
15680411	439	444	R194W	ProteinMutation	p|R|194|W
15680411	446	451	R399Q	ProteinMutation	p|R|399|Q
15680411	532	537	T241M	ProteinMutation	p|T|241|M
15680411	593	598	I134T	ProteinMutation	p|I|134|T

15649253|t|Primary malignant lymphoma of the brain: frequent abnormalities and inactivation of p14 tumor suppressor gene.
15649253|a|Ten primary central nervous system lymphomas (PCNSL, brain lymphomas) were examined for p14 gene exon 1beta deletion, mutation and methylation by Southern blot analysis, nucleotide analysis of polymerase chain reaction clones and Southern blot-based methylation assay. In Southern blot analysis, from the signal densities of the hybridized bands and their similarities to those of exons 2 and 3 in our previous quantitative study, we found that exon 1beta was homozygously deleted in four cases, hemizygously deleted in five cases and not deleted in one case. Thus, the same deletion patterns covered the entire p14 gene for all cases except for one case, which suggested the hemizygous deletion of exons 1beta and 2 and homozygous deletion of exon 3. In addition, although exon 1beta mutation is rare in various tumors, we detected a missense mutation (L50R) in one case with a hemizygous deletion. Methylation of the 5'CpG island of the p14 gene was not suggested for any case without homozygous deletion. Our observation of frequent p14 gene abnormalities (90%) and inactivation (40-60%) was in striking contrast to the same pathological subtype of systemic lymphoma in which p14 gene abnormalities and inactivation were infrequent, suggesting a difference in carcinogenesis between PCNSL and systemic lymphoma.
15649253	965	969	L50R	ProteinMutation	p|L|50|R

15609295|t|Compound heterozygosity for a novel nine-nucleotide deletion and the Asn45Ser missense mutation in the glycoprotein IX gene in a patient with Bernard-Soulier syndrome.
15609295|a|Bernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder due to quantitative or qualitative abnormalities in the platelet glycoprotein (GP) Ib/IX/V complex, the major von Willebrand factor receptor. The complex comprises four subunits, each encoded by a separate gene. Several mutations have been described for each of the subunits, except for GPV, as a cause of BSS. We describe here the genetic basis of the disorder in a child with BSS. Flow-cytometric analysis of the patient's platelets showed a markedly reduced surface expression of all three glycoproteins of the GPIb/IX/V complex. DNA sequencing analysis showed the patient to be a compound heterozygote for two mutations in the GPIX gene, a novel nine-nucleotide deletion starting at position 1952 of the gene that changes asparagine 86 for alanine and eliminates amino acids 87, 88, and 89 (arginine, threonine, and proline) and a previously reported point mutation that changes the codon asparagine (AAC) for serine (AGC) at residue 45. Her mother was heterozygous for the Asn45Ser mutation, and her father, for the nine-nucleotide deletion. Our findings suggest that the additive effects of both mutations in the GPIX gene are responsible for the BSS phenotype of the patient.
15609295	69	77	Asn45Ser	ProteinMutation	p|N|45|S
15609295	1215	1223	Asn45Ser	ProteinMutation	p|N|45|S

15607529|t|Leydig cell hypoplasia due to inactivation of luteinizing hormone receptor by a novel homozygous nonsense truncation mutation in the seventh transmembrane domain.
15607529|a|Inactivating mutations in the LH receptor are the predominant cause for male pseudohermaphroditism in subjects with Leydig cell hypoplasia (LCH). The severity of the mutations, correlates with residual receptor activities. Here, we detail the clinical presentation of one subject with complete male pseudohermaphroditism and LCH. We identify within the proband and her similarly afflicted sibling a homozygous T to G transversion at nucleotide 1836 in exon 11 of the LH/CGR gene. This causes conversion of a tyrosine codon into a stop codon at codon 612 in the seventh transmembrane domain, resulting in a truncated receptor that lacks a cytoplasmic tail. In vitro, in contrast to cells expressing a normal LHR, cells transfected with the mutant cDNA exhibit neither surface binding of radiolabeled hCG nor cAMP generation. In vitro expression under the control of the LHR signal peptide of either a wild type or mutant LHR-GFP fusion protein shows no differences in receptor cellular localization. In conclusion, the in vitro studies suggest that residues in the seventh transmembrane domain and cytoplasmic tail are important for receptor binding and activation without playing a major role in receptor cellular trafficking.

15599941|t|Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer.
15599941|a|BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.
15599941	294	297	G/A	DNAMutation	|G||A
15599941	935	938	G/A	DNAMutation	|G||A

15557460|t|Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36.
15557460|a|PURPOSE: To identify the chromosomal location of the gene causing snowflake vitreoretinal degeneration (SVD), an autosomal dominant retinal degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment. METHODS: Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage.rockefeller.edu/soft/list.html). Direct DNA sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis. RESULTS: The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at theta; = 0 within this region. Direct DNA sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion. CONCLUSIONS: The genetic locus for SVD lies in a 9 Mb region flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for vitreoretinal degeneration. Snowflake vitreoretinal degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous.

15528217|t|Polymorphisms in the MMP1 and MMP3 promoter and non-small cell lung carcinoma in North China.
15528217|a|Matrix metalloproteinases (MMPs) are proteolytic enzymes that regulate various cell behaviors in cancer biology, via their basic function of degradation of proteins. Genetic variations in several MMP promoters may influence transcription and expression of MMPs. The aim of this study is to assess the effects of the two single nucleotide polymorphisms (SNPs), the guanine insertion polymorphism in the MMP1 promoter and the adenosine insertion polymorphism in the MMP3 promoter, on risk of the development and lymphatic metastasis of non-small cell lung carcinoma (NSCLC). The MMP1 and MMP3 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 243 NSCLC patients and 350 control subjects in North China. The overall genotype and allelotype distribution of both the variants in cancer patients and controls was not significantly different (all P values are above 0.05). However, stratification analysis showed that smoking individuals with the MMP3 5A allele had a >1.5-fold increased risk to develop NSCLC, compared with those harboring the 6A homozygous [the age and gender adjusted odds ratio (OR) = 1.68, 95% confidence interval (CI) = 1.04-2.70]. In addition, the frequency of the MMP3 5A homozygote in NSCLC patients with lymphatic metastasis was significantly higher than that in lymph node negative ones (5.7 versus 0%, P = 0.04). Moreover, the MMP 1G/5A haplotype significantly increased the risk of lymphatic metastasis (OR = 3.36, 95% CI = 1.42-7.94), compared with the 2G/6A haplotype. The present result suggested that the MMP3 promoter polymorphism may modify susceptibility to NSCLC, and the MMP 1G/5A haplotype may predicate the risk of lymphatic metastasis of this tumor.

15517085|t|Lack of evidence for mutations or deletions in the CDKN2A/p16 and CDKN2B/p15 genes of Brazilian neuroblastoma patients.
15517085|a|Neuroblastoma, the most common extracranial tumor in childhood, has a wide spectrum of clinical and biological features. The loss of heterozygosity within the 9p21 region has been reported as a prognostic factor. Two tumor suppressor genes located in this region, the CDKN2B/p15 and CDKN2A/p16 (cyclin-dependent kinase inhibitors 2B and 2A, respectively) genes, play a critical role in cell cycle progression and are considered to be targets for tumor inactivation. We analyzed CDKN2B/p15 and CDKN2A/p16 gene alterations in 11 patients, who ranged in age from 4 months to 13 years (male/female ratio was 1.2:1). The most frequent stage of the tumor was stage IV (50%), followed by stages II and III (20%) and stage I (10%). The samples were submitted to the multiplex PCR technique for homozygous deletion analysis and to single-strand conformation polymorphism and nucleotide sequencing for mutation analysis. All exons of both genes were analyzed, but no deletion was detected. One sample exhibited shift mobility specific for exon 2 in the CDKN2B/p15 gene, not confirmed by DNA sequencing. Homozygous deletions and mutations are not involved in the inactivation mechanism of the CDKN2B/p15 and CDKN2A/p16 genes in neuroblastoma; however, these two abnormalities do not exclude other inactivation pathways. Recent evidence has shown that the expression of these genes is altered in this disease. Therefore, other mechanisms of inactivation, such as methylation of promoter region and unproperly function of proteins, may be considered in order to estimate the real contribution of these genes to neuroblastoma genesis or disease progression.

15353880|t|Fabry disease female proband with clinical manifestations similar to hypertrophic cardiomyopathy.
15353880|a|Fabry's disease is an X-linked inborn error of glycosphingolipid catabolism, resulting from a deficiency in alpha-galactosidase A (alpha-Gal A). A 56-year-old Japanese woman was at first suspected of having hypertrophic cardiomyopathy. The patient and her son had alpha-Gal A activity in leukocytes that was remarkably below the limit of controls. DNA analysis of the alpha-Gal A gene revealed a novel missense mutation at codon 19 in exon 1, resulting in leucine-to-proline substitution. As a result she was confirmed as a classic Fabry heterozygote. Recent advances in enzyme replacement therapy can reverse the storage of glycosphingolipids in Fabry's disease. Thus, in patients with cardiac hypertrophy, it is important to differentiate Fabry's disease from other causes of hypertrophy. Therefore, it is necessary to measure alpha-Gal A activity in all suspected cases and to analyze genetic abnormalities in heterozygotes.

15316799|t|Genetic variation in apolipoprotein D and Alzheimer's disease.
15316799|a|Apolipoprotein D (apoD) is a lipoprotein-associated glycoprotein, structurally unrelated to apoE, that transports small hydrophobic ligands including cholesterol and sterols. Levels are increased in the hippocampus and CSF of Alzheimer's disease (AD) patients. We tested whether variation in the APOD gene affects AD risk. Four single nucleotide polymorphisms (SNPs) were investigated (in map order): exon 2, 15T-->C encodes an amino acid substitution Phe-->Ser at codon 15; intron 2, -352G-->A; intron 3, +45C-->T; intron 4, +718C-->T, determined by SNaPshot assay. SNP frequencies for 394 eastern Finnish AD patients were compared with those found for 470 control subjects, dividing subjects also into early-onset AD (EOAD; < or = 65 years) and late-onset AD (LOAD; >65 years) groups. The -352G allele was associated with a significant 3-fold increase in the risk of EOAD (OR: 2.7; 95% CI: 1.1-6.5). The -352G containing haplotypes were more common for EOAD cases (TGCC: 0.48 vs 0.41; TGCT: 0.08 vs 0.01 (p = 0.002). In the Grade-of-membership analysis, APOD genotype frequencies at each SNP site and disease status were used to construct two latent groups: the affected group carried -352 as GG or GA and +45 CC, was often women and enriched in APOE epsilon4. Each method suggested that the -352G allele frequency is higher for EOAD in the eastern Finnish population.
15316799	472	479	15T-->C	DNAMutation	|T|CODON15|C
15316799	515	536	Phe-->Ser at codon 15	ProteinMutation	p|F|15|S
15316799	538	557	intron 2, -352G-->A	DNAMutation	c|G|IVS2-352|A
15316799	559	577	intron 3, +45C-->T	DNAMutation	c|C|IVS3+45|T
15316799	579	598	intron 4, +718C-->T	DNAMutation	c|C|IVS4+718|T

15205584|t|Genetic analyses and expression studies identified a novel mutation (W486C) as a molecular basis of congenital coagulation factor XII deficiency.
15205584|a|We analyzed the factor XII (FXII) gene of a patient with congenital FXII deficiency and identified a novel amino acid substitution (W486C) in the catalytic domain. The proband was an asymptomatic 49-year-old Japanese female with abnormal coagulation test, discovered by chance. The FXII activity and antigen level were both under 10%, suggesting a cross-reacting material-negative FXII deficiency. Sequence analysis of the proband's FXII gene revealed a homozygous nucleotide substitution G --> C in exon 12, resulting in the amino acid substitution W486C in the catalytic domain. We constructed the mutant FXII cDNA in an expression plasmid vector and transfected it into Chinese hamster ovary cells. The recombinant wild-type FXII antigen was detected in the culture medium by immunoprecipitation assay, but the mutant FXII (W486C) was not observed. On the other hand, both the wild-type FXII and W486C cell lysates contained FXII antigen and FXII mRNA, as estimated by western blotting and quantitative reverse transcriptase-polymerase chain reaction. These findings suggest that the W486C substitution of FXII impairs intracellular processing of the protein and/or transport system.
15205584	69	74	W486C	ProteinMutation	p|W|486|C
15205584	278	283	W486C	ProteinMutation	p|W|486|C
15205584	635	642	G --> C	DNAMutation	|G||C
15205584	696	701	W486C	ProteinMutation	p|W|486|C
15205584	973	978	W486C	ProteinMutation	p|W|486|C
15205584	1045	1050	W486C	ProteinMutation	p|W|486|C
15205584	1233	1238	W486C	ProteinMutation	p|W|486|C

15200408|t|Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity.
15200408|a|BACKGROUND: Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis. METHODS: To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. RESULTS: Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P= 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls). CONCLUSION: Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.
15200408	1495	1502	Ala7Val	ProteinMutation	p|A|7|V
15200408	1566	1575	Pro154Ala	ProteinMutation	p|P|154|A

15198485|t|Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene.
15198485|a|Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism (-134delA) located in the 5'-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo.
15198485	18	27	Lys198Asn	ProteinMutation	p|K|198|N
15198485	32	40	-134delA	DNAMutation	c|DEL|-134|A
15198485	315	324	Lys198Asn	ProteinMutation	p|K|198|N
15198485	440	448	-134delA	DNAMutation	c|DEL|-134|A
15198485	542	551	Lys198Asn	ProteinMutation	p|K|198|N
15198485	1358	1367	Lys198Asn	ProteinMutation	p|K|198|N
15198485	1503	1512	Lys198Asn	ProteinMutation	p|K|198|N
15198485	1610	1619	Lys198Asn	ProteinMutation	p|K|198|N

15177686|t|Altered replication timing of the HIRA/Tuple1 locus in the DiGeorge and Velocardiofacial syndromes.
15177686|a|DiGeorge and Velocardiofacial syndromes (DGS/VCFS) are endowed by a similar complex phenotype including cardiovascular, craniofacial, and thymic malformations, and are associated with heterozygous deletions of 22q11 chromosomal band. The Typically Deleted Region in the 22q11.21 subband (here called TDR22) is very gene-dense, and the extent of the deletion has been defined precisely in several studies. However, to date there is no evidence for a mechanism of haploinsufficiency that can fully explain the DGS/VCFS phenotype. In this study, we show that the candidate gene HIRA/Tuple1 mapping on the non-deleted TDR22, in DGS/VCFS subjects presents a delayed replication timing. Moreover, we observed an increase in the cell ratio showing the HIRA/Tuple1 locus localised toward the nuclear periphery. It is known that replication timing and nuclear location are generally correlated to the transcription activity of the relative DNA region. We propose that the alteration in the replication/nuclear location pattern of the non-deleted TDR22 indicates an altered gene regulation hence an altered transcritpion in DGS/VCFS.

15122708|t|Desmin-related myopathy with Mallory body-like inclusions is caused by mutations of the selenoprotein N gene.
15122708|a|Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of classical multiminicore disease. The finding of Mallory body-like inclusions in two cases of genetically documented SEPN-RM led us to suspect a relationship between MB-DRM and SEPN1. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus (1p36), and subsequently a homozygous SEPN1 deletion (del 92 nucleotide -19/+73) in the affected patients. A comparative reevaluation showed that MB-DRM and SEPN-RM share identical clinical features. Therefore, we propose that MB-DRM should be categorized as SEPN-RM. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM, and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.
15122708	1143	1168	del 92 nucleotide -19/+73	DNAMutation	c|DEL|-19_+73|92

15111599|t|CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype.
15111599|a|PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene.
15111599	1002	1011	279delGAG	DNAMutation	|DEL|279|GAG
15111599	1311	1319	DeltaG91	ProteinMutation	p|DEL|91|G
15111599	1442	1451	IVS3+1G/A	DNAMutation	c|G|IVS3+1|A

15041272|t|A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation.
15041272|a|Clinical, laboratory and genetic defect of a Taiwanese family with type 2B von Willebrand disease (VWD) were studied. The proband was a 55-year-old woman who gave birth to two daughters and one son aged 30, 29 and 27, respectively. All had abnormal mucocutaneous bleedings since their childhood. In proband, PT, PTT and platelet count were normal; template bleeding time was 14 min; VIII:C was 51%, von Willebrand factor antigen (VWF:Ag), 42% and von Willerand factor ristocetin-cofactor (VWF:RCo, 15%); ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.6 mg/ml of ristocetin was 16% and 68%, respectively. The enhanced response to ristocetin was identified to be in plasma, not in platelet itself, by mixing studies. Analysis of von Willebrand factor (VWF) multimer of plasma but not of platelets showed absence of high-molecular weight (HMW) multimer. All three children had similar laboratory findings. Exon 28 of VWF gene was amplified using polymerase chain reaction (PCR) and sequenced. The proband and three children were all found to be heterozygous for C to T transition at nucleotide 3916 resulting in Arg 1306 Trp (R1306W) substitution. This mutation in the glycoprotein Ib (GPIb)-binding site has been found to increase the affinity of plasma VWF for platelets, and thus cause loss of HMW multimers and often thrombocytopenia. In conclusion, a first report of type 2B VWD in a Taiwanese Chinese family who show R1306W mutation in VWF gene was described.
15041272	72	78	R1306W	ProteinMutation	p|R|1306|W
15041272	1211	1223	Arg 1306 Trp	ProteinMutation	p|R|1306|W
15041272	1225	1231	R1306W	ProteinMutation	p|R|1306|W
15041272	1522	1528	R1306W	ProteinMutation	p|R|1306|W

15018851|t|Comparison of sequential cytomegalovirus isolates in a patient with lymphoma and failing antiviral therapy.
15018851|a|BACKGROUND: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised patients are hampered by resistance to antiviral drugs. Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates. OBJECTIVE: To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain-specific variability in a patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments failed. STUDY DESIGN: The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2-year follow-up period were retrospectively analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13-sequence analysis to study CMV interstrain variability. RESULTS: The patient was infected by at least three CMV strains plus variants of the parental strains. Resistance to ganciclovir, cidofovir and foscarnet was successively detected during the follow-up period. UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592, and then at position 594. Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase, whereas cross-resistance to ganciclovir and cidofovir was due to the L501I substitution. CONCLUSIONS: The CMV isolates obtained from our patient were complex mixtures of strains. Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation.
15018851	1328	1333	N495K	ProteinMutation	p|N|495|K
15018851	1422	1427	L501I	ProteinMutation	p|L|501|I

15003823|t|Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations.
15003823|a|Acute intermittent porphyria (AIP) is a very rare autosomal dominant disorder with low penetrance. Mutations in the gene of the porphobilinogen deaminase (PBG-D), also called hydroxymethylbilane synthase (HMBS), cause a partial deficiency of this enzyme of the heme biosynthetic pathway. Overstimulation of heme biosynthesis causes clinical symptoms. Because of the variability of the symptoms, diagnosis is often delayed. Using two approaches for genetic analysis, first in a stepwise manner, then sequencing extensive parts of the gene, the screening of the DNA of 20 unrelated individuals revealed 20 different mutations, 11 of which had not been reported previously. The novel mutations affected intron 1 (33 + 2 T-->C), exon 5 (181 G-->C), intron 6 (267-61 del 8 bp), intron 7 (345-1 G-->C), intron 9 (498 + 15 G-->T and 499-13 Delta-14 bp indel TGA), intron 13 (825 + 1 G-->C and 825 + 2 T-->C), exon 15 (962 G-A, 1067 del A and 1067-1068 ins 5 bp). The other nine mutations detected affected intron 14, exons 6, 7, 8, 9, 10 (3x) and 12. In the majority of AIP patients, the genotype does not predict phenotypic expression. Since the sudden manifestation of the disease maybe prevented by early diagnosis, identification of AIP gene carriers is the best preventive measure. This was performed in five families, revealing 10 additional AIP gene carriers.
15003823	835	847	33 + 2 T-->C	DNAMutation	c|T|33+2|C
15003823	858	867	181 G-->C	DNAMutation	c|G|181|C
15003823	880	895	267-61 del 8 bp	DNAMutation	c|DEL|267-61_267-54|8
15003823	908	919	345-1 G-->C	DNAMutation	c|G|345-1|C
15003823	932	946	498 + 15 G-->T	DNAMutation	c|G|498+15|T
15003823	951	979	499-13 Delta-14 bp indel TGA	DNAMutation	c|INDEL|499-13_499|TGA
15003823	993	1006	825 + 1 G-->C	DNAMutation	c|G|825+1|C
15003823	1011	1024	825 + 2 T-->C	DNAMutation	c|T|825+2|C
15003823	1036	1043	962 G-A	DNAMutation	c|G|962|A
15003823	1045	1055	1067 del A	DNAMutation	c|DEL|1067|A
15003823	1060	1078	1067-1068 ins 5 bp	DNAMutation	c|INS|1067_1068|5

14962306|t|Identification of the Kna/Knb polymorphism and a method for Knops genotyping.
14962306|a|BACKGROUND: DNA mutations resulting in the McCoy and Swain-Langley polymorphisms have been identified on complement receptor 1 (CR1)-a ligand for rosetting of Plasmodium falciparum-infected RBCs. The molecular identification of the Kna/Knb polymorphism was sought to develop a genotyping method for use in the study of the Knops blood group and malaria. STUDY DESIGN AND METHODS: CR1 deletion constructs were used in inhibition studies of anti-Kna. PCR amplification of Exon 29 was followed by DNA sequencing. A PCR-RFLP was developed with NdeI, BsmI, and MfeI for the detection of Kna/Knb, McCa/McCb, and Sl1/Sl2, respectively. Knops phenotypes were determined with standard serologic techniques. RESULTS: A total of 310 Malian persons were phenotyped for Kna with 200 (64%) Kn(a+) and 110 (36%) Kn(a-). Many of the Kn(a-) exhibited the Knops-null phenotype, that is, Helgeson. The Kna/b DNA polymorphism was identified as a V1561M mutation with allele frequencies of Kna (V1561) 0.9 and Knb (M1561) 0.1. CONCLUSION: The high frequency (18%) of Knb in West African persons suggests that it is not solely a Caucasian trait. Furthermore, because of the high incidence of heterozygosity as well as amorphs, accurate Knops typing of donors of African descent is best accomplished by a combination of molecular and serologic techniques.
14962306	1004	1010	V1561M	ProteinMutation	p|V|1561|M

14722925|t|Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis.
14722925|a|Mutations in the serine protease inhibitor Kazal type 1 gene (SPINK1) encoding pancreatic secretory trypsin inhibitor (PSTI) have recently been found to be associated with chronic pancreatitis. Nevertheless, knowledge of severe mutations is particularly scarce, both in terms of number and in the extent of clinical information. The aim of this study was to expand the known spectrum of such mutations. 46 unrelated families, each including at least two pancreatitis patients and carrying neither cationic trypsinogen (PRSS1) mutations nor the frequent SPINK1 N34S mutation, participated in this study. The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing. A heterozygous microdeletion mutation (c.27delC), which occurs within a symmetric element, was identified in two families. In one family, c.27delC showed segregation with the disease across two generations, with a penetrance of up to 75%. But in the other family, however, the same mutation manifested as a low-penetrance susceptibility factor. In addition, a novel heterozygous splicing mutation, c.87+1G>A (G>A substitution at nucleotide +1 of intron 2) was found in one family with familial pancreatitis. Our results also helped to resolve the sharply differing views about PSTI's role in pancreatitis.
14722925	694	698	N34S	ProteinMutation	p|N|34|S
14722925	976	984	c.27delC	DNAMutation	c|DEL|27|C
14722925	1075	1083	c.27delC	DNAMutation	c|DEL|27|C
14722925	1335	1344	c.87+1G>A	DNAMutation	c|G|87+1|A
14722925	1346	1391	G>A substitution at nucleotide +1 of intron 2	DNAMutation	c|G|IVS2+1|A

14709355|t|A novel two nucleotide deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein deficiency, corneal opacities, planar xanthomas, and premature coronary artery disease.
14709355|a|Familial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure. Her plasma HDL-cholesterol (C) and apoA-I concentrations were 0.08mmol/l and 1mg/dl, respectively. She exhibited corneal opacities and planar xanthomas on eyelids and elbows. Coronary angiography demonstrated extensive obstructions in two major vessels. Genomic DNA sequencing of the patient's apoA-I gene revealed a homozygosity for a GC deletion between 5 GC repeats in exon 4, creating a frameshift and a stop codon at residue 178. We designated this mutation as apoA-I Shinbashi. The proband's father, son, and daughter were found to be heterozygous for this mutation and their HDL-C and apoA-I levels were about half of normal levels, demonstrating a gene dosage effect. The father underwent coronary bypass surgery at age of 70 years. Lecithin-cholesterol acyltransferase (LCAT) activity was decreased by 63% in the homozygote and 31% in heterozygotes, respectively. This new case of apoA-I deficiency, apoA-I Shinbashi, is the first case involving a single gene defect of the apoA-I gene to develop all the characteristics for apoA-I deficiency, including premature coronary heart disease.

14708104|t|Gonadal mosaicism in severe Pallister-Hall syndrome.
14708104|a|Pallister-Hall syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc.
14708104	830	846	c.3385_3386delTT	DNAMutation	c|DEL|3385_3386|TT
14708104	906	914	p.F1129X	ProteinMutation	p|F|1129|X

14633686|t|High-resolution deletion mapping of 15q13.2-q21.1 in transitional cell carcinoma of the bladder.
14633686|a|Deletions found in several types of human tumor, including carcinomas of the colorectum, breast, and lung, suggest the presence of a potential tumor suppressor gene(s) on chromosome 15. Common regions of deletion in these tumors are at 15q15 and 15q21. Here, we have analyzed loss of heterozygosity (LOH) on chromosome 15 to ascertain its potential involvement in the development and progression of transitional cell carcinoma (TCC) of the bladder. A panel of 26 polymorphic markers, spanning 15q12-15q22, were used to map regions of LOH in 51 TCCs. LOH was found for at least one marker in the region 15q14-15q15.3 in 20 of 51 (39%) tumors. Deletion mapping defined two minimum regions of deletion: a distal region between the markers D15S514 and D15S537 at 15q15.1-15q15.3 (estimated as 3 Mb) and a more proximal region between the markers D15S971 and D15S1042 at 15q14 (estimated as 1.1 Mb). Analysis of a panel of 33 bladder tumor cell lines revealed regions of contiguous homozygosity for markers in 15q15, indicating likely LOH. Fluorescence in situ hybridization analysis demonstrated that mitotic recombination is the predicted mechanism of LOH in two of these. These regions of LOH on 15q may contain tumor suppressor genes the loss or inactivation of which is associated with TCC development. The DNA repair gene RAD51 at 15q15.1 represents a candidate 15q tumor suppressor gene. Expression analysis of rad51 protein in tumor cell lines revealed variable levels of expression but no significant loss of expression in cell lines with likely 15q LOH.

14568816|t|Muscle glycogenosis and mitochondrial hepatopathy in an infant with mutations in both the myophosphorylase and deoxyguanosine kinase genes.
14568816|a|OBJECTIVES: To document 2 apparently incongruous clinical disorders occurring in the same infant: congenital myopathy with myophosphorylase deficiency (McArdle disease) and mitochondrial hepatopathy with liver failure and mitochondrial DNA depletion. METHODS: An infant girl born to consanguineous Moroccan parents had severe congenital hypotonia and hepatomegaly, developed liver failure, and died at 5 months of age. We studied muscle and liver biopsy specimens histochemically and biochemically, and we sequenced the whole coding regions of the deoxyguanosine kinase (dGK) and myophosphorylase (PYGM) genes. RESULTS: Muscle biopsy specimens showed subsarcolemmal glycogen accumulation and negative histochemical reaction for phosphorylase. Liver biopsy specimens showed micronodular cirrhosis and massive mitochondrial proliferation. Biochemical analysis showed phosphorylase deficiency in muscle and cytochrome c oxidase deficiency in liver. We identified a novel homozygous missense G-to-A mutation at codon 456 in exon 11 of PYGM, as well as a homozygous 4-base pair GATT duplication (nucleotides 763-766) in exon 6 of dGK, which produces a frame shift and a premature TGA stop codon at nucleotides 766 to 768, resulting in a truncated 255-amino acid protein. Both mutations were absent in 100 healthy individuals. CONCLUSIONS: Our data further expand the genetic heterogeneity in patients with McArdle disease; confirm the strong relationship between mitochondrial DNA depletion syndrome, liver involvement, and dGK mutations; and suggest that genetic "double trouble" should be considered in patients with unusual severe phenotypes.

12915882|t|Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk.
12915882|a|Microsomal epoxide hydrolase (mEH) plays a dual role in the detoxification and activation of tobacco procarcinogens. Two polymorphisms affecting enzyme activity have been described in the exons 3 and 4 of the mEH gene, which result in the substitution of amino acids histidine to tyrosine at residue 113, and arginine to histidine at residue 139, respectively. We performed a hospital-based case-control study consisting of 277 newly diagnosed lung cancer patients and 496 control subjects to investigate a possible association between these two polymorphisms and lung cancer risk. The polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism and TaqMan assay using DNA from peripheral white blood cells. Logistic regression was performed to calculate odds ratios (ORs), confidence limits (CL) and to control for possible confounders. The exon 3 polymorphism of the mEH gene was associated with a significantly decreased risk of lung cancer. The adjusted OR, calculated relative to subjects with the Tyr113/Tyr113 wild type, for the His113/His113 genotype was 0.38 (95% CL 0.20-0.75). An analysis according to histological subtypes revealed a statistically significant association for adenocarcinomas; the adjusted OR for the His113/His113 genotype was 0.40 (95% CL 0.17-0.94). In contrast, no relationship between the exon 4 polymorphism and lung cancer risk was found. The adjusted OR, calculated relative to the His139/His139 wild type, was for the Arg139/Arg139 genotype 1.83 (0.76-4.44). Our results support the hypothesis that genetically reduced mEH activity may be protective against lung cancer.

