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[ { "id": "6", "type": "title", "text": [ "Variation in the CXCR1 gene (IL8RA) is not associated with susceptibility to chronic periodontitis." ], "offsets": [ [ 0, 99 ] ] }, { "id": "7", "type": "abstract", "text": [ "BACKGROUND: The chemokine receptor 1 CXCR-1 (or IL8R-alpha) is a specific receptor for the interleukin 8 (IL-8), which is chemoattractant for neutrophils and has an important role in the inflammatory response. The polymorphism rs2234671 at position Ex2+860G>C of the CXCR1 gene causes a conservative amino acid substitution (S276T). This single nucleotide polymorphism (SNP) seemed to be functional as it was associated with decreased lung cancer risk. Previous studies of our group found association of haplotypes in the IL8 and in the CXCR2 genes with the multifactorial disease chronic periodontitis. In this study we investigated the polymorphism rs2234671 in 395 Brazilian subjects with and without chronic periodontitis. FINDINGS: Similar distribution of the allelic and genotypic frequencies were observed between the groups (p>0.05). CONCLUSIONS: The polymorphism rs2234671 in the CXCR1 gene was not associated with the susceptibility to chronic periodontitis in the studied Brazilian population." ], "offsets": [ [ 100, 1104 ] ] } ]

[ { "id": "1", "type": "SNP", "text": [ "rs2234671" ], "offsets": [ [ 327, 336 ] ], "normalized": [] }, { "id": "2", "type": "DNAMutation", "text": [ "Ex2+860G>C" ], "offsets": [ [ 349, 359 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2234671" } ] }, { "id": "3", "type": "ProteinMutation", "text": [ "S276T" ], "offsets": [ [ 425, 430 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2234671" } ] }, { "id": "4", "type": "SNP", "text": [ "rs2234671" ], "offsets": [ [ 751, 760 ] ], "normalized": [] }, { "id": "5", "type": "SNP", "text": [ "rs2234671" ], "offsets": [ [ 972, 981 ] ], "normalized": [] } ]

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[ { "id": "12", "type": "title", "text": [ "A case of Werner syndrome without metabolic abnormality: implications for the early pathophysiology." ], "offsets": [ [ 0, 100 ] ] }, { "id": "13", "type": "abstract", "text": [ "Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN DNA helicase. It is characterized by the graying and loss of hair, juvenile cataracts, sclerosis and ulceration of skin, insulin-resistant diabetes mellitus, dyslipidemia, abdominal adiposity, osteoporosis, atherosclerosis, and malignant neoplasm. Patients are usually diagnosed in their 30s or 40s, but the early pathophysiology of the syndrome is still not fully understood. Here we report a 29-year-old female patient who displayed cataracts, hair graying, and tendinous calcinosis. Her parents were first cousins. Interestingly, the patient lacked the metabolic signs typical for WS, including glucose intolerance, dyslipidemia, and visceral fat accumulation. A hyperinsulinemic response at 30 min was observed in an oral glucose tolerance test. Mutational analysis for the WRN gene revealed a homozygous nucleotide substitution 3190C>T in exon 24, resulting in a protein product with replacement of an arginine residue at position 573 by termination codon (Arg987Ter). The mutated WRN protein was unable to translocate into the nucleus in an in vitro cell assay. A WS patient with an Arg987Ter mutation has been previously reported in Switzerland, the present case is the first to be identified in Asia. This case demonstrates the early clinical features of WS and suggests that metabolic abnormality, including insulin resistance, is not an essential component of WS at disease onset. Moreover, a follow-up study of such case would be useful to understand how the various clinical symptoms in WS develop and progress over the years." ], "offsets": [ [ 101, 1736 ] ] } ]

[ { "id": "9", "type": "DNAMutation", "text": [ "3190C>T" ], "offsets": [ [ 1031, 1038 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "747319628" } ] }, { "id": "10", "type": "ProteinMutation", "text": [ "Arg987Ter" ], "offsets": [ [ 1160, 1169 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "747319628" } ] }, { "id": "11", "type": "ProteinMutation", "text": [ "Arg987Ter" ], "offsets": [ [ 1287, 1296 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "747319628" } ] } ]

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[ { "id": "16", "type": "title", "text": [ "A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome." ], "offsets": [ [ 0, 147 ] ] }, { "id": "17", "type": "abstract", "text": [ "BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome." ], "offsets": [ [ 148, 1949 ] ] } ]

[ { "id": "15", "type": "ProteinMutation", "text": [ "p.Asp50Asn" ], "offsets": [ [ 374, 384 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931594" } ] } ]

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[ { "id": "22", "type": "title", "text": [ "Familial pycnodysostosis: identification of a novel mutation in the CTSK gene (cathepsin K)." ], "offsets": [ [ 0, 92 ] ] }, { "id": "23", "type": "abstract", "text": [ "BACKGROUND: Pycnodysostosis, an autosomal recessive skeletal dysplasia, is characterized by short stature, osteosclerosis, delayed cranial suture closure, hypoplastic mandible, acro-osteolysis, hypoplastic clavicle, and dental anomalies. The disorder is caused by CTSK gene defects, a gene localized on 1q21. PURPOSE: To describe the clinical, radiological, and molecular findings in a family with pycnodysostosis. METHODS: The CTSK gene was analyzed from genomic DNA in a nonconsanguinity Mexican family with 3 affected members with pycnodysostosis and 100 healthy controls. RESULTS AND INTERPRETATION: We identified the novel homozygous mutation c.908G>A within exon 8 of the CTSK gene. This missense mutation leads to the substitution of the amino acid glycine at position 303 by glutamic acid (G303E) in cathepsin K protease. No genotype/phenotype correlation was present in affected members of the family with pycnodysostosis." ], "offsets": [ [ 93, 1024 ] ] } ]

[ { "id": "19", "type": "DNAMutation", "text": [ "c.908G>A" ], "offsets": [ [ 741, 749 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "756250449" } ] }, { "id": "20", "type": "ProteinMutation", "text": [ "glycine at position 303 by glutamic acid" ], "offsets": [ [ 849, 889 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "756250449" } ] }, { "id": "21", "type": "ProteinMutation", "text": [ "G303E" ], "offsets": [ [ 891, 896 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "756250449" } ] } ]

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[ { "id": "29", "type": "title", "text": [ "Association study of polymorphisms in the promoter region of DRD4 with schizophrenia, depression, and heroin addiction." ], "offsets": [ [ 0, 119 ] ] }, { "id": "30", "type": "abstract", "text": [ "This study investigated the possible association between three functional polymorphisms in the promoter region of the dopamine D4 receptor (DRD4) gene and schizophrenia, depression, and heroin addiction. Genomic DNA was isolated from the venous blood leukocytes of 322 unrelated patients with schizophrenia, 156 patients with depression, 300 patients with heroin addiction, and 300 healthy unrelated individuals. Polymorphisms in the promoter region of DRD4 (-120 bp duplication, -616C/G, and -521C/T) were genotyped using allele-specific polymerase chain reaction analysis. Genotype and allele were analyzed using SPSS 11.5 software. Results of this analysis indicated that there is a strong finding of -120 bp duplication allele frequencies with schizophrenia (p=0.008) and weak finding with -1240 L/S and for paranoid schizophrenia (p=0.022). Interestingly, there is a stronger finding with -521 C/T allele frequencies with heroin dependence (p=0.0002). These observations strongly suggest that the -120-bp duplication polymorphism of DRD4 is associated with schizophrenia and that the -521 C/T polymorphism is associated with heroin addiction." ], "offsets": [ [ 120, 1267 ] ] } ]

[ { "id": "25", "type": "DNAMutation", "text": [ "-616C/G" ], "offsets": [ [ 600, 607 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "747302" } ] }, { "id": "26", "type": "DNAMutation", "text": [ "-521C/T" ], "offsets": [ [ 613, 620 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800955" } ] }, { "id": "27", "type": "DNAMutation", "text": [ "-521 C/T" ], "offsets": [ [ 1014, 1022 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800955" } ] }, { "id": "28", "type": "DNAMutation", "text": [ "-521 C/T" ], "offsets": [ [ 1209, 1217 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800955" } ] } ]

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[ { "id": "35", "type": "title", "text": [ "The dopamine b-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project." ], "offsets": [ [ 0, 125 ] ] }, { "id": "36", "type": "abstract", "text": [ "BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine b-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here." ], "offsets": [ [ 126, 1787 ] ] } ]

[ { "id": "32", "type": "DNAMutation", "text": [ "-1021C/T" ], "offsets": [ [ 27, 35 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1611115" } ] }, { "id": "33", "type": "SNP", "text": [ "rs1611115" ], "offsets": [ [ 400, 409 ] ], "normalized": [] }, { "id": "34", "type": "SNP", "text": [ "rs1800587" ], "offsets": [ [ 1261, 1270 ] ], "normalized": [] } ]

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[ { "id": "43", "type": "title", "text": [ "Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy." ], "offsets": [ [ 0, 102 ] ] }, { "id": "44", "type": "abstract", "text": [ "Background: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. Material and Methods: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. Results: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. Conclusion: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans." ], "offsets": [ [ 103, 1538 ] ] } ]