12862311|t|Detection of PHKA2 gene mutation in four Japanese patients with hepatic phosphorylase kinase deficiency.
12862311|a|We analyzed the PHKA2 gene in four Japanese families with hepatic phosphorylase kinase (PhK) deficiency. Mutational analysis of PHKA2 cDNA was performed by reverse-transcribed polymerase chain reaction (RT-PCR) and direct sequencing, and each mutation was confirmed on the genomic DNA. In boys with low erythrocyte PhK activity (i.e., x-linked liver glycogenosis [XLG] type I), deletion of exon 2 (splice site mutation of 79-1 G > T) or nonsense mutation of Q1169X or R497X was identified. However, missense mutation of R295C was identified in one boy with normal erythrocyte PhK activity (i.e., XLG type II). This mutation was not found in 100 control alleles, and was considered responsible for presentation of the XLG type II phenotype. Excluding Q1169X, all mutations detected in this study represented novel mutations. All mothers were found to be heterozygous carriers of the mutations. Gene analysis was confirmed to represent a useful procedure for diagnosing XLG type II, for which liver biopsy had previously been required to detect hepatic PhK deficiency.
12862311	527	537	79-1 G > T	DNAMutation	c|G|79-1|T
12862311	563	569	Q1169X	ProteinMutation	p|Q|1169|X
12862311	573	578	R497X	ProteinMutation	p|R|497|X
12862311	625	630	R295C	ProteinMutation	p|R|295|C
12862311	855	861	Q1169X	ProteinMutation	p|Q|1169|X

12820697|t|Mutation analysis of SLC7A9 in cystinuria patients in Sweden.
12820697|a|Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas nontype I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.
12820697	1010	1015	P261L	ProteinMutation	p|P|261|L
12820697	1020	1025	V330M	ProteinMutation	p|V|330|M
12820697	1063	1072	1009 delA	DNAMutation	|DEL|1009|A
12820697	1116	1121	A182T	ProteinMutation	p|A|182|T
12820697	1178	1183	V330M	ProteinMutation	p|V|330|M
12820697	1188	1196	1009delA	DNAMutation	|DEL|1009|A
12820697	1411	1416	P261L	ProteinMutation	p|P|261|L

12791036|t|A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.
12791036|a|In 1982, one of us reported a cluster of eight individuals affected by spondylocostal dysostosis (SD, MIM 277300) in four nuclear families indigenous to a village from eastern Switzerland. We tested the hypothesis that the molecular basis for this cluster was segregation of a single mutation in the DLL3 gene, recently linked to SD. Marker haplotypes around the DLL3 locus contradicted this hypothesis as three different haplotypes were seen in affected individuals, but sequence analysis showed that three unreported DLL3 mutations were segregating: a duplication of 17 bp in exon 8 (c.1285-1301dup), a single-nucleotide deletion in exon 5 (c.615delC), and a R238X nonsense mutation in exon 6. Contrary to our initial assumption of a single allele segregating in this small community, three different pathogenic alleles were observed, with a putative founder mutation occurring at the homozygous state but also compounding with, and thus revealing, two other independent mutations. As all three mutations predict truncation of the DLL3 protein and loss of the membrane-attaching domain, the results confirm that autosomal recessive spondylocostal dysostosis represents the null phenotype of DLL3, with remarkable phenotypic consistency across families.
12791036	725	739	c.1285-1301dup	DNAMutation	c|DUP|1285_1301|
12791036	782	791	c.615delC	DNAMutation	c|DEL|615|C
12791036	800	805	R238X	ProteinMutation	p|R|238|X

12737948|t|A "null allele" mutation is responsible for erythropoietic protoporphyria in an Israeli patient who underwent liver transplantation: relationships among biochemical, clinical, and genetic parameters.
12737948|a|Mutations in the human ferrochelatase gene (FECH) are the primary cause of the inborn disorder erythropoietic protoporphyria (EPP). While the majority of the EPP patients exhibit only photosensitivity, a small percentage of patients (approximately 2%) develop liver complications in addition to the cutaneous symptoms. In this study, the FECH gene of an Israeli EPP patient who suffered from EPP-related liver complications was sequenced. A splicing defect IVS10+1, g-->t, which is known to cause the deletion of exon 10, was identified in the index patient as well as in his symptomatic older sister and his asymptomatic mother. Like the other 12 known FECH mutations associated with liver complications, IVS10+1, g-->t is a "null-allele" mutation. Although the two siblings with overt EPP share an identical genotype with respect to both the mutation on one FECH allele and three intragenic single nucleotide polymorphisms, -251G, IVS1-23T, and IVS3-48C on the other allele, the sister of the index patient has so far shown no signs of liver involvement, suggesting that additional factors might account for the liver disease in EPP.
12737948	657	671	IVS10+1, g-->t	DNAMutation	r|G|IVS10+1|T
12737948	906	920	IVS10+1, g-->t	DNAMutation	r|G|IVS10+1|T
12737948	1126	1131	-251G	DNAMutation	c||-251|G
12737948	1133	1141	IVS1-23T	DNAMutation	c||IVS1-23|T
12737948	1147	1155	IVS3-48C	DNAMutation	c||IVS3-48|C

12701064|t|A novel compound heterozygous mutation in the CYP17 (P450 17alpha-hydroxylase) gene leading to 17alpha-hydroxylase/17,20-lyase deficiency.
12701064|a|Mutations in the CYP17 gene impair steroid biosynthesis in the adrenals and gonads and often cause 17alpha-hydroxylase/17,20-lyase deficiency, leading to amenorrhea, sexual infantilism, and hypokalemic low aldosterone hypertension. Several CYP17 mutations resulting in 17alpha-hydroxylase/17,20-lyase deficiency have been reported previously. In the present study, we found a novel CYP17 mutation from the molecular analysis of a Korean patient with primary amenorrhea with a 46,XX karyotype, and hypokalemic hypertension. We sequenced all 8 exons of the CYP17 gene that were amplified from patient's genomic DNA using polymerase chain reaction (PCR) and found a compound heterozygous mutation in the CYP17 structural gene; a 1-base deletion and a 1-base transversion (TAC-->AA) at codon 329, leading to the production of a truncated protein (1-417 amino acids), and a 3-base deletion (TCC, either 350-351 or 351-352 codon) in the other allele. Restriction enzyme digestion analysis of patient's and parental DNA showed that the 1-base deletion and the 3-base deletion are inherited from mother and father, respectively. Here we conclude that these novel compound heterozygous mutations might account for the patient's clinical manifestations of 17alpha-hydroxylase/17,20-lyase deficiency.
12701064	907	930	(TAC-->AA) at codon 329	DNAMutation	|TAC|CODON329|AA

12668609|t|Haplotypes extending across ACE are associated with Alzheimer's disease.
12668609|a|Numerous genes have been implicated in Alzheimer's disease (AD), but, with the exception of a demonstrated association with the epsilon 4 allele of APOE, findings have not been consistently replicated across populations. One of the most widely studied is the gene for angiotensin I converting enzyme (ACE ). A meta-analysis of published data on a common Alu indel polymorphism in ACE was performed which indicated highly significant association of the insertion allele with AD (OR 1.30; 95% CI 1.19 - 1.41; P=4 x 10(-8)). To further explore the influence of ACE on AD, several single-nucleotide polymorphisms (SNPs) were genotyped in five independent populations represented by over 3100 individuals. Analyses based upon single markers and haplotypes revealed strong evidence of association in case-control models and also in a model examining the influence of variation in ACE upon cerebrospinal fluid levels of amyloid beta42 peptide (Abeta42). The most significant evidence for association with AD was found for an SNP, A-262T, located in the ACE promoter (OR 1.64; 95% CI 1.33 -1.94; P=2 x 10(-5)). Estimates of population attributable risk for the common allele of this SNP suggest that it, or an allele in tight linkage disequilibrium (LD) with it, may contribute to as much as 35% of AD in the general population. Results support a model whereby decreased ACE activity may influence AD susceptibility by a mechanism involving beta-amyloid metabolism.
12668609	1096	1102	A-262T	DNAMutation	c|A|-262|T

12636044|t|Identification of new polymorphisms in the CACNA1S gene.
12636044|a|We identified four novel polymorphisms in the CACNA1S gene that encodes the alpha1-subunit of the dihydropyridine receptor. Mutations in this gene are associated with two genetic diseases: malignant hyperthermia and hypokalemic periodic paralysis. The nucleotide substitutions c2403T --> C and c5398T --> C did not result in amino acid replacement, the nucleotide substitution c4475C --> A caused the replacement of the Ala1492 with an Asp residue and an A insertion was identified in intron 36. By using methods based on digestion with restriction enzymes we calculated the frequencies of these novel polymorphisms, as well as heterozygosity, in normal subjects from southern Italy.
12636044	334	346	c2403T --> C	DNAMutation	c|T|2403|C
12636044	351	363	c5398T --> C	DNAMutation	c|T|5398|C
12636044	434	446	c4475C --> A	DNAMutation	c|C|4475|A

12631337|t|Association of an IL-1A 3'UTR polymorphism with end-stage renal disease and IL-1 alpha expression.
12631337|a|BACKGROUND: We evaluated polymorphisms in the interleukin-1 alpha 3'-untranslated region (IL-1A 3'[UTR]) for association with type 2 diabetes-associated (DM) and nondiabetic-associated (non-DM) end-stage renal disease (ESRD) in two ethnic groups. METHODS: IL-1A 3'UTR polymorphisms were identified by alignment of overlapping human expressed sequence tags (ESTs). Sequence ambiguities were experimentally confirmed and variants genotyped to test for association with ESRD in 75 unrelated Caucasians with DM ESRD, 95 unrelated Caucasian controls and, in a parallel study, 92 unrelated African Americans with type 2 DM ESRD, 95 unrelated African Americans with non-DM ESRD, and 86 unrelated African American controls. IL-1A 3' UTR genotype and lipopolysaccharide (LPS)-stimulated IL-1 alpha protein levels were measured in healthy Caucasians (N = 112) and African Americans (N = 101) to evaluate association between genotype and protein level. RESULTS: A polymorphism in the 3' UTR of the human IL-1A gene was associated with ESRD and IL-1 alpha protein expression. The polymorphism consists of two single nucleotide polymorphisms (SNPs) and an insertion/deletion generating four different haplotypes: TN7TTCAA, AN7TTCAA, TN7TTCAG and an allele deleted for four internal bases, TN7(delTTCA)A. The 4 bp deletion allele, TN7(delTTCA)A, was significantly less common among Caucasian DM ESRD and African American non-DM ESRD patients (recessive model; P = 0.0364 and P = 0.0293, respectively). In vitro, this polymorphism is associated with the amount of IL-1 alpha protein synthesized in LPS-stimulated lymphocytes from healthy subjects (P = 0.0013, additive model), with the TN7(delTTCA)A haplotype associated with higher levels of stimulated IL-1 alpha. CONCLUSION: The association of the TN7(delTTCA)A haplotype with higher levels of IL-1 alpha expression and reduced risk for ESRD is consistent with involvement of cytokines in risk for developing nephropathy.
12631337	1379	1386	delTTCA	DNAMutation	|DEL||TTCA
12631337	1420	1427	delTTCA	DNAMutation	|DEL||TTCA
12631337	1774	1781	delTTCA	DNAMutation	|DEL||TTCA
12631337	1889	1896	delTTCA	DNAMutation	|DEL||TTCA

22106692|t|The association between GJB2 mutation and GJB6 gene in non syndromic hearing loss school children.
22106692|a|Recently, molecular testing for GJB2 mutations has become the standard of care for the diagnosis of patients with non syndromic hearing impairment of unknown cause. The aims of this study are to determine the association between GJB2 mutation and GJB6 and to report the variation of mutations in deaf students who have heterozygous GJB2. This retrospective study was conducted at Universiti Kebangsaan Malaysia Medical Center (UKMMC). Data was collected from previous files and records from Tissue Engineering and Human Genetic Research Group Laboratory. Approval from Ethical Committee was obtained prior to the study. A total of 138 students have been screened in previous studies in UKMMC for the presence of GJB2 mutations as a cause for hearing loss. Thirty four of the 138 subjects have GJB2 mutations; 2 showed homozygous mutations whereas another 32 were heterozygous for GJB2 gene mutation. Only 31 DNA samples of students presented with sensorineural hearing loss with heterozygous mutation in GJB2 gene were included in this study. The sequencing results obtained were analyzed. The degree of hearing loss of those students with association between GJB2 mutation and GJB6 mutation will be discussed. Five out of 31 subjects (16.2%) have mutations in their GJB6 gene, suggesting a digenic inheritance of GJB2/GJB6 mutation. In total, four novel mutations were identified; E137D (n=1), R32Q (n=1), E101K (n=1) and Y156H (n=1) and one mutation deletion; 366delT (n=1). All students with association GJB2 mutation and GJB6 showed severe to profound hearing loss in both ears. Interestingly this study not detected the large deletion of 342 kb in GJB6 gene suggesting that the mutation is very rare in this region compared to certain parts of the world.
22106692	1481	1486	E137D	ProteinMutation	p|E|137|D
22106692	1494	1498	R32Q	ProteinMutation	p|R|32|Q
22106692	1506	1511	E101K	ProteinMutation	p|E|101|K
22106692	1522	1527	Y156H	ProteinMutation	p|Y|156|H
22106692	1561	1568	366delT	DNAMutation	|DEL|366|T

21750150|t|Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells.
21750150|a|Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.

21699520|t|PTCH1 gene mutations in exon 17 and loss of heterozygosity on D9S180 microsatellite in sporadic and inherited human basal cell carcinomas.
21699520|a|BACKGROUND: Basal cell carcinomas (BCCs) are the most frequent human cancer that results from malignant transformation of basal cells in the epidermis. Gorlin syndrome is a rare inherited autosomal dominant disease that predisposes with multiple BCCs and other birth defects. Both sporadic and inherited BCCs are associated with mutations in the tumor suppressor gene PTCH1, but there is still uncertainty on the role of its homolog PTCH2. OBJECTIVES: To search for mutations and genomic instability in sporadic and inherited BCCs. METHODS: DNA obtained from leukocytes and tumor cells was amplified by polymerase chain reaction regarding five exons of PTCH1 and PTCH2 and neighboring microsatellites. Exons were sequenced and compared with the GenBank database. RESULTS: Only D9S180, of six microsatellites, showed loss of heterozygosity in three BCCs (two sporadic and one inherited). One sporadic BCC presented the mutation g.2885G>C in exon 17 of PTCH1, which predicts the substitution p.R962T in an external domain of the protein. In addition, the leukocytes and tumor cells of one patient with Gorlin syndrome showed the mutation g.2839T>G in the same exon and gene, which predicts a p.E947stop and truncated protein. All control and tumor samples presented IVS9 + 217T in intron 9 of PTCH1. CONCLUSION: Mutations found in the PTCH1 gene and neighboring repetitive sequences may have contributed to the development of the studied BCCs.
21699520	1066	1075	g.2885G>C	DNAMutation	g|G|2885|C
21699520	1129	1136	p.R962T	ProteinMutation	p|R|962|T
21699520	1275	1284	g.2839T>G	DNAMutation	g|T|2839|G
21699520	1329	1339	p.E947stop	ProteinMutation	p|E|947|X
21699520	1403	1414	IVS9 + 217T	DNAMutation	c||IVS9+217|T

21542403|t|Chasing the ubiquitous RET proto-oncogene in South African MEN2 families--implications for the surgeon.
21542403|a|The RET proto-oncogene (REarranged during Transfection; RET) plays an important role in the causation of many thyroid tumours. Germline RET proto-oncogene missense mutations have been clearly linked to medullary thyroid carcinoma (MTC) and the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2A, MEN2B). METHODS: We investigated a cohort of MEN2-related patients referred to Tygerberg Hospital, W Cape (2003-2009). The study cohort was divided into three groups based on pathology (viz. MEN/MTC, phaeochromocytoma, and a miscellaneous group of MEN pathologies). Families with identified high-risk factors were recalled. Serum calcitonin levels were monitored where indicated. DNA was extracted from whole blood by standard techniques and polymerase chain reaction (PCR) products screened for RET gene variations by heteroduplex single-strand duplication techniques (heteroduplex single-strand conformation polymorphism analysis) being validated with automated sequencing techniques showing conformational variants in acrylamide gel. RESULTS: We screened 40 persons, male/female ratio 1:1.5. Three ethnic groups were represented (white (12), black (11) and mixed race (17)). Nine were index MTC cases, 5 phaeochromocytoma, 3 Hirschsprung's disease-MEN associations and 2 miscellaneous (1 neuroblastoma, 1 intestinal neuronal dysplasia), while 1 fell into the MEN2B category. The remaining 19 were unaffected relatives screened for carrier status, among whom afamilial recurrence was observed in 7. On genetic testing, an RET point mutation at the high-risk 634 cysteine allele was identified in 11 cases. A further cysteine radical mutation at the 620 position was related to MEN2 in 3 families plus 1 other family referred from elsewhere. Other less-recognised gene variations were detected throughout the RET gene in 70% of cases and included the 691 position on codon 11 (11 cases); the 432 position (4 cases, 1 homozygous) intronic mutations on exon 4 (1 case); and an IVS19-37G/C and a D1017N variation in exon 19 in 2 MEN families. Fifteen MTC patients have had thyroidectomies, of which 2 were prophylactic (C-cell hyperplasia; early occult MTC). A further 3 are awaiting prophylactic surgery. CONCLUSION: RET gene mutation carries a risk of MEN2 and MTC in all ethnic groups in South Africa. Prophylactic surgery may prevent MTC, so genetic screening is important to identify and treat high-risk patients.
21542403	2094	2105	IVS19-37G/C	DNAMutation	c|G|IVS19-37|C
21542403	2112	2118	D1017N	ProteinMutation	p|D|1017|N

21903317|t|Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD.
21903317|a|Homozygous or compound heterozygous mutations in renin (REN) cause renal tubular dysgenesis, which is characterized by death in utero due to kidney failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia, and chronic kidney disease (CKD). To date, only 3 different heterozygous REN mutations have been published. We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD (uromodulin) and HNF1B (hepatocyte nuclear factor 1b) genes. We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA, corresponding to a tryptophan to arginine substitution at amino acid 10, which is found within the signal sequence (c.28T>C; p.W10R). On this basis, we conclude that REN mutations are rare events in patients with CKD. Within the kindred, we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia, hyperuricemia, and CKD. Anemia was severe and disproportional to the degree of decreased kidney function. Because all heterozygous REN mutations that have been described are localized in the signal sequence, screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1, which encodes the signal peptide.
21903317	1075	1082	c.28T>C	DNAMutation	c|T|28|C
21903317	1084	1090	p.W10R	ProteinMutation	p|W|10|R

22303603|t|Detection of possible restriction sites for type II restriction enzymes in DNA sequences.
22303603|a|In order to make a step forward in the knowledge of the mechanism operating in complex polygenic disorders such as diabetes and obesity, this paper proposes a new algorithm (PRSD -possible restriction site detection) and its implementation in Applied Genetics software. This software can be used for in silico detection of potential (hidden) recognition sites for endonucleases and for nucleotide repeats identification. The recognition sites for endonucleases may result from hidden sequences through deletion or insertion of a specific number of nucleotides. Tests were conducted on DNA sequences downloaded from NCBI servers using specific recognition sites for common type II restriction enzymes introduced in the software database (n = 126). Each possible recognition site indicated by the PRSD algorithm implemented in Applied Genetics was checked and confirmed by NEBcutter V2.0 and Webcutter 2.0 software. In the sequence NG_008724.1 (which includes 63632 nucleotides) we found a high number of potential restriction sites for ECO R1 that may be produced by deletion (n = 43 sites) or insertion (n = 591 sites) of one nucleotide. The second module of Applied Genetics has been designed to find simple repeats sizes with a real future in understanding the role of SNPs (Single Nucleotide Polymorphisms) in the pathogenesis of the complex metabolic disorders. We have tested the presence of simple repetitive sequences in five DNA sequence. The software indicated exact position of each repeats detected in the tested sequences. Future development of Applied Genetics can provide an alternative for powerful tools used to search for restriction sites or repetitive sequences or to improve genotyping methods.

22337303|t|Carboxy-terminal sequence variation of LMP1 gene in Epstein-Barr-virus-associated mononucleosis and tumors from Serbian patients.
22337303|a|Seven strains of Epstein-Barr virus (EBV) are defined based on C-terminal sequence variations of the latent membrane protein 1 (LMP1). Some strains, especially those with a 30-bp deletion, are thought to be related to tumorigenic activity and geographical localization. The aims of the study were to determine the prevalence of different LMP1 strains and to investigate sequence variation in the C-terminal region of LMP1 in Serbian isolates. This study included 53 EBV-DNA-positive plasma and tissue block samples from patients with mononucleosis syndrome, renal transplantation, and tumors, mostly nasopharyngeal carcinoma. The sequence of the 506-bp fragment of LMP1   C terminus was used for phylogenetic analyses and identification of LMP1 strains, deletions, and mutations. The majority of isolates were non-deleted (66%), and the rest had 30-bp, rare 69-bp, or yet unknown 27-bp deletions, which were not related to malignant or non-malignant isolate origin. However, the majority of 69-bp deletion isolates were derived from patients with nasopharyngeal carcinoma. Less than five 33-bp repeats were found in the majority of non-deleted isolates (68.6%), whereas most 69-bp deletion isolates (75%) had five or six repeats. Serbian isolates were assigned to four LMP1 strains: B95-8 (32.1%), China 1 (24.5%), North Carolina (NC; 18.9%), and Mediterranean (Med; 24.5%). In NC isolates, three new mutations unique for this strain were identified. EBV EBNA2 genotypes 1 and 2 were both found, with dominance of genotype 1 (90.7%). This study demonstrated noticeable geographical-associated characteristics in the LMP1 C terminus of investigated isolates.

21666969|t|Roles of G1359A polymorphism of the cannabinoid receptor gene (CNR1) on weight loss and adipocytokines after a hypocaloric diet.
21666969|a|BACKGROUND: A intragenic biallelic polymorphism (1359 G/A) of the CB1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in Caucasian populations. Intervention studies with this polymorphism have not been realized. OBJECTIVE: We decided to investigate the role of the polymorphism (G1359A) of CB1 receptor gene on adipocytokines response and weight loss secondary to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. DESIGN: A population of 94 patients with obesity was analyzed. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined G1359A and A1359A as a group and wild type G1359G as second group, with a dominant model. Results: Forty seven patients (50%) had the genotype G1359G (wild type group) and 47 (50%) patients G1359A (41 patients, 43.6%) or A1359A (6 patients, 6.4%) (mutant type group) had the genotype. In wild and mutant type groups, weight, body mass index, fat mass, waist circumference and systolic blood pressure decreased. In mutant type group, resistin (4.15    1.7 ng/ml vs. 3.90    2.1 ng/ml: P < 0.05), leptin (78.4    69 ng/ml vs 66.2    32 ng/ml: P < 0.05) and IL-6 (1.40    1.9 pg/ml vs 0.81    1.5 pg/ml: P < 0.05) levels decreased after dietary treatment. CONCLUSION: The novel finding of this study is the association of the mutant allele (A1359) with a decrease of resistin, leptin and interleukin-6 secondary to weight loss.
21666969	178	186	1359 G/A	DNAMutation	g|G|1359|A

21684788|t|Large contiguous gene deletions in Sj  gren-Larsson syndrome.
21684788|a|Sj  gren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.
21684788	1186	1194	c.407C>T	DNAMutation	c|C|407|T
21684788	1196	1201	P136L	ProteinMutation	p|P|136|L

22042570|t|OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy.
22042570|a|PURPOSE: To report three types of heterozygous mutations in the OPA1 gene in five patients from three families with autosomal dominant optic atrophy (ADOA, MIM#165500). METHODS: DNA was extracted from the leukocytes of the peripheral blood. For mtDNA, mutations were examined at positions 11778, 3460 and 14484. For the OPA1 gene, the exons were amplified by PCR and mutations were detected by restriction enzymes or the dye terminator method. RESULTS: We detected three types of OPA1 mutation but no mtDNA mutations. In the OPA1 gene, heterozygous frameshift mutations from codon 903 due to a four-base pair deletion in exon 27 were detected in three patients from one family (c.2708_2711delTTAG, p.V903GfsX905). A heterozygous mutation due to a three-base pair deletion in exon 17, leading to a one-amino acid deletion (c.1618_1620delACT, p.T540del), and a heterozygous mutation due to a one-base substitution in exon 11, leading to a stop codon (c.1084G>T, p.E362X), were detected in sporadic cases. CONCLUSION: OPA1 mutations existed in three Japanese families with ADOA. After a detailed clinical assessment of the proband, the screening of the OPA1 gene may be helpful for precise diagnosis of ADOA, provided the relevant information of the family members is limited.
22042570	766	784	c.2708_2711delTTAG	DNAMutation	c|DEL|2708_2711|TTAG
22042570	786	799	p.V903GfsX905	ProteinMutation	p|V|903|G|FSX|905
22042570	910	927	c.1618_1620delACT	DNAMutation	c|DEL|1618_1620|ACT
22042570	929	938	p.T540del	ProteinMutation	p|DEL|540|T
22042570	1037	1046	c.1084G>T	DNAMutation	c|G|1084|T
22042570	1048	1055	p.E362X	ProteinMutation	p|E|362|X

21615796|t|Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia.
21615796|a|INTRODUCTION: IL-17F is a novel inflammatory cytokine and plays an important role in some autoimmune diseases. We investigated the association between chronic ITP and the frequency of the single-nucleotide polymorphism rs763780 (7488T/C), which causes a His-to-Arg substitution at amino acid 161. PATIENTS AND METHODS: We examined 102 patients (men/women, 40/62; median age, 42) diagnosed with chronic ITP and 188 healthy controls (men/women, 78/110; median age, 38). Genotyping was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Compared with the control group, patients with chronic ITP had a significantly lower frequency of the IL-17F 7488CC genotype (0% vs. 4.8%, P<0.05). The number of IL-17F 7488C alleles among the patients with chronic ITP was also significantly lower than in the control group (8.7% vs. 15.2% OR=0.48, 95%CI=0.27-0.84, P=0.016). Furthermore, patients with the IL-17F 7488TT genotype showed a severe thrombocytopenic state (platelet count<10 10(9) /L) at diagnosis than those with the IL-17F 7488TC genotype (20.9% vs. 0%, P=0.04). CONCLUSION: These findings suggest that the IL-17F 7488 T allele is significantly associated with the development of chronic ITP, suggesting a role for IL-17F in the pathogenesis of chronic ITP.
21615796	303	311	rs763780	SNP	rs763780
21615796	313	320	7488T/C	DNAMutation	g|T|7488|C

21533187|t|Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.
21533187|a|Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.

21937424|t|The TREX1 exonuclease R114H mutation in Aicardi-Gouti  res syndrome and lupus reveals dimeric structure requirements for DNA degradation activity.
21937424|a|Mutations in the TREX1 gene cause Aicardi-Gouti  res syndrome (AGS) and are linked to the autoimmune disease systemic lupus erythematosus. The TREX1 protein is a dimeric 3' DNA exonuclease that degrades DNA to prevent inappropriate immune activation. One of the most common TREX1 mutations, R114H, causes AGS as a homozygous and compound heterozygous mutation and is found as a heterozygous mutation in systemic lupus erythematosus. The TREX1 proteins containing R114H and the insertion mutations aspartate at position 201 (D201ins) and alanine at position 124 (A124ins), found in compound heterozygous AGS with R114H, were prepared and the DNA degradation activities were tested. The homodimer TREX1(R114H/R114H) exhibits a 23-fold reduced single-stranded DNA (ssDNA) exonuclease activity relative to TREX1(WT). The TREX1(D201ins/D201ins) and TREX1(A124ins/A124ins) exhibit more than 10,000-fold reduced ssDNA degradation activities. However, the TREX1(R114H/D201ins) and TREX1(R114H/A124ins) compound heterodimers exhibit activities 10-fold greater than the TREX1(R114H/R114H) homodimer during ssDNA and double-stranded DNA (dsDNA) degradation. These higher levels of activities measured in the TREX1(R114H/D201ins) and TREX1(R114H/A124ins) compound heterodimers are attributed to Arg-114 residues of TREX1(D201ins) and TREX1(A124ins) positioned at the dimer interface contributing to the active sites of the opposing TREX1(R114H) protomer. This interpretation is further supported by exonuclease activities measured for TREX1 enzymes containing R114A and R114K mutations. These biochemical data provide direct evidence for TREX1 residues in one protomer contributing to DNA degradation catalyzed in the opposing protomer and help to explain the dimeric TREX1 structure required for full catalytic competency.
21937424	22	27	R114H	ProteinMutation	p|R|114|H
21937424	438	443	R114H	ProteinMutation	p|R|114|H
21937424	610	615	R114H	ProteinMutation	p|R|114|H
21937424	671	678	D201ins	ProteinMutation	p|INS|201|D
21937424	709	716	A124ins	ProteinMutation	p|INS|124|A
21937424	759	764	R114H	ProteinMutation	p|R|114|H
21937424	848	853	R114H	ProteinMutation	p|R|114|H
21937424	854	859	R114H	ProteinMutation	p|R|114|H
21937424	970	977	D201ins	ProteinMutation	p|INS|201|D
21937424	978	985	D201ins	ProteinMutation	p|INS|201|D
21937424	997	1004	A124ins	ProteinMutation	p|INS|124|A
21937424	1005	1012	A124ins	ProteinMutation	p|INS|124|A
21937424	1101	1106	R114H	ProteinMutation	p|R|114|H
21937424	1107	1114	D201ins	ProteinMutation	p|INS|201|D
21937424	1126	1131	R114H	ProteinMutation	p|R|114|H
21937424	1132	1139	A124ins	ProteinMutation	p|INS|124|A
21937424	1213	1218	R114H	ProteinMutation	p|R|114|H
21937424	1219	1224	R114H	ProteinMutation	p|R|114|H
21937424	1350	1355	R114H	ProteinMutation	p|R|114|H
21937424	1356	1363	D201ins	ProteinMutation	p|INS|201|D
21937424	1375	1380	R114H	ProteinMutation	p|R|114|H
21937424	1381	1388	A124ins	ProteinMutation	p|INS|124|A
21937424	1456	1463	D201ins	ProteinMutation	p|INS|201|D
21937424	1475	1482	A124ins	ProteinMutation	p|INS|124|A
21937424	1573	1578	R114H	ProteinMutation	p|R|114|H
21937424	1695	1700	R114A	ProteinMutation	p|R|114|A
21937424	1705	1710	R114K	ProteinMutation	p|R|114|K

22180037|t|Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population.
22180037|a|Glutathione-S-transferase P1 (GSTP1) is a critical enzyme of the phase II detoxification pathway. One of the common functional polymorphisms of GSTP1 is A > G at nucleotide 313, which results in an amino acid substitution (Ile105Val) at the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. To investigate the GSTP1 Ile105Val genotype frequency in prostate cancer cases in the Kashmiri population, we designed a case-control study, in which 50 prostate cancer cases and 45 benign prostate hyperplasia cases were studied for GSTP1 Ile105Val polymorphism, compared to 80 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of GSTP1 Ile105Val in our ethnic Kashmir population, i.e., Ile/Ile, Ile/Val and Val/Val, to be 52.4, 33.3 and 14.3% among prostate cancer cases, 48.5, 37.5 and 14% among benign prostate hyperplasia cases and 73.8, 21.3 and 5% in the control population, respectively. There was a significant association between the GSTP1 Ile/Val genotype and the advanced age group among the cases. We conclude that GSTP1 Ile/Val polymorphism is involved in the risk of prostate cancer development in our population.
22180037	289	312	A > G at nucleotide 313	DNAMutation	c|A|313|G
22180037	359	368	Ile105Val	ProteinMutation	p|I|105|V
22180037	475	484	Ile105Val	ProteinMutation	p|I|105|V
22180037	689	698	Ile105Val	ProteinMutation	p|I|105|V
22180037	871	880	Ile105Val	ProteinMutation	p|I|105|V

22125978|t|Identification of LIPH gene mutation in a consanguineous family segregating the woolly hair/hypotrichosis phenotype.
22125978|a|OBJECTIVE: To identify the disease causing gene in a four generation consanguineous family in which eleven family members were suffering from Woolly hair/hypotrichosis phenotype. METHODS: Linkage analysis was carried out to identify the disease-causing gene in this family. Genomic DNA of all the available family members was genotyped for the microsatellite markers for all the known woolly hair/hypotrichosis loci.Automated DNA sequencing of the candidate gene was performed to identify the disease-causing mutation. RESULTS: By using homozygosity linkage analysis we have mapped the family on chromosome 3q27.3 with a two point LOD score of 4.04, Mutation screening of the LIPH gene revealed a homozygous c.659_660delTA deletion mutation segregating with the disease phenotype. CONCLUSION: The results indicate that the c.659_660delTA mutation in the LIPH gene cause autosomal recessive WH/hypotrichosis phenotype in this family. This mutation has been reported in several Pakistani and Guyanese families suggesting a founder mutation in the LIPH gene in Indo-Pak sub-continent.
22125978	825	839	c.659_660delTA	DNAMutation	c|DEL|659_660|TA
22125978	940	954	c.659_660delTA	DNAMutation	c|DEL|659_660|TA

21042587|t|Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess.
21042587|a|Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11b-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension.
21042587	687	698	p.R469[R,X]	ProteinMutation	p|R|469|X

20693575|t|cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.
20693575|a|BACKGROUND: HCN channels activate the pacemaker current I(f), which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation. METHODS AND RESULTS: In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia. Biophysical properties determined by whole-cell patch-clamp recording of HEK293 cells demonstrated that mutant subunits (HCN4-695X) were insensitive to cAMP. Heteromeric channels composed of wild-type and mutant subunits failed to respond to cAMP-like homomeric mutant channels, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Pedigree analysis identified 7 additional living carriers showing similar clinical phenotypes, that is, sinus node dysfunction with mean resting heart rate of 45.9  4.6 bpm (n=8) compared with 66.5  9.1 bpm of unaffected relatives (n=6; P<0.01). Clinical evaluation revealed no ischemic or structural heart disease in any family member. Importantly, mutant carriers exhibited normal heart rate variance and full ability to accelerate heart rate under physical activity or pharmacological stimulation. Moreover, mutant carriers displayed distinctive sinus arrhythmias and premature beats linked to adrenergic stress. CONCLUSIONS: In humans, cAMP responsiveness of I(f) determines basal heart rate but is not critical for maximum heart rate, heart rate variability, or chronotropic competence. Furthermore, cAMP-activated I(f) may stabilize heart rhythm during chronotropic response.

21182502|t|A novel homozygous splice site mutation in COL7A1 in a Chinese patient with severe recessive dystrophic epidermolysis bullosa and squamous cell carcinoma.
21182502|a|BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disorder caused by mutations in COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils in the dermo-epidermal junction. The development of cutaneous squamous cell carcinoma (SCC) is one of the most serious complications of this disease. We report herein a Chinese patient with the severe generalized subtype of RDEB (RDEB-sev gen) complicated by SCC. METHODS: Skin biopsies were examined for histology, basement membrane ultrastructure, and type VII collagen expression. Genomic DNA was extracted from the peripheral blood samples and subjected to polymerase chain reaction amplification and direct automated DNA sequencing. RESULTS: Histopathological examination of the patient's skin revealed an undetectable expression of type VII collagen polypeptides in the basement membrane zone. Mutation analysis identified a novel splice site mutation in intron 64 (IVS64+5g->a) of COL7A1 gene, which resulted in an in-frame deletion of exon 64 in both alleles. CONCLUSIONS: This report contributes to the expanding database of COL7A1 mutations and emphasizes the need to elucidate the underlying genetic mechanisms associated with the increased incidence of SCC in RDEB patients.
21182502	1134	1145	IVS64+5g->a	DNAMutation	r|g|IVS64+5|a

20583543|t|Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene.
20583543|a|Phenotypic presentation of 46,XY DSD depends on the underlying defects. Defect in androgen action on the target tissues or production of active metabolite share common morphological features. Molecular study may help differentiating these abnormalities with precision. Mutational analysis of androgen receptor (AR) and SRD5A2 genes was performed in 29 patients with 46,XY DSD, by PCR-SSCP. The amplicons that showed an aberrant migration in SSCP were subjected to sequencing. Interestingly, six patients from 4 unrelated families (a pair of sibs, uncle/nephew and other two isolated) were identified with mutations in SRD5A2 gene. In five patients p.R246Q missense mutation was detected, of which four were homozygous and one was compound heterozygous: g.80_87delT CGCGAAG (p.A27fsX132) and p.R246Q. Another patient with isolated micropenis harbored a heterozygous p.G196S missense mutation. No AR gene mutation was detected. In conclusion, our study suggests that p.R246Q mutation is common amongst patients with SRD5A2 gene defect from the Northern states of India. Also, it records a novel deletion in exon 1 of SRD5A2 gene in a patient with severe hypospadias.
20583543	763	770	p.R246Q	ProteinMutation	p|R|246|Q
20583543	868	887	g.80_87delT CGCGAAG	DNAMutation	g|DEL|80_87|TCGCGAAG
20583543	889	900	p.A27fsX132	ProteinMutation	p|A|27||FSX|132
20583543	906	913	p.R246Q	ProteinMutation	p|R|246|Q
20583543	980	987	p.G196S	ProteinMutation	p|G|196|S
20583543	1080	1087	p.R246Q	ProteinMutation	p|R|246|Q

21219851|t|A novel mutation screening system for Ehlers-Danlos Syndrome, vascular type by high-resolution melting curve analysis in combination with small amplicon genotyping using genomic DNA.
21219851|a|Ehlers-Danlos syndrome, vascular type (vEDS) (MIM #130050) is an autosomal dominant disorder caused by type III procollagen gene (COL3A1) mutations. Most COL3A1 mutations are detected by using total RNA from patient-derived fibroblasts, which requires an invasive skin biopsy. High-resolution melting curve analysis (hrMCA) has recently been developed as a post-PCR mutation scanning method which enables simple, rapid, cost-effective, and highly sensitive mutation screening of large genes. We established a hrMCA method to screen for COL3A1 mutations using genomic DNA. PCR primers pairs for COL3A1 (52 amplicons) were designed to cover all coding regions of the 52 exons, including the splicing sites. We used 15 DNA samples (8 validation samples and 7 samples of clinically suspected vEDS patients) in this study. The eight known COL3A1 mutations in validation samples were all successfully detected by the hrMCA. In addition, we identified five novel COL3A1 mutations, including one deletion (c.2187delA) and one nonsense mutation (c.2992C>T) that could not be determined by the conventional total RNA method. Furthermore, we established a small amplicon genotyping (SAG) method for detecting three high frequency coding-region SNPs (rs1800255:G>A, rs1801184:T>C, and rs2271683:A>G) in COL3A1 to differentiate mutations before sequencing. The use of hrMCA in combination with SAG from genomic DNA enables rapid detection of COL3A1 mutations with high efficiency and specificity. A better understanding of the genotype-phenotype correlation in COL3A1 using this method will lead to improve in diagnosis and treatment.
21219851	1181	1191	c.2187delA	DNAMutation	c|DEL|2187|A
21219851	1220	1229	c.2992C>T	DNAMutation	c|C|2992|T
21219851	1422	1431	rs1800255	SNP	rs1800255
21219851	1432	1435	G>A	DNAMutation	|G||A
21219851	1437	1446	rs1801184	SNP	rs1801184
21219851	1447	1450	T>C	DNAMutation	|T||C
21219851	1456	1465	rs2271683	SNP	rs2271683
21219851	1466	1469	A>G	DNAMutation	|A||G

20579626|t|Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta.
20579626|a|Osteogenesis imperfecta, or "brittle bone disease," is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation. The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif. This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development.
20579626	394	404	c.1052delA	DNAMutation	c|DEL|1052|A
20579626	847	857	c.1052delA	DNAMutation	c|DEL|1052|A

21126715|t|A Taiwanese boy with congenital generalized lipodystrophy caused by homozygous Ile262fs mutation in the BSCL2 gene.
21126715|a|Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG (Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian.
21126715	79	87	Ile262fs	ProteinMutation	p|I|262||FS
21126715	1234	1241	783insG	DNAMutation	|INS|783|G
21126715	1243	1251	Ile262fs	ProteinMutation	p|I|262||FS

20634801|t|8q24 allelic imbalance and MYC gene copy number in primary prostate cancer.
20634801|a|Four independent regions within 8q24 near the MYC gene are associated with risk for prostate cancer (Pca). Here, we investigated allelic imbalance (AI) at 8q24 risk variants and MYC gene DNA copy number (CN) in 27 primary Pcas. Heterozygotes were observed in 24 of 27 patients at one or more 8q24 markers and 27% of the loci exhibited AI in tumor DNA. The 8q24 risk alleles were preferentially favored in the tumors. Increased MYC gene CN was observed in 33% of tumors, and the co-existence of increased MYC gene CN with AI at risk loci was observed in 86% (P<0.004 exact binomial test) of the informative tumors. No AI was observed in tumors, which did not reveal increased MYC gene CN. Higher Gleason score was associated with tumors exhibiting AI (P=0.04) and also with increased MYC gene CN (P=0.02). Our results suggest that AI at 8q24 and increased MYC gene CN may both be related to high Gleason score in Pca. Our findings also suggest that these two somatic alterations may be due to the same preferential chromosomal duplication event during prostate tumorigenesis.

20843112|t|Lack of p16 gene mutations in gastric cancers in Kashmir.
20843112|a|BACKGROUND AND AIM: The focus of the study was to investigate the frequencies of homozygous deletions and mutations of p16 gene in gastric carcinomas in the Kashmiri population. METHODS: A total of 84 gastric carcinoma patients were screened by the single strand conformation polymorphism (SSCP) technique and later by DNA sequencing to detect mutations of the p16 gene. Also PCR was applied further to further detect any homozygous deletions. RESULTS: SSCP and DNA sequencing performed encompassing all the three exons of p16 gene could not detect any mutations in any ofl 84 cases. Though we could observe mobility shifts in SSCP of two samples, subsequent DNA sequencing did not show any mutation. Further PCR could not detect any homozygous deletion in P16 in any case. CONCLUSION: Though Kashmir is a high incidence area of gastric carcinomas, p16gene mutations /or deletions do not appear to be involved.

20630757|t|Clinical and genetic characterization of manifesting carriers of DMD mutations.
20630757|a|Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.

21130517|t|Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors.
21130517|a|AIMS: EGFR mutations now guide the clinical use of EGFR-targeted therapy in lung cancer. However, standard EGFR mutation analysis requires a minimum amount of tumor tissue, which may not be available in certain situations. In this study, we combined a mass spectrometry genotyping assay (Sequenom) with a mutant-enriched PCR (ME-PCR) to detect EGFR mutations in free plasma DNA from patients with lung cancer. METHOD: DNAs were extracted from 31 plasma samples from 31 patients and analyzed by both methods for EGFR Exon 19 deletion and EGFR L858R mutation. Results in plasma DNA samples were compared with EGFR mutation status obtained in tumor DNA (18/31 EGFR mutant). The relationship of EGFR mutation status in tumor and/or plasma samples to overall survival was assessed. RESULTS: The EGFR mutation status in plasma DNA was identical to the primary tumor in 61% of patients (19/31). By mass spectrometry genotyping, the plasma samples contained mutant DNA corresponding to 5/14 EGFR Exon 19 deletions and 3/4 EGFR L858R mutations previously diagnosed in the matched tumors. Two samples were positive in plasma DNA but negative in primary tumor tissue. Results were similar for samples studied by ME-PCR. For patients treated with erlotinib, overall survival was correlated with the presence of EGFR mutation in plasma and/or tumor tissue (p=0.002), with the two patients positive only in plasma DNA showing responses and favorable outcomes. CONCLUSION: The detection of EGFR mutations in plasma DNA samples by mass spectrometry genotyping and ME-PCR is feasible. A positive EGFR result in plasma DNA has a high predictive value for tumor EGFR status and for favorable clinical course on EGFR-targeted therapy and could therefore be useful in guiding clinical decisions in patients with insufficient or unavailable tumor specimens.
21130517	710	715	L858R	ProteinMutation	p|L|858|R
21130517	1187	1192	L858R	ProteinMutation	p|L|858|R

21030903|t|Recombinant phenotyping of cytomegalovirus sequence variants detected after 200 or 100 days of valganciclovir prophylaxis.
21030903|a|BACKGROUND: In a phase III controlled trial IMproved Protection Against Cytomegalovirus in Transplantation (IMPACT) comparing 200 with 100 days of valganciclovir prophylaxis in 318 cytomegalovirus D+/R- kidney transplant recipients, an equal number of patients (n=3 per arm) had known ganciclovir resistance mutations detected during viral breakthrough. In addition, many other viral sequence variants were observed that were of unknown significance for ganciclovir resistance. Recombinant phenotyping was performed to determine whether the previously uncharacterized genotypic changes affected ganciclovir susceptibility, especially in those receiving the longer duration of prophylaxis. METHODS: Sequences encoding individual amino acid substitutions in the UL97 kinase or UL54 DNA polymerase gene were transferred by recombination into a cloned cytomegalovirus laboratory strain, followed by reporter-based yield reduction phenotypic assay of the resulting virus for ganciclovir susceptibility. RESULTS: Twenty-six uncharacterized amino acid substitutions were detected, 2 in UL97 and 24 in UL54. All 10 substitutions in the 200-day arm and 9 of 17 substitutions in the 100-day arm (prioritized based on location and conservation) were selected for phenotyping; one substitution was detected in both subsets. Results were generated for nine of ten 200-day and eight of nine 100-day substitutions, with no substitution demonstrating a significant reduction in ganciclovir susceptibility. The two remaining amino acid substitutions, both in UL54, were not evaluated because of poor viral viability. CONCLUSION: Phenotypic evaluation of previously uncharacterized viral genotypes in the 200-day valganciclovir prophylaxis group showed no evidence of an increased incidence of genotypic ganciclovir resistance when compared with those in the 100-day prophylaxis group.

21340161|t|Monoallelic thyroid peroxidase gene mutation in a patient with congenital hypothyroidism with total iodide organification defect.
21340161|a|The aim of this study was to identify the genetic defect of a patient with dyshormonogenetic congenital hypothyroidisms (CH) with total iodide organification defect (TIOD). A male child diagnosed with CH during neonatal screening. Laboratory tests confirmed the permanent and severe CH with TIOD (99% perchlorate release). The coding sequence of TPO, DUOX2, and DUOXA2 genes and 2957 base pairs (bp) of the TPO promoter were sequenced. Molecular analysis of patient's DNA identified the heterozygous duplication GGCC (c.1186_1187insGGCC) in exon 8 of the TPO gene. No additional mutation was detected either in the TPO gene, TPO promoter, DUOX2 or DUOXA2 genes. We have described a patient with a clear TIOD causing severe goitrous CH due to a monoallelic TPO mutation. A plausible explanation for the association between an autosomal recessive disorder with a single TPO-mutated allele is the presence of monoallelic TPO expression.
21340161	648	666	c.1186_1187insGGCC	DNAMutation	c|INS|1186_1187|GGCC

21163864|t|The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy.
21163864|a|INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM.
21163864	4	9	M235T	ProteinMutation	p|M|235|T
21163864	327	332	T704C	DNAMutation	c|T|704|C
21163864	913	918	M235T	ProteinMutation	p|M|235|T

20606392|t|Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain.
20606392|a|BACKGROUND/AIMS: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity. METHOD: Serum and DNA samples from the proband and his parents were analyzed. RESULTS: The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration. CONCLUSION: Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.
20606392	837	842	R211H	ProteinMutation	p|R|211|H
20606392	903	910	899dupC	DNAMutation	|DUP|899|C

21406173|t|Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses.
21406173|a|We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses.
21406173	1064	1069	E441G	ProteinMutation	p|E|441|G

20577006|t|Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.
20577006|a|BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.
20577006	931	936	P799L	ProteinMutation	p|P|799|L
20577006	1019	1026	F471del	ProteinMutation	p|DEL|471|F
20577006	1087	1092	R594H	ProteinMutation	p|R|594|H

20534142|t|Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion.
20534142|a|BACKGROUND: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. METHODS: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. RESULTS: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model <or= 0.009, effect sizes 8/8%, rs6232: pdominant model <or= 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom <or= 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. CONCLUSIONS: Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.
20534142	383	389	rs6232	SNP	rs6232
20534142	394	400	rs6235	SNP	rs6235
20534142	613	619	rs6232	SNP	rs6232
20534142	624	630	rs6235	SNP	rs6235
20534142	916	922	rs6235	SNP	rs6235
20534142	936	942	rs6232	SNP	rs6232
20534142	1010	1016	rs6235	SNP	rs6235
20534142	1021	1027	rs6232	SNP	rs6232
20534142	1232	1238	rs6235	SNP	rs6235
20534142	1289	1295	rs6232	SNP	rs6232
20534142	1472	1478	rs6232	SNP	rs6232
20534142	1736	1742	rs6235	SNP	rs6235
20534142	1968	1974	rs6232	SNP	rs6232
20534142	2009	2014	N221D	ProteinMutation	p|N|221|D

20538085|t|A single heterozygous nucleotide substitution displays two different altered mechanisms in the FBN1 gene of five Italian Marfan patients.
20538085|a|The Fibrillin-1 gene (FBN1; chromosome 15q21.1) encodes a major glycoprotein component of the extracellular matrix. Mutations in FBN1, TGFBR1, TGFBR2 are known to cause Marfan syndrome (MIM 154700), a pleiotropic disorder. In the present study, we describe five novel missense FBN1 mutations in five Marfan patients that have the peculiarity to activate two contemporary mutational mechanisms: a missense mutation and exon skipping.

20515563|t|Correlation between thymidylate synthase gene variants, RNA and protein levels in primary colorectal adenocarcinomas.
20515563|a|This study was designed to compare thymidylate synthase (TS) genotype, mRNA and protein levels in primary colorectal adenocarcinoma, and to examine the correlation between microsatellite instability (MSI) and TS expression. The TS genotype of 68 patients with colorectal cancer was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis in peripheral blood mononuclear cells and tumour tissue. The TS mRNA levels in tumour tissue were measured by reverse-transcription PCR, and TS protein levels and MSI status were assessed using immunohistochemistry. Significantly higher mRNA and protein levels were observed in patients with the TS 3R/3R versus the 2R/2R and 2R/3R genotypes. There was no correlation between TS single nucleotide polymorphism and TS expression. Individuals homozygous for the six base-pair insertion in the 3'-untranslated region had significantly higher TS mRNA levels than heterozygous and homozygous wild type individuals. The TS mRNA and protein levels were significantly higher in microsatellite unstable tumours compared with microsatellite stable tumours. There was a significant association between the number of TS enhancer region repeats (in blood) and intratumoural TS mRNA and protein levels. A larger case series investigating the role of TS gene polymorphisms as predictors of sensitivity to 5-fluorouracil-based chemotherapy is required.

20227423|t|A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome.
20227423|a|AIMS: Disrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS. MAIN METHODS: Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. KEY FINDINGS: We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele. SIGNIFICANCE: DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.
20227423	884	893	Ser704Cys	ProteinMutation	p|S|704|C
20227423	1029	1038	Ser704Cys	ProteinMutation	p|S|704|C
20227423	1153	1162	Ser704Cys	ProteinMutation	p|S|704|C
20227423	1512	1521	Ser704Cys	ProteinMutation	p|S|704|C

20143913|t|Large deletion involving exon 5 of the arylsulfatase B gene caused apparent homozygosity in a mucopolysaccharidosis type VI patient.
20143913|a|Apparent homozygosity for the mutation p.R315X present on exon 5 of the arylsulfatase B (ARSB) gene in a mucopolysaccharidosis type VI patient was solved in this study by further testing for a second mutation. Patient cDNA analysis revealed that the entire exon 5 of the ARSB gene was lacking; this new mutation was identified as c.899-1142del. As the genomic DNA sequencing excluded the presence of splicing mutations, polymerase chain reaction analysis was performed for polymorphisms listed in the NCBI SNP database for the ARSB gene. This allowed the mutation at the genomic DNA level to be identified as g.99367-102002del; this gross deletion, involving the entire exon 5 of the gene and parts of introns 4 and 5 led to a frameshift starting at amino acid 300 and resulting in a protein with 39% amino acids different from the normal enzyme. We stress that extensive DNA analysis needs to be performed in case of apparent homozygosity to avoid potential errors in genetic counseling.
20143913	172	179	p.R315X	ProteinMutation	p|R|315|X
20143913	463	476	c.899-1142del	DNAMutation	c|DEL|899_1142|
20143913	742	759	g.99367-102002del	DNAMutation	g|DEL|99367_102002|

20086182|t|The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck.
20086182|a|Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (-652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted.
20086182	358	373	-652 6N ins/del	DNAMutation	c|INDEL|-652|6
20086182	403	408	D302H	ProteinMutation	p|D|302|H
20086182	654	665	-652 6N del	DNAMutation	c|DEL|-652|6
20086182	935	946	-652 6N del	DNAMutation	c|DEL|-652|6
20086182	1265	1276	-652 6N del	DNAMutation	c|DEL|-652|6
20086182	1472	1483	-652 6N del	DNAMutation	c|DEL|-652|6

20026870|t|Angiotensin-converting enzyme insertion/deletion and angiotensin type 1 receptor A1166C polymorphisms as genetic risk factors in benign prostatic hyperplasia and prostate cancer.
20026870|a|INTRODUCTION: Prostate cancer is one of the most common malignant neoplasias in developed countries. In 2003, 6,536 new cases and 4,602 related deaths were reported in Mexico. The renin-angiotensin system has been shown to play a role in prostate cancer pathology. Two previous studies investigated the association of prostate cancer with the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene; both studies reported an association between prostate cancer and the DD genotype. The present study was aimed at searching for an association of prostate cancer and benign prostatic hyperplasia with the I/D polymorphism in the ACE gene and the A1166C polymorphism in the angiotensin type 1 receptor (AGT1R) gene and at comparing allele frequencies between both groups and the general population. MATERIALS AND METHODS: DNA was extracted from 20 samples from individuals with a prostate cancer diagnosis and from 20 samples from individuals with a benign prostatic hyperplasia diagnosis. Genotyping was performed by PCR-RFLP analysis. Polymorphism frequency results obtained for the test groups were compared with the frequencies in 66 individuals from the general population, which were previously obtained at the same molecular medicine laboratory in the context of other studies. RESULTS: The comparative analysis of the three groups revealed significant differences for allele frequencies in the two genes in patients groups (prostate cancer and benign prostatic hyperplasia) versus the general population. The D allele in the ACE gene was closely associated with a significant higher risk of developing both benign prostatic hyperplasia (odds ratio [OR]=21.87; 95% confidence interval [CI]=2.314-206.479) or prostate cancer (OR=31.66; 95% CI=0.091-1.272), and the AGT1R A1166 allele in the homozygote state was identified as a risk genotype for benign prostatic hyperplasia (OR=56.07). CONCLUSIONS: Genotypes in ACE and AGT1R polymorphisms could be considered as genetic risk markers for benign prostatic hyperplasia or prostate cancer.
20026870	81	87	A1166C	DNAMutation	|A|1166|C
20026870	853	859	A1166C	DNAMutation	|A|1166|C

19958188|t|Molecular analysis of gamma-globin promoters, HS-111 and 3'HS1, in beta-thalassemia intermedia patients associated with high levels of Hb F.
19958188|a|The nucleotide (nt) variations in the promoter region of the gamma-globin genes, HS-111 and 3'HS1 regions, were studied in Iranian patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta-TM) and healthy individuals. Of the five nt variations at the 5' end of the (A)gamma-globin gene, -369 (C>G), -611 (-T) and -603/604 (GA>AG) were found in all samples, whereas -588 (A>G) and -AAGC at -222 to -225 were found at different frequencies in the studied groups. Therefore, the -369, -611 and -603/604 variations were considered common mutations in this population, and the difference with respect to the -AAGC deletion was not significant. However, the A allele of the -588 variation and [+] allele of the XmnI polymorphism were more frequent in beta-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of -588 variation. The HS-111 (-21 A) variation also showed association with beta-TI patients who had high levels of Hb F. Bearing in mind that the -588 variation lies within the postulated adult-specific silencer region and that the majority of beta-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of -588, [+] allele of XmnI and HS-111 (-21 A) variation are useful genetic markers to differentiate between beta-TM and beta-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production.
19958188	452	462	-369 (C>G)	DNAMutation	c|C|-369|G
19958188	464	473	-611 (-T)	DNAMutation	c|DEL|-611|T
19958188	478	494	-603/604 (GA>AG)	DNAMutation	c|GA|-603_-604|AG
19958188	530	540	-588 (A>G)	DNAMutation	c|A|-588|G
19958188	545	566	-AAGC at -222 to -225	DNAMutation	c|DEL|-222_-225|AAGC
19958188	957	970	IVS-II-1(G>A)	DNAMutation	c|G|IVS2-1|A
19958188	971	984	IVS-II-1(G>A)	DNAMutation	c|G|IVS2-1|A

19929939|t|Multiple trichoepitheliomas--a novel mutation in the CYLD gene.
19929939|a|BACKGROUND: Trichoepitheliomas are benign neoplasms with follicular differentiation. They may present as a solitary lesion or as multiple lesions. Multiple trichoepitheliomas are inherited in an autosomal dominant pattern within families, with both variable penetrance and expressivity. Recent investigations support that mutations in CYLD, the gene affected in familial cylindromatosis as well as in Brooke-Spiegler syndrome, are also responsible for multiple trichoepitheliomas. OBJECTIVE: The authors report the case of a 9-year-old African girl with multiple facial trichoepitheliomas in whom a mutation in the CYLD gene was hypothesised. MATERIALS AND METHODS: After genomic DNA extraction from the peripheral blood, a molecular analysis of the CYLD gene was performed by PCR, DHPLC and automated sequencing. RESULTS: A novel heterozygous mutation in exon 18 of the CYLD gene (c.2449delT) was identified, with a deletion of one nucleotide resulting in a premature translational termination codon at amino acid position 831 on the affected allele (p.Cys817Valfs X15). CONCLUSIONS: The predominating tumours define the classification of these three entities. Nevertheless, studies suggest that they can simply represent phenotypic variations of the same disease spectrum, sharing common genetic mutations.
19929939	946	956	c.2449delT	DNAMutation	c|DEL|2449|T
19929939	1116	1133	p.Cys817Valfs X15	ProteinMutation	p|C|817|V|FSX|15

19918264|t|FGFR4 Gly388Arg polymorphism and prostate cancer risk in Scottish men.
19918264|a|Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan.
19918264	6	15	Gly388Arg	ProteinMutation	p|G|388|R
19918264	1179	1190	Gly(388)Arg	ProteinMutation	p|G|388|R

19804530|t|A LDR-PCR approach for multiplex polymorphisms genotyping of severely degraded DNA with fragment sizes <100 bp.
19804530|a|Reducing amplicon sizes has become a major strategy for analyzing degraded DNA typical of forensic samples. However, amplicon sizes in current mini-short tandem repeat-polymerase chain reaction (PCR) and mini-sequencing assays are still not suitable for analysis of severely degraded DNA. In this study, we present a multiplex typing method that couples ligase detection reaction with PCR that can be used to identify single nucleotide polymorphisms and small-scale insertion/deletions in a sample of severely fragmented DNA. This method adopts thermostable ligation for allele discrimination and subsequent PCR for signal enhancement. In this study, four polymorphic loci were used to assess the ability of this technique to discriminate alleles in an artificially degraded sample of DNA with fragment sizes <100 bp. Our results showed clear allelic discrimination of single or multiple loci, suggesting that this method might aid in the analysis of extremely degraded samples in which allelic drop out of larger fragments is observed.

19728872|t|A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant.
19728872|a|BACKGROUND: beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish beta-mannosidase activity. In this study, we characterized the molecular defect of a new case of beta-mannosidosis, presenting with a severe neurological disorder. METHODS: Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The beta-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells. RESULTS: A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity. CONCLUSION: Correlations between MANBA mutations, residual activity of beta-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of beta-mannosidase is also discussed.
19728872	1198	1207	c.1922G>A	DNAMutation	c|G|1922|A
19728872	1209	1220	p.Arg641His	ProteinMutation	p|R|641|H
19728872	1755	1764	c.1922G>A	DNAMutation	c|G|1922|A

19664890|t|Screening of the LIX1 gene in Japanese and Malaysian patients with SMA and/or SMA-like disorder.
19664890|a|BACKGROUND: The majority of spinal muscular atrophy (SMA) patients showed homozygous deletion or other mutations of SMN1. However, the genetic etiology of a significant number of SMA patients has not been clarified. Recently, mutation in the gene underlying cat SMA, limb expression 1 (LIX1), has been reported. Similarity in clinical and pathological features of cat and human SMA may give an insight into possible similarity of the genetic etiology. PATIENTS AND METHODS: In this study, we screened for a mutation in LIX1 using direct DNA sequencing in our SMA and/or SMA-like patients who retained SMN1. A total of 33 patients were enrolled in this study, of which 22 were Japanese and 11 were Malaysians. All these patients possessed at least two copies of SMN1. RESULTS: We did not identify any pathogenic mutations in the coding regions or splice sites of LIX1 in the patients. In addition, we described a polymorphism within LIX1 intron 3, c.387+107A>T. We found that A-allele is significantly more frequent in SMA patients compared to normal individuals. CONCLUSION: Molecular genetic analysis of our SMA and/or SMA-like patients suggests that LIX1 is not associated with the development of their disorders. However, the number of patients analyzed in this study was very limited, and a larger study with bigger sample size is needed to confirm this result.
19664890	1044	1056	c.387+107A>T	DNAMutation	c|A|387+107|T

19645056|t|Single nucleotide polymorphism discovery in TBX1 in individuals with and without 22q11.2 deletion syndrome.
19645056|a|BACKGROUND: Children with 22q11.2 deletion syndrome (22q11.2DS) have a wide range of clinical features. TBX1 has been proposed as a candidate gene for some of the features in this condition. Polymorphisms in the nondeleted TBX1, which may affect the function of the sole TBX1 gene in individuals with the 22q11.2DS, may be a key to understanding the phenotypic variability among individuals with a shared deletion. Comprehensive single nucleotide polymorphism (SNP) discovery by resequencing candidate genes can identify genetic variants that influence a given phenotype. The purpose of this study was to further characterize the sequence variability in TBX1 by identifying all common SNPs in this gene. METHODS: We resequenced TBX1 in 29 children with a documented 22q11.2 deletion and 95 nondeleted, healthy individuals. We estimated allele frequencies, performed tagSNP selection, and inferred haplotypes. We also compared SNP frequencies between 22q11.2DS and control samples. RESULTS: We identified 355 biallelic markers among the 190 chromosomes resequenced in the control panel. The vast majority of the markers identified were SNPs (n = 331), and the remainder indels (n = 24). We did not identify SNPs or indels in the cis- regulatory element (FOX-binding site) upstream of TBX1. In children with 22q11.2DS we detected 187 biallelic markers, six of which were indels. Four of the seven coding SNPs identified in the controls were identified in children with 22q11.2DS. CONCLUSIONS: This comprehensive SNP discovery data can be used to select SNPs to genotype for future association studies assessing the role of TBX1 and phenotypic variability in individuals with 22q11.2DS.