[ { "id": "38", "type": "DNAMutation", "text": [ "c.-17T>C" ], "offsets": [ [ 1077, 1085 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1474867" } ] }, { "id": "39", "type": "DNAMutation", "text": [ "c.171T>C" ], "offsets": [ [ 1087, 1095 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3749921" } ] }, { "id": "40", "type": "DNAMutation", "text": [ "c.465G>T" ], "offsets": [ [ 1097, 1105 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "139923590" } ] }, { "id": "41", "type": "DNAMutation", "text": [ "c.465G>T" ], "offsets": [ [ 1144, 1152 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "139923590" } ] }, { "id": "42", "type": "ProteinMutation", "text": [ "p.Glu155Asp" ], "offsets": [ [ 1201, 1212 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "139923590" } ] } ]

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[ { "id": "50", "type": "title", "text": [ "The fibrinogen gamma 10034C>T polymorphism is not associated with Peripheral Arterial Disease." ], "offsets": [ [ 0, 94 ] ] }, { "id": "51", "type": "abstract", "text": [ "Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case-control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD." ], "offsets": [ [ 95, 1533 ] ] } ]

[ { "id": "46", "type": "DNAMutation", "text": [ "10034C>T" ], "offsets": [ [ 21, 29 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2066865" } ] }, { "id": "47", "type": "DNAMutation", "text": [ "10034C>T" ], "offsets": [ [ 493, 501 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2066865" } ] }, { "id": "48", "type": "SNP", "text": [ "rs2066865" ], "offsets": [ [ 503, 512 ] ], "normalized": [] }, { "id": "49", "type": "DNAMutation", "text": [ "10034C>T" ], "offsets": [ [ 1337, 1345 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2066865" } ] } ]

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[ { "id": "54", "type": "title", "text": [ "Mutation and association analysis of GEN1 in breast cancer susceptibility." ], "offsets": [ [ 0, 74 ] ] }, { "id": "55", "type": "abstract", "text": [ "GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility." ], "offsets": [ [ 75, 1924 ] ] } ]

[ { "id": "53", "type": "DNAMutation", "text": [ "c.2515_2519delAAGTT" ], "offsets": [ [ 722, 741 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "149936944" } ] } ]

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[ { "id": "60", "type": "title", "text": [ "Mutation analysis of the LCE3B/LCE3C genes in Psoriasis." ], "offsets": [ [ 0, 56 ] ] }, { "id": "61", "type": "abstract", "text": [ "BACKGROUND: An association between a common deletion comprising the late cornified envelope LCE3B and LCE3C genes (LCE3C_LCE3B-del) and Psoriasis (Ps) has been reported. The expression of these LCE genes was induced after skin barrier disruption and was also strong in psoriatic lesions. The damage to the skin barrier could trigger an epidermal response that includes the expression of genes involved in the formation of skin barrier. METHODS: We determined the LCE3C_LCE3B-del genotype in 405 Ps patients and 400 healthy controls from a Northern Spain region (Asturias). These patients and controls were also genotyped for the rs4112788 single nucleotide polymorphism, in strong linkage disequilibrium with the LCE3C_B cluster. The LCE3B and LCE3C gene variant was determined in the patients through SSCA, DHPLC, and direct sequencing. RESULTS: Allele and genotype frequencies did not differ between patients and controls for the rs4112788 and LCE3C_LCE3B-del polymorphisms. However, del/del homozygotes were significantly higher among patients with chronic plaque type Ps who did not develop arthritis (p = 0.03; OR = 1.4; 95%CI = 1.03-1.92). The analysis of the coding sequence of LCE3B and LCE3C in the patients who had at least one copy of this showed that only one patient has a no previously reported LCE3B variant (R68C). CONCLUSION: Our work suggested that homozygosity for a common LCE3C_LCE3B deletion contributes to the risk of developing chronic plaque type Ps without psoriatic arthritis. Our work confirmed previous reports that described an association of this marker with only skin manifestations, and supported the concept of different genetic risk factors contributing to skin and joint disease." ], "offsets": [ [ 57, 1772 ] ] } ]

[ { "id": "57", "type": "SNP", "text": [ "rs4112788" ], "offsets": [ [ 686, 695 ] ], "normalized": [] }, { "id": "58", "type": "SNP", "text": [ "rs4112788" ], "offsets": [ [ 989, 998 ] ], "normalized": [] }, { "id": "59", "type": "ProteinMutation", "text": [ "R68C" ], "offsets": [ [ 1381, 1385 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "201393572" } ] } ]

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[ { "id": "68", "type": "title", "text": [ "hOGG1 Ser326Cys polymorphism and risk of lung cancer by histological type." ], "offsets": [ [ 0, 74 ] ] }, { "id": "69", "type": "abstract", "text": [ "Human 8-oxoguanine DNA glycosylase 1 (hOGG1) has a major role in the repair of 8-hydroxyguanine, a major promutagenic DNA lesion. The genetic polymorphism rs1052133, which leads to substitution of the amino acid at codon 326 from Ser to Cys, shows functional differences, namely a decrease in enzyme activity in hOGG1-Cys326. Although several studies have investigated the association between rs1052133 and lung cancer susceptibility, the effect of this locus on lung cancer according to histology remains unclear. We therefore conducted a case-control study with 515 incident lung cancer cases and 1030 age- and sex-matched controls without cancer, and further conducted a meta-analysis. In overall analysis, the homozygous Cys/Cys genotype showed a significant association with lung cancer compared to Ser allele carrier status (odds ratio (OR)=1.31, 95% confidence interval (CI)=1.02-1.69). By histology-based analysis, the Cys/Cys genotype showed a significantly positive association with small-cell carcinoma (OR=2.40, 95% CI=1.32-4.49) and marginally significant association with adenocarcinoma (OR=1.32, 95% CI=0.98-1.77). A meta-analysis of previous and our present study revealed that this polymorphism is positively associated with adenocarcinoma, although suggestive associations were also found for squamous- and small-cell lung cancers. These results indicate that rs1052133 contributes to the risk of adenocarcinoma of lung." ], "offsets": [ [ 75, 1513 ] ] } ]

[ { "id": "63", "type": "ProteinMutation", "text": [ "Ser326Cys" ], "offsets": [ [ 6, 15 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1052133" } ] }, { "id": "64", "type": "SNP", "text": [ "rs1052133" ], "offsets": [ [ 230, 239 ] ], "normalized": [] }, { "id": "65", "type": "ProteinMutation", "text": [ "326 from Ser to Cys" ], "offsets": [ [ 296, 315 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1052133" } ] }, { "id": "66", "type": "SNP", "text": [ "rs1052133" ], "offsets": [ [ 468, 477 ] ], "normalized": [] }, { "id": "67", "type": "SNP", "text": [ "rs1052133" ], "offsets": [ [ 1453, 1462 ] ], "normalized": [] } ]

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[ { "id": "75", "type": "title", "text": [ "RPGR ORF15 genotype and clinical variability of retinal degeneration in an Australian population." ], "offsets": [ [ 0, 97 ] ] }, { "id": "76", "type": "abstract", "text": [ "BACKGROUND: Mutations in the retinitis pigmentosa GTPase regulator gene (RPGR) are estimated to cause up to 20% of all Caucasian retinitis pigmentosa and up to 75% of cases of X-Linked RP (XLRP). Exon open reading frame 15 (ORF15) is a purine-rich mutation hotspot. Mutations in RPGR ORF15 have also been documented to cause X linked cone-rod dystrophy (XLCORD) and atrophic macular degeneration at an unknown frequency. METHODS: From a hospital clinic population, probands with probable XLRP and XLCORD were screened for RPGR ORF15 mutations and fully phenotyped. RESULTS: Four different RPGR ORF15 mutations were found in four probands. All mutations in the ORF15 exon resulted in premature truncation of the RPGR protein. Three were nonsense mutations: c.507G>T (p.E169stop), c.867G>T (p.G289stop), c.897G>T (p.E299stop) and the fourth a single nucleotide insertion c.1558-1559insA (p.S522fs 525stop). One family exhibited typical XLRP, two XLCORD and one a combination of the phenotypes. CONCLUSION: RPGR ORF15 mutations produce intrafamilial and interfamilial clinical variability with varying degrees of cone degeneration. In an Australian clinic population RPGR ORF15 mutations cause XLCORD in addition to XLRP." ], "offsets": [ [ 98, 1316 ] ] } ]

[ { "id": "71", "type": "DNAMutation", "text": [ "c.507G>T" ], "offsets": [ [ 854, 862 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "369037463" } ] }, { "id": "72", "type": "ProteinMutation", "text": [ "p.E169stop" ], "offsets": [ [ 864, 874 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "369037463" } ] }, { "id": "73", "type": "DNAMutation", "text": [ "c.897G>T" ], "offsets": [ [ 900, 908 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852549" } ] }, { "id": "74", "type": "ProteinMutation", "text": [ "p.E299stop" ], "offsets": [ [ 910, 920 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852549" } ] } ]

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[ { "id": "79", "type": "title", "text": [ "Novel promoter and exon mutations of the BMPR2 gene in Chinese patients with pulmonary arterial hypertension." ], "offsets": [ [ 0, 109 ] ] }, { "id": "80", "type": "abstract", "text": [ "Pulmonary arterial hypertension (PAH), which is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality, is caused by intense remodeling of small pulmonary arteries by endothelial and smooth muscle proliferation. Genetic studies in familial PAH (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2), a receptor for the transforming growth factor (TGF)-beta/BMP superfamily. In this study, we conducted mutation screening in the promoter region and the entire coding regions as well as the intron/exon boundaries of the BMPR2 gene in 20 Chinese patients with either idiopathic or FPAH. All novel detected mutations were excluded by their presence in a panel of 200 chromosomes from normal individuals. A novel mutation, G-669A, in the promoter sequence of the BMPR2 gene was identified in one patient with FPAH, and no exonic mutations were detected in the proband. This mutation abolished a potential specificity protein 3 (sp3) transcription factor-binding site, and a dual luciferase assay showed that the promoter carrying the -669A allele had significantly decreased transcriptional activity compared with -669G allele. Of the other 19 patients, three novel heterozygous exonic mutations were identified: a frame shift mutation with deletion of TG at the nucleotide position 608-609 in exon 5 (Leu203fsX15), a nonsense mutation at the nucleotide position 292 in exon 3 (Glu98X) and a missense single nucleotide substitution in exon 12 (Ser863Asn)." ], "offsets": [ [ 110, 1694 ] ] } ]

[ { "id": "78", "type": "DNAMutation", "text": [ "G-669A" ], "offsets": [ [ 962, 968 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "115604088" } ] } ]

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[ { "id": "85", "type": "title", "text": [ "Hemodynamic parameters and heart rate variability during a tilt test in relation to gene polymorphism of renin-angiotensin and serotonin system." ], "offsets": [ [ 0, 144 ] ] }, { "id": "86", "type": "abstract", "text": [ "PURPOSE: The aim of the study was to evaluate the renin-angiotensin system and serotonin transporter gene polymorphisms in relation to hemodynamic parameters and heart rate variability during a head-up tilt test (HUT) in patients with vasovagal syncope. METHODS: DNA was collected from 191 patients (mean age 44+/-18 years, 61 men, 130 women). The following gene polymorphisms were determined in genomic DNA: angiotensin-converting enzyme insertion/deletion polymorphism (I/D ACE), angiotensinogen gene polymorphism (M 235), angiotensin II receptor type 1 (ATR1) polymorphism (A 11666C), and polymorphism of serotonin transporter gene (5HTTLPR).Heart rate variability during HUT was assessed in 5-minute intervals by low frequency, high frequency, standard deviation of the normal-to-normal (SDNN), and root mean square successive difference parameters. RESULTS: AA genotype of A 1166C polymorphism was associated with lower minimal systolic blood pressure (SBP) and diastolic blood pressure (DBP) during HUT compared with other genotypes (minimal SBP: AA 59.6+/-21,8, AC 79.9+/-22.7, CC 65.4+/-22.7 mmHg, P=0.007), (minimal DBP: AA 36.4+/-22.7, AC 52.3+/-22.9, CC 45.4+/-19.5 mmHg, P=0.007).AA genotype was also associated with higher SDNN compared to other genotypes in the early phase of HUT (SDNN in 5 minutes of tilt: AA 59.7+/-24.6, AC 50.6+/-20.6, CC 46.0+/-13.2, P=0.01) and at syncope occurrence (SDNN: AA 71.0+/-20.9, AC 58.2+/-17.9, CC 58+/-10, P=0.04) CONCLUSION: AA genotype of A 1166C polymorphism in the ATR1 gene may be associated with hypotension and decline in sympathetic tone during HUT. Its role in genetic predisposition to vasovagal syncope cannot be excluded." ], "offsets": [ [ 145, 1828 ] ] } ]

[ { "id": "82", "type": "DNAMutation", "text": [ "A 11666C" ], "offsets": [ [ 722, 730 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] }, { "id": "83", "type": "DNAMutation", "text": [ "A 1166C" ], "offsets": [ [ 1023, 1030 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] }, { "id": "84", "type": "DNAMutation", "text": [ "A 1166C" ], "offsets": [ [ 1636, 1643 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] } ]

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[ { "id": "94", "type": "title", "text": [ "GATA4 mutations in 486 Chinese patients with congenital heart disease." ], "offsets": [ [ 0, 70 ] ] }, { "id": "95", "type": "abstract", "text": [ "Recent studies have reported germline mutations in GATA4 gene in some types of congenital heart disease (CHD). However, the prevalence of GATA4 mutations in CHD and the correlation between the GATA4 genotype and CHD phenotype have not been extensively studied. We screened germline mutations in the coding exons and the flanking intron sequences of the GATA4 gene in 486 CHD patients by denaturing high-performance liquid chromatography (DHPLC), and confirmed the mutations by sequencing. Nine distinct mutations including one small deletion mutation (46delS), two small insertion mutations (118-119insA and 125-126insAA), and six non-synonymous mutations (A6V, P163S, E359K, P407Q, S429T and A442V) were identified in 12 of the 486 patients (nine with ventricular septal defect, two with Tetralogy of Fallot, and one with endocardial cushion defect). Of them, two patients carrying E359K mutation were from two generations in one family with ventricular septal defect (VSD). Interestingly, a nucleotide insertion of c.1146+25insA in exon 6 was detected in five VSD patients, but not in 486 normal healthy controls. Our findings are useful in understanding the prevalence of GATA4 mutations and the correlation between the GATA4 genotype and the CHD phenotype in Chinese patients." ], "offsets": [ [ 71, 1351 ] ] } ]

[ { "id": "88", "type": "ProteinMutation", "text": [ "A6V" ], "offsets": [ [ 728, 731 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199922907" } ] }, { "id": "89", "type": "ProteinMutation", "text": [ "P163S" ], "offsets": [ [ 733, 738 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "387906769" } ] }, { "id": "90", "type": "ProteinMutation", "text": [ "E359K" ], "offsets": [ [ 740, 745 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "368489876" } ] }, { "id": "91", "type": "ProteinMutation", "text": [ "P407Q" ], "offsets": [ [ 747, 752 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "115099192" } ] }, { "id": "92", "type": "ProteinMutation", "text": [ "A442V" ], "offsets": [ [ 764, 769 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "146017816" } ] }, { "id": "93", "type": "ProteinMutation", "text": [ "E359K" ], "offsets": [ [ 954, 959 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "368489876" } ] } ]

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[ { "id": "98", "type": "title", "text": [ "Variable phenotypic expression of homozygous familial hypobetalipoproteinaemia due to novel APOB gene mutations." ], "offsets": [ [ 0, 112 ] ] }, { "id": "99", "type": "abstract", "text": [ "Homozygous familial hypobetalipoproteinaemia (Ho-FHBL) is a rare co-dominant disorder characterized by extremely low levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Most patients with Ho-FHBL have mutations in APOB gene resulting in truncated apoBs. Some patients are asymptomatic, while others have fatty liver, intestinal fat malabsorption and neurological dysfunctions. We investigated three adult subjects with severe hypobetalipoproteinaemia and a family history of FHBL. Proband FHBL-47 had liver cirrhosis with hepatocarcinoma and a renal carcinoma but no clinical manifestations related to FHBL. He was a compound heterozygote for a 7-bp deletion in exon 21 and a base insertion in exon 26 resulting in truncated apoBs (apoB-22.46/apoB-66.51). Proband FHBL-53, with severe hepatic steatosis and fibrosis, had a nonsense mutation in exon 19 resulting in a truncated apoB (apoB-20.61) and a rare nucleotide substitution in intron 14 (c.2068-4T>A). The latter was also present in her daughter, found to have low plasma LDL-C and apoB. Proband FHBL-82 had chronic diarrhoea and steatorrhoea. She was found to be homozygous for a nonsense mutation in exon 24 resulting in a truncated apoB (apoB-26.65). In adult subjects, the presence of chronic liver disease and chronic diarrhoea, when associated with severe hypobetalipoproteinaemia, may lead to the diagnosis of Ho-FHBL." ], "offsets": [ [ 113, 1525 ] ] } ]

[ { "id": "97", "type": "DNAMutation", "text": [ "c.2068-4T>A" ], "offsets": [ [ 1088, 1099 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41291161" } ] } ]

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[ { "id": "107", "type": "title", "text": [ "L1503R is a member of group I mutation and has dominant-negative effect on secretion of full-length VWF multimers: an analysis of two patients with type 2A von Willebrand disease." ], "offsets": [ [ 0, 179 ] ] }, { "id": "108", "type": "abstract", "text": [ "Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF); this in turn is associated with an absence of high-molecular-weight multimers. Sequence analysis of the VWF gene from two unrelated type 2A VWD patients showed an identical, novel, heterozygous T-->G transversion at nucleotide 4508, resulting in the substitution of L1503R in the VWF A2 domain. This substitution, which was not found in 60 unrelated normal individuals, was introduced into a full-length VWF cDNA and subsequently expressed in 293T cells. Only trace amount of the mutant VWF protein was secreted but most of the same was retained in 293T cells. Co-transfection experiment of both wild-type and mutant plasmids indicated the dominant-negative mechanism of disease development; as more of mutant DNA was transfected, VWF secretion was impaired in the media, whereas more of VWF was stored in the cell lysates. Molecular dynamic simulations of structural changes induced by L1503R indicated that the mean value of all-atom root-mean-squared-deviation was shifted from those with wild type or another mutation L1503Q that has been reported to be a group II mutation, which is susceptible to ADAMTS13 proteolysis. Protein instability of L1503R may be responsible for its intracellular retention and perhaps the larger VWF multimers, containing more mutant VWF subunits, are likely to be mal-processed and retained within the cell." ], "offsets": [ [ 180, 1648 ] ] } ]