19592582|t|Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.
19592582|a|Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C>A and c.468C>T in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency.
19592582	498	504	P686fs	ProteinMutation	p|P|686||FS
19592582	571	587	2172_2173insCCCC	DNAMutation	c|INS|2172_2173|CCCC
19592582	715	723	c.467C>A	DNAMutation	c|C|467|A
19592582	728	736	c.468C>T	DNAMutation	c|C|468|T
19592582	781	786	A118D	ProteinMutation	p|A|118|D
19592582	1025	1030	A118D	ProteinMutation	p|A|118|D

19521089|t|Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy.
19521089|a|Parkinson's disease (PD) is a neurodegenerative disorder causing muscular rigidity, resting tremor and bradykinesia. We conducted an association study assessing how PD risk in Italy was influenced by the serotonin transporter gene (SLC6A4) polymorphic region 5-HTTLPR, consisting of an insertion/deletion (long allele-L/short allele-S) of 43 bp in the SLC6A4 promoter region. The SLC6A4 promoter single nucleotide polymorphism rs25531(A-->G) was evaluated too. We collected 837 independent subjects (393 PD, 444 controls). An association between the 5-HTTLPR polymorphism and risk of PD (S/S genotype OR [95% CI]: 1.7[1.2-2.5], p = 0.002) was found. The rs25531 and the haplotype 5-HTTLPR/rs25531 did not associate with risk of PD. Our data indicate that the 5-HTTLPR polymorphic element within the SLC6A4 promoter may govern the genetic risk of PD in Italians.
19521089	544	551	rs25531	SNP	rs25531
19521089	552	557	A-->G	DNAMutation	|A||G
19521089	771	778	rs25531	SNP	rs25531
19521089	806	813	rs25531	SNP	rs25531

19484664|t|Angiotensin converting enzyme gene polymorphism in Turkish asthmatic patients.
19484664|a|Asthma is a chronic inflammatory disease of the airways. Several candidate genes have been identified with a potential role in the pathogenesis of asthma, including the angiotensin converting enzyme (ACE) gene. We aimed to investigate the frequency of an ACE gene polymorphism in Turkish asthmatic patients and to determine its impact on clinical parameters and disease severity. Ninety-seven asthmatic patients (M/F 25/72, mean age 39 +/- 13 years) and 96 healthy subjects (M/F 26/70, mean age 38 +/- 12 years) were included. At baseline, all participants completed a questionnaire on demographics, symptoms, triggering factors, severity of asthma, and the presence of atopism. Blood samples were obtained from all patients and genomic DNA was isolated. The frequency of the ACE genotypes (I = insertion and D = deletion) among asthmatics and controls were compared: asthmatics showed a 40.2% prevalence of the DD genotype (n = 39), ID was 45.4% (n = 44), and II was 14.4% (n = 14.4). In the control subjects, the frequency of DD was 18.8% (n = 18), ID was 50% (n = 48) and II was 31.3% (n = 30). The DD ACE genotype was significantly more frequent in asthmatics compared with controls (p < 0.001). Asthmatics with the ID ACE genotype showed a higher frequency of drug allergies, although this was not statistically significant (p = 0.08). Asthmatics with the DD genotype appeared to have a higher incidence of asthmatic episode exacerbations due to viral infections, but again this was not statistically significant (p = 0.08). Patients with mild or moderate-severe asthma had similar frequencies of these mutations. We found a higher frequency of the ACE DD gene mutation in Turkish asthmatic patients compared with non-asthmatics, suggesting that this ACE gene polymorphism may be a risk factor for asthma but does not increase the severity of the disease.

19476483|t|The role of the CCR5 Delta32 polymorphism in abdominal aortic aneurysms.
19476483|a|BACKGROUND: C-C chemokine receptor 5 (CCR5) is involved in the regulation of the inflammatory response. Abdominal aortic aneurysms (AAA) may arise as the result of a chronic inflammatory process which is influenced by genetic predisposition. The CCR5 gene is associated with a 32 base pair deletion (the Delta32 polymorphism). The aim of this study was to investigate the role of the CCR5 Delta32 polymorphism in the development of AAA. METHODS: A case-control study was conducted including 285 patients with AAA and 273 control subjects. A blood sample was taken from each individual and DNA was extracted. CCR5 genotype was determined using the polymerase chain reaction (PCR). Flow cytometry was used to investigate the biological activity of the Delta32 polymorphism. RESULTS: There was no significant difference between the AAA and the control group in relation to the Delta32 allele frequency (AAA group 10%, control group = 12%, P = 0.82, chi-squared analysis). Genotype analysis revealed no significant difference between the groups (AAA vs. controls, wild-type homozygotes = 82% vs. 77%, heterozygotes = 16% vs. 21%, vs. Delta32 homozygotes = 2% and 2%, respectively, P = 0.33, chi-squared analysis). The polymorphism was shown to be biologically active with the number of Delta32 alleles correlating with cell expression of ccr5 as detected with flow cytometry (P < or = 0.05). CONCLUSION: This study demonstrates that the ccr5 Delta32 is a biologically active genetic polymorphism; however, there is no association between this polymorphism and AAA.
19476483	21	28	Delta32	DNAMutation	|DEL||32
19476483	377	384	Delta32	DNAMutation	|DEL||32
19476483	462	469	Delta32	DNAMutation	|DEL||32
19476483	823	830	Delta32	DNAMutation	|DEL||32
19476483	947	954	Delta32	DNAMutation	|DEL||32
19476483	1203	1210	Delta32	DNAMutation	|DEL||32
19476483	1355	1362	Delta32	DNAMutation	|DEL||32
19476483	1511	1518	Delta32	DNAMutation	|DEL||32

19473658|t|Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion).
19473658|a|We report a novel apolipoprotein A-I (apoA-I) mutation identified in a 64-year-old patient with marked plasma high density lipoprotein (HDL) cholesterol (4 mg/dl) and apoA-I (5mg/dl) deficiency, prior myocardial infarction, and moderate corneal opacities. Coronary angiography revealed extensive atherosclerosis in all three major vessels. Genomic DNA sequencing of the proband revealed a homozygous novel deletion of two successive adenine residues in codon 138 in the apoA-I gene, resulting in a frameshift mutation at amino acid residues 138-178, which we have designated as apoA-I Tomioka. His elder brother was also homozygous for apoA-I Tomioka with marked HDL cholesterol and apoA-I deficiency, but had no clinical evidence of coronary heart disease. Other family members including three siblings and two sons were heterozygous for the mutation, and had approximately 50% of normal plasma HDL cholesterol, and apoA-I. Analysis of apoA-I-containing HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I HDL particles in the homozygotes, while in heterozygotes, the mean concentrations of apoA-I in large alpha-1 and very small prebeta-1 HDL subpopulations were significantly decreased at about 35% of normal. Thus, apoA-I Tomioka, a novel deletion mutation in codon 138 of the apoA-I gene, is the causative defect in this case of HDL deficiency.

19448408|t|Correlation of polymorphism of the coding region of glutathione S- transferase M1 to susceptibility of nasopharyngeal carcinoma in South China population.
19448408|a|BACKGROUND AND OBJECTIVE: Glutathione S-transferase M1 (GSTM1) deficiency may increase the risk of nasopharyngeal carcinoma (NPC). This study was to evaluate the correlation of the single nucleotide polymorphism (SNP) in the coding region of GSTM1 gene to NPC susceptibility in southern China population. METHODS: In total 239 NPC patients and 286 age-matched healthy controls were entered into the study. Among them, 225 out of 239 NPC patients and 273 out of 286 controls were used for statistical analysis. SNP screening of all exons, relevant intron-exon boundaries, and the promoter region of GSTM1, in total 4739bp, was performed by PCR direct sequencing. The loci T1270533G and C1256088C were selected for the case-control study using the tetra-Primer ARMS-PCR, as well as the sequencing method. RESULTS: In total 29 SNPs of GSTM1 were identified by sequencing. Missense mutation occurred in the polymorphic loci of T1270533G and C1256088C. However, no evident relationships between the variants of T1270533G and clinical phenotypes of NPC were observed in the NPC group and healthy control group (OR = 0.170, 95%CI = 0.95-0.306 for homozygote TT). The deletion frequency of C1256088C was 45% (45/100) for NPC patients and 42% (42/100) for controls. CONCLUSIONS: The polymorphism of T1270533G does not affect the detoxification function of GSTM1. The T1270533G locus has no apparent association with genetic susceptibility to NPC in the southern China population. The loss rate of C1256088C is high in this study.
19448408	826	835	T1270533G	DNAMutation	g|T|1270533|G
19448408	1078	1087	T1270533G	DNAMutation	g|T|1270533|G
19448408	1161	1170	T1270533G	DNAMutation	g|T|1270533|G
19448408	1445	1454	T1270533G	DNAMutation	g|T|1270533|G
19448408	1513	1522	T1270533G	DNAMutation	g|T|1270533|G

19435819|t|High-resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray.
19435819|a|Glioblastoma multiforme (GBM) is an extremely malignant brain tumor. To identify new genomic alterations in GBM, genomic DNA of tumor tissue/explants from 55 individuals and 6 GBM cell lines were examined using single nucleotide polymorphism DNA microarray (SNP-Chip). Further gene expression analysis relied on an additional 56 GBM samples. SNP-Chip results were validated using several techniques, including quantitative PCR (Q-PCR), nucleotide sequencing, and a combination of Q-PCR and detection of microsatellite markers for loss of heterozygosity with normal copy number [acquired uniparental disomy (AUPD)]. Whole genomic DNA copy number in each GBM sample was profiled by SNP-Chip. Several signaling pathways were frequently abnormal. Either the p16(INK4A)/p15(INK4B)-CDK4/6-pRb or p14(ARF)-MDM2/4-p53 pathways were abnormal in 89% (49 of 55) of cases. Simultaneous abnormalities of both pathways occurred in 84% (46 of 55) samples. The phosphoinositide 3-kinase pathway was altered in 71% (39 of 55) GBMs either by deletion of PTEN or amplification of epidermal growth factor receptor and/or vascular endothelial growth factor receptor/platelet-derived growth factor receptor alpha. Deletion of chromosome 6q26-27 often occurred (16 of 55 samples). The minimum common deleted region included PARK2, PACRG, QKI, and PDE10A genes. Further reverse transcription Q-PCR studies showed that PARK2 expression was decreased in another collection of GBMs at a frequency of 61% (34 of 56) of samples. The 1p36.23 region was deleted in 35% (19 of 55) of samples. Notably, three samples had homozygous deletion encompassing this site. Also, a novel internal deletion of a putative tumor suppressor gene, LRP1B, was discovered causing an aberrant protein. AUPDs occurred in 58% (32 of 55) of the GBM samples and five of six GBM cell lines. A common AUPD was found at chromosome 17p13.3-12 (included p53 gene) in 13 of 61 samples and cell lines. Single-strand conformational polymorphism and nucleotide sequencing showed that 9 of 13 of these samples had homozygous p53 mutations, suggesting that mitotic recombination duplicated the abnormal p53 gene, probably providing a growth advantage to these cells. A significantly shortened survival time was found in patients with 13q14 (RB) deletion or 17p13.1 (p53) deletion/AUPD. Taken together, these results suggest that this technique is a rapid, robust, and inexpensive method to profile genome-wide abnormalities in GBM.

19404517|t|A large Swiss family with Bernard-Soulier syndrome - Correlation phenotype and genotype.
19404517|a|Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive inherited bleeding disorder associated with thrombocytopenia, thrombocytopathy and giant platelets. BSS is caused by genetic alterations of the glycoprotein (GP) Ib/V/IX complex. We report on a large Swiss family of whom four family members suffer from BSS. Here, a homozygous missense mutation in position 1829 (A(R)G) of the GPIX gene constituting a N45S substitution is the cause for the bleeding symptoms. A total of 38 family members within two generations were analyzed regarding the N45S mutation by DNA sequencing and restriction fragment length polymorphism. The laboratory parameters which are characteristically for BSS such as platelet count, platelet volume and the expression of CD42a (GPIX), CD42b (GPIbalpha) and CD41 (GPIIb) were measured for all 38 individuals. The four homozygous patients showed bleeding symptoms, thrombocytopenia and giant platelets. In these patients, the expression of CD42a (GPIX), CD42b (GPIbalpha) was diminished. Interestingly, the intensity of the bleeding symptoms of the 4 homozygous family members seemed to vary although they carry the same mutation. The 24 heterozygous carriers did not differ significantly from their 10 wildtype family members regarding bleeding symptoms and laboratory analysis.
19404517	503	507	N45S	ProteinMutation	p|N|45|S
19404517	641	645	N45S	ProteinMutation	p|N|45|S

19370764|t|Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma.
19370764|a|Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610-2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.
19370764	478	485	p.T286M	ProteinMutation	p|T|286|M
19370764	501	508	p.W111X	ProteinMutation	p|W|111|X
19370764	607	617	c.610-2A>G	DNAMutation	c|A|610-2|G
19370764	677	686	c.611delG	DNAMutation	c|DEL|611|G
19370764	691	705	c.640_667del28	DNAMutation	c|DEL|640_667|28
19370764	758	776	c.609+28_610-16del	DNAMutation	c|DEL|609+28_610-16|
19370764	839	849	c.610-2A>G	DNAMutation	c|A|610-2|G
19370764	1005	1019	p.G204_K247del	ProteinMutation	p|DEL|204_247|
19370764	1058	1070	p.G204VfsX28	ProteinMutation	p|G|204|V|FSX|28
19370764	1151	1169	c.609+28_610-16del	DNAMutation	c|DEL|609+28_610-16|
19370764	1237	1255	c.609+28_610-16del	DNAMutation	c|DEL|609+28_610-16|
19370764	1656	1668	p.G204VfsX17	ProteinMutation	p|G|204|V|FSX|17

19353688|t|Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1).
19353688|a|Insertional translocations (IT) are rare structural rearrangements. Offspring of IT balanced carriers are at high risk to have either pure partial trisomy or monosomy for the inserted segment as manifested by "pure" phenotypes. We describe an IT between chromosomes 3 and 13 segregating in a three-generation pedigree. Short tandem repeat (STR) segregation analysis and array-comparative genomic hybridization were used to define the IT as a 25.1 Mb segment spanning 13q21.2-q31.1. The phenotype of pure monosomy included deafness, duodenal stenosis, developmental and growth delay, vertebral anomalies, and facial dysmorphisms; the trisomy was manifested by only minor dysmorphisms. As the AUNA1 deafness locus on 13q14-21 overlaps the IT in the PCDH9 (protocadherin-9) gene region, PCDH9 was investigated as a candidate gene for deafness in both families. Genotyping of STRs and single nucleotide polymorphisms defined the AUNA1 breakpoint as 35 kb 5' to PCDH9, with a 2.4 Mb area of overlap with the IT. DNA sequencing of coding regions in the AUNA1 family and in the retained homologue chromosome in the monosomic patient revealed no mutations. We conclude that AUNA1 deafness does not share a common etiology with deafness associated with monosomy 13q21.2-q31.3; deafness may result from monosomy of PCHD9 or another gene in the IT, as has been demonstrated in contiguous gene deletion syndromes. Precise characterization of the breakpoints of the translocated region is useful to identify which genes may be contributing to the phenotype, either through haploinsufficiency or extra dosage effects, in order to define genotype-phenotype correlations.

19309272|t|A simple multiplex real-time PCR methodology for the SMN1 gene copy number quantification.
19309272|a|Spinal muscular atrophy (SMA) is an autosomal recessive disease caused, in about 95% of SMA cases, by homozygous deletion of the survival motor neuron 1 (SMN1) gene or its conversion to the highly homologous SMN2 gene. The molecular diagnosis of SMA is usually carried out by a PCR-Restriction fragment length polymorphism (RFLP) approach. However, this approach is not useful for identification of healthy deletion carriers. TaqMan technology is one of the most reliable and widely adopted techniques for the SMN1 copy number evaluation. However, several limitations of this technique have been described. Particularly, DNA extraction methods and accurate template quantification have been shown to be critical for reliable results. In this work, we set up a reliable, highly reproducible, and easy-to-perform TaqMan technology-based protocol to obtain the SMN1 gene copy number assessment. We demonstrate that PCR amplification of both target gene and reference gene in the same reaction mix, instead of separated mixes, greatly reduces reported criticisms of simplex TaqMan technology. The multiplex real-time PCR we describe allows interlaboratory samples and data exchange, without the need to equalize the DNA isolation technique. Further, the protocol described below requires fewer replica tests than the simplex methodology does, leading to reduced overall cost for the diagnostic assay.

19218574|t|Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene Met326Ile polymorphism in women with polycystic ovary syndrome.
19218574|a|BACKGROUND: Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Phosphatidylinositol (PI) 3-kinase is an important enzyme in the early insulin signaling cascade and plays a key role in insulin-mediated glucose transport. In its regulatory subunit, p85alpha, there is a common amino acid substitution (the Met326Ile polymorphism), and this amino acid may be crucial for the function of the p85alpha regulatory subunit and PI3-kinase. METHODS: Analysis of the Met326Ile polymorphism was carried out on DNA samples from 256 PCOS patients and 283 controls. Clinical and biochemical profiles of participants were also compared. RESULTS: The genotype distribution of the Met326Ile polymorphism in the PCOS group was not different from that of the controls (Met326Met/Met326Ile/Ile326Ile rates were 73.4%/23.4%/3.2% and 70.3%/26.1%/3.6% for the PCOS and control groups, respectively, P = 0.72). The PCOS group was divided into two subgroups according to the presence of the variant 326Ile allele. Compared with those carrying at least one variant 326Ile allele, carriers with the Met326Met genotype had higher serum 17-hydroxyprogesterone (17-OHP) {1.1 [95% confidence interval (CI) 1.1-1.3] ng/ml in those with the Met326Met genotype versus 0.8 (95% CI 0.7-1.0) ng/ml in those with Ile326Ile and Met326Ile genotypes, P = 0.0073} and free testosterone levels [1.2 (95% CI 1.1-1.4) pg/ml for Met326Met genotype versus 0.9 (95% CI 0.6-1.3) pg/ml for Ile326Ile and Met326Ile genotypes, P = 0.038]. CONCLUSIONS: Our results suggest that the PI3-kinase gene Met326Ile polymorphism may not be a major determinant for the development of PCOS, but it may modulate the concentrations of serum 17-OHP or free testosterone in PCOS patients.
19218574	63	72	Met326Ile	ProteinMutation	p|M|326|I
19218574	454	463	Met326Ile	ProteinMutation	p|M|326|I
19218574	607	616	Met326Ile	ProteinMutation	p|M|326|I
19218574	814	823	Met326Ile	ProteinMutation	p|M|326|I
19218574	910	919	Met326Ile	ProteinMutation	p|M|326|I
19218574	1439	1448	Met326Ile	ProteinMutation	p|M|326|I
19218574	1604	1613	Met326Ile	ProteinMutation	p|M|326|I
19218574	1695	1704	Met326Ile	ProteinMutation	p|M|326|I

19144556|t|Identification of newly polymorphic intron 40 markers of the von Willebrand factor gene in a Japanese population.
19144556|a|We investigated a region of repetitive DNA located in intron 40 of the von Willebrand factor (vWF) gene (nucleotides [nt] 1639-2404; i.e., F8VWF). We identified 13 alleles and 33 genotypes in 49 unrelated Japanese individuals. The heterozygosity of the region was 0.897. Direct sequence analyses revealed five single-base substitutions, one tetranucleotide (TTAT) insertion, and seven short tandem repeats (STRs) in the intron; four of the STRs and one single-base substitution had been reported previously. The four new base substitutions we identified were 1849T>A, 2122C>T, 2180C>T, and 2192C>T. The novel TTAT tetranucleotide was inserted between nt 2057 and 2058. The three newly identified STRs were 1978(TATC)(1-2), 2193(ATCT)(5-13), and 2234(TGTA)(5-7). The five single-base substitutions and the TTAT insertion were identified only with 3' downstream of vWA allele 14.
19144556	673	680	1849T>A	DNAMutation	|T|1849|A
19144556	682	689	2122C>T	DNAMutation	|C|2122|T
19144556	691	698	2180C>T	DNAMutation	|C|2180|T
19144556	704	711	2192C>T	DNAMutation	|C|2192|T
19144556	820	835	1978(TATC)(1-2)	DNAMutation	|DUP|1978|TATC|1-2
19144556	837	853	2193(ATCT)(5-13)	DNAMutation	|DUP|2193|ATCT|5-13
19144556	859	874	2234(TGTA)(5-7)	DNAMutation	|DUP|2234|TGTA|5-7

19048115|t|Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations.
19048115|a|Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma-derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly reduced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. Similarly, NF1 alterations including homozygous deletions and splicing mutations were identified in 9 (22%) of 41 primary OSCs. As expected, tumors and cell lines with NF1 defects lacked mutations in KRAS or BRAF but showed Ras pathway activation based on immunohistochemical detection of phosphorylated MAPK (primary tumors) or increased levels of GTP-bound Ras (cell lines). The TP53 tumor-suppressor gene was mutated in all OSCs with documented NF1 mutation, suggesting that the pathways regulated by these two tumor-suppressor proteins often cooperate in the development of ovarian carcinomas with serous differentiation.

18798060|t|The influence of interstitial collagenase-1 genotype polymorphism on colorectal cancer risk in Iranian population.
18798060|a|Interstitial collagenase-1 degrades a variety of extracellular matrix components. A single guanine insertion polymorphism in the promoter has been found that influences on the transcription and expression level of the gene. It is suggested that this polymorphism may enhance susceptibility to some types of cancer. Therefore, this case-control study evaluated the association of this genotype polymorphism with susceptibility to initiation and invasion of colorectal cancer. For this reason, whole blood samples were obtained from 150 CRC patients and 100 control subjects in Tehran. Genomic DNA was extracted and genotyped by PCR-RFLP method. We showed that 2G allele and 2G/2G genotype had higher frequencies in patients (60% and 39%, respectively) than in controls (47% and 23%, respectively). The CRC patients were divided into two groups: with metastasis (M+) and without metastasis (M-) groups. The 2G allele was more frequent in M+ group compared with control group. However, no significantly difference was observed between M-group and control (chi(2) = 0.48, P = 0.78 for 2G/2G genotype). Further stratification analyses showed that only gender (OR = 2.58, 95% CI = 0.89-7.52 for women and OR = 4.12, 95% CI = 1.62-10.42 for men) and smoking (OR = 3.03, 95% CI = 1.28-7.16 for non-smokers and OR = 4.09, 95% CI = 1.18-4.15 for smoker) may modify the risk of colorectal invasion related to 2G/2G genotype. Furthermore, individual with 2G/2G genotype seems to spread metastasis, 3 years earlier than those who were 1G/1G and 1G/2G. In conclusion, to our knowledge, the present epidemiological study for the first time indicates the relationship of 2G/2G genotype polymorphism with invasion risk of colorectal cancer in subgroups of gender and smoking, especially in smoker men.

18791947|t|A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding.
18791947|a|More than 20 DNA mutations with different inheritance pattern have been described in patients with Bernard-Soulier Syndrome (BSS), leading to abnormal or absent synthesis and/or expression of GPIbalpha. Clinical phenotype shows considerable variation between individuals, such as bleeding, platelet count and the percentage of large platelets. We describe in a BSS patient the first case of homozygous four bases deletion (TGAG) in the gpIbalpha gene coding sequence, leading to a premature stop codon. In the propositus, blood smears revealed giant platelets (30 x 10(9) platelets/L), and platelet agglutination to ristocetin was absent. Propositus' parents are consanguineous. His father and paternal grandmother showed a mild thrombocytopenia (108 x 10(9)/L and 120 x 10(9)/L platelets respectively) while mothers and sister's referred normal platelet counts. The surface expression of GPIbalpha was practically undetectable by flow-cytometry and western blot in the patient and was reduced in the father. Proband's DNA analysis revealed a homozygous four-base-pair deletion (TGAG), starting from the last base of the codon for Ser39, leading to a coding frame shift with a new termination codon after 11 novel amino acids. The same mutation was seen in heterozygosis in both parents. This is the first report of GPIbalpha TGAG deletion in homozygous state even if the defect has already been described in a case of compound heterozygosis. Surprisingly, the propositus does not report any spontaneous bleeding tendency.

18790087|t|Is the European spatial distribution of the HIV-1-resistant CCR5-Delta32 allele formed by a breakdown of the pathocenosis due to the historical Roman expansion?
18790087|a|We studied the possible effects of the expansion of ancient Mediterranean civilizations during the five centuries before and after Christ on the European distribution of the mutant allele for the chemokine receptor gene CCR5 which has a 32-bp deletion (CCR5-Delta32). There is a strong evidence for the unitary origin of the CCR5-Delta32 mutation, this it is found principally in Europe and Western Asia, with generally a north-south downhill cline frequency. Homozygous carriers of this mutation show a resistance to HIV-1 infection and a slower progression towards AIDS. However, HIV has clearly emerged too recently to have been the selective force on CCR5. Our analyses showed strong negative correlations in Europe between the allele frequency and two historical parameters, i.e. the first colonization dates by the great ancient Mediterranean civilizations, and the distances from the Northern frontiers of the Roman Empire in its greatest expansion. Moreover, other studies have shown that the deletion frequencies in both German Bronze Age and Swedish Neolithic populations were similar to those found in the corresponding modern populations, and this deletion has been found in ancient DNA of around 7000 years ago, suggesting that in the past, the deletion frequency could have been relatively high in European populations. In addition, in West Nile virus pathogenesis, CCR5 plays an antimicrobial role showing that host genetic factors are highly pathogen-specific. Our results added to all these previous data suggest that the actual European allele frequency distribution might not be due to genes spreading, but to a negative selection resulting in the spread of pathogens principally during Roman expansion. Indeed, as gene flows from colonizers to European native populations were extremely low, the mutational changes might be associated with vulnerability to imported infections. To date, the nature of the parasites remains unknown; however, zoonoses could be incriminated.
18790087	65	72	Delta32	DNAMutation	|DEL||32
18790087	419	426	Delta32	DNAMutation	|DEL||32
18790087	491	498	Delta32	DNAMutation	|DEL||32

18681856|t|Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene.
18681856|a|OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease.
18681856	102	109	p.M453T	ProteinMutation	p|M|453|T
18681856	803	814	c.1358T-->C	DNAMutation	c|T|1358|C
18681856	899	906	p.M453T	ProteinMutation	p|M|453|T

18600483|t|Identification of rifampin-resistant genotypes in Mycobacterium tuberculosis by PCR-reverse dot blot hybridization.
18600483|a|A PCR-reverse dot blot hybridization (RDBH) assay was developed for rapid identification of rifampin (RFP)-resistant genotypes in Mycobacterium tuberculosis clinical isolates. The assay used the rpoB gene as target and was used to evaluate 148 clinical isolates (97 RFP-resistant isolates and 51 RFP-susceptible isolates). At the same time, the isolates were subjected to DNA sequencing and conventional drug susceptibility test. One hundred and forty one (95.3%) and 136 (91.9%) of the 148 strains were correctly identified by DNA sequencing and RDBH assay, respectively. None of the 51 RFP-susceptible isolates examined had alterations in rpoB. The sensitivity and specificity of the DNA sequencing were 92.8% and 100%, and the positive predictive value (PPV) and negative predictive value (NPV) were 100% and 87.9%, respectively. The sensitivity and specificity of the RDBH assay were 87.6% and 100%, and the PPV and NPV were 100% and 81.0%, respectively. Codons 531 and 526 of the rpoB were found to be the most common sites of nucleotide substitutions. Mutations at codons 511, 513, 515, 516, 517, 518, and 533 were also found. There were two-codon mutations in four isolates. No deletion and insertion was found in the rpoB gene. These results indicate that the RDBH assay is a rapid, simple, and reliable method for routine identification of RFP resistance in M. tuberculosis.