[ { "id": "101", "type": "ProteinMutation", "text": [ "L1503R" ], "offsets": [ [ 0, 6 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61750097" } ] }, { "id": "102", "type": "DNAMutation", "text": [ "T-->G transversion at nucleotide 4508" ], "offsets": [ [ 501, 538 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61750097" } ] }, { "id": "103", "type": "ProteinMutation", "text": [ "L1503R" ], "offsets": [ [ 573, 579 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61750097" } ] }, { "id": "104", "type": "ProteinMutation", "text": [ "L1503R" ], "offsets": [ [ 1194, 1200 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61750097" } ] }, { "id": "105", "type": "ProteinMutation", "text": [ "L1503Q" ], "offsets": [ [ 1329, 1335 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61750097" } ] }, { "id": "106", "type": "ProteinMutation", "text": [ "L1503R" ], "offsets": [ [ 1455, 1461 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61750097" } ] } ]

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[ { "id": "115", "type": "title", "text": [ "RNASEL and RNASEL-inhibitor variation and prostate cancer risk in Afro-Caribbeans." ], "offsets": [ [ 0, 82 ] ] }, { "id": "116", "type": "abstract", "text": [ "BACKGROUND: Afro-Caribbeans from Tobago are at high risk of developing prostate cancer. This elevated risk of prostate cancer is shared by populations of African ancestry living in diverse environments in the Western hemisphere. Variation in the ribonuclease L (RNASEL) gene has recently been reported to be associated with an increased risk of prostate cancer. However, whether RNASEL variation contributes to the increased risk of prostate cancer observed in populations of African ancestry remains unclear. METHODS: We resequenced the positional candidate gene RNASEL in 48 prostate cancer cases and genotyped the previously reported R462Q and D541E polymorphisms in 230 prostate cancer cases and 458 controls. We also examined the inhibitor of RNASEL (ABCE1) for variation associated with prostate cancer risk. RESULTS: We found no evidence of association between R462Q and D541E polymorphisms and prostate cancer risk in our case/control analysis. A novel variant (K294E) was identified in a single heterozygous individual with prostate cancer. We also observed a 20 bp insertion/deletion polymorphism 1,109 bp upstream of the initiation codon, but this variant was not associated with prostate cancer. We identified 16 single nucleotide polymorphisms in the ABCE1 gene, only 3 of which had a minor allele frequency >5%. A common A/G transition -1,071 bp from the transcriptional start site was genotyped and showed no evidence of association with prostate cancer. CONCLUSIONS: Our results suggest that common variation in the putative prostate cancer susceptibility gene, RNASEL, or its inhibitor does not contribute significantly to prostate cancer risk in this Afro-Caribbean population." ], "offsets": [ [ 83, 1778 ] ] } ]

[ { "id": "110", "type": "ProteinMutation", "text": [ "R462Q" ], "offsets": [ [ 720, 725 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "486907" } ] }, { "id": "111", "type": "ProteinMutation", "text": [ "D541E" ], "offsets": [ [ 730, 735 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "627928" } ] }, { "id": "112", "type": "ProteinMutation", "text": [ "R462Q" ], "offsets": [ [ 951, 956 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "486907" } ] }, { "id": "113", "type": "ProteinMutation", "text": [ "D541E" ], "offsets": [ [ 961, 966 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "627928" } ] }, { "id": "114", "type": "ProteinMutation", "text": [ "K294E" ], "offsets": [ [ 1053, 1058 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "143544690" } ] } ]

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[ { "id": "121", "type": "title", "text": [ "Genetic investigation of four meiotic genes in women with premature ovarian failure." ], "offsets": [ [ 0, 84 ] ] }, { "id": "122", "type": "abstract", "text": [ "OBJECTIVE: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). DESIGN: Case-control study. METHODS: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). RESULTS: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. This mutation resulted in replacement of a non-polar amino acid (proline) with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation. Another POF patient of African origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). CONCLUSIONS: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patients with a heterozygous substitution in exon 2 of the MSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon." ], "offsets": [ [ 85, 1595 ] ] } ]

[ { "id": "118", "type": "ProteinMutation", "text": [ "amino acid (proline) with a polar amino acid (serine) at position 29" ], "offsets": [ [ 880, 948 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2075789" } ] }, { "id": "119", "type": "ProteinMutation", "text": [ "P29S" ], "offsets": [ [ 950, 954 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2075789" } ] }, { "id": "120", "type": "ProteinMutation", "text": [ "M200V" ], "offsets": [ [ 1224, 1229 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2227914" } ] } ]

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[ { "id": "130", "type": "title", "text": [ "Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate." ], "offsets": [ [ 0, 112 ] ] }, { "id": "131", "type": "abstract", "text": [ "In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the L beck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G>A substitution in the 3'-untranslated region. Two patients carried a c.262G>A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C>T (Ser424Ser) and c.1284T>C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development." ], "offsets": [ [ 113, 1846 ] ] } ]

[ { "id": "124", "type": "DNAMutation", "text": [ "c.262G>A" ], "offsets": [ [ 1234, 1242 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72667003" } ] }, { "id": "125", "type": "ProteinMutation", "text": [ "Ala88Thr" ], "offsets": [ [ 1280, 1288 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72667003" } ] }, { "id": "126", "type": "DNAMutation", "text": [ "c.1272C>T" ], "offsets": [ [ 1366, 1375 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61753348" } ] }, { "id": "127", "type": "ProteinMutation", "text": [ "Ser424Ser" ], "offsets": [ [ 1377, 1386 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61753348" } ] }, { "id": "128", "type": "DNAMutation", "text": [ "c.1284T>C" ], "offsets": [ [ 1392, 1401 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2293783" } ] }, { "id": "129", "type": "ProteinMutation", "text": [ "Tyr428Tyr" ], "offsets": [ [ 1403, 1412 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2293783" } ] } ]

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[ { "id": "141", "type": "title", "text": [ "The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population." ], "offsets": [ [ 0, 149 ] ] }, { "id": "142", "type": "abstract", "text": [ "BACKGROUND/AIMS: The genetic predisposition on the development of nonalcoholic steatohepatitis (NASH) has been poorly understood. A functional polymorphism Val175Met was reported in phosphatidylethanolamine N-methyltransferase (PEMT) that catalyzes the conversion of phosphatidylethanolamine to phosphatidylcholine. The aim of this study was to investigate whether the carriers of Val175Met variant impaired in PEMT activity are more susceptible to NASH. METHODS: Blood samples of 107 patients with biopsy-proven NASH and of 150 healthy volunteers were analyzed by the polymerase chain reaction (PCR) and restriction fragment length polymorphism. RESULTS: Val175Met variant allele of the PEMT gene was significantly more frequent in NASH patients than in healthy volunteers (p<0.001), and carriers of Val175Met variant were significantly more frequent in NASH patients than in healthy volunteers (p<0.01). Among NASH patients, body mass index was significantly lower (p<0.05), and non-obese patients were significantly more frequent (p<0.001) in carriers of Val175Met variant than in homozygotes of wild type PEMT. CONCLUSIONS: Val175Met variant of PEMT could be a candidate molecule that determines the susceptibility to NASH, because it is more frequently observed in NASH patients and non-obese persons with Val175Met variant of PEMT are facilitated to develop NASH." ], "offsets": [ [ 150, 1519 ] ] } ]

[ { "id": "133", "type": "ProteinMutation", "text": [ "V175M" ], "offsets": [ [ 54, 59 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "134", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 306, 315 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "135", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 531, 540 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "136", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 806, 815 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "137", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 951, 960 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "138", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 1208, 1217 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "139", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 1278, 1287 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "140", "type": "ProteinMutation", "text": [ "Val175Met" ], "offsets": [ [ 1461, 1470 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] } ]

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[ { "id": "146", "type": "title", "text": [ "A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension." ], "offsets": [ [ 0, 112 ] ] }, { "id": "147", "type": "abstract", "text": [ "We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS." ], "offsets": [ [ 113, 1781 ] ] } ]

[ { "id": "144", "type": "ProteinMutation", "text": [ "serine by leucine at amino acid position 555" ], "offsets": [ [ 708, 752 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "148038173" } ] }, { "id": "145", "type": "ProteinMutation", "text": [ "p.Ser555Leu" ], "offsets": [ [ 754, 765 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "148038173" } ] } ]

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[ { "id": "150", "type": "title", "text": [ "Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy." ], "offsets": [ [ 0, 101 ] ] }, { "id": "151", "type": "abstract", "text": [ "Retinal signal transmission depends on the activity of high voltage-gated l-type calcium channels in photoreceptor ribbon synapses. We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones. The Cacna2d4 gene encodes an l-type calcium-channel auxiliary subunit of the alpha (2) delta type. Mutations in its human orthologue, CACNA2D4, were not yet known to be associated with a disease. We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness, and, in two affected siblings, we detected a homozygous nucleotide substitution (c.2406C-->A) in CACNA2D4. The mutation introduces a premature stop codon that truncates one-third of the corresponding open reading frame. Both patients share symptoms of slowly progressing cone dystrophy. These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy." ], "offsets": [ [ 102, 1190 ] ] } ]

[ { "id": "149", "type": "DNAMutation", "text": [ "c.2406C-->A" ], "offsets": [ [ 823, 834 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "71454844" } ] } ]

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[ { "id": "156", "type": "title", "text": [ "A haplotype-based analysis of the PTPN22 locus in type 1 diabetes." ], "offsets": [ [ 0, 66 ] ] }, { "id": "157", "type": "abstract", "text": [ "A recent addition to the list of widely confirmed type 1 diabetes risk loci is the PTPN22 gene encoding a lymphoid-specific phosphatase (Lyp). However, evidence supporting a role for PTPN22 in type 1 diabetes derives entirely from the study of just one coding single nucleotide polymorphism, 1858C/T. In the current study, the haplotype structure of the PTPN22 region was determined, and individual haplotypes were tested for association with type 1 diabetes in family-based tests. The 1858T risk allele occurred on only a single haplotype that was strongly associated with type 1 diabetes (P = 7.9 x 10(-5)). After controlling for the effects of this allele, two other haplotypes were observed to be weakly associated with type 1 diabetes (P < 0.05). Sequencing of the coding region of PTPN22 on these haplotypes revealed a novel variant (2250G/C) predicted to result in a nonsynonymous amino acid substitution. Analysis of PTPN22 transcripts from a subject heterozygous for this variant indicated that it interfered with normal mRNA splicing, resulting in a premature termination codon after exon 17. These results support the conclusion that the 1858C/T allele is the major risk variant for type 1 diabetes in the PTPN22 locus, but they suggest that additional infrequent coding variants at PTPN22 may also contribute to type 1 diabetes risk." ], "offsets": [ [ 67, 1412 ] ] } ]

[ { "id": "153", "type": "DNAMutation", "text": [ "1858C/T" ], "offsets": [ [ 359, 366 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2476601" } ] }, { "id": "154", "type": "DNAMutation", "text": [ "2250G/C" ], "offsets": [ [ 907, 914 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "56048322" } ] }, { "id": "155", "type": "DNAMutation", "text": [ "1858C/T" ], "offsets": [ [ 1216, 1223 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2476601" } ] } ]

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[ { "id": "162", "type": "title", "text": [ "A functional Tyr1306Cys variant in LARG is associated with increased insulin action in vivo." ], "offsets": [ [ 0, 92 ] ] }, { "id": "163", "type": "abstract", "text": [ "Diminished insulin sensitivity is a characteristic feature of type 2 diabetes. Inhibition of insulin action, resulting in reduced skeletal muscle glucose uptake, is mediated in part through stimulation of RhoA activity. One regulator of RhoA activity is leukemia-associated Rho guanine nucleotide exchange factor (LARG). The LARG gene maps to a region on chromosome 11q23-24 that shows genetic linkage to BMI and type 2 diabetes in Pima Indians. Because of its role in RhoA activation, the LARG gene was analyzed as a positional candidate gene for this linkage. Sequencing of the LARG gene and genotyping of variants identified several polymorphisms that were associated with in vivo rates of insulin-mediated glucose uptake, at both physiological and maximally stimulating insulin concentrations, among 322 nondiabetic Pima Indians who had undergone a hyperinsulinemic-euglycemic clamp. The strongest association with rate of glucose uptake was found with a Tyr1306Cys polymorphism (P < 0.0001, adjusted for age, sex, percent body fat, and nuclear family membership). In transient transfection studies in NIH3T3 cells, the LARG(Cys1306) protein had reduced activity compared with LARG(Tyr1306) protein (P < 0.05). We propose that the Tyr1306Cys substitution in LARG, through its differential activation of RhoA, increases insulin sensitivity in nondiabetic Pima Indians." ], "offsets": [ [ 93, 1464 ] ] } ]

[ { "id": "159", "type": "ProteinMutation", "text": [ "Tyr1306Cys" ], "offsets": [ [ 13, 23 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "148969251" } ] }, { "id": "160", "type": "ProteinMutation", "text": [ "Tyr1306Cys" ], "offsets": [ [ 1052, 1062 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "148969251" } ] }, { "id": "161", "type": "ProteinMutation", "text": [ "Tyr1306Cys" ], "offsets": [ [ 1328, 1338 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "148969251" } ] } ]

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[ { "id": "167", "type": "title", "text": [ "A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis." ], "offsets": [ [ 0, 93 ] ] }, { "id": "168", "type": "abstract", "text": [ "PURPOSE: To identify the genetic basis of recessive inheritance of high hyperopia and Leber congenital amaurosis (LCA) in a family of Middle Eastern origin. MATERIALS AND METHODS: The patients were examined using standard ophthalmic techniques. DNA samples were obtained and genetic linkage was carried out using polymorphic markers flanking the known genes and loci for LCA. Exons were amplified and sequenced. RESULTS: All four members of this family affected by LCA showed high to extreme hyperopia, with average spherical refractive errors ranging from +5.00 to +10.00. Linkage was obtained to 1q31.3 with a maximal LOD score of 5.20 and a mutation found in exon 9 of the CRB1 gene, causing a G1103R substitution at a highly conserved site in the protein. CRB1 is a vertebrate homolog of the Drosophila crumbs gene, which is required for photoreceptor morphogenesis, and has been associated with either retinitis pigmentosa (RP) or LCA. This sequence variant has previously been reported as a compound heterozygote in one sporadic LCA patient. CONCLUSION: Although hyperopia has been associated with LCA, it is typically moderate and variable between patients with the same mutation. In addition, some CRB1 mutations can be associated with either RP or LCA. We have shown that hyperopia and LCA are linked to the mutant CRB1 gene itself and are not dependent on unlinked modifiers." ], "offsets": [ [ 94, 1479 ] ] } ]

[ { "id": "165", "type": "ProteinMutation", "text": [ "G1103R" ], "offsets": [ [ 2, 8 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62636275" } ] }, { "id": "166", "type": "ProteinMutation", "text": [ "G1103R" ], "offsets": [ [ 791, 797 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62636275" } ] } ]

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[ { "id": "172", "type": "title", "text": [ "Mutations in coagulation factor XIII A gene in eight unrelated Indians. Five novel mutations identified by a novel PCR-CSGE approach." ], "offsets": [ [ 0, 133 ] ] }, { "id": "173", "type": "abstract", "text": [ "Factor XIII deficiency is a rare autosomal (1:2,000,000) recessive disorder of blood coagulation usually attributed to mutations in the coagulation factor XIII (FXIII) A gene. We have studied the molecular basis of FXIII deficiency in eight unrelated South Indian patients. Their diagnosis was based on clinical history, normal plasma clotting times and increased solubility of fibrin clot in 5 mol/l urea. Genomic DNA was screened for FXIII A gene defects by a novel PCR and CSGE strategy. Mutations were identified in all these patients. Five of these were novel mutations occurring in four patients. These included a novel c.210T > G transversion in homozygosity in exon 3 predicting a Tyr69X in the beta-sandwich domain in one patient. Another patient was compound heterozygote for a novel c.791C > T transition predicting a Ser263Phe in the core domain and a novel c.2045-1G > A transition at the acceptor splice junction of intron 14. Two novel frame shifts were also identified in two patients in a homozygous condition. One of them resulted from a single base 'G' duplication (c.892_895dupG) at codons Ser290/Ala291fs affecting the core domain and the other was due to a single base 'A' duplication (c.1642_1644dupA) and at codonTyr547fs affecting barrel-1 domain. The remaining four patients had the previously reported Arg260His, Ser413Leu, and Val414Phe (n = 2) missense mutations in the core domain. The novel mutations identified were considered to be disease causative by studying the nature of mutation, the degree of conservation of the mutated aminoacid among transglutaminases of different species and by molecular modeling. Apart from describing a significant number of novel mutations, this report is the first study from Southern India to describe FXIII A gene mutations." ], "offsets": [ [ 134, 1926 ] ] } ]

[ { "id": "170", "type": "ProteinMutation", "text": [ "Arg260His" ], "offsets": [ [ 1463, 1472 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121913071" } ] }, { "id": "171", "type": "ProteinMutation", "text": [ "Val414Phe" ], "offsets": [ [ 1489, 1498 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121913070" } ] } ]