19808398|t|Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy.
19808398|a|BACKGROUND: Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. METHODS AND RESULTS: Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the beta1 subunit, the mutated channels exhibited a -4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na(+) current reduction and a moderate increase in late Na(+) current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. CONCLUSIONS: A1180V expresses a mild Na(+) channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na(+) influx and, hence, cellular Na(+) homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block.
19808398	802	808	A1180V	ProteinMutation	p|A|1180|V
19808398	1508	1514	A1180V	ProteinMutation	p|A|1180|V
19808398	1651	1657	A1180V	ProteinMutation	p|A|1180|V
19808398	1801	1807	A1180V	ProteinMutation	p|A|1180|V

18470323|t|Anticipation in familial lattice corneal dystrophy type I with R124C mutation in the TGFBI (BIGH3) gene.
18470323|a|PURPOSE: To report the clinical, ophthalmic, and genetic characteristics for lattice corneal dystrophy type I (LCDI) in a Chilean family. METHODS: Six affected family members were examined clinically including visual acuity, color cornea photography, applanation tonography, and fundoscopy. Genomic DNA was extracted from peripheral leukocytes from six affected and three unaffected members of a family with lattice corneal dystrophy type I. Exon 4 of the transforming growth factor-induced gene (TGFBI) was screened for the most frequent mutation, R124C, in the proband by sequencing. We also designed a rapid polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the same mutation, amplifying exon 4 and digesting with PstI restriction enzyme. Using this strategy, we analyzed the mutation in six affected and three healthy family members. RESULTS: Three generations of family members were positively diagnosed with lattice corneal dystrophy. Six participants demonstrated LCD1 in both eyes, most of whom were symmetric. Age at onset of symptoms was variable (3-42 years old). Moreover, in this family, the age of onset of the disease decreased in succeeding generations, which could be interpreted as anticipation. Visual acuity varied from 1.0 to 0.13. Two patients, ages 69 and 44 years old, demonstrated a degree of severity "Bad" according to best-corrected vision and corneal commitment. The exon 4 sequence of TGFBI of the proband exhibits the heterozygous single-nucleotide mutation, C417T, leading to amino acid substitution (R124C) in the encoded TGF-induced protein. Using PCR-RFLP, we confirmed the heterozygous mutation in six affected family members and excluded it in three healthy members. CONCLUSIONS: The R124C mutation in TGFBI cosegregated with LCD type I in the investigated family. This is the first report of a molecular analysis of LCD type I in Chilean patients. The early onset affected persons in the fourth generation raises the possibility of anticipation.
18470323	63	68	R124C	ProteinMutation	p|R|124|C
18470323	654	659	R124C	ProteinMutation	p|R|124|C
18470323	1641	1646	C417T	DNAMutation	c|C|417|T
18470323	1684	1689	R124C	ProteinMutation	p|R|124|C
18470323	1872	1877	R124C	ProteinMutation	p|R|124|C

18457324|t|Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer.
18457324|a|BACKGROUND: Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline-related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline-related CHF. METHODS: A nested case-control study was conducted within a cohort of 1979 patients enrolled in the Childhood Cancer Survivor Study who received treatment with anthracyclines and had available DNA. Thirty patients with CHF (cases) and 115 matched controls were genotyped for polymorphisms in NQO1 (NQO1*2) and CBR3 (the CBR3 valine [V] to methionine [M] substitution at position 244 [V244M]). Enzyme activity assays with recombinant CBR3 isoforms (CBR3 V244 and CBR3 M244) and the anthracycline substrate doxorubicin were used to investigate the functional impact of the CBR3 V244M polymorphism. RESULTS: Multivariate analyses adjusted for sex and primary disease recurrence were used to test for associations between the candidate genetic polymorphisms (NQO1*2 and CBR3 V244M) and the risk of CHF. Analyses indicated no association between the NQO1*2 polymorphism and the risk of anthracycline-related CHF (odds ratio [OR], 1.04; P=.97). There was a trend toward an association between the CBR3 V244M polymorphism and the risk of CHF (OR, 8.16; P=.056 for G/G vs A/A; OR, 5.44; P=.092 for G/A vs A/A). In line, recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR3 V244 [8.26+/-3.57 nmol/hour.mg] vs CBR3 M244 [3.22+/-0.67 nmol/hour.mg]; P=.01). CONCLUSIONS: The functional CBR3 V244M polymorphism may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors by modulating the intracardiac formation of cardiotoxic anthracycline alcohol metabolites. Larger confirmatory case-control studies are warranted.
18457324	1164	1169	V244M	ProteinMutation	p|V|244|M
18457324	1356	1361	V244M	ProteinMutation	p|V|244|M
18457324	1551	1556	V244M	ProteinMutation	p|V|244|M
18457324	1776	1781	V244M	ProteinMutation	p|V|244|M
18457324	2139	2144	V244M	ProteinMutation	p|V|244|M

18439317|t|Association between promoter -1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese.
18439317|a|BACKGROUND: Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD. METHODS: Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test. RESULTS: Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04-1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01-2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033-2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029-2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele. CONCLUSION: We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.
18439317	272	275	G/D	DNAMutation	|DEL||G

18426832|t|Association between gynecomastia and aromatase (CYP19) polymorphisms.
18426832|a|OBJECTIVE: Aromatase cytochrome P45019 (CYP19) is a key enzyme in estrogen biosynthesis, and polymorphisms within its gene are associated with an increased risk of estrogen-dependent diseases. Enhanced estrogen stimulation of breast tissue in men may lead to gynecomastia. We assessed whether intron 4 (TTTA)n repeat and TCT deletion/insertion polymorphisms and an exon 10 (3'-UTR) C/T single nucleotide polymorphism of CYP19 are associated with gynecomastia. DESIGN/METHODS: We performed a genetic association study of 100 patients referred to the endocrinological outpatient clinic with breast glandular tissue enlargement confirmed by clinical and ultrasound examinations and 99 healthy volunteers without gynecomastia. Microsatellite (TTTA)n and insertion/deletion polymorphisms were studied using capillary electrophoresis, and the C/T polymorphism in the 3'-UTR was analyzed using the TaqMan assay. RESULTS: Significantly increased risk of gynecomastia was found in subjects carrying a CYP19 exon 10 T allele that was previously related to the high aromatase activity. Frequency of the TT genotype was significantly higher in patients when compared with controls (40.6 vs 26.3%; TT versus CT and CC genotypes; P(c)<0.05). We found strong linkage disequilibrium between the alleles of studied polymorphic loci. T allele in the 3'-UTR was in linkage disequilibrium with the long alleles of the intron 4 polymorphism, mainly (TTTA)11. However, our findings did not show significant correlation of alleles having more than nine TTTA repeats with gynecomastia. CONCLUSIONS: The CYP19 polymorphisms might contribute to the incidence of gynecomastia, but further studies in larger groups are needed to confirm these results.
18426832	452	455	C/T	DNAMutation	|C||T
18426832	907	910	C/T	DNAMutation	|C||T

18410548|t|Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas.
18410548|a|OBJECTIVE: Pituitary adenomas occur rarely in childhood and adolescence. Pituitary adenoma predisposition (PAP) has been recently associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The aim of the study was to examine the proportion of germline AIP mutations in apparently sporadic paediatric pituitary adenomas. DESIGN: Genomic DNA was analysed for mutations in the AIP gene, by PCR amplification and direct sequencing. PATIENTS: A population-based cohort consisting of 36 apparently sporadic paediatric pituitary adenoma patients, referred to two medical centres in Italy, was included in the study. Patients were either less than 18 years at diagnosis, or showed clinical evidence of adenoma development before the age of 18 years. RESULTS: A heterozygous in-frame deletion Y248del (c.742_744delTAC) was identified in one GH-secreting adenoma patient. Loss of heterozygosity (LOH) analysis of tumour DNA revealed the loss of the wild-type allele. First degree relatives carrying the mutation were clinically unaffected. CONCLUSIONS: While mutations were absent in non-GH-secreting adenoma patients, germline AIP mutations can be found in children and adolescents with GH-secreting tumours, even in the absence of family history. The present study reports the AIP mutation analysis results on patients of a single ethnic origin. Clearly, further studies are needed to improve our knowledge on the role of AIP in paediatric pituitary adenomas.
18410548	962	969	Y248del	ProteinMutation	p|DEL|248|Y
18410548	971	986	c.742_744delTAC	DNAMutation	c|DEL|742_744|TAC

18408250|t|A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population.
18408250|a|OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, which regulate the production of proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to systemic lupus erythaematosus (SLE) in Caucasian and Asian populations, but their involvement in other autoimmune diseases is still uncertain. Here, we assessed the genetic role of IRF5 in susceptibility to rheumatoid arthritis (RA) in Japanese subjects. METHODS: We selected 13 single nucleotide polymorphisms (SNPs) and a CGGGG insertion-deletion polymorphism in the IRF5 gene. We performed 2 sets of case-control comparisons using Japanese subjects (first set: 830 patients with RA and 658 controls; second set: 1112 patients with RA and 940 controls), and then performed a stratified analysis using human leukocyte antigen (HLA)-DRB1 shared epitope (SE) status. We genotyped the SNPs using TaqMan assays. RESULTS: A significant association of the rs729302 A allele with RA susceptibility was found in both sets (odds ratio (OR) 1.22, 95% CI 1.09 to 1.35, p<0.001 in the combined analysis). When the patients were stratified by the SE, the rs729302 A allele was found to confer increased risk to RA in patients that were SE negative (OR 1.50, 95% CI 1.17 to 1.92, p = 0.001) as compared with patients carrying the SE (OR 1.11, 95% CI 0.93 to 1.33, p = 0.24). In both sets, no genotyped polymorphisms were significantly associated with RA susceptibility, but rs729302 was significantly associated. CONCLUSIONS: These findings indicate that the promoter polymorphism of IRF5 is a genetic factor conferring predisposition to RA, and that it contributes considerably to disease pathogenesis in patients that were SE negative.
18408250	1139	1147	rs729302	SNP	rs729302
18408250	1331	1339	rs729302	SNP	rs729302
18408250	1649	1657	rs729302	SNP	rs729302

18391980|t|Functional inactivation of the WTX gene is not a frequent event in Wilms' tumors.
18391980|a|For many years the precise genetic etiology of the majority of Wilms' tumors has remained unexplained. Recently, the WTX gene, mapped to chromosome Xq11.1, has been reported to be lost or mutated in approximately one-third of Wilms' tumors. Moreover, in female cases, the somatically inactivated alleles were found to invariantly derive from the active chromosome X. Consequently, WTX has been proposed as a 'one-hit' tumor suppressor gene. To provide further insights on the contribution of WTX to the development of the disease, we have examined 102 Wilms' tumors, obtained from 43 male and 57 female patients. Quantitative PCR analyses detected WTX deletions in 5 of 45 (11%) tumors from males, whereas loss of heterozygosity at WTX-linked microsatellites was observed in 9 tumors from 50 informative females (19%). However, in the latter group, using a combination of HUMARA assay and bisulfite-modified DNA sequencing, we found that the deletion affected the active chromosome X only in two cases (4%). Sequence analyses detected an inactivating somatic mutation of WTX in a single tumor, in which a strongly reduced expression of the mutant allele respect to the wild-type allele was observed, a finding not consistent with its localization on the active chromosome X. Overall, a functional somatic nullizygosity of the WTX gene was ascertained only in seven of the Wilms' tumors included in the study (approximately 7%). Our findings indicate that previously reported estimates on the proportion of Wilms' tumors due to WTX alterations should be reconsidered.

18385794|t|Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia.
18385794|a|PURPOSE: Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and/or microphthalmia. In this study, we evaluated 34 anophthalmic/microphthalmic patient DNA samples (two sets of siblings included) for mutations and sequence variants in SOX2 and CHX10. METHODS: Conformational sensitive gel electrophoresis (CSGE) was used for the initial SOX2 and CHX10 screening of 34 affected individuals (two sets of siblings), five unaffected family members, and 80 healthy controls. Patient samples containing heteroduplexes were selected for sequence analysis. Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples. RESULTS: Two novel heterozygous mutations and two sequence variants (one known) in SOX2 were identified in this cohort. Mutation c.310 G>T (p. Glu104X), found in one patient, was in the region encoding the high mobility group (HMG) DNA-binding domain and resulted in a change from glutamic acid to a stop codon. The second mutation, noted in two affected siblings, was a single nucleotide deletion c.549delC (p. Pro184ArgfsX19) in the region encoding the activation domain, resulting in a frameshift and premature termination of the coding sequence. The shortened protein products may result in the loss of function. In addition, a novel nucleotide substitution c.*557G>A was identified in the 3'-untranslated region in one patient. The relationship between the nucleotide change and the protein function is indeterminate. A known single nucleotide polymorphism (c. *469 C>A, SNP rs11915160) was also detected in 2 of the 34 patients. Screening of CHX10 identified two synonymous sequence variants, c.471 C>T (p.Ser157Ser, rs35435463) and c.579 G>A (p. Gln193Gln, novel SNP), and one non-synonymous sequence variant, c.871 G>A (p. Asp291Asn, novel SNP). The non-synonymous polymorphism was also present in healthy controls, suggesting non-causality. CONCLUSIONS: These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort.
18385794	943	952	c.310 G>T	DNAMutation	c|G|310|T
18385794	954	964	p. Glu104X	ProteinMutation	p|E|104|X
18385794	1212	1221	c.549delC	DNAMutation	c|DEL|549|C
18385794	1223	1240	p. Pro184ArgfsX19	ProteinMutation	p|P|184|R|FSX|19
18385794	1476	1485	c.*557G>A	DNAMutation	c|G|*557|A
18385794	1677	1688	c. *469 C>A	DNAMutation	c|C|*469|A
18385794	1694	1704	rs11915160	SNP	rs11915160
18385794	1813	1822	c.471 C>T	DNAMutation	c|C|471|T
18385794	1824	1835	p.Ser157Ser	ProteinMutation	p|S|157|S
18385794	1837	1847	rs35435463	SNP	rs35435463
18385794	1853	1862	c.579 G>A	DNAMutation	c|G|579|A
18385794	1864	1876	p. Gln193Gln	ProteinMutation	p|Q|193|Q
18385794	1931	1940	c.871 G>A	DNAMutation	c|G|871|A
18385794	1942	1954	p. Asp291Asn	ProteinMutation	p|D|291|N

18257781|t|Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease.
18257781|a|BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.
18257781	559	570	c.1445T > G	DNAMutation	c|T|1445|G
18257781	718	725	p.F482C	ProteinMutation	p|F|482|C
18257781	783	795	IVS21-2delAG	DNAMutation	c|DEL|IVS21-2|AG
18257781	1535	1542	p.F482C	ProteinMutation	p|F|482|C

18241046|t|A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids.
18241046|a|Depressed calcium handling by the sarcoplasmic reticulum (SR) Ca-ATPase and its regulator phospholamban (PLN) is a key characteristic of human and experimental heart failure. Accumulating evidence indicates that increases in the relative levels of PLN to Ca-ATPase in failing hearts and resulting inhibition of Ca sequestration during diastole, impairs contractility. Here, we identified a genetic variant in the PLN promoter region, which increases its expression and may serve as a genetic modifier in dilated cardiomyopathy (DCM). The variant AF177763.1:g.203A>C (at position -36 bp relative to the PLN transcriptional start site) was found only in the heterozygous form in 1 out of 296 normal subjects and in 22 out of 381 cardiomyopathy patients (heart failure at age of 18-44 years, ejection fraction=22+/-9%). In vitro analysis, using luciferase as a reporter gene in rat neonatal cardiomyocytes, indicated that the PLN-variant increased activity by 24% compared to the wild type. Furthermore, the g.203A>C substitution altered the specific sequence of the steroid receptor for the glucocorticoid nuclear receptor (GR)/transcription factor in the PLN promoter, resulting in enhanced binding to the mutated DNA site. These findings suggest that the g.203A>C genetic variant in the human PLN promoter may contribute to depressed contractility and accelerate functional deterioration in heart failure.
18241046	681	689	g.203A>C	DNAMutation	g|A|203|C
18241046	1129	1137	g.203A>C	DNAMutation	g|A|203|C
18241046	1379	1387	g.203A>C	DNAMutation	g|A|203|C

18235024|t|Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2.
18235024|a|PURPOSE: Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior RESULTS:                 <AbstractText Label="METHODS" NlmCategory="METHODS">Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. results. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS: The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.

18202102|t|SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer.
18202102|a|Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers.

18050247|t|Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform.
18050247|a|OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.
18050247	1029	1034	N673S	ProteinMutation	p|N|673|S
18050247	1104	1109	C203S	ProteinMutation	p|C|203|S

17994380|t|Screening of Iranian thalassemic families for the most common deletions of the beta-globin gene cluster.
17994380|a|Deltabeta-thalassemia (thal) is a disorder, characterized by increased levels of fetal hemoglobin (Hb F) in adult life. A considerable number of deletions of variable size and position in the beta-globin gene cluster are associated with the clinical manifestation of deltabeta-thal. In this study we have determined the presence of the eight most common deletions in Iranian patients. Thirty-two patients from 19 families were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran (a private genetics center), within the past 3 years with elevated levels of Hb F and low mean corpuscular volume (MCV). After obtaining their informed consent, DNA was extracted from whole blood by the salting-out method. Detection of eight deletions was performed using polymerase chain reaction (PCR). These deletions included the hereditary persistence of fetal Hb (HPFH) 1 (Black) and 3 (Indian), Spanish (-114 kb), Sicilian (-13,377 bp), Chinese (G)gamma((A)gammadeltabeta)(0)-thal (-100 kb), Asian-Indian inversion-deletion (G)gamma((A)gammadeltabeta)(0)-thal, and the Turkish form of inversion-deletion (deltabeta)(0)-thal, as well as the Hbs Lepore, which are characterized by unequal crossovers between the delta- and beta-globin genes. We found the Sicilian (-13,377 bp) and Hb Lepore deletions as well as the Asian-Indian (G)gamma((A)gammadeltabeta)(0)-thal in 11 (57.89%), three (15.78%) and five (26.31%) families, respectively. None of the aforementioned deletions were found in one of the patients. This is the first study of the deletions involved in deltabeta-thal in Iranian patients. Our study highlights the importance of detecting these mutations for prenatal diagnosis carrier detection and genotype/phenotype prediction.

17990063|t|Clinical and molecular characterization of Italian patients affected by Cohen syndrome.
17990063|a|Cohen syndrome is an autosomal recessive disorder with variability in the clinical manifestations, characterized by developmental delay, visual disability, facial dysmorphisms and intermittent neutropenia. We described a cohort of 10 patients affected by Cohen syndrome from nine Italian families ranging from 5 to 52 years at assessment. Characteristic age related facial changes were well documented. Visual anomalies, namely retinopathy and myopia, were present in 9/10 patients (retinopathy in 9/10 and myopia in 8/10). Truncal obesity has been described in all patients older than 6 years (8/8). DNA samples from all patients were analyzed for mutations in COH1 by DHPLC. We detected 15 COH1 alterations most of them were truncating mutations, only one being a missense change. Partial gene deletions have been found in two families. Most mutations were private. Two were already reported in the literature just once. A single base deletion leading to p.T3708fs3769, never reported before, was found in three apparently unrelated families deriving from a restricted area of the Veneto's lowland, between Padova town and Tagliamento river, in heterozygous state. Given the geographical conformation of this region, which is neither geographically or culturally isolated, a recent origin of the mutation could be hypothesized.
17990063	1045	1058	p.T3708fs3769	ProteinMutation	p|T|3708||FS|3769

17962394|t|Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene.
17962394|a|AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females.
17962394	77	84	p.R229G	ProteinMutation	p|R|229|G
17962394	725	733	c.686C>G	DNAMutation	c|C|686|G
17962394	837	844	p.R229G	ProteinMutation	p|R|229|G
17962394	1179	1186	p.R229G	ProteinMutation	p|R|229|G

17959715|t|Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma.
17959715|a|BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
17959715	634	643	rs1800734	SNP	rs1800734

17910065|t|A novel missense mutation in the paired domain of human PAX9 causes oligodontia.
17910065|a|PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype.
17910065	484	489	C139T	DNAMutation	c|C|139|T
17910065	624	629	C139T	DNAMutation	c|C|139|T
17910065	712	716	R47W	ProteinMutation	p|R|47|W
17910065	1008	1012	R47W	ProteinMutation	p|R|47|W

17876530|t|Role of homozygous DC-SIGNR 5/5 tandem repeat polymorphism in HIV-1 exposed seronegative North Indian individuals.
17876530|a|Despite multiple sexual exposures to HIV-1 virus, some individuals remain HIV-1 seronegative. Although several genetic factors have been related to HIV-1 resistance, the homozygosity for a mutation in CCR5 gene (the 32-bp deletion, i.e., CCR5-Delta32 allele) is presently considered the most relevant one. The C-type lectins, DC-SIGN (present on dendritic cells and macrophages) and DC-SIGNR (present on endothelial cells in liver and lymph nodes) efficiently bind and transmit HIV-1 to susceptible cell in trans, thereby augmenting the infection. A potential association of the DC-SIGN and DC-SIGNR neck domain repeat polymorphism and risk of HIV-1 infection is currently under debate. To determine the influence of host genetic factors on HIV-1 resistance, we conducted genetic risk association study in HIV-1-exposed seronegative (n = 47) individuals, HIV-1 seronegative (n = 262) healthy control, and HIV-1-infected seropositive patients (n = 168) for polymorphism in neck domain of DC-SIGN and DC-SIGNR genes. The DC-SIGN and DC-SIGNR genotypes were identified by polymerase chain reaction method in DNA extracted from peripheral blood and confirmed by sequencing. Fisher exact or chi (2) test was used for static analysis. DC-SIGN genotype and allele distribution was fairly similar in HIV-1-exposed seronegative, HIV-1 seropositive, and HIV-1 seronegative control. There was no statistical significance in the differences in the distribution of DC-SIGN genotypes. A total of 13 genotypes were found in DC-SIGNR neck repeat region polymorphism. Among all the genotypes, only 5/5 homozygous showed significant reduced risk of HIV-1 infection in HIV-1-exposed seronegative individuals (p = 0.009). A unique genotype 8/5 heterozygous was also found in HIV-1 seropositive individual, which is not reported elsewhere.
17876530	358	365	Delta32	DNAMutation	|DEL||32

17710578|t|Angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor (AT1R) gene polymorphism and its association with preeclampsia in Chinese women.
17710578|a|OBJECTIVE: To investigate whether polymorphisms of angiotensin converting enzyme gene (ACE) and angiotensin II receptor type 1 gene (AT1R) are associated with etiology of preeclampsia and renal impact in women with preeclampsia. METHODS: DNA was extracted from peripheral blood of 133 patients with preeclampsia and 105 healthy pregnant women. The I/D polymorphism of the ACE gene was assessed by polymerase chain reaction, and the A1166C polymorphism of the AT(1)R gene was additionally assessed by DdeI digestion. The level of proteinuria, fasting serum urea, creatinine and uric acid were investigated according to different genotypes of ACE and AT1R genes. RESULTS: The frequency of genotypes of the ACE gene and the AT1R gene was similar in preeclampsia and normal pregnancy. DD and ID genotype predominated in patients with severe proteinuria, as well as increased serum urea and uric acid. Serum creatinine was also increased, but no significant difference was found among three genotypes. The level of proteinuria, serum uric acid, urea, and creatinine did not vary between different AT1R genotypes. Compared with patients without renal dysfunction, the frequency of DD and ID genotypes of ACE gene was much higher in those with renal dysfunction, but AC and CC genotypes of AT1R gene were not. CONCLUSION: We found no association of the two gene polymorphisms with preeclampsia. However, ACE gene I/D polymorphisms were associated with the severe proteinuria and renal dysfunction seen in preeclampsia. Preeclampsia patients carrying the D allele may be susceptible to renal dysfunction.
17710578	607	613	A1166C	DNAMutation	|A|1166|C

17683901|t|An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia.
17683901|a|Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in "low-tech" laboratories.
17683901	69	74	G380R	ProteinMutation	p|G|380|R
17683901	332	339	p.G380R	ProteinMutation	p|G|380|R
17683901	482	491	c.1138G>A	DNAMutation	c|G|1138|A
17683901	496	505	c.1138G>C	DNAMutation	c|G|1138|C
17683901	606	615	c.1138G>A	DNAMutation	c|G|1138|A
17683901	962	971	c.1138G>A	DNAMutation	c|G|1138|A
17683901	1133	1140	p.G380R	ProteinMutation	p|G|380|R

17671968|t|Association study between Gilles de la Tourette Syndrome and two genes in the Robo-Slit pathway located in the chromosome 11q24 linked/associated region.
17671968|a|Gilles de la Tourette Syndrome (GTS) is an inherited neuropsychiatric disorder characterized by the presence of motor and phonic tics. Previous genetic studies have identified linkage and association between GTS and the 11q24 chromosomal region. We selected for study, within this region, two possible susceptibility genes for GTS, the ROBO3 and ROBO4 genes. These two genes were selected because of the recent identification of SLITRK1 as a potential susceptibility gene for GTS based on a translocation breakpoint and the further finding of two mutations in the SLITRK1 gene in three patients with GTS. While thus far, the SLITRK1 gene appears to account for only a few cases of GTS, these findings, if confirmed, point to other genes in these pathways that may contribute to GTS. Based on this, we examined two genes in the Slit-Robo pathway involved in cell migration, axonal pathfinding, and/or neuronal differentiation because of their location in 11q24, a region previously identified as linked and associated with GTS. We selected six haplotype tagging single nucleotide polymorphisms (SNPs) for ROBO3 and four for ROBO4 and genotyped them in our sample of trios and sibpair families diagnosed with GTS. Based on 155 nuclear families with 255 affected children, we did not find evidence for association between GTS and either the ROBO3 or ROBO4 genes. Thus, these two genes are unlikely to be the susceptibility genes contributing to GTS on 11q24.

17671735|t|Coincidence of mutations in different connexin genes in Hungarian patients.
17671735|a|Mutations in the GJB2 gene are the most common cause of hereditary prelingual sensorineural hearing impairment in Europe. Several studies indicate that different members of the connexin protein family interact to form gap junctions in the inner ear. Mutations in different connexin genes may accumulate and, consequently lead to hearing impairment. Therefore, we screened 47 Hungarian GJB2- heterozygous (one mutation in coding exon of the GJB2 gene) patients with hearing impairment for DNA changes in two further connexin genes (GJB6 and GJB3) and in the 5' non-coding region of GJB2 including the splice sites. Eleven out of 47 GJB2-heterozygous patients analyzed carried the splice site mutation -3170G>A in the 5'UTR region of GJB2. One out of these 11 patients showed homozygous -3170G>A genotype in combination with p.R127H. Next to the GJB2 mutations we noted 2 cases of deletion in GJB6 [Delta(GJB6-D13S1830)] and 3 (2 new and 1 described) base substitutions in GJB3 [c.357C>T, c.798C>T and c.94C>T (p.R32W)] which are unlikely disease-causing. Our results suggest the importance of routine screening for the rather frequent -3170G>A mutation (in addition to c.35delG) in patients with hearing impairment.
17671735	776	784	-3170G>A	DNAMutation	c|G|-3170|A
17671735	861	869	-3170G>A	DNAMutation	c|G|-3170|A
17671735	899	906	p.R127H	ProteinMutation	p|R|127|H
17671735	1053	1061	c.357C>T	DNAMutation	c|C|357|T
17671735	1063	1071	c.798C>T	DNAMutation	c|C|798|T
17671735	1076	1083	c.94C>T	DNAMutation	c|C|94|T
17671735	1085	1091	p.R32W	ProteinMutation	p|R|32|W
17671735	1210	1218	-3170G>A	DNAMutation	c|G|-3170|A
17671735	1244	1252	c.35delG	DNAMutation	c|DEL|35|G

17614823|t|Characterisation of a large complex intragenic re-arrangement in the FVII gene (F7) avoiding misdiagnosis in inherited factor VII deficiency.
17614823|a|Inherited factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder mostly caused by point mutations. Large genomic re-arrangements at F7 locus could account for a fraction of mutant alleles that remain unidentified after DNA sequencing, because they escape conventional polymerase chain reaction (PCR)-based techniques. We report the first systematic screening of F7 for large re-arrangements, by semi-quantitative multiplex PCR of fluorescent fragments targeting the 9 exons and the promoter region. A well-characterised cohort of 43 unrelated patients either apparently homozygous for a F7 point mutation or carrying at least one unidentified F7 mutant allele participated in this study. Two large F7 re-arrangements were identified in two FVII-deficient pedigrees, including a discontinuous deletion involving two distinct portions of F7 whose proximal and distal end junctions were characterised. A simple and efficient method for the routine detection of gross alterations of F7, which accounted for 2.3% of mutant alleles in our sample, is now available in inherited FVII deficiency. This test should complement conventional PCR-based techniques not only in unsolved cases, but also where inheritance pattern analysis is not achievable.

17549393|t|A novel IRF6 nonsense mutation (Y67X) in a German family with Van der Woude syndrome.
17549393|a|Van der Woude syndrome (VWS) is the most common type of syndromic orofacial cleft, which accounts for approximately 2% of all cleft lip and palate cases. It is characterised by variable association of lower lip pits, cleft lip and cleft palate, and hypodontia. VWS arises as the result of mutations in the gene encoding interferon regulatory factor 6 (IRF6). The disorder is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Very recently, mutations of the IRF6 gene in exons 2-9 have been found in VWS patients, suggesting that this gene plays an important role in orofacial development. We report a novel mutation of the IRF6 gene in a German family. Five out of the 12 persons affected were able to be investigated. The mutation produced a stop codon within exon 4 of the IRF6 gene. All 5 patients were heterozygous for a base substitution c.201C>A changing the tyrosine codon at amino acid position 67 into a stop codon (p.Y67X) in exon 4. The premature stop codon was responsible for a truncated protein lacking parts of the DNA- binding domain and the complete Smad-interferon regulatory factor-binding domain probably essential for interactions with the Smad transcription factors.
17549393	32	36	Y67X	ProteinMutation	p|Y|67|X
17549393	972	980	c.201C>A	DNAMutation	c|C|201|A
17549393	1054	1060	p.Y67X	ProteinMutation	p|Y|67|X

17392687|t|Subfertility in mice harboring a mutation in betaB2-crystallin.
17392687|a|PURPOSE: betaB2-crystallin is one of the most abundant proteins of the adult ocular lens of mammals although it is expressed at lower levels in several extralenticular locations. While mutations in betaB2-crystallin are known to result in lens opacities, alterations in tissues besides the lens have not been previously investigated in these mutants. Since we found mice harboring the Crybb2Phil mutation bred poorly, here we assess the contribution of betaB2-crystallin to mouse fertility and determine the expression pattern of betaB2-crystallin in the testis. METHODS: The expression pattern of betaB2-crystallin in the testis was analyzed by rt-PCR, western blotting, and immunohistochemistry. The fecundity of wildtype and Crybb2Phil mice was analyzed by quantitative fertility testing. The morphology of testes and ovaries was assessed by hematoxylin and eosin staining. RESULTS: In the mouse testis, betaB2-crystallin mRNA is found at low levels at birth, but its expression upregulates in this tissue as the testis is primed to initiate spermatogenesis. Western blotting detected betaB2-crystallin protein in sperm obtained from mice, cattle, and humans while immunolocalization detected this protein in developing sperm from the spermatocyte stage onward. Male and female mice homozygous for a 12 nucleotide inframe deletion mutation in betaB2-crystallin are subfertile when analyzed on a Swiss Webster derived background due to defects in egg and sperm production. However, mice harboring the same mutation on the C57Bl/6 genetic background did not exhibit any defects in reproductive function. CONCLUSIONS: betaB2-crystallin is expressed in developing and mature sperm and mice of both sexes harboring the Philly mutation in the betaB2-crystallin gene are subfertile when analyzed on a Swiss Webster genetic background. While these data are suggestive of a role for betaB2-crystallin in fertility, definitive determination of this will await the creation of a betaB2-crystallin null mouse.

17356395|t|Monitoring the isochromosome i(7)(q10) in the bone marrow of patients with Shwachman syndrome by real-time quantitative PCR.
17356395|a|Clonal chromosome anomalies may be found in the bone marrow (BM) of patients with Shwachman syndrome, who are at risk to develop myelodysplastic syndromes and/or acute myeloid leukemias. In particular, an isochromosome i(7)(q10) is frequent, and is usually monitored by chromosome analyses. We tested an approach by real-time quantitative polymerase chain reaction (RQ-PCR) on a chromosome 7 polymorphism. Five DNA samples of 2 Shwachman syndrome patients with clonal i(7)(q10) in the BM were used. Both were heterozygous for the diallelic indel polymorphism MID1064, which maps in 7q35. The percentage of i(7)(q10)-positive cells was extrapolated from the ratio of the 2 alleles measured by means of an allele-specific RQ-PCR assay. The results were compared with cytogenetic analyses on the same material used for RQ-PCR. In 1 patient, the RQ-PCR results matched well with those of chromosome analyses, whereas in the other one RQ-PCR showed that around 40% of the BM cells were abnormal, while they resulted to be nearly 80% with conventional monitoring assays. As the results obtained by RQ-PCR refer to the DNA of around 128,000 BM cells, our method proved to be feasible and more efficient in the quantitative evaluation of the i(7)(q10)-positive clone than conventional ones.