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[ { "id": "188", "type": "title", "text": [ "Phenylketonuria mutations in Northern China." ], "offsets": [ [ 0, 44 ] ] }, { "id": "189", "type": "abstract", "text": [ "Mutation spectrum of phenylalanine hydroxylase (PAH) gene in patients with phenylketonuria (PKU) in Northern China is described with a discussion on genotype-phenotype correlation. By using PCR/SSCP and DNA sequencing, all exons of PAH gene in the 185 unrelated patients with PKU from Northern China were studied. A total of 70 different mutations, including 42 missense, 12 splice, 7 nonsense, 5 deletion, 3 insertion, and 1 silence/splice mutations, were detected in 349/370 mutant alleles (94.3%). Deletion, insertion, and frameshift mutations were found for the first time in China PKU patients. The mutations R243Q, EX6-96A>G, R111X, Y356X, and R413P were the prevalent mutations with relative frequencies of 22.2, 11.1, 8.7, 6.5, and 6.5%, respectively. Fifteen novel mutations were identified in this study: I38fsX19, IVS4+3G>C, Y154H, R157K, R157I, T200fsX6, Q267H, Q267E, F302fsX39, G346R, S349A, L367L, R400K, IVS12+4A>G, and IVS12+6T>A. Each of them occurs at very low frequency (0.3-1.1%). The mutation spectrum of PKU in Chinese is similar to other Asian populations but significantly different from European populations. Altogether, 70 different mutations are found in 109 genotypes distributed among 185 PKU patients. As shown by the analysis, the predicted residual activity found in the majority of PKU individuals match their in vivo phenotypes, though evidence is also found for both phenotypic inconsistencies among subjects with similar genotypes and discordance between the in vitro and in vivo effects of some mutant alleles. The study enables us to construct a national database in China serving as a valuable tool for genetic counseling and prognostic evaluation of future cases of PKU." ], "offsets": [ [ 45, 1756 ] ] } ]

[ { "id": "175", "type": "ProteinMutation", "text": [ "R243Q" ], "offsets": [ [ 659, 664 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62508588" } ] }, { "id": "176", "type": "ProteinMutation", "text": [ "R111X" ], "offsets": [ [ 677, 682 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "76296470" } ] }, { "id": "177", "type": "ProteinMutation", "text": [ "Y356X" ], "offsets": [ [ 684, 689 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62516095" } ] }, { "id": "178", "type": "ProteinMutation", "text": [ "R413P" ], "offsets": [ [ 695, 700 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "79931499" } ] }, { "id": "179", "type": "ProteinMutation", "text": [ "Y154H" ], "offsets": [ [ 881, 886 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199475587" } ] }, { "id": "180", "type": "ProteinMutation", "text": [ "R157K" ], "offsets": [ [ 888, 893 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199475611" } ] }, { "id": "181", "type": "ProteinMutation", "text": [ "R157I" ], "offsets": [ [ 895, 900 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199475611" } ] }, { "id": "182", "type": "ProteinMutation", "text": [ "Q267H" ], "offsets": [ [ 912, 917 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199475675" } ] }, { "id": "183", "type": "ProteinMutation", "text": [ "Q267E" ], "offsets": [ [ 919, 924 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199475676" } ] }, { "id": "184", "type": "ProteinMutation", "text": [ "G346R" ], "offsets": [ [ 937, 942 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62508688" } ] }, { "id": "185", "type": "ProteinMutation", "text": [ "S349A" ], "offsets": [ [ 944, 949 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62508646" } ] }, { "id": "186", "type": "ProteinMutation", "text": [ "L367L" ], "offsets": [ [ 951, 956 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "62508648" } ] }, { "id": "187", "type": "ProteinMutation", "text": [ "R400K" ], "offsets": [ [ 958, 963 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199475658" } ] } ]

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[ { "id": "199", "type": "title", "text": [ "Polymorphisms of the DNA mismatch repair gene HMSH2 in breast cancer occurence and progression." ], "offsets": [ [ 0, 95 ] ] }, { "id": "200", "type": "abstract", "text": [ "The response of the cell to DNA damage and its ability to maintain genomic stability by DNA repair are crucial in preventing cancer initiation and progression. Therefore, polymorphism of DNA repair genes may affect the process of carcinogenesis. The importance of genetic variability of the components of mismatch repair (MMR) genes is well documented in colorectal cancer, but little is known about its role in breast cancer. hMSH2 is one of the crucial proteins of MMR. We performed a case-control study to test the association between two polymorphisms in the hMSH2 gene: an A --> G transition at 127 position producing an Asn --> Ser substitution at codon 127 (the Asn127Ser polymorphism) and a G --> A transition at 1032 position resulting in a Gly --> Asp change at codon 322 (the Gly322Asp polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 age-matched women (controls) by restriction fragment length polymorphism and allele-specific PCR. We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom-Richardson grading. A strong association between breast cancer occurrence and the Gly/Gly phenotype of the Gly322Asp polymorphism (odds ratio 8.39; 95% confidence interval 1.44-48.8) was found. Therefore, MMR may play a role in the breast carcinogenesis and the Gly322Asp polymorphism of the hMSH2 gene may be considered as a potential marker in breast cancer." ], "offsets": [ [ 96, 1663 ] ] } ]

[ { "id": "191", "type": "DNAMutation", "text": [ "A --> G transition at 127 position" ], "offsets": [ [ 674, 708 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "780496649" } ] }, { "id": "192", "type": "ProteinMutation", "text": [ "Asn --> Ser substitution at codon 127" ], "offsets": [ [ 722, 759 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "17217772" } ] }, { "id": "193", "type": "ProteinMutation", "text": [ "Asn127Ser" ], "offsets": [ [ 765, 774 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "17217772" } ] }, { "id": "194", "type": "DNAMutation", "text": [ "G --> A transition at 1032 position" ], "offsets": [ [ 795, 830 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4987188" } ] }, { "id": "195", "type": "ProteinMutation", "text": [ "Gly --> Asp change at codon 322" ], "offsets": [ [ 846, 877 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4987188" } ] }, { "id": "196", "type": "ProteinMutation", "text": [ "Gly322Asp" ], "offsets": [ [ 883, 892 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4987188" } ] }, { "id": "197", "type": "ProteinMutation", "text": [ "Gly322Asp" ], "offsets": [ [ 1410, 1419 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4987188" } ] }, { "id": "198", "type": "ProteinMutation", "text": [ "Gly322Asp" ], "offsets": [ [ 1565, 1574 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4987188" } ] } ]

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[ { "id": "204", "type": "title", "text": [ "Characterization of Bietti crystalline dystrophy patients with CYP4V2 mutations." ], "offsets": [ [ 0, 80 ] ] }, { "id": "205", "type": "abstract", "text": [ "PURPOSE: Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. METHODS: Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). RESULTS: Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3' splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. CONCLUSIONS: This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity." ], "offsets": [ [ 81, 1847 ] ] } ]

[ { "id": "202", "type": "ProteinMutation", "text": [ "S482X" ], "offsets": [ [ 874, 879 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "146494374" } ] }, { "id": "203", "type": "ProteinMutation", "text": [ "K386T" ], "offsets": [ [ 884, 889 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199476200" } ] } ]

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[ { "id": "217", "type": "title", "text": [ "Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome." ], "offsets": [ [ 0, 127 ] ] }, { "id": "218", "type": "abstract", "text": [ "Alpers syndrome is an autosomal recessive mitochondrial DNA depletion disorder that affects children and young adults. It is characterized by a progressive, fatal brain and liver disease. This syndrome has been associated with mutations in POLG, the gene encoding the mitochondrial DNA polymerase (pol gamma). Most patients with Alpers syndrome have been found to be compound heterozygotes, carrying two pathogenic mutations in trans at the POLG locus. POLG is a nuclear-encoded gene whose protein product is imported into mitochondria, where it is essential for mtDNA replication and repair. We studied the skin fibroblasts of a patient with Alpers syndrome having the genotype E873stop/A467T. The E873stop mutation produces a premature termination codon (TAG) in exon 17. The A467T mutation produces a threonine to alanine substitution at a highly conserved site in exon 7. The allele bearing the stop codon (E873-TAG) is predicted to produce a truncated, catalytically inactive polymerase. However, only full-length pol gamma protein was detected by Western blot analysis. Here, we show that transcripts containing this stop codon undergo nonsense-associated alternative splicing and nonsense-mediated decay. More than 95% of the functional POLG mRNA was derived from the allele bearing the A467T mutation and less than 5% contained the E873stop mutation. These events ensured that virtually all POLG protein in the cell was expressed from the A467T allele. Therefore, the Alpers phenotype in this patient was a consequence of a single-copy gene dose of the A467T allele, and selective elimination of transcripts bearing the E873stop mutation." ], "offsets": [ [ 128, 1774 ] ] } ]

[ { "id": "207", "type": "ProteinMutation", "text": [ "E873stop" ], "offsets": [ [ 807, 815 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121918047" } ] }, { "id": "208", "type": "ProteinMutation", "text": [ "A467T" ], "offsets": [ [ 816, 821 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] }, { "id": "209", "type": "ProteinMutation", "text": [ "E873stop" ], "offsets": [ [ 827, 835 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121918047" } ] }, { "id": "210", "type": "ProteinMutation", "text": [ "A467T" ], "offsets": [ [ 906, 911 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] }, { "id": "211", "type": "ProteinMutation", "text": [ "E873-TAG" ], "offsets": [ [ 1039, 1047 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121918047" } ] }, { "id": "212", "type": "ProteinMutation", "text": [ "A467T" ], "offsets": [ [ 1422, 1427 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] }, { "id": "213", "type": "ProteinMutation", "text": [ "E873stop" ], "offsets": [ [ 1468, 1476 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121918047" } ] }, { "id": "214", "type": "ProteinMutation", "text": [ "A467T" ], "offsets": [ [ 1575, 1580 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] }, { "id": "215", "type": "ProteinMutation", "text": [ "A467T" ], "offsets": [ [ 1689, 1694 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] }, { "id": "216", "type": "ProteinMutation", "text": [ "E873stop" ], "offsets": [ [ 1756, 1764 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121918047" } ] } ]

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[ { "id": "223", "type": "title", "text": [ "Novel amino acid substitution in the Y-position of collagen type II causes spondyloepimetaphyseal dysplasia congenita." ], "offsets": [ [ 0, 118 ] ] }, { "id": "224", "type": "abstract", "text": [ "We report on monozygotic twins with short stature and severe spondyloepimetaphyseal dysplasia congenita (SEMDC) from the Polish population. Phenotype of the twin girls resembles spondyloepiphyseal dysplasia congenita Spranger-Wiedemann (SEDC-SW), but shortening of the stature is more severe and the cranioface is normal. The distinctive radiographic features, in spite of similarity to SEDC-SW, indicate different spinal and, notably, severe metaphyseal involvement. Molecular analysis of the COL2A1 gene revealed an A to G transition at nucleotide +79 of exon 41 that converted the codon for arginine at amino acid 792 to a codon for glycine (Arg792Gly). The twins were heterozygous for the mutation and neither parent had this change. The Arg792Gly substitution is located at the Y-position of Gly-X-Y triplet, and it is likely that this substitution decreased the thermal stability of the triple helix and may affect fibril growth by replacement of an arginine residue, which is important for a conformation of the triple helix." ], "offsets": [ [ 119, 1151 ] ] } ]

[ { "id": "220", "type": "ProteinMutation", "text": [ "arginine at amino acid 792 to a codon for glycine" ], "offsets": [ [ 713, 762 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121912895" } ] }, { "id": "221", "type": "ProteinMutation", "text": [ "Arg792Gly" ], "offsets": [ [ 764, 773 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121912895" } ] }, { "id": "222", "type": "ProteinMutation", "text": [ "Arg792Gly" ], "offsets": [ [ 861, 870 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121912895" } ] } ]

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[ { "id": "230", "type": "title", "text": [ "Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD)." ], "offsets": [ [ 0, 93 ] ] }, { "id": "231", "type": "abstract", "text": [ "Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis. PEMT knockout mice have fatty livers, and it is possible that, in humans, nonalcoholic fatty liver disease (NAFLD) might be associated with PEMT gene polymorphisms. DNA samples from 59 humans without fatty liver and from 28 humans with NAFLD were genotyped for a single nucleotide polymorphism in exon 8 of PEMT, which leads to a V175M substitution. V175M is a loss of function mutation, as determined by transiently transfecting McArdle-RH7777 cells with constructs of wild-type PEMT open reading frame or the V175M mutant. Met/Met at residue 175 (loss of function SNP) occurred in 67.9% of the NAFLD subjects and in only 40.7% of control subjects (P<0.03). For the first time we report that a polymorphism of the human PEMT gene (V175M) is associated with diminished activity and may confer susceptibility to NAFLD." ], "offsets": [ [ 94, 1004 ] ] } ]

[ { "id": "226", "type": "ProteinMutation", "text": [ "V175M" ], "offsets": [ [ 517, 522 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "227", "type": "ProteinMutation", "text": [ "V175M" ], "offsets": [ [ 537, 542 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "228", "type": "ProteinMutation", "text": [ "V175M" ], "offsets": [ [ 698, 703 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] }, { "id": "229", "type": "ProteinMutation", "text": [ "V175M" ], "offsets": [ [ 919, 924 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7946" } ] } ]

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[ { "id": "243", "type": "title", "text": [ "The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe." ], "offsets": [ [ 0, 117 ] ] }, { "id": "244", "type": "abstract", "text": [ "We investigated the molecular basis of hereditary fructose intolerance (HFI) in 80 patients from 72 families by means of a PCR-based mutation screening strategy, consisting of heteroduplex analysis, restriction enzyme digest, DNA single strand electrophoresis, and direct sequencing. For a subset of patients mutation screening with DHPLC was established which turned out to be as fast and as sensitive as the more conventional methods. Fifteen different mutations of the aldolase B (ALDOB) gene were identified in HFI patients. As in smaller previous studies, p.A150P (65%), p.A175D (11%) and p.N335K (8%) were the most common mutated alleles, followed by c.360_363delCAAA, p.R60X, p.Y204X, and c.865delC. Eight novel mutations were identified in eight families with HFI: a small indel mutation (c.1044_1049delTTCTGGinsACACT), two small deletions (c.345_372del28; c.841_842delAC), two splice site mutations (c.113-1G>A, c.799+2T>A), one nonsense mutation (c.612T>G (p.Y204X)), and two missense mutations (c.532T>C (p.C178R), c.851T>C (p.L284P)). By mutation screening for the three most common ALDOB mutations by DHPLC in 2,000 randomly selected newborns we detected 21 heterozygotes. Based on these data and after correction for less common and private ALDOB mutations, HFI prevalence in central Europe is estimated to be 1:26,100 (95% confidence interval 1: 12,600-79,000)." ], "offsets": [ [ 118, 1494 ] ] } ]

[ { "id": "233", "type": "ProteinMutation", "text": [ "p.A150P" ], "offsets": [ [ 679, 686 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800546" } ] }, { "id": "234", "type": "ProteinMutation", "text": [ "p.A175D" ], "offsets": [ [ 694, 701 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "76917243" } ] }, { "id": "235", "type": "ProteinMutation", "text": [ "p.N335K" ], "offsets": [ [ 712, 719 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "78340951" } ] }, { "id": "236", "type": "DNAMutation", "text": [ "c.360_363delCAAA" ], "offsets": [ [ 775, 791 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "762198323" } ] }, { "id": "237", "type": "ProteinMutation", "text": [ "p.R60X" ], "offsets": [ [ 793, 799 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "118204429" } ] }, { "id": "238", "type": "ProteinMutation", "text": [ "p.Y204X" ], "offsets": [ [ 801, 808 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370793608" } ] }, { "id": "239", "type": "DNAMutation", "text": [ "c.865delC" ], "offsets": [ [ 814, 823 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "864309533" } ] }, { "id": "240", "type": "DNAMutation", "text": [ "c.113-1G>A" ], "offsets": [ [ 1027, 1037 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "748663340" } ] }, { "id": "241", "type": "DNAMutation", "text": [ "c.612T>G" ], "offsets": [ [ 1075, 1083 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370793608" } ] }, { "id": "242", "type": "ProteinMutation", "text": [ "p.Y204X" ], "offsets": [ [ 1085, 1092 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370793608" } ] } ]

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[ { "id": "259", "type": "title", "text": [ "New mutations, hotspots, and founder effects in Brazilian patients with steroid 5alpha-reductase deficiency type 2." ], "offsets": [ [ 0, 115 ] ] }, { "id": "260", "type": "abstract", "text": [ "Mutations of the steroid 5alpha-reductase type 2 (SRD5A2) gene in 46,XY subjects cause masculinization defects of varying degrees, due to reduced or impaired enzymatic activity. In this study, sequence abnormalities of the SRD5A2 gene were assessed by polymerase chain reaction with specific primers and automated sequencing analysis in DNA samples from 20 patients with suspected steroid 5alpha-reductase type 2 deficiency from 18 Brazilian families. Eleven subjects presented SRD5A2 homozygous single-base mutations (two first cousins and four unrelated patients with G183S, two with R246W, one with del642T, one with G196S, and one with 217_218insC plus the A49T variant in heterozygosis), whereas four were compound heterozygotes (one with Q126R/IVS3+1G>A, one with Q126R/del418T, and two brothers with Q126R/G158R). Three patients were heterozygous for A207D, G196S, and R266W substitutions. The V89L polymorphism was found in heterozygosis in one of them (with A207D) and in one case with an otherwise normal gene sequence. The A49T variant was also detected in heterozygosis in the second case without other sequencing abnormalities. Four patients harbor yet non-described SRD5A2 gene mutations: a single nucleotide deletion (del642T), a G158R amino acid substitution, a splice junction mutation (IVS3+1G>A), and the insertion of a cytosine (217_218insC) occurring at a CCCC motif. This is the first report of a single-nucleotide insertion in the coding sequence of the SRD5A2 gene. In addition to these new mutations, this investigation reveals the prevalence of G183S substitution among a subset of African-Brazilian patients and presents evidences of the recurrence of already known mutations." ], "offsets": [ [ 116, 1819 ] ] } ]

[ { "id": "246", "type": "ProteinMutation", "text": [ "G183S" ], "offsets": [ [ 686, 691 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434247" } ] }, { "id": "247", "type": "ProteinMutation", "text": [ "R246W" ], "offsets": [ [ 702, 707 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434244" } ] }, { "id": "248", "type": "ProteinMutation", "text": [ "G196S" ], "offsets": [ [ 736, 741 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434250" } ] }, { "id": "249", "type": "ProteinMutation", "text": [ "A49T" ], "offsets": [ [ 777, 781 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9282858" } ] }, { "id": "250", "type": "ProteinMutation", "text": [ "Q126R" ], "offsets": [ [ 860, 865 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "368386747" } ] }, { "id": "251", "type": "ProteinMutation", "text": [ "Q126R" ], "offsets": [ [ 886, 891 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "368386747" } ] }, { "id": "252", "type": "ProteinMutation", "text": [ "Q126R" ], "offsets": [ [ 923, 928 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "368386747" } ] }, { "id": "253", "type": "ProteinMutation", "text": [ "A207D" ], "offsets": [ [ 974, 979 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "767564684" } ] }, { "id": "254", "type": "ProteinMutation", "text": [ "G196S" ], "offsets": [ [ 981, 986 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434250" } ] }, { "id": "255", "type": "ProteinMutation", "text": [ "V89L" ], "offsets": [ [ 1017, 1021 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "523349" } ] }, { "id": "256", "type": "ProteinMutation", "text": [ "A207D" ], "offsets": [ [ 1083, 1088 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "767564684" } ] }, { "id": "257", "type": "ProteinMutation", "text": [ "A49T" ], "offsets": [ [ 1150, 1154 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9282858" } ] }, { "id": "258", "type": "ProteinMutation", "text": [ "G183S" ], "offsets": [ [ 1687, 1692 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434247" } ] } ]

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[ { "id": "264", "type": "title", "text": [ "Novel somatic MEN1 gene alterations in sporadic primary hyperparathyroidism and correlation with clinical characteristics." ], "offsets": [ [ 0, 122 ] ] }, { "id": "265", "type": "abstract", "text": [ "Primary hyperparathyroidism (pHPT) is a common endocrine disease that in more than 95% of cases is sporadic and only in some cases is caused by inherited disorders, isolated or as part of multiple endocrine neoplasia (MEN1 and 2). Somatic mutations of MEN1 gene have also been described in sporadic parathyroid tumors. In our study, we examined the presence of alterations in MEN1 gene in a series of 39 patients who had undergone surgery for sporadic pHPT (35 with parathyroid adenoma or hyperplasia, 4 with a carcinoma). A genotype-phenotype correlation was also analysed. After DNA extraction from paraffin-embedded tissues, we amplified by PCR and sequenced the exons 2-10 of the MEN1 gene. Somatic MEN1 mutations were detected in 6 of the 35 patients with a benign parathyroid lesion examined (17.1%), whereas no alterations were found in the carcinomas. Four novel MEN1 gene mutations were identified as follows: one frameshift mutation (222insT, exon 2), one frameshift deletion (912delTA, exon 5), one in-frame deletion (835del18, exon 4) and one missense mutation (P291A, exon 6). In addition, one missense mutation (L89R, exon 2) and one nonsense mutation (Q536X, exon 10) were previously reported. Moreover, two polymorphisms were also found: one allele carried a R171Q polymorphism (1/39 tumors), while a D418D polymorphism (GAC/GAT) was found in 15 and 8 tumors in hetero (CT) and homozygosity (TT), respectively. In no case (mutations and/or polymorphisms) did we find a genotype-phenotype correlation. In conclusion, our data demonstrate the presence of somatic alterations of the MEN1 tumor suppressor gene in about one fifth of benign sporadic parathyroid tumors. The absence of a genotype-phenotype correlation, however, suggests the involvement of other genetic/epigenetic factors for the full expression of the disease." ], "offsets": [ [ 123, 1962 ] ] } ]

[ { "id": "262", "type": "ProteinMutation", "text": [ "R171Q" ], "offsets": [ [ 1398, 1403 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "607969" } ] }, { "id": "263", "type": "ProteinMutation", "text": [ "D418D" ], "offsets": [ [ 1440, 1445 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2071313" } ] } ]

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[ { "id": "279", "type": "title", "text": [ "Two novel mutations, L490R and V561X, of the transferrin receptor 2 gene in Japanese patients with hemochromatosis." ], "offsets": [ [ 0, 115 ] ] }, { "id": "280", "type": "abstract", "text": [ "BACKGROUND AND OBJECTIVES: The low prevalence of the C282Y mutation of the HFE gene in Japan means that the genetic background of hemochromatosis in Japanese patients remains unclear. In a previous report, we showed that 3 patients from one family had an AVAQ 594-597 deletion of the transferrin receptor (TfR2) gene. This suggests that the TfR2 gene is involved in hemochromatosis in Japanese patients. DESIGN AND METHODS: Nine patients clinically diagnosed with hemochromatosis were included in the study. DNA was extracted from whole blood samples collected with informed consent. The HFE and TfR2 genes were analyzed by sequencing the coding region and splicing sites. RESULTS: There were no mutations in the HFE gene. In the TfR2 gene, 2 novel mutations, 1469T->G (L490R) and 1665delC (V561X), were found in 2 patients. A known variation, 714C-> (I238M), was also found in the patient with L490R. The patient homozygous for both L490R and I238M presented with a mild manifestation of hemochromatosis at the age of 41 years. His liver was cirrhotic with parenchymal iron deposits and the result of a glucose tolerance test was compatible with diabetes mellitus. The patient homozygous for V561X had severe iron overload with the triad of cirrhosis, diabetes mellitus and skin pigmentation at the age of 58 years. INTERPRETATION AND CONCLUSIONS: Taken together with the previous report, 5 of our 12 patients with hemochromatosis manifesting in middle age had mutations in the TfR2 gene. Thus, TfR2 plays a role in the pathogenesis of hemochromatosis in Japan." ], "offsets": [ [ 116, 1678 ] ] } ]

[ { "id": "267", "type": "ProteinMutation", "text": [ "L490R" ], "offsets": [ [ 21, 26 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338886" } ] }, { "id": "268", "type": "ProteinMutation", "text": [ "V561X" ], "offsets": [ [ 31, 36 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338887" } ] }, { "id": "269", "type": "ProteinMutation", "text": [ "C282Y" ], "offsets": [ [ 169, 174 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800562" } ] }, { "id": "270", "type": "DNAMutation", "text": [ "1469T->G" ], "offsets": [ [ 876, 884 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338886" } ] }, { "id": "271", "type": "ProteinMutation", "text": [ "L490R" ], "offsets": [ [ 886, 891 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338886" } ] }, { "id": "272", "type": "DNAMutation", "text": [ "1665delC" ], "offsets": [ [ 897, 905 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338887" } ] }, { "id": "273", "type": "ProteinMutation", "text": [ "V561X" ], "offsets": [ [ 907, 912 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338887" } ] }, { "id": "274", "type": "ProteinMutation", "text": [ "I238M" ], "offsets": [ [ 968, 973 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34242818" } ] }, { "id": "275", "type": "ProteinMutation", "text": [ "L490R" ], "offsets": [ [ 1011, 1016 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338886" } ] }, { "id": "276", "type": "ProteinMutation", "text": [ "L490R" ], "offsets": [ [ 1050, 1055 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338886" } ] }, { "id": "277", "type": "ProteinMutation", "text": [ "I238M" ], "offsets": [ [ 1060, 1065 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34242818" } ] }, { "id": "278", "type": "ProteinMutation", "text": [ "V561X" ], "offsets": [ [ 1309, 1314 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338887" } ] } ]

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[ { "id": "287", "type": "title", "text": [ "Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers." ], "offsets": [ [ 0, 100 ] ] }, { "id": "288", "type": "abstract", "text": [ "The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population." ], "offsets": [ [ 101, 1590 ] ] } ]

[ { "id": "282", "type": "ProteinMutation", "text": [ "N372H" ], "offsets": [ [ 177, 182 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "144848" } ] }, { "id": "283", "type": "ProteinMutation", "text": [ "N372H" ], "offsets": [ [ 381, 386 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "144848" } ] }, { "id": "284", "type": "ProteinMutation", "text": [ "N372H" ], "offsets": [ [ 1017, 1022 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "144848" } ] }, { "id": "285", "type": "ProteinMutation", "text": [ "N372H" ], "offsets": [ [ 1322, 1327 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "144848" } ] }, { "id": "286", "type": "ProteinMutation", "text": [ "N372H" ], "offsets": [ [ 1538, 1543 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "144848" } ] } ]

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[ { "id": "291", "type": "title", "text": [ "Polymorphic changes in the KAL1 gene: not all of them should be classified as polymorphisms." ], "offsets": [ [ 0, 92 ] ] }, { "id": "292", "type": "abstract", "text": [ "The KAL1 gene has a closely related nonfunctional pseudogene on the Y chromosome; a high degree of X-Y sequence similarity is observed. Some individuals present a T to C substitution at position 1833 (exon 12). Because this nucleotide differs in the X (thymine) and in the Y (cytosine) chromosome, we investigated if this was truly a polymorphism, or if in some cases the Y sequence had been amplified. The complete sequence of exon 12 of KAL1 was analyzed in 11 Kallmann Syndrome (KS) males, in 50 normal males, in 50 normal females, and in 16 patients with