17353905|t|DFF45/ICAD restores cisplatin-induced nuclear fragmentation but not DNA cleavage in DFF45-deficient neuroblastoma cells.
17353905|a|We have previously defined a homozygously deleted region at chromosome 1p36.2-p36.3 in human neuroblastoma cell lines, NB-1 and NB-C201, and identified six genes including DFF45/ICAD within this region. In this study, we found that NB-C201 cells are much more resistant to various genotoxic stresses such as cisplatin (CDDP) than CHP134 and SH-SY5Y cells that do not have the homozygous deletion. To examine a role(s) of DFF45 in the regulation of apoptosis in response to CDDP, we have established stably DFF45-expressing NB-C201 cell clones (DFF45-1 and DFF45-3) and a control cell clone (NB-C201-C) using a retrovirus-mediated gene transfer. In contrast to NB-C201-C cells, DFF45-3 cells displayed apoptotic nuclear fragmentation in response to CDDP. Although CDDP-induced proteolytic cleavage of procaspase-3 and DFF45 in DFF45-3 cells, we could not detect a typical apoptotic DNA fragmentation. Additionally, deletion analysis revealed that C-terminal region of DFF45 is required for inducing nuclear fragmentation. Unexpectedly, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that DFF45 has undetectable effect on CDDP sensitivity of NB-C201 cells. Taken together, our present results suggest that DFF45/DFF40 system may be sufficient for CDDP-induced nuclear fragmentation but not DNA cleavage.

17327131|t|Molecular analysis of the CYP2F1 gene: identification of a frequent non-functional allelic variant.
17327131|a|The CYP2F1 is a human cytochrome P450 that is selectively expressed in lung tissue and involved in the metabolism of various pneumotoxicants with potential carcinogenic effects. In the present study, we report the first systematic investigation of the genetic polymorphism of this enzyme. We analyzed the nucleotidic sequence of the CYP2F1 gene in DNA samples from 90 French Caucasians consisting in 44 patients with lung cancer and 46 control individuals, using single-strand conformation polymorphism analysis of PCR products (PCR-SSCP). We identified 24 novel mutations distributed in the promoter region of the gene, as well as in the coding regions and their flanking intronic sequences. In addition to the wild-type CYP2F1*1 allele, seven allelic variant, CYP2F1*2A, *2B, *3, *4, *5A, *5B and *6, were characterized. The most frequent allelic variant, CYP2F1*2A (25.6%), harbors a combination of 9 mutations, including 2 missense mutations (Asp218Asn and Gln266His) and a 1-bp insertion (c.14_15insC) that creates a premature stop codon in exon 2, probably leading to the synthesis of a severely truncated protein with no catalytic activity. The identification of around 7% of homozygotes for the frameshift mutation in our Caucasian population suggests the existence of an interindividual variation of the CYP2F1 activity and, consequently, the possibility of interindividual differences in the toxic response to some pneumotoxicants and in the susceptibility to certain chemically induced diseases. However, our preliminary results did not show any evidence that the CYP2F1 genetic polymorphism has implications in the pathogenesis of lung cancer.
17327131	1047	1056	Asp218Asn	ProteinMutation	p|D|218|N
17327131	1061	1070	Gln266His	ProteinMutation	p|Q|266|H
17327131	1094	1105	c.14_15insC	DNAMutation	c|INS|14_15|C

17273972|t|Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.
17273972|a|Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.
17273972	749	754	H194Q	ProteinMutation	p|H|194|Q

17250667|t|A possible bichromatid mutation in a male gamete giving rise to a female mosaic for two different mutations in the X-linked gene WAS.
17250667|a|In genetic disorders caused by point mutations or small frameshift mutations, affected members of the same family are expected to have the same mutation in the causative gene. We have recently evaluated a family in which this was not the case. Maternal cousins with Wiskott-Aldrich syndrome (WAS; MIM 301000) had two different but contiguous single base pair deletions in WAS. The proband had an A deletion in codon 242 in exon 7 of WAS; his two cousins had a C deletion in codon 241. The mother of the proband was heterozygous for the A deletion allele, but her three sisters, including the mother of the affected cousins, were heterozygous for the C deletion. Both deletions occurred on the haplotype from the unaffected maternal great-grandfather. The maternal grandmother, who was a carrier of WAS, based on a non-random pattern of X chromosome inactivation in T cells, was mosaic for both deletions. These findings are most consistent with the mutations originating in a male gamete with different mutations on the two strands of DNA, a bichromatid mutation.

17250663|t|A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1.
17250663|a|We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype.
17250663	678	685	p.D572H	ProteinMutation	p|D|572|H
17250663	687	695	c.G1714C	DNAMutation	c|G|1714|C
17250663	824	831	p.D572N	ProteinMutation	p|D|572|N
17250663	833	841	c.G1714A	DNAMutation	c|G|1714|A
17250663	1037	1044	p.D572H	ProteinMutation	p|D|572|H
17250663	1080	1087	p.D572N	ProteinMutation	p|D|572|N

17192049|t|Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer.
17192049|a|CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer.
17192049	401	410	Ile462Val	ProteinMutation	p|I|462|V
17192049	415	421	T3801C	DNAMutation	g|T|3801|C

17175380|t|Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations.
17175380|a|We examined chromosome 3 in 32 childhood acute lymphoblastic leukemia (ALL) bone marrow samples. Using interphase multipoint FISH (mp-FISH), which was developed by our group, with 42 chromosome 3-specific probes, we detected clonal chromosome 3 aberrations in 4 T-cell ALL (T-ALL) cases. Four out of seven T-ALL cases carried 3q trisomies. One T-ALL case carried either trisomy 3 (in 15% of the cells) or a 23-megabase (Mb) 3p13 approximately p12 deletion in a different subpopulation of cells of 32%. Another T-ALL case had either 3q trisomy in 11% or a 12-Mb 3p12 approximately p13 deletion in 19% of the cells. The deletions were overlapping. In both cases, the majority of the bone marrow cells (47 and 70%, respectively) were normal chromosome 3 disomics. The interstitial deletions detected harbor a known homozygous deletion region between 72.6 and 78.8 Mb, which has been described in lung and breast tumors and contains the DUTT1/ROBO1 tumor suppressor gene. These deletions detected by mp-FISH would have remained unnoticed by conventional cytogenetics and multiplex FISH, as well as by current methods based on total tumor DNA analysis such as comparative genomic hybridization (CGH), array CGH, and loss of heterozygosity (LOH).

17169596|t|Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.
17169596|a|Succinyl-CoA:3-ketoacid CoA transferase (SCOT, EC 2.8.3.5) is the key enzyme for ketone body utilization. Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We identified a homozygous point mutation (c.671G>A) , which is a single-base substitution at the last nucleotide of exon 6, in a Turkish patient (GS12) with SCOT deficiency. This point mutation resulted in the skipping of exon 6, and exons 6 and 7 in human SCOT genes. To understand why the c.671G>A causes exons 6 and 7 skipping, nuclear RNA was separated from cytoplasmic RNA and both were analyzed by RT-PCR. In nuclear RNA, SCOT mRNA with exon 6 skipping was predominant and mRNA with exons 6 and 7 skipping was hardly detected, whereas the latter became one of major mRNA species in cytoplasmic RNA. This discrepancy was interpreted as follows: exon 6 skipping causes a frameshift and nonsense-mediated RNA decay in the cytosol, so mRNA with exon 6 skipping was unstable. On the other hand, SCOT mRNA with exons 6 and 7 is a minor transcript but it retains the reading-frame and is stable in cytosol. As a result, the latter mRNA is more abundant under steady-state conditions as compared to the former mRNA.
17169596	59	67	c.671G>A	DNAMutation	c|G|671|A
17169596	416	424	c.671G>A	DNAMutation	c|G|671|A
17169596	665	673	c.671G>A	DNAMutation	c|G|671|A

17083016|t|Genetic polymorphism of the binding domain of surfactant protein-A2 increases susceptibility to meningococcal disease.
17083016|a|BACKGROUND: Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)-A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules. METHODS: Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects. RESULTS: Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3-42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1-0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4-31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1-7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease. CONCLUSIONS: Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.

17050029|t|Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma.
17050029|a|BACKGROUND/AIMS: The hepatitis B virus (HBV) genotype C is associated with the development of hepatocellular carcinoma (HCC). In addition, the HBV X gene, which encodes the pleiotropic transactivator HBx, has also been associated with the development of HCC. In this study, we investigated whether nucleotide changes in the X gene of genotype C are associated with the development of HCC. METHODS/RESULTS: We sequenced the X gene in age- and sex-matched 39 HBV-infected patients with HCC and 36 HBV-infected patients without HCC. A novel nucleotide change that resulted in a proline to serine substitution at codon 38 in HBx (codon-38 change) was preferentially found in patients with HCC. Then, sera were collected from a new group of age- and sex-matched 52 patients with HCC and 51 patients without HCC. In this cohort also, the codon-38 change was associated with HCC. Multiple logistic regression analysis showed the prevalence of the codon-38 change was significantly associated with HCC in all patients (P=0.001, odds ratio: 4.89). CONCLUSION: The codon-38 change in genotype C is an independent risk factor for the development of HCC and may serve as a useful molecular marker for predicting the clinical outcomes in patients infected with HBV.

17000021|t|No independent role of the -1123 G>C and+2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations.
17000021|a|INTRODUCTION: The PTPN22 is a negative regulator of the T cell response. Its +1858C>T (R620W) polymorphism has been shown to associate with a risk for multiple autoimmune diseases, including type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The minor (susceptibility) allele is absent in Asian populations, but a recent study suggested an independent involvement of another polymorphism located within the promoter -1123 nucleotides relative to the translational start site. AIMS: We aimed to analyse the association of three PTPN22 polymorphisms in two distinct Caucasian populations, the Czechs (with T1D and with JIA) and Azeri (with T1D). METHODS: The single nucleotide polymorphisms (SNP) at positions -1123 (rs2488457), +1858 (rs2476601, the R620W substitution), and +2740 (rs1217412) were genotyped using TaqMan assays in 372 subjects with childhood-onset T1D, 130 subjects with JIA, and 400 control subjects of Czech origin, and in 160 subjects with T1D and 271 healthy controls of Azeri origin. RESULTS: In the Czechs, all three SNPs were in a tight linkage disequlibrium, while in the Azeri, the linkage disequlibrium was limited to between the promoter and 3'-UTR polymorphism, D'(-1123, +2740)=0.99, r(2)=0.72. Haplotype reconstruction via the expectation-maximization algorithm showed in both populations that only the haplotype containing the minor (W) allele at codon 620 was associated with T1D (OR=2.26, 95% CI 1.68-3.02 in Czechs, OR=14.8, 95% CI 2.0-651 in Azeri) or JIA (OR=2.43, 95% CI 1.66-3.56 in Czechs). The haplotypes having the wild-type (R) allele at codon 620 and minor alleles at -1123 and/or +2740 were neutral as to the risk of autoimmune conditions in both populations. CONCLUSIONS: In two different Caucasian populations, the Czechs and the Azeri, no independent contribution can be detected either of the -1123 promoter SNP or the +2740 3'-UTR SNP, and only the minor allele at PTPN22 codon 620 contributes to the risk of autoimmunity.
17000021	27	36	-1123 G>C	DNAMutation	c|G|-1123|C
17000021	40	49	+2740 A>G	DNAMutation	c|A|+2740|G
17000021	250	258	+1858C>T	DNAMutation	c|C|+1858|T
17000021	260	265	R620W	ProteinMutation	p|R|620|W
17000021	900	909	rs2488457	SNP	rs2488457
17000021	919	928	rs2476601	SNP	rs2476601
17000021	934	939	R620W	ProteinMutation	p|R|620|W
17000021	966	975	rs1217412	SNP	rs1217412

16970763|t|Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity.
16970763|a|BACKGROUND: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP). METHODS: A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing. RESULTS: Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation. CONCLUSION: Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome.
16970763	960	969	Leu103Val	ProteinMutation	p|L|103|V
16970763	994	1002	His43Arg	ProteinMutation	p|H|43|R

16849419|t|Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria.
16849419|a|CONTEXT: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia and rickets/osteomalacia with increased serum 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] resulting in hypercalciuria. OBJECTIVE: Our objective was to determine whether mutations in the SLC34A3 gene, which encodes sodium-phosphate cotransporter type IIc, are responsible for the occurrence of HHRH. DESIGN AND SETTING: Mutation analysis of exons and adjacent introns in the SLC34A3 gene was conducted at an academic research laboratory and medical center. PATIENTS OR OTHER PARTICIPANTS: Members of two unrelated families with HHRH participated in the study. RESULTS: Two affected siblings in one family were homozygous for a 101-bp deletion in intron 9. Haplotype analysis of the SLC34A3 locus in the family showed that the two deletions are on different haplotypes. An unrelated individual with HHRH was a compound heterozygote for an 85-bp deletion in intron 10 and a G-to-A substitution at the last nucleotide in exon 7. The intron 9 deletion (and likely the other two mutations) identified in this study causes aberrant RNA splicing. Sequence analysis of the deleted regions revealed the presence of direct repeats of homologous sequences. CONCLUSION: HHRH is caused by biallelic mutations in the SLC34A3 gene. Haplotype analysis suggests that the two intron 9 deletions arose independently. The identification of three independent deletions in introns 9 and 10 suggests that the SLC34A3 gene may be susceptible to unequal crossing over because of sequence misalignment during meiosis.

16843501|t|DNA damage and repair in gastric cancer--a correlation with the hOGG1 and RAD51 genes polymorphisms.
16843501|a|The cell's susceptibility to mutagens and its ability to repair DNA lesions are important for cancer induction, promotion and progression. Both the mutagens' sensitivity and the efficacy of DNA repair may be affected by variation in several genes, including DNA repair genes. The hOGG1 gene encodes glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both can be involved in the repair of oxidative DNA lesions, which can contribute to stomach cancer. In the present work we determined the level of basal and oxidative DNA damage and the kinetics of removal of DNA damage induced by hydrogen peroxide in peripheral blood lymphocytes of 30 gastric cancer patients and 30 healthy individuals. The metrics from DNA damage and repair study were correlated with the genotypes of common polymorphisms of the hOGG1 and RAD51 genes: a G-->C transversion at 1245 position of the hOGG1 gene producing a Ser-->Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G-->C substitution at position 135 (5'-untranslated region) of the RAD51 gene (the G135C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis (comet assay) assisted by DNA repair enzymes: endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg), preferentially recognizing oxidized DNA bases. The genotypes of the polymorphism were determined by restriction fragment length polymorphism PCR. We observed a strong association between gastric cancer occurrence, impaired DNA repair in human lymphocytes and the G/C genotype of the G135C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and stomach cancer occurrence in subjects with high level of oxidatively damaged DNA. We did not observe any correlation between the Ser1245Cys polymorphism of the hOGG1 gene and gastric cancer, including subjects with impaired DNA repair and/or high levels of endogenous oxidative DNA lesions. Therefore, our result suggest that the G135C polymorphism of the RAD51 gene may be linked with gastric cancer by the modulation of the cellular response to oxidative stress and this polymorphism may be a useful additional marker in this disease along with the genetic or/and environmental indicators of oxidative stress.
16843501	982	1017	G-->C transversion at 1245 position	DNAMutation	g|G|1245|C
16843501	1048	1087	Ser-->Cys substitution at the codon 326	ProteinMutation	p|S|326|C
16843501	1093	1102	Ser326Cys	ProteinMutation	p|S|326|C
16843501	1123	1157	G-->C substitution at position 135	DNAMutation	g|G|135|C
16843501	1206	1211	G135C	DNAMutation	g|G|135|C
16843501	1707	1712	G135C	DNAMutation	g|G|135|C
16843501	1941	1951	Ser1245Cys	ProteinMutation	p|S|1245|C
16843501	2142	2147	G135C	DNAMutation	g|G|135|C

16822828|t|Genotyping of five chinese patients with 17alpha-hydroxylase deficiency diagnosed through high-performance liquid chromatography serum adrenal profile: identification of two novel CYP17 mutations.
16822828|a|CONTEXT: 17alpha-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia caused by CYP17 gene mutations. OBJECTIVE: Five Chinese patients with 17alpha-hydroxylase deficiency were genotyped. PATIENTS: The five patients derived from four families living in Shandong Province, China. The diagnosis of 17alpha-hydroxylase deficiency was initially established through HPLC serum adrenal profiles in Qilu Hospital, China, from 1983-1993. RESULTS: Three CYP17 gene mutations were identified from these patients. Among them, V311fs and Y329fs are two novel frame-shifting mutations. V311fs is an 8-bp nucleotide (TTAAATGG) deletion in exon 5. Y329fs is a deletion-insertion combined mutation (TAC-->AA) at codon 329 in exon 6. Two homozygotes for Y329fs and one compound heterozygote for Y329fs and V311fs were identified from three different families. Two homozygous sisters for the D487_S488_F489 deletion were identified. CONCLUSION: The results confirmed the diagnostic value of the HPLC serum adrenal profile for 17alpha-hydroxylase deficiency. The D487_S488_F489 deletion had been identified in two previously genotyped Chinese families. In our present study, a third Chinese family with this mutation was identified, suggesting that this mutation is a prevalent CYP17 mutation in the Chinese population. The identification of Y329fs mutation in addition to three previously identified mutations at codon 329 suggests that codon 329 is an unstable point of the CYP17 gene. The mutations identified from our five patients appear to be random, but the recurrence of the Y329fs mutation may be attributed to a founder effect. Our studies suggest that 17alpha-hydroxylase deficiency may not be rare in the Chinese population.
16822828	730	736	V311fs	ProteinMutation	p|V|311||FS
16822828	741	747	Y329fs	ProteinMutation	p|Y|329||FS
16822828	788	794	V311fs	ProteinMutation	p|V|311||FS
16822828	848	854	Y329fs	ProteinMutation	p|Y|329||FS
16822828	897	920	(TAC-->AA) at codon 329	DNAMutation	|TAC|CODON329|AA
16822828	952	958	Y329fs	ProteinMutation	p|Y|329||FS
16822828	993	999	Y329fs	ProteinMutation	p|Y|329||FS
16822828	1004	1010	V311fs	ProteinMutation	p|V|311||FS
16822828	1538	1544	Y329fs	ProteinMutation	p|Y|329||FS
16822828	1779	1785	Y329fs	ProteinMutation	p|Y|329||FS

16628674|t|A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus.
16628674|a|A single nucleotide polymorphism characterized by the substitution of valine for glutamate (V1188E) in exon 25 of the multidrug resistance protein 2 gene was found in a group of patients with primary biliary cirrhosis. This heterozygous mutation was significantly associated with the presence of pruritus.
16628674	224	230	V1188E	ProteinMutation	p|V|1188|E

16601880|t|Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy.
16601880|a|Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402-1C > G, c.2316-1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized.
16601880	840	848	c.28delC	DNAMutation	c|DEL|28|C
16601880	850	860	c.1175delC	DNAMutation	c|DEL|1175|C
16601880	862	872	c.2186delC	DNAMutation	c|DEL|2186|C
16601880	874	884	c.2422delA	DNAMutation	c|DEL|2422|A
16601880	909	924	c.1002_1003insT	DNAMutation	c|INS|1002_1003|T
16601880	949	967	c.1285_1286insCAAA	DNAMutation	c|INS|1285_1286|CAAA
16601880	994	1021	c.2153_2155delinsTCCTGGTTTA	DNAMutation	c|INDEL|2153_2155|TCCTGGTTTA
16601880	1049	1056	p.E153X	ProteinMutation	p|E|153|X
16601880	1058	1065	p.R236X	ProteinMutation	p|R|236|X
16601880	1067	1074	p.E270X	ProteinMutation	p|E|270|X
16601880	1076	1083	p.R337X	ProteinMutation	p|R|337|X
16601880	1085	1092	p.R424X	ProteinMutation	p|R|424|X
16601880	1126	1138	c.861+1G > T	DNAMutation	c|G|861+1|T
16601880	1140	1153	c.1402-1C > G	DNAMutation	c|C|1402-1|G
16601880	1155	1168	c.2316-1G > A	DNAMutation	c|G|2316-1|A
16601880	1170	1183	c.2919+1G > A	DNAMutation	c|G|2919+1|A
16601880	1272	1285	c.2838+5G > A	DNAMutation	c|G|2838+5|A
16601880	1397	1404	p.T269M	ProteinMutation	p|T|269|M
16601880	1406	1413	p.R461Q	ProteinMutation	p|R|461|Q
16601880	1415	1422	p.G771R	ProteinMutation	p|G|771|R
16601880	1495	1502	p.S132W	ProteinMutation	p|S|132|W
16601880	1504	1511	p.Y138F	ProteinMutation	p|Y|138|F
16601880	1513	1520	p.G171A	ProteinMutation	p|G|171|A
16601880	1522	1529	p.T187K	ProteinMutation	p|T|187|K
16601880	1531	1538	p.R212K	ProteinMutation	p|R|212|K
16601880	1540	1547	p.T269M	ProteinMutation	p|T|269|M
16601880	1549	1556	p.R373W	ProteinMutation	p|R|373|W
16601880	1558	1565	p.I440N	ProteinMutation	p|I|440|N
16601880	1567	1574	p.R461Q	ProteinMutation	p|R|461|Q
16601880	1576	1583	p.N533Y	ProteinMutation	p|N|533|Y
16601880	1585	1592	p.C644F	ProteinMutation	p|C|644|F
16601880	1594	1601	p.H651R	ProteinMutation	p|H|651|R
16601880	1603	1610	p.V705M	ProteinMutation	p|V|705|M
16601880	1612	1619	p.N732K	ProteinMutation	p|N|732|K
16601880	1621	1628	p.G771R	ProteinMutation	p|G|771|R
16601880	1630	1637	p.H775R	ProteinMutation	p|H|775|R
16601880	1639	1646	p.T830M	ProteinMutation	p|T|830|M
16601880	1648	1655	p.A841P	ProteinMutation	p|A|841|P
16601880	1657	1664	p.D880V	ProteinMutation	p|D|880|V
16601880	1666	1673	p.S957P	ProteinMutation	p|S|957|P
16601880	1678	1685	p.R966G	ProteinMutation	p|R|966|G
16601880	1857	1864	p.Y138F	ProteinMutation	p|Y|138|F
16601880	1866	1873	p.T269M	ProteinMutation	p|T|269|M
16601880	1878	1885	p.E153X	ProteinMutation	p|E|153|X
16601880	1965	1972	p.V705M	ProteinMutation	p|V|705|M
16601880	1977	1984	p.R212K	ProteinMutation	p|R|212|K

16418600|t|Genetic investigation of the TSPYL1 gene in sudden infant death syndrome.
16418600|a|BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes.
16418600	816	823	p.F366L	ProteinMutation	p|F|366|L
16418600	1223	1234	457_458insG	DNAMutation	|INS|457_458|G

16379540|t|Indirect CFTR mutation identification by PCR/OLA anomalous electropherograms.
16379540|a|Mutations of CFTR gene are responsible for cystic fibrosis (CF) and other clinical conditions such as congenital absence of the vas deferens (CAVD), chronic pancreatitis (IP), and idiopathic disseminated bronchiectasis (DBE) classified as CFTR-related disorders. The PCR/OLA assay is designed to detect 31 known mutations including the 24 most common CF mutations worldwide, as identified by the CF Consortium. In order to define the CFTR genotype a series of 1812 individuals from central-southern Italy with and without CF manifestations were screened by using the PCR/OLA assay. Here we report the description of five cases of anomalous electropherograms obtained after PCR/OLA analysis, that led to the identification, in the homozygous state, of two point mutations (D110H and S589N) not included in the assay test panel, a large gene deletion (CFTRdel14b_17b), and an exonic polymorphism (c.4002A > G). Haplotype and real time PCR analysis were also performed in the subject carrying the large CFTR deletion. The study demonstrates that the PCR/OLA assay, besides being an efficient and user-friendly method to screen known mutations in the CFTR gene, may also function as a mutation/polymorphism-scanning assay, at least for certain nucleotide changes located in some critical regions of the gene.
16379540	850	855	D110H	ProteinMutation	p|D|110|H
16379540	860	865	S589N	ProteinMutation	p|S|589|N
16379540	932	942	del14b_17b	DNAMutation	c|DEL|14_17|
16379540	973	984	c.4002A > G	DNAMutation	c|A|4002|G

16321363|t|Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation.
16321363|a|We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal DNA markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation.
16321363	404	410	338G>A	DNAMutation	|G|338|A

16211251|t|A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases.
16211251|a|Cysteinyl leukotrienes (cysLTs) play important roles in bronchial asthma, and can mediate bronchial smooth muscle constriction and increase mucous secretion, vascular permeability and cellular infiltration. We identified a novel heterozygous single-nucleotide substitution 10G>A (Glu 4 Lys) in the first exon of the leukotriene C4 synthase gene (LTC4S). This substitution was detected in 5 of 141 allergic patients, but not in 110 nonallergic subjects. There was a difference in the Glu 4 Lys frequency between the allergic patients and nonallergic subjects (Fisher's exact test, p=0.0460). The five patients with Glu 4 Lys had allergic diseases such as bronchial asthma and/or allergic dermatitis. Furthermore, a familial analysis of Glu 4 Lys revealed a link with allergic diseases. Thus, our results suggest that Glu 4 Lys in the LTC4S might be associated with allergic diseases.
16211251	40	49	Glu 4 Lys	ProteinMutation	p|E|4|K
16211251	395	400	10G>A	DNAMutation	c|G|10|A
16211251	402	411	Glu 4 Lys	ProteinMutation	p|E|4|K
16211251	605	614	Glu 4 Lys	ProteinMutation	p|E|4|K
16211251	736	745	Glu 4 Lys	ProteinMutation	p|E|4|K
16211251	857	866	Glu 4 Lys	ProteinMutation	p|E|4|K
16211251	938	947	Glu 4 Lys	ProteinMutation	p|E|4|K

16200390|t|A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach.
16200390|a|Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility.

16157158|t|A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study.
16157158|a|Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.
16157158	2	15	Cys 23-Ser 23	ProteinMutation	p|C|23|S
16157158	422	432	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	494	504	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	600	610	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	801	811	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	986	996	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	1222	1232	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	1356	1366	Cys 23 Ser	ProteinMutation	p|C|23|S
16157158	1518	1528	Cys 23 Ser	ProteinMutation	p|C|23|S

16018252|t|Two novel mutations in SRY gene form Chinese sex reversal XY females.
16018252|a|The SRY gene (sex determining region on Y chromosome) acts as TDF and is required for regulating male sex determination. SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG-box motif (high-mobility group-box), which acts as DNA binding region. Deletion and inactivating mutations of SRY are among the known causes of XY sex reversal. Here, we described the screening of 10 patients who presented with 46,XY sex reversal for mutations in open reading frame (ORF) of SRY gene. DNA was isolated from blood samples using standard techniques. A 609 bp fragment from the central portion of the SRY gene was amplified, using primers XES-2 and XES-7. The amplified PCR fragments were cloned into the pUCm-T vectors, and direct sequencing were carried out on an ABI 377-3 automated DNA sequencer to detect the mutation. PCR-restriction enzyme digestion was applied to detect the results of DNA sequencing. In two patients,de novo mutations led to an amino acid substitution. An A was replaced by a G in codon 38 upstream of the 5' border outside the HMG box of the SRY gene, resulting in the replacement of the amino acid glutamate by glycine. Another heterozygous T to A transition at the nucleotide position +387 which encodes for a Tyrosine (Tyr) instead of a Term, whereas her father was proven to have the wild-type sequence. These point mutations have been confirmed with PCR-restrict enzyme method. As demonstrated by the Human Gene Mutation Database analysis,homology search, and review of the literature, these two mutations were not described previously and brought the total number of SRY gene nucleotide substitutions (missense/nonsense) to 45. These findings indicated that these amino acid substitutions may be responsible for the sex reversal,not only inside the HMG-box but also outside the HMG-box. The two novel mutations in SRY gene provided valuable information for understanding the molecular mechanism of the patient with 46,XY female sex reversal.

16000134|t|Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency.
16000134|a|A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.
16000134	722	737	Glu 272 to stop	ProteinMutation	p|E|272|X

15851735|t|Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.
15851735|a|BACKGROUND: Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. OBJECTIVE: To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. METHODS: Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. RESULTS: Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c.2607C>A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c.2607C>A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. CONCLUSIONS: The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy.
15851735	1083	1092	c.2607C>A	DNAMutation	c|C|2607|A
15851735	1305	1314	c.2607C>A	DNAMutation	c|C|2607|A

15837627|t|Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.
15837627|a|Polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) are clonal disorders arising from hematopoietic progenitors. An internet-based protocol was used to collect clinical information and biological specimens from patients with these diseases. High-throughput DNA resequencing identified a recurrent somatic missense mutation JAK2V617F in granulocyte DNA samples of 121 of 164 PV patients, of which 41 had homozygous and 80 had heterozygous mutations. Molecular and cytogenetic analyses demonstrated that homozygous mutations were due to duplication of the mutant allele. JAK2V617F was also identified in granulocyte DNA samples from 37 of 115 ET and 16 of 46 MMM patients, but was not observed in 269 normal individuals. In vitro analysis demonstrated that JAK2V617F is a constitutively active tyrosine kinase.

15827093|t|Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b.
15827093|a|CONTEXT: The central clinical feature of GH insensitivity (GHI) is severe growth failure associated with elevated serum concentrations of GH and abnormally low serum levels of IGF-I. GHI can be the result of an abnormality in the GH receptor or aberrancies downstream of the GH receptor. OBJECTIVE: We investigated the GH-IGF-I axis in a young female GHI subject who presented with a height of 114 cm (-7.8 sd score) at age 16.4 yr. PATIENT: The subject, from a consanguineous pedigree, had circulating levels of GH and GH-binding protein that were normal to elevated, whereas IGF-I (7.2 ng/ml; normal, 242-600), IGF-binding protein-3 (543 ng/ml; normal, 2500-4800), and acid-labile subunit (1.22 microg/ml; normal, 5.6-16) levels were abnormally low and failed to increase during an IGF-I generation test. DESIGN: Dermal fibroblast cultures were established with the consent of the patient and family. Immunoblot analysis of cell lysates and DNA sequencing of her signal transducer and activator of transcription 5b (STAT5b), a critical intermediate of the GH-IGF-I axis, were performed. RESULTS: Sequencing of the STAT5b gene revealed a novel homozygous insertion of a single nucleotide in exon 10. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein. CONCLUSION: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.

15818664|t|Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate.
15818664|a|OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.

15814629|t|The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism.
15814629|a|PURPOSE: In the present study, we aimed to substantiate the putative significance of angiotensin I-converting enzyme (ACE) on gastric cancer biology by investigating the influence of its gene polymorphism on gastric cancer progression. EXPERIMENTAL DESIGN: Genomic DNA was purified from peripheral blood mononuclear cells or tissue specimens. Amplified ACE gene fragments were separated on agarose gels. D or I alleles were identified by the presence of 190- or 490-bp fragments, respectively. Local expression of ACE was investigated by immunohistochemistry. RESULTS: Twenty-four of 113 (21%) gastric cancer patients had the II, 57 (51%) the ID, and 32 (28%) the DD genotype. The distribution of the ACE genotypes did not differ significantly from the control group of 189 patients without gastric cancer. However, the ACE genotypes correlated with the number of lymph node metastases and the Unio Internationale Contra Cancrum (UICC) tumor stage. Patients with the II genotype had a highly significantly smaller number of lymph node metastases (P < 0.001) and a significantly lower UICC tumor stage (P = 0.01) than patients with the DD genotype. No correlation was found between tumor type, tumor location, local tumor growth, distant metastases, and the ACE genotype. The expression of ACE in gastric cancer was investigated by immunohistochemistry in 100 of 113 patients. ACE was expressed by endothelial cells in all (100%) specimens and by tumor cells in 56 (56%) specimens. CONCLUSIONS: Our study shows that ACE is expressed locally in gastric cancer and that the gene polymorphism influences metastatic behavior.

15807692|t|Identification of novel type VII collagen gene mutations resulting in severe recessive dystrophic epidermolysis bullosa.
15807692|a|In this work, we studied the proband in a small nuclear family of Chinese and Dutch/German descent and identified two novel mutations in the type VII collagen gene leading to recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens variant (HS-RDEB). The maternal mutation is a single base pair deletion of a cytosine nucleotide in exon 26, designated 3472delC, resulting in a frameshift and a premature termination codon (PTC) within the same exon, 7 bp downstream of the site of the mutation. The paternal mutation is a G-->A transition located at the 5' donor splice site within intron 51, designated IVS51 + 1G-->A. This mutation leads to the activation of a cryptic splice site, 32 bp downstream of the mutation site and to subsequent aberrant out-of-frame splicing, resulting in two alternative mRNA transcripts and a downstream PTC. To our knowledge, these two mutations have not been previously reported. These findings extend the body of evidence for compound heterozygous mutations leading to HS-RDEB and provide the basis for prenatal diagnosis in this family.
15807692	478	486	3472delC	DNAMutation	c|DEL|3472|C
15807692	648	653	G-->A	DNAMutation	|G||A
15807692	730	744	IVS51 + 1G-->A	DNAMutation	c|G|IVS51+1|A

15710861|t|Adult onset metachromatic leukodystrophy without electroclinical peripheral nervous system involvement: a new mutation in the ARSA gene.
15710861|a|BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ARSA). Clinically, the disease is heterogeneous with respect to the age of onset, affection of peripheral and central nervous systems, and progression. OBJECTIVES: To analyze mutations in the ARSA gene of a patient with adult-onset MLD with no signs of peripheral polyneuropathy and to emphasize the clinical, neuroradiologic, neuropathologic, and genetic features of the disease. DESIGN: Case study of a patient clinically presenting with rapidly progressive dementia and behavioral abnormalities. We report the findings of clinical evaluation and neurophysiologic and neuropathologic studies of peripheral nerves; we also performed DNA sequence analysis, transfections, metabolic labeling, and immunoprecipitation of mutant ARSA polypeptides. SETTING: Genetic research and clinical unit, university hospital. RESULTS: Genetic analysis revealed homozygosity for a novel mutation in exon 3 of ARSA (F219V). This substitution leads to a misfolded unstable enzyme with a specific activity less than 1% of normal. There were no clinical or neurophysiologic signs of peripheral nervous system dysfunction. Typical neuropathologic signs for MLD were absent from nerve biopsy specimens. CONCLUSIONS: This novel mutation is associated with progressive psychocognitive impairment without clinical or electrophysiologic signs and only minor morphologic signs of peripheral nerve affection. The F219V substitution causes reduction in enzyme activity to an extent unexpected for an adult patient with MLD.
15710861	1159	1164	F219V	ProteinMutation	p|F|219|V
15710861	1645	1650	F219V	ProteinMutation	p|F|219|V

15642853|t|Parkin mutations and early-onset parkinsonism in a Taiwanese cohort.
15642853|a|BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic "parkin-proven" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific.
15642853	951	956	G284R	ProteinMutation	p|G|284|R
15642853	1413	1418	R396G	ProteinMutation	p|R|396|G

15623763|t|TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients.
15623763|a|PURPOSE: To identify mutations in the TGFBI gene in Indian patients with lattice corneal dystrophy (LCD) or granular corneal dystrophy (GCD) and to look for genotype-phenotype correlations. METHODS: Thirty-seven unrelated patients were studied, 18 with LCD and 19 with GCD. The diagnosis of LCD or GCD was made on the basis of clinical and/or histopathological evaluation. Exons and flanking intron sequences of the TGFBI gene were amplified by PCR with specific primers. PCR products were screened by the method of single-strand conformation polymorphism followed by sequencing. Mutations were confirmed by screening at least 100 unrelated normal control subjects. RESULTS: Mutations were identified in 14 of 18 patients with LCD and in all 19 patients with GCD. In LCD, three novel heterozygous mutations found were glycine-594-valine (Gly594Val) in 2 of 18 patients, valine-539-aspartic acid (Val539Asp) in 1 patient, and deletion of valine 624, valine 625 (Val624-Val625del) in 1 patient. In addition, mutation of arginine 124-to-cysteine (Arg124Cys) was found in 8 of 18 patients and histidine 626-to-arginine (His626Arg) in 2 of 18 patients. Atypical clinical features for LCD were noted in patients with the Gly594Val and Val624-Val625del mutations. In GCD, 18 patients with GCD type I had a mutation of arginine 555-to-tryptophan (Arg555Trp) and 1 patient with GCD type III (Reis-Bucklers dystrophy), had the Arg124Leu mutation. Seven novel single-nucleotide polymorphisms (SNPs) were also found, of which a change of leucine 269 to phenylalanine (Leu269Phe) was found in 12 of 18 patients with the Arg555Trp mutation. CONCLUSIONS: Arg124Cys and Arg555Trp appear to be the predominant mutations causing LCD and GCD, respectively, in the population studied. The novel mutations identified in this study are associated with distinct phenotypes.
15623763	908	926	glycine-594-valine	ProteinMutation	p|G|594|V
15623763	928	937	Gly594Val	ProteinMutation	p|G|594|V
15623763	960	979	valine-539-aspartic	ProteinMutation	p|V|539|D
15623763	986	995	Val539Asp	ProteinMutation	p|V|539|D
15623763	1051	1067	Val624-Val625del	ProteinMutation	p|DEL|624_625|VV
15623763	1108	1132	arginine 124-to-cysteine	ProteinMutation	p|R|124|C
15623763	1134	1143	Arg124Cys	ProteinMutation	p|R|124|C
15623763	1179	1204	histidine 626-to-arginine	ProteinMutation	p|H|626|R
15623763	1206	1215	His626Arg	ProteinMutation	p|H|626|R
15623763	1305	1314	Gly594Val	ProteinMutation	p|G|594|V
15623763	1319	1335	Val624-Val625del	ProteinMutation	p|DEL|624_625|VV
15623763	1401	1427	arginine 555-to-tryptophan	ProteinMutation	p|R|555|W
15623763	1429	1438	Arg555Trp	ProteinMutation	p|R|555|W
15623763	1507	1516	Arg124Leu	ProteinMutation	p|R|124|L
15623763	1616	1644	leucine 269 to phenylalanine	ProteinMutation	p|L|269|F
15623763	1646	1655	Leu269Phe	ProteinMutation	p|L|269|F
15623763	1697	1706	Arg555Trp	ProteinMutation	p|R|555|W
15623763	1730	1739	Arg124Cys	ProteinMutation	p|R|124|C
15623763	1744	1753	Arg555Trp	ProteinMutation	p|R|555|W

15481887|t|Two new beta-chain variants: Hb Tripoli [beta26(B8)Glu-->Ala] and Hb Tizi-Ouzou [beta29(B11)Gly-->Ser].
15481887|a|Two new beta-globin chain variants: Hb Tripoli: codon 26, GAG-->GCG [beta26(B8)Glu-->Ala] and Hb Tizi-Ouzou: codon 29, GGC-->AGC [beta29(B11)Gly-->Ser] are described on the first exon of the beta-globin gene. The two variants are characterized by DNA sequencing and mass spectrometry (MS). Hematological abnormalities were found in the two carriers. The presence of microcytosis and hypochromia is explained by an additional homozygous 3.7 kb alpha(+) thalassemic deletion for the carrier of Hb Tizi-Ouzou. Hb Tizi-Ouzou showed a slight instability in vitro. The same hematological abnormalities associated with anemia are difficult to explain for Hb Tripoli's carrier in the absence of an alpha-globin genes abnormality and could suggest a possible abnormal splicing.
15481887	51	60	Glu-->Ala	ProteinMutation	p|E||A
15481887	92	101	Gly-->Ser	ProteinMutation	p|G||S
15481887	152	171	codon 26, GAG-->GCG	DNAMutation	|GAG|CODON26|GCG
15481887	183	192	Glu-->Ala	ProteinMutation	p|E||A
15481887	213	232	codon 29, GGC-->AGC	DNAMutation	|GGC|CODON29|AGC
15481887	245	254	Gly-->Ser	ProteinMutation	p|G||S

15459183|t|CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B.
15459183|a|We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72.
15459183	204	213	Ile232Thr	ProteinMutation	p|I|232|T

15377356|t|Features of epidermolysis bullosa simplex due to mutations in the ectodomain of type XVII collagen.
15377356|a|BACKGROUND: Mutations in COL17A1, coding for type XVII collagen, cause junctional epidermolysis bullosa with an ultrastructural plane of cleavage through the lamina lucida of the epidermal basement membrane. OBJECTIVES: To identify the COL17A1 mutations in a child with reduced type XVII collagen expression and intraepidermal blister formation. PATIENT AND METHODS: Protein expression and level of tissue separation were studied by immunofluorescence and electron microscopy. The mutations were identified by analysing the patient's DNA and mRNA. RESULTS: Immunofluorescence microscopy performed on nonlesional skin demonstrated absence of the type XVII collagen endodomain and presence, although reduced, of the shed ectodomain. Electron microscopy showed that the plane of cleavage was through the basal cells, not through the lamina lucida. Two heterozygous mutations were identified in COL17A1: a new 3'-acceptor splice-site mutation in intron 21 (1877-2A-->C), and a deletion in exon 48 (3432delT). The splice-site mutation in intron 21 results in alternative transcripts of which two are in-frame, with deletions of the first nine codons of exon 22 and the entire exon 22, respectively. By Western blot analysis, a type XVII collagen molecule was detected that was slightly smaller than normal. CONCLUSIONS: Occasionally mutations in the COL17A1 gene may result in split levels suggesting epidermolysis bullosa simplex rather than junctional epidermolysis bullosa.
15377356	1053	1064	1877-2A-->C	DNAMutation	c|A|1877-2|C
15377356	1094	1102	3432delT	DNAMutation	c|DEL|3432|T

15282322|t|Deletion of mouse rad9 causes abnormal cellular responses to DNA damage, genomic instability, and embryonic lethality.
15282322|a|The fission yeast Schizosaccharomyces pombe rad9 gene promotes cell survival through activation of cell cycle checkpoints induced by DNA damage. Mouse embryonic stem cells with a targeted deletion of Mrad9, the mouse ortholog of this gene, were created to evaluate its function in mammals. Mrad9(-/-) cells demonstrated a marked increase in spontaneous chromosome aberrations and HPRT mutations, indicating a role in the maintenance of genomic integrity. These cells were also extremely sensitive to UV light, gamma rays, and hydroxyurea, and heterozygotes were somewhat sensitive to the last two agents relative to Mrad9(+/+) controls. Mrad9(-/-) cells could initiate but not maintain gamma-ray-induced G(2) delay and retained the ability to delay DNA synthesis rapidly after UV irradiation, suggesting that checkpoint abnormalities contribute little to the radiosensitivity observed. Ectopic expression of Mrad9 or human HRAD9 complemented Mrad9(-/-) cell defects, indicating that the gene has radioresponse and genomic maintenance functions that are evolutionarily conserved. Mrad9(+/-) mice were generated, but heterozygous intercrosses failed to yield Mrad9(-/-) pups, since embryos died at midgestation. Furthermore, Mrad9(-/-) mouse embryo fibroblasts were not viable. These investigations establish Mrad9 as a key mammalian genetic element of pathways that regulate the cellular response to DNA damage, maintenance of genomic integrity, and proper embryonic development.

15272913|t|Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS?
15272913|a|OBJECTIVE: Endometriosis is a steroid-dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease. DESIGN: In a case-control study, we examined the PROGINS polymorphism of the progesterone receptor gene in 131 Italian women affected by endometriosis diagnosed according to published criteria for the definition of the definite disease. Control subjects were represented by 127 Italian women without laparoscopic evidence of the disease. MEASUREMENTS: Peripheral blood samples, DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: We found a statistically significant difference in the distribution of PROGINS genotypes between patients with and without endometriosis. The frequency of the PROGINS allele T2 was 17.2% and 11%, respectively, in affected women and in controls [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.0-2.8]. This association was stronger in patients with more severe forms of endometriosis, such as an infiltrating disease or a disease characterized by severe pelvic adhesions (OR 2.4, 95% CI 1.2-4.8; and OR 2.7, 95% CI 1.4-5.3, respectively). Combination of the results from an earlier study and the current data indicates that carrying the allele variant T2 is associated with a twofold increase in the risk of developing endometriosis (OR 2.0, 95% CI 1.3-2.9). CONCLUSIONS: Our results further support the idea that the PROGINS polymorphism of the progesterone receptor may be associated with an increased risk of endometriosis.

15258261|t|Mre11 deficiency in Arabidopsis is associated with chromosomal instability in somatic cells and Spo11-dependent genome fragmentation during meiosis.
15258261|a|The Mre11/Rad50/Nbs1 complex is involved in many aspects of chromosome metabolism. Aberrant function of the complex is associated with defects in the DNA checkpoint, double-strand break repair, meiosis, and telomere maintenance. In this article, we report the consequences of Mre11 dysfunction for the stability of mitotic and meiotic chromosomes in Arabidopsis thaliana. Although plants homozygous for a T-DNA insertion in a conserved region of the MRE11 gene are viable, they exhibit growth defects and are infertile. Analysis of mitotic chromosomes prepared from the mutant plants revealed abundant dicentric chromosomes and chromosomal fragments. Fluorescence in situ hybridization showed that anaphase bridges are often formed by homologous chromosome arms. The frequency of chromosome fusions was not reduced in mre11 ku70 double mutants, suggesting that plants possess DNA end-joining activities independent of the Ku70/80 and Mre11 complexes. Cytogenetic examination of pollen mother cells revealed massive chromosome fragmentation and the absence of synapsis in the initial stages of meiosis. The fragmentation was substantially suppressed in mre11 spo11-1 double mutants, indicating that Mre11 is required for repair but not for the induction of Spo11-dependent meiotic DNA breaks in Arabidopsis.

15191352|t|Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene.
15191352|a|Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta). We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S (1123T-->G) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta.
15191352	612	617	I280S	ProteinMutation	p|I|280|S
15191352	619	628	1123T-->G	DNAMutation	g|T|1123|G
15191352	738	743	I280S	ProteinMutation	p|I|280|S
15191352	995	1000	I280S	ProteinMutation	p|I|280|S

15184540|t|Microevolution between paired antral and paired antrum and corpus Helicobacter pylori isolates recovered from individual patients.
15184540|a|Sequence variations located at the signal sequence and mid-region within the vacA gene, the 3'-end of the cagA gene, the indel motifs at the 3'-end of the cag pathogenicity island and the regions upstream of the vacA and ribA genes were determined by PCR in 19 paired antral or antrum and corpus Helicobacter pylori isolates obtained at the same endoscopic session, and three antral pairs taken sequentially. Random amplification of polymorphic DNA (RAPD)-PCR and fluorescent amplified fragment length polymorphism (FAFLP)-PCR fingerprinting were applied to these paired clinical isolates. The FAFLP-PCR profiles generated were phylogenetically analysed. For the 22 paired isolates there were no differences within pairs at five of the genetic loci studied. However, six pairs of isolates (27%), of which four were antrum and corpus pairs, showed differences in the numbers of repeats located at the 3'-end of the cagA gene. RAPD-PCR fingerprinting showed that 16 (73%) pairs, nine of which were antrum and corpus pairs, possessed identical profiles, while six (27%) displayed distinctly different profiles, indicating mixed infections. Three of the six pairs showing differences at the 3'-end of the cagA gene yielded identical RAPD-PCR fingerprints. FAFLP-PCR fingerprinting and phylogenetic analysis revealed that all 16 pairs that displayed identical RAPD-PCR profiles had highly similar, but not identical, fingerprints, demonstrating that these pairs were ancestrally related but had undergone minor genomic alterations. Two antrum and corpus pairs of isolates, within the latter group, were isolates obtained from two siblings from the same family. This analysis demonstrated that each sibling was colonized by ancestrally related strains that exhibited differences in vacA genotype characteristics.

15148206|t|A novel arginine substitution mutation in 1A domain and a novel 27 bp insertion mutation in 2B domain of keratin 12 gene associated with Meesmann's corneal dystrophy.
15148206|a|AIM: To determine the disease causing gene defects in two patients with Meesmann's corneal dystrophy. METHODS: Mutational analysis of domains 1A and 2B of the keratin 3 (K3) and keratin 12 (K12) genes from two patients with Meesmann's corneal dystrophy was performed by polymerase chain reaction amplification and direct sequencing. RESULTS: Novel mutations of the K12 gene were identified in both patients. In one patient a heterozygous point mutation (429A-->C = Arg135Ser) was found in the 1A domain of the K12 gene. This mutation was confirmed by restriction digestion. In the second patient a heterozygous 27 bp duplication was found inserted in the 2B domain at nucleotide position 1222 (1222ins27) of the K12 gene. This mutation was confirmed by gel electrophoresis. The mutations were not present in unaffected controls. CONCLUSION: Novel K12 mutations were linked to Meesmann's corneal dystrophy in two different patients. A missense mutation replacing a highly conserved arginine residue in the beginning of the helix initiation motif was found in one patient, and an insertion mutation, consisting of a duplication of 27 nucleotides, was found before the helix termination motif in the other.
15148206	621	629	429A-->C	DNAMutation	|A|429|C
15148206	632	641	Arg135Ser	ProteinMutation	p|R|135|S
15148206	861	870	1222ins27	DNAMutation	|INS|1222|27

15135245|t|A new but frequent mutation of apoB-100-apoB His3543Tyr.
15135245|a|ApolipoproteinB 100 (apoB-100) is an important component of atherogenic lipoproteins such as LDL and serves as a ligand for the LDL-receptor. Familial defective apolipoproteinB 100 (FDB) is caused by a R3500Q mutation of the apoB gene and results in decreased binding of LDL to the LDL-receptor. So far FDB is the most frequent and best studied alteration of apoB-100. Apart from this, three other apoB mutations, R3500W, R3531C and R3480W, affecting binding to the LDL-receptor are known to date. We screened the apoB gene segment of codons 3448-3561 by denaturing gradient gel electrophoresis (DGGE) analysis in a total of 853 consecutively sampled German patients undergoing diagnostic coronary angiography for suspected CAD. By this, a new single base mutation was detected and confirmed by DNA sequencing. The mutation, CAC(3543)TAC results in a His3543Tyr substitution in apoB-100 (H3543Y). The prevalence of heterozygotes for H3543Y in the study population was 0.47% compared to 0.12% for the known Arg 3500 Gln (R3500Q) mutation. In conclusion, the new mutation is four times more frequent than "classical" FDB and thus appears to be the most common apoB mutation in Germany.
15135245	45	55	His3543Tyr	ProteinMutation	p|H|3543|Y
15135245	259	265	R3500Q	ProteinMutation	p|R|3500|Q
15135245	471	477	R3500W	ProteinMutation	p|R|3500|W
15135245	479	485	R3531C	ProteinMutation	p|R|3531|C
15135245	490	496	R3480W	ProteinMutation	p|R|3480|W
15135245	882	894	CAC(3543)TAC	DNAMutation	|C|CODON3543|T
15135245	908	918	His3543Tyr	ProteinMutation	p|H|3543|Y
15135245	945	951	H3543Y	ProteinMutation	p|H|3543|Y
15135245	990	996	H3543Y	ProteinMutation	p|H|3543|Y
15135245	1063	1075	Arg 3500 Gln	ProteinMutation	p|R|3500|Q
15135245	1077	1083	R3500Q	ProteinMutation	p|R|3500|Q

15122711|t|POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion.
15122711|a|Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein.
15122711	556	566	Glu873Stop	ProteinMutation	p|E|873|X
15122711	689	695	G1681A	DNAMutation	c|G|1681|A
15122711	730	739	Ala467Thr	ProteinMutation	p|A|467|T

15086325|t|Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees.
15086325|a|To investigate the molecular defects in two Chinese pedigrees with inherited factor V (FV) deficiency. A 37-year-old male (proband 1) and an 18-month-old boy (proband 2) were diagnosed as inherited coagulation FV deficiency by severely reduced plasma levels of FV activity and antigen. All 25 exons and their flanking sequence of F5 gene were amplified by polymerase chain reaction (PCR) for both probands and the PCR products were directly sequenced. Total RNA was extracted from the peripheral lymphocytes of proband 1 for detecting the changes at mRNA level. The homozygous deletion IVS8 -2A>G was identified in the F5 gene of proband 1 and complementary DNA (cDNA) analysis revealed the abolishment of the canonical splicing site by the mutation and the activation of the cryptic acceptor site 24 bp upstream instead. The insertion introduced eight additional amino acids (AA) into the FV protein. Two heterozygous mutations of F5 gene were discovered in proband 2. The 2238-9del AG in exon 13 introduced a premature termination code at 689 AA and the substitution of G6410 by T in exon 23 lead to the missense mutation Gly2079Val. Three F5 gene mutations, IVS8 -2A>G, 2238-9del AG and G6410T, have been identified in two Chinese pedigree with congenital FV deficiency, respectively.
15086325	712	722	IVS8 -2A>G	DNAMutation	c|A|IVS8-2|G
15086325	1100	1112	2238-9del AG	DNAMutation	c|DEL|2238_2239|AG
15086325	1198	1208	G6410 by T	DNAMutation	g|G|6410|T
15086325	1250	1260	Gly2079Val	ProteinMutation	p|G|2079|V
15086325	1287	1297	IVS8 -2A>G	DNAMutation	c|A|IVS8-2|G
15086325	1299	1311	2238-9del AG	DNAMutation	c|DEL|2238_2239|AG
15086325	1316	1322	G6410T	DNAMutation	g|G|6410|T

15069170|t|Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.
15069170|a|BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations.
15069170	930	938	c.185C>T	DNAMutation	c|C|185|T
15069170	940	948	Thr60Met	ProteinMutation	p|T|60|M
15069170	951	960	c.1712C>T	DNAMutation	c|C|1712|T
15069170	962	971	Ala569Val	ProteinMutation	p|A|569|V
15069170	974	983	c.1930C>T	DNAMutation	c|C|1930|T
15069170	985	994	Arg642Cys	ProteinMutation	p|R|642|C
15069170	997	1006	c.2552T>A	DNAMutation	c|T|2552|A
15069170	1008	1017	Leu849His	ProteinMutation	p|L|849|H
15069170	1023	1033	c.1932delC	DNAMutation	c|DEL|1932|C
15069170	1155	1161	c.7A>T	DNAMutation	c|A|7|T
15069170	1163	1170	Met1Leu	ProteinMutation	p|M|1|L
15069170	1173	1192	c.1181_1186+20del26	DNAMutation	c|DEL|1181_1186+20|26
15069170	1194	1210	c.1811_1812delAT	DNAMutation	c|DEL|1811_1812|AT
15069170	1215	1225	IVS16+1G>A	DNAMutation	c|G|IVS16+1|A
15069170	1275	1294	c.1181_1186+20del26	DNAMutation	c|DEL|1181_1186+20|26
15069170	1408	1418	IVS16+1G>A	DNAMutation	c|G|IVS16+1|A

15064320|t|Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin.
15064320|a|The goal of this study was to perform 5-alpha-reductase type 2 gene (SRD5A2) analysis in a male pseudohermaphrodite (MPH) patient with normal testosterone (T) production and normal androgen receptor (AR) gene coding sequences. A patient of Chinese origin with ambiguous genitalia at 14 months, a 46,XY karyotype, and normal T secretion under human chorionic gonadotropin (hCG) stimulation underwent a gonadectomy at 20 months. Exons 1-8 of the AR gene and exons 1-5 of the SRD5A2 gene were sequenced from peripheral blood DNA. AR gene coding sequences were normal. SRD5A2 gene analysis revealed 2 consecutive mutations in exon 4, each located in a different allele: 1) a T nucleotide deletion, which predicts a frameshift mutation from codon 219, and 2) a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine (R227Q). Testes located in the inguinal canal showed a normal morphology for age. The patient was a compound heterozygote for SRD5A2 mutations, carrying 2 mutations in exon 4. The patient showed an R227Q mutation that has been described in an Asian population and MPH patients, along with a novel frameshift mutation, Tdel219. Testis morphology showed that, during early infancy, the 5-alpha-reductase enzyme deficiency may not have affected interstitial or tubular development.
15064320	1006	1011	R227Q	ProteinMutation	p|R|227|Q
15064320	1203	1208	R227Q	ProteinMutation	p|R|227|Q
15064320	1323	1330	Tdel219	DNAMutation	|DEL|CODON219|T

15000256|t|Single-strand conformation polymorphism analysis of the FMR1 gene in autistic and mentally retarded children in Japan.
15000256|a|Fragile X syndrome is one of the most common causes of mental retardation in males, and patients with fragile X syndrome occasionally develop autism. It is usually caused by an expansion of the trinucleotide repeat in the 5'-untranslated region of the FMR1 gene, but in a small number of patients deletions and point mutations have been identified. We screened all 17 exons of the FMR1 gene for mutations in 90 autistic or mentally retarded children using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations were found in 76 male patients. However, one female patient was heterozygous for a normal allele and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This mutation was not found in 50 controls. Reverse transcription-PCR revealed that a large proportion of the mutant transcripts were spliced aberrantly, causing premature termination of the protein synthesis. Although uncommon, point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients.

14999772|t|Expression mapping at 12p12-13 in advanced prostate carcinoma.
14999772|a|We have previously mapped a putative prostate cancer tumor-suppressor gene to a 1-2 Mb region of 12p12-13. Initial work to identify the tumor suppressor at this locus focused on candidates previously implicated in malignancy; however, mutational and methylation analyses failed to identify significant genomic events. An alternative approach is to use expression analysis to prioritize the genes within the region of interest. This experimental design is based on the hypothesis that tumor-suppressor genes demonstrate decreased expression in tumors compared to normals. Herein, we narrow the region of interest using deletion mapping data and employ expression analysis to prioritize the genes in the minimal deleted region. Highly informative polymorphic markers spanning our region were used to assess for loss of heterozygosity in 99 tumor and normal DNA pairs. The minimal region of deletion was determined to be approximately 500 kb bounded by D12S391 and A002Q26. Publically available databases place 7 genes within this minimal deletion region. An additional 3 genes lie just outside this minimal deletion region and could possibly be inactivated by deletion of promoter, 3'-untranslated region sequences or alternative splice variants. Relative levels of expression of these 10 candidate genes were determined in 6 normal prostates, 5 local prostate tumors, 9 prostate lymph node metastases, 6 prostate cancer cell lines and 12 prostate cancer xenografts using quantitative RT-PCR. DUSP16, FLJ10298 and BCLG were significantly downregulated in both clinical tumors and cultured prostate cancer tissue, indicating that one or all may be critical to initiation or progression of prostate carcinoma.

14979495|t|The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease.
14979495|a|Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an important role in recognition of, and subsequent immune response activation against, mycobacteria. The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. The aim of the present study was to investigate the Arg753Gln single nucleotide polymorphism of the TLR2 gene in tuberculosis (TB) patients compared to healthy controls. A retrospective case/control study was carried out. The Arg753Gln polymorphism of the TLR2 gene was studied in 151 TB patients compared to 116 ethnically and age-matched healthy control subjects. The TLR2 polymorphism (adenine (A) allele) was observed in 17.9 and 7.7% of TB patients and controls, respectively. When the ratios of the three genotypes were compared between the two groups, the AA genotype was found to be more significantly associated with TB. Allele frequencies for guanine (G) and A were found to be 0.95 and 0.05 in the control group and 0.86 and 0.14 in the TB patient group, respectively. The risk of developing TB disease was increased 6.04- and 1.60-fold for carriers of the AA and GA genotypes, respectively. In conclusion, the present data suggest that the arginine to glutamine substitution at residue 753 polymorphism of the Toll-like receptor 2 gene influences the risk of developing tuberculosis.
14979495	4	13	Arg753GLn	ProteinMutation	p|R|753|Q
14979495	356	365	Arg753Gln	ProteinMutation	p|R|753|Q
14979495	556	565	Arg753Gln	ProteinMutation	p|R|753|Q
14979495	730	739	Arg753Gln	ProteinMutation	p|R|753|Q

14978789|t|Homozygous deletions within the 11q13 cervical cancer tumor-suppressor locus in radiation-induced, neoplastically transformed human hybrid cells.
14978789|a|Studies on nontumorigenic and tumorigenic human cell hybrids derived from the fusion of HeLa (a cervical cancer cell line) with GM00077 (a normal skin fibroblast cell line) have demonstrated "functional" tumor-suppressor activity on chromosome 11. It has been shown that several of the neoplastically transformed radiation-induced hybrid cells called GIMs (gamma ray induced mutants), isolated from the nontumorigenic CGL1 cells, have lost one copy of the fibroblast chromosome 11. We hypothesized, therefore, that the remaining copy of the gene might be mutated in the cytogenetically intact copy of fibroblast chromosome 11. Because a cervical cancer tumor suppressor locus has been localized to chromosome band 11q13, we performed deletion-mapping analysis of eight different GIMs using a total of 32 different polymorphic and microsatellite markers on the long arm (q arm) of chromosome 11. Four irradiated, nontumorigenic hybrid cell lines, called CONs, were also analyzed. Allelic deletion was ascertained by the loss of a fibroblast allele in the hybrid cell lines. The analysis confirmed the loss of a fibroblast chromosome 11 in five of the GIMs. Further, homozygous deletion (complete loss) of chromosome band 11q13 band sequences, including that of D11S913, was observed in two of the GIMs. Detailed mapping with genomic sequences localized the homozygous deletion to a 5.7-kb interval between EST AW167735 and EST F05086. Southern blot hybridization using genomic DNA probes from the D11S913 locus confirmed the existence of homozygous deletion in the two GIM cell lines. Additionally, PCR analysis showed a reduction in signal intensity for a marker mapped 31 kb centromeric of D11S913 in four other GIMs. Finally, Northern blot hybridization with the genomic probes revealed the presence of a novel >15-kb transcript in six of the GIMs. These transcripts were not observed in the nontumorigenic hybrid cell lines. Because the chromosome 11q13 band deletions in the tumorigenic hybrid cell lines overlapped with the minimal deletion in cervical cancer, the data suggest that the same gene may be involved in the development of cervical cancer and in radiation-induced carcinogenesis. We propose that a gene localized in proximity to the homozygous deletion is the candidate tumor-suppressor gene.

14742428|t|Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients: a proposed mechanism for the thiamin-responsive phenotype.
14742428|a|Maple syrup urine disease (MSUD) results from mutations affecting different subunits of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex. In this study, we identified seven novel mutations in MSUD patients from Israel. These include C219W-alpha (TGC to TGG) in the E1alpha subunit; H156Y-beta (CAT to TAT), V69G-beta (GTT to GGT), IVS 9 del[-7:-4], and 1109 ins 8bp (exon 10) in the E1beta subunit; and H391R (CAC to CGC) and S133stop (TCA to TGA) affecting the E2 subunit of the branched-chain alpha-ketoacid dehydrogenase complex. Recombinant E1 proteins carrying the C219W-alpha or H156Y-beta mutation show no catalytic activity with defective subunit assembly and reduced binding affinity for cofactor thiamin diphosphate. The mutant E1 harboring the V69G-beta substitution cannot be expressed, suggesting aberrant folding caused by this mutation. These E1 mutations are ubiquitously associated with the classic phenotype in homozygous-affected patients. The H391R substitution in the E2 subunit abolishes the key catalytic residue that functions as a general base in the acyltransfer reaction, resulting in a completely inactive E2 component. However, wild-type E1 activity is enhanced by E1 binding to this full-length mutant E2 in vitro. We propose that the augmented E1 activity is responsible for robust thiamin responsiveness in homozygous patients carrying the H391R E2 mutation and that the presence of a full-length mutant E2 is diagnostic of this MSUD phenotype. The present results offer a structural and biochemical basis for these novel mutations and will facilitate DNA-based diagnosis for MSUD in the Israeli population.
14742428	424	429	C219W	ProteinMutation	p|C|219|W
14742428	473	478	H156Y	ProteinMutation	p|H|156|Y
14742428	498	502	V69G	ProteinMutation	p|V|69|G
14742428	522	538	IVS 9 del[-7:-4]	DNAMutation	c|DEL|IVS9-7_-4|
14742428	544	556	1109 ins 8bp	DNAMutation	c|INS|1109|8
14742428	594	599	H391R	ProteinMutation	p|H|391|R
14742428	617	625	S133stop	ProteinMutation	p|S|133|X
14742428	761	766	C219W	ProteinMutation	p|C|219|W
14742428	776	781	H156Y	ProteinMutation	p|H|156|Y
14742428	946	950	V69G	ProteinMutation	p|V|69|G
14742428	1154	1159	H391R	ProteinMutation	p|H|391|R
14742428	1563	1568	H391R	ProteinMutation	p|H|391|R

14673473|t|Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden.
14673473|a|Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T(4)) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5'- and 3'-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population.
14673473	153	157	V30M	ProteinMutation	p|V|30|M
14673473	761	769	Val30Met	ProteinMutation	p|V|30|M
14673473	981	985	V30M	ProteinMutation	p|V|30|M
14673473	1228	1232	V30M	ProteinMutation	p|V|30|M
14673473	1597	1601	V30M	ProteinMutation	p|V|30|M

14623461|t|Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.
14623461|a|Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3 approximately q43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (MSI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted.

14587045|t|Beta-thalassemia in association with a new delta-chain hemoglobin variant [delta116(g18)Arg-->Leu]: implications for carrier screening and prenatal diagnosis.
14587045|a|We describe a complicated genetic counseling and prenatal diagnostic case involving an East Indian couple that had lost two consecutive pregnancies. Hemoglobinopathy screening was conducted to investigate the possibility of Hb Bart's hydrops fetalis or Hb H hydrops fetalis. The initial work-up indicated that alpha-thalassemia was not a contributing factor, with both parents being carriers of single gene deletions (-alpha(3.7)/alphaalpha). However, the Hb electrophoresis results indicated that the couple might be at risk for having children with Hb E/Hb Lepore disease. Subsequent DNA testing demonstrated that the father carried the Hb E mutation, but failed to confirm that the mother carries the Hb Lepore deletion. Sequence analysis revealed that the mother was heterozygous for a common East Indian beta(0)-thalassemia mutation, yet had a normal level of Hb A(2). The mother also carried a previously unreported missense mutation of the delta-globin gene, in cis with the beta(0)-thalassemia mutation, which gave rise to the minor Hb variant originally misidentified as Hb Lepore. This case illustrates the importance of comprehensive molecular analyses for accurate assessment of genetic risks for hemoglobinopathy syndromes.
14587045	88	97	Arg-->Leu	ProteinMutation	p|R||L

14576201|t|Novel polypyrimidine variation (IVS46: del T -39...-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease.
14576201|a|Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.
14576201	32	54	IVS46: del T -39...-46	DNAMutation	c|DEL|IVS46(-39_-46)|T
14576201	594	600	G5947A	DNAMutation	g|G|5947|A
14576201	615	621	R1851Q	ProteinMutation	p|R|1851|Q
14576201	878	900	IVS46: del T -39...-46	DNAMutation	c|DEL|IVS46(-39_-46)|T
14576201	1367	1373	R1851Q	ProteinMutation	p|R|1851|Q
14576201	1415	1437	IVS46: del T -39...-46	DNAMutation	c|DEL|IVS46(-39_-46)|T

14533983|t|Frequency of polymorphisms of genes coding for HIV-1 co-receptors CCR5 and CCR2 in a Brazilian population.
14533983|a|Entry of human immunodeficiency type 1 virus (HIV-1) into target cells requires both CD(4)and one of the chemokine receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 and CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. A 32-nucleotide deletion (D32) within the b-chemokine receptor 5 gene (CCR5) has been described in subjects who remain uninfected despite extensive exposition to HIV-1. The heterozygous genotype delays disease progression. This allele is common among Caucasians, but has not been found in people of African or Asian ancestry. A more common transition involving a valine to isoleucine switch in transmembrane domain I of CCR2B (64I), with unknown functional consequences, was found to delay disease progression but not to reduce infection risk. As the Brazilian population consists of a mixture of several ethnic groups, we decided to examine the genotype frequency of these polymorphisms in this country. There were 11.5% CCR5 heterozygotes among the HIV-1 infected population and 12.5% among uninfected individuals, similar to data from North America and Western Europe. The prevalence of CCR2-64I homozygotes and heterozygotes was 0.06 and 15.2%, respectively, also similar to what is known for North America and Western Europe.

14510916|t|Progressive decline of vasopressin secretion in familial autosomal dominant neurohypophyseal diabetes insipidus presenting a novel mutation in the vasopressin-neurophysin II gene.
14510916|a|OBJECTIVE: Familial autosomal dominant neurohypophyseal diabetes insipidus (FNDI) is a rare form of central diabetes insipidus (DI), which is caused by mutations in the vasopressin-neurophysin II (AVP-NPII) gene. The present study evaluated the AVP secretion over time and analysed the structure of the AVP-NPII gene in a Brazilian family with FNDI. SUBJECTS AND DESIGN: Four affected members and one nonaffected member from one Brazilian family with FNDI were studied. The diagnosis of central DI was established by fluid deprivation test and hypertonic saline infusion. Two affected members were assessed twice within a 6-year interval. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction. RESULTS: The functional assessment of patients with FNDI over time confirmed a progressive loss in AVP secretion. Two patients were first diagnosed as partial central DI and, several years later, they developed severe central DI. Sequencing analysis revealed a heterozygous new point mutation in the nucleotide 1892 in the coding sequence for neurophysin-II of the AVP-NPII gene (1892G>C) predicting an amino acid substitution (A68P) in all affected members. CONCLUSION: Our data demonstrate a gradual vasopressinergic deficiency due to a novel mutation in the AVP-NPII gene in a Brazilian family with FNDI. The accumulation of A68P mutated precursor might have a cytotoxicity effect, leading to a gradual death of magnocellular neurones, and a progressive decline in AVP secretion.
14510916	1315	1322	1892G>C	DNAMutation	c|G|1892|C
14510916	1363	1367	A68P	ProteinMutation	p|A|68|P
14510916	1563	1567	A68P	ProteinMutation	p|A|68|P

14510914|t|Congenital hypothyroidism due to a new deletion in the sodium/iodide symporter protein.
14510914|a|OBJECTIVE: Iodide transport defect (ITD) is a rare disorder characterised by an inability of the thyroid to maintain an iodide gradient across the basolateral membrane of thyroid follicular cells, that often results in congenital hypothyroidism. When present the defect is also found in the salivary glands and gastric mucosa and it has been shown to arise from abnormalities of the sodium/iodide symporter (NIS). PATIENT: We describe a woman with hypothyroidism identified at the 3rd month of life. The diagnosis of ITD was suspected because of nodular goitre, and little if any iodide uptake by the thyroid and salivary glands. Treatment with iodide partially corrected the hypothyroidism; however, long-term substitution therapy with L-thyroxine was started. MEASUREMENTS: Thyroid radioiodide uptake was only 1.4% and 0.3% at 1 and 24 h after the administration of recombinant human TSH. The saliva to plasma I- ratio was 1.1 indicating that the inability of the thyroid gland to concentrate I- was also present in the salivary glands. RESULTS: Analysis of the patient's NIS gene revealed a 15 nucleotide (nt) deletion of the coding sequence (nt 1314 through nt 1328) and the insertion of 15 nt duplicating the first 15 nt of the adjacent intron. The patient was homozygous for this insertion/deletion, while both consanguineous parents were heterozygous. This deletion predicts the production of a protein lacking the five terminal amino acids of exon XI (439-443) which are located in the 6th intracellular loop. COS-7 cells transfected with a vector expressing the mutant del-(439-443) NIS failed to concentrate iodide, suggesting that the mutation was the direct cause of the ITD in this patient. CONCLUSION: In conclusion we describe the first Italian case of congenital hypothyroidism due to a new deletion in the NIS gene.
14510914	1666	1679	del-(439-443)	DNAMutation	c|DEL|-443_-439|

12968672|t|Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly.
12968672|a|A Cdx-2 binding site polymorphism (G to A) in the promoter region of the human vitamin D receptor gene was reported. In an ecological study in eight ethnic groups and an association study in 2848 elderly whites, we found the A-allele to be associated with decreased fracture risk. Our findings expand previous similar findings in a Japanese study to whites and show a relationship with fracture risk of this functional polymorphism. INTRODUCTION: A single nucleotide polymorphism (SNP) within a binding site of the intestinal-specific transcription factor Cdx-2 in the promoter region of the human vitamin D receptor (VDR) gene was previously reported. It was found to modulate the transcription of the hVDR gene and to be associated with decreased bone mineral density in a small group of postmenopausal Japanese women. In this study, we investigated the relationship between the VDR Cdx-2 genotype and risk of fracture. METHODS: We first determined the location of this SNP in the VDR gene by sequencing analysis, and we developed an allele-specific multiplex polymerase chain reaction test to determine the Cdx-2 genotype. We then performed an ecological study in eight ethnic groups and an association analysis in a large epidemiological cohort of 2848 Dutch white men and women, > or = 55 years old. RESULTS AND CONCLUSIONS: The location of the G to A substitution was found in the promoter region of exon le (le-G-1739A) of the VDR gene. By comparing the frequency of the A-allele in eight different ethnic groups, we observed a negative correlation between prevalence of the A-allele and published hip fracture incidence rates in these ethnic groups (p = 0.006 for men and p = 0.02 for women), suggesting a protective effect of this allele on fracture risk. Subsequently, in the association study, the A-allele (population frequency 19%) was observed to have a protective effect on occurrence of osteoporotic fractures, especially for nonvertebral fracture in women (relative risk of AA versus GG genotype is 0.2; 95% CI, 0.05-0.8). This effect remained after adjustment for age, weight, and bone mineral density. We conclude that the A-allele of the VDR Cdx-2 polymorphism is present in whites, albeit at low frequency, and show a protective effect of this allele on risk of fracture.

12925722|t|A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia.
12925722|a|BACKGROUND: Spondyloepimetaphyseal dysplasia (SEMD) is one of a clinically heterogeneous group of skeletal disorders, characterized by defective growth and modelling of the spine and long bones. Common clinical features include disproportionate short stature, malformed vertebrae and abnormal epiphyses or metaphyses. Some cases have been associated with mutations in the COL2A1 gene. AIM: To determine whether the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis, might be caused by a novel COL2A1 mutation. DESIGN: Genetic testing and clinical examination of family members. METHODS: Direct sequencing of PCR-amplified genomic DNA from the COL2A1 gene. RESULTS: A point mutation within exon 20 of the COL2A1 gene was identified that substituted a glycine for an aspartic acid residue at codon 262. DISCUSSION: All previously reported autosomal dominant mutations causing SEMD have substituted an obligate glycine within the triple helix, in particular at codons 292, 304 and 709 in the three reported Strudwick-type patients. Additionally, a recurrent glycine substitution at codon 154 has been identified in two unrelated Finnish cases with radiological features consistent with the Strudwick subtype. Our sixth helical glycine substitution extends the mutational spectrum and genotype/phenotype correlations of Strudwick-type SEMD.

12898858|t|Genetic polymorphisms of renin-angiotensin system and progression of interstitial nephritis.
12898858|a|Genes of the renin-angiotensin system (RAS) are involved in the progression of renal failure. Among them, the angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) genes are of particular interest. We examined polymorphisms of these three genes for association with the development of interstitial nephritis and progression to end-stage renal failure. The allele frequency and genotype distribution were compared in 90 patients with interstitial nephritis and 200 healthy controls. DNA samples were genotyped by polymerase chain reaction (PCR). We did not find statistically significant differences between groups in the insertion/deletion polymorphism of the ACE gene. An involvement of M235T polymorphism of the AGT gene in renal disease was observed in our study. The frequency of the T allele was higher in patients than in controls (32% vs. 24%). In the A1166C AT1R polymorphism the homozygous CC genotype was also more frequent in interstitial nephritis patients (7% vs. 3.5%). In patients carrying the C allele, an average time to ESRD was significantly shorter than in subjects with the AA genotype. Our study shows the association of the AGT and AT1R gene polymorphisms with the development and progression of interstitial nephritis. The C allele of the A1166C polymorphism appears to be a risk factor for faster disease progression.
12898858	828	833	M235T	ProteinMutation	p|M|235|T
12898858	999	1005	A1166C	DNAMutation	|A|1166|C
12898858	1403	1409	A1166C	DNAMutation	|A|1166|C

12832681|t|Epidemiology of tuberculosis on Gran Canaria: a 4 year population study using traditional and molecular approaches.
12832681|a|BACKGROUND: In recent years several population based studies using restriction fragment length polymorphism (RFLP) analysis have shown a higher rate of recent transmission of tuberculosis than previously thought. This study was undertaken to determine the transmission patterns of tuberculosis and the potential causes of recent transmission on the island of Gran Canaria (Spain). METHODS: The strains of all patients diagnosed with tuberculosis confirmed by culture between 1 January 1993 and 31 December 1996 were typed by RFLP using the insertion sequence IS6110. A cluster was defined as two or more isolates with an identical RFLP pattern. Epidemiological linkage through contact tracing was investigated. RESULTS: Of the total of 719 patients, 153 (21.3%) were excluded because there was inadequate bacterial DNA for genotyping (n=129) or the isolates of Mycobacterium tuberculosis had less than five copies of IS6110 (n=24). The isolates from 409 patients (72.3%) were grouped into 78 different clusters with an estimated 58.5% of the cases being due to recent transmission. Young age was the only significant predictor of clustering. Only in 147 (35.9%) of the 409 patients belonging to a cluster could an epidemiological link be found. 111 patients (19.6%) were identified as having had previous contact with a tuberculosis patient and 81 of them (72.9%) belonged to a cluster. The three largest clusters included 75, 49 and 20 patients, respectively. CONCLUSION: Recent transmission is frequent among patients with tuberculosis on Gran Canaria and could be associated with certain aspects of control measures. Some of the clusters described in the study could be due to the prevalence of particular strains of M tuberculosis on the island.

12809638|t|Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missense mutation (C488R) and an MLD mutation (R84Q) in cis with a pseudodeficiency allele.
12809638|a|We describe three novel mutations in the human arylsulfatase A gene in three patients with MLD, an autosomal recessive lysosomal storage disorder. An insertion, 2590_2591insCCCC in exon 8 and a deletion, 752_758delGCCGGCC, in exon 3 will both result in frameshifts. A mutation in exon 8, 2566T-->C, results in a missense mutation C488R, disrupting an unusual cysteine-knot at the C-terminal end of the protein. All three mutations are heterozygous with previously documented mutations. A previously reported mutation, R84Q was identified on a pseudodeficiency allele. These mutations are part of a heterogeneous spectrum of mutations found in a collection of DNA samples from MLD patients from across Canada and the USA.
12809638	146	151	C488R	ProteinMutation	p|C|488|R
12809638	174	178	R84Q	ProteinMutation	p|R|84|Q
12809638	380	396	2590_2591insCCCC	DNAMutation	|INS|2590_2591|CCCC
12809638	423	440	752_758delGCCGGCC	DNAMutation	|DEL|752_758|GCCGGCC
12809638	507	516	2566T-->C	DNAMutation	|T|2566|C
12809638	549	554	C488R	ProteinMutation	p|C|488|R
12809638	737	741	R84Q	ProteinMutation	p|R|84|Q

12752111|t|The molecular basis for the thalassaemias in Sri Lanka.
12752111|a|The beta-globin gene mutations and the alpha-globin genes of 620 patients with the phenotype of severe to moderate thalassaemia from seven centres in Sri Lanka were analysed. Twenty-four beta-globin gene mutations were identified, three accounting for 84.5% of the 1240 alleles studied: IVSI-5 (G-->C) 56.2%; IVSI-1 (G-->A) 15.2%; and haemoglobin E (codon (CD)26 GAG-->GAA) 13.1%. Three new mutations were found; a 13-bp deletion removing the last nucleotide in CD6 to CD10 inclusively, IVSI-129 (A-->C) in the consensus splice site, and a frame shift, CD55 (-A). The allele frequency of alpha+ thalassaemia was 6.5% and 1.1% for -alpha3.7 and -alpha4.2 deletions respectively. Non-deletion alpha-thalassaemia was not observed. Triplicate or quadruplicate alpha-globin genes were unusually common. In 1.5% of cases it was impossible to identify beta-thalassaemia alleles, but in Kurunegala detailed family studies led to an explanation for the severe thalassaemia phenotype in every case, including a previously unreported instance of homozygosity for a quadruplicated alpha-globin gene together with beta-thalassaemia trait. These findings have implications for the control of thalassaemia in high-frequency populations with complex ethnic histories.
12752111	343	357	IVSI-5 (G-->C)	DNAMutation	c|G|IVSI-5|C
12752111	365	379	IVSI-1 (G-->A)	DNAMutation	c|G|IVSI-1|A
12752111	406	428	codon (CD)26 GAG-->GAA	DNAMutation	|GAG|CODON26|GAA
12752111	543	559	IVSI-129 (A-->C)	DNAMutation	c|A|IVSI-129|C

12750403|t|Pacemaker channel dysfunction in a patient with sinus node disease.
12750403|a|The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.
12750403	440	448	1631delC	DNAMutation	|DEL|1631|C

12736721|t|Genetic changes and expression of the mannose 6-phosphate/insulin-like growth factor II receptor gene in human hepatitis B virus-associated hepatocellular carcinoma.
12736721|a|It was reported that 60-70% of hepatitis B virus (HBV)-negative hepatocellular carcinoma (HCC) had loss of heterozygosity (LOH) at the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) locus and this gene was mutated in 55% of these patients with LOH. In this study, genomic DNA from 29 pairs of HBV-positive HCC and corresponding non-tumor tissues was used to analyze LOH at the M6P/IGF2R locus and single deoxyguanosine deletion in this gene by PCR. Total RNA from 19 of the 29 patients was utilized to determine a 192 bp insert in the M6P/IGF2R mRNA and expression of this gene by RT-PCR. Twenty-eight of 29 (97%) HBV-positive HCC were found to be informative at the M6P/IGF2R locus but LOH at this region was only detected in 4/28 (14%) informative patients. Neither single deoxyguanosine deletion in this gene nor 192 bp insert in its mRNA occurred in these patients. Compared with corresponding non-tumor tissues, expression of the M6P/IGF2R mRNA was decreased in 13/19 (68%) HBV-positive HCC tissues, suggesting that M6P/IGF2R may be involved in HBV-associated hepatocarcinogenesis by the regulation of its expression level. In the development of HBV-associated HCC, M6P/IGF2R mutation may not be a major agent.

12729343|t|NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy.
12729343|a|SETTING: Nrampl encoded by the NRAMP1 gene influences the phagolysosomal function of alveolar macrophage against Mycobacterium tuberculosis. Genetic polymorphisms of NRAMP1 affect innate host resistance through the defective production and function of Nrampl. OBJECTIVE: To investigate this relationship, the NRAMP1 polymorphisms in patients with tuberculous pleurisy were determined. DESIGN: Pleural biopsy proven 56 patients were designated to the pleurisy group and 45 healthy adults were designated to the healthy control group. Three NRAMP1 polymorphisms such as single nucleotide change in intron 4(469 + 14G/C, INT4), a non-conservative single-base substitution at codon 543(D543N) and TGTG deletion in the 3' untranslated region (1729 + 55del4, 3'UTR) were determined. RESULTS: The frequencies of mutant genotypes of INT4 and 3'UTR were significantly high in the pleurisy group (P = 0.01, P = 0.02), but the frequencies of D543N were not significantly different between the two groups. Odds ratios (OR), which are a comparison of the wild with the mutant genotype, were 8.02 (95%CI 2.42 approximately 26.57) for INT4 and 5.73 (95%CI 1.14 approximately 28.92) for 3'UTR which were statistically significant. In the combined analysis of the INT4 and 3'UTR, the ORs were 6.00 (95%CI 1.46 approximately 24.64) for GC/++ genotype and 14.00 (95%CI 1.61 approximately 121.75) for GC/+del when compared with GG/++; these differences were statistically significant. CONCLUSION: The NRAMP1 genetic polymorphisms, especially INT4 and 3'UTR, were closely related to tuberculous pleurisy.
12729343	676	687	469 + 14G/C	DNAMutation	c|G|469+14|C
12729343	753	758	D543N	ProteinMutation	p|D|543|N
12729343	809	822	1729 + 55del4	DNAMutation	c|DEL|1729+55_1729+59|4
12729343	1002	1007	D543N	ProteinMutation	p|D|543|N

12719097|t|A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness.
12719097|a|PURPOSE: To describe a French family with the incomplete type of X-linked congenital stationary night blindness (CSNB2) associated with a novel mutation in the retina-specific calcium channel alpha(1) subunit gene (CACNA1F). DESIGN: Interventional case report. METHODS: Two family members with a history of nonprogressive night blindness and subnormal visual acuity were clinically examined and the genotype determined by molecular genetic analysis. RESULT: Both patients had clinical manifestations characteristic of CSNB2. Electrophysiologically, we found a predominant reduction of the ERG B-wave in the maximal response. Both rod and cone function were subnormal, with the latter tending to be more attenuated. We identified a C deletion at nucleotide position 4548, resulting in a frameshift with a predicted premature termination at codon 1524. CONCLUSIONS: The clinical and genetic study of a novel mutation in the CACNA1F gene adds further support to the contention that CSNB2 represents a genetically distinct retinal disorder of a calcium channel.

12673366|t|Analysis of the G/C polymorphism in the 5'-untranslated region of the RAD51 gene in breast cancer.
12673366|a|The breast cancer suppressor proteins BRCA1 and BRCA2 interact with RAD51, a protein essential for maintaining genomic stability by playing a central role in homology-dependent recombinational repair of the DNA double-strand breaks. Therefore, genetic variability in the RAD51 gene may contribute to the appearance and/or progression of breast cancer. A single nucleotide polymorphism in the 5'- untranslated region of RAD51 (a G to C substitution at position 135, the G/C polymorphism) is reported to modulate breast cancer risk. We investigated the distribution of genotypes and frequency of alleles of the G/C polymorphism in breast cancer. Tumor tissues were obtained from postmenopausal women with node-negative and node-positive breast carcinoma with uniform tumor size. Blood samples from age matched healthy women served as control. The G/C polymorphism was determined by PCR-based MvaI restriction fragment length polymorphism. The distribution of the genotypes of the G/C polymorphism did not differ significantly (P > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no differences in the genotype distribution and allele frequencies between node-positive and node-negative patients. There were no significant differences between distributions of the genotypes in subgroups assigned to histological grades according to Scarf-Bloom-Richardson criteria and the distribution predicted by Hardy-Weinberg equilibrium (P > 0.05). Our study implies that the G/C polymorphism of the RAD51 gene may not be directly involved in the development and/or progression of breast cancer and so it may not be useful as an independent marker in this disease.
12673366	16	19	G/C	DNAMutation	|G||C
12673366	568	571	G/C	DNAMutation	|G||C
12673366	708	711	G/C	DNAMutation	|G||C
12673366	944	947	G/C	DNAMutation	|G||C
12673366	1077	1080	G/C	DNAMutation	|G||C
12673366	1586	1589	G/C	DNAMutation	|G||C

12672033|t|Mutation analysis of DMBT1 in glioblastoma, medulloblastoma and oligodendroglial tumors.
12672033|a|DMBT1 has been implicated as a candidate tumor suppressor gene on chromosome 10q for brain, gastrointestinal and lung cancer. Homozygous deletion and lack of expression are 2 known mechanisms for inactivating DMBT1. We evaluated whether somatic mutation, which represents a major inactivation mechanism for most tumor suppressor genes, occurs in the DMBT1 gene. A total of 102 primary brain tumors, consisting of 25 glioblastoma multiforme, 24 medulloblastoma and 53 oligodendroglial tumors, were analyzed by conformation-sensitive gel electrophoresis in all 54 coding exons of DMBT1. Twelve different base substitutions were detected in 26 (25%) tumors. Eight base substitutions resulted in amino acid changes and 4 were silent. These base changes were also detected in tumor-matched blood samples, however, indicating that the base variations represent genetic polymorphisms. We also assessed homozygous deletions of the DMBT1 gene in the series and found that 16 of 95 (5 glioblastomas, 5 medulloblastomas, 6 oligodendroglial tumors; total 17%) tumors harbor such alteration. High-quality blood DNA samples were available in 5 tumors carrying homozygous deletion and, using long-range PCR, 3 of these blood samples showed germline hemizygous deletions in a region between introns 10 and 26 of DMBT1. Our results showed that mutation does not play a role in inactivation of DMBT1 in brain tumors. Intragenic homozygous deletion of DMBT1 is common in brain tumors and is likely a result of a germline deletion of 1 allele followed by loss of the second allele during tumor development.

12668354|t|Relation of shyness in grade school children to the genotype for the long form of the serotonin transporter promoter region polymorphism.
12668354|a|OBJECTIVE: Studies have shown that genetic factors are significant in predisposing individuals to shyness and social phobia. Toward further elucidating the genetic structure of shyness, the authors examined four functional polymorphisms that make biological sense for contributing to the development of this phenotype: serotonin transporter promoter region 44 base pair insertion/deletion (5-HTTLPR), dopamine D(4) receptor exon III repeat (DRD4), catechol O-methyltransferase (COMT), and monoamine oxidase A promoter region repeat (MAO(A)). METHOD: The authors assessed shyness after recruitment of a nonclinical sample (N=118, unscreened second-grade children) using a composite scale derived from questionnaires administered to the children, parents, and teachers. DNA from buccal smears successfully obtained from 98 children was genotyped by polymerase chain reaction methods for the 5-HTTLPR, DRD4, COMT, and MAO(A) polymorphisms. RESULTS: Significant correlations were observed for parents', teachers', and children's ratings of shyness, and Cronbach's alpha reliability was high for all three scales. A significant association was observed between the long 5-HTTLPR polymorphism and shyness, both by the functional classification of Lesch as well as by consideration of all three genotypes. No significant association was observed for the DRD4, COMT, or MAO(A) polymorphisms. CONCLUSIONS: This study provisionally identifies a common genetic polymorphism, 5-HTTLPR, that modestly (effect size=7%) contributed to greater shyness scores in a nonclinical group of second-grade students. These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism.

12653841|t|Restricted genetic defects underlie human complement C6 deficiency.
12653841|a|Complement C6 homozygous deficiency (C6D) has been rarely observed in Caucasians but was reported at higher prevalence among African-Americans. We report on the molecular basis of C6D in seven unrelated black individuals of North or Central Africa descent who live in France. These patients have presented Neisseria meningitidis infection (four cases), focal and segmental glomerulosclerosis with hyalinosis (one case), systemic lupus erythematosus (one case) or Still's disease (one case). All patients exhibited undetectable antigenic C6 by using a sensitive ELISA assay. An additional four cases of complete C6 deficiency with no associated disease have been characterized after family studies. Exons 6, 7 and 12 have been described recently as the location of molecular defects on the C6 gene in randomly chosen black Americans. Genomic DNA from the seven patients were subjected to direct polymerase chain reaction amplification of these three exons. Nucleotide sequencing analysis of the amplified DNA fragments revealed a homozygous single-base deletion (1936delG) in exon 12 in three cases and four compound heterozygous deletions for a single base in exon 7 (1195delC) or in exon 6 (878delA) associated with the same deletion in exon 12 (1936delG). Our observations further establish the restricted pattern of genetic defects associated with homozygous C6 complement deficiency in individuals of African descent.
12653841	1130	1138	1936delG	DNAMutation	|DEL|1936|G
12653841	1236	1244	1195delC	DNAMutation	|DEL|1195|C
12653841	1260	1267	878delA	DNAMutation	|DEL|878|A
12653841	1315	1323	1936delG	DNAMutation	|DEL|1936|G

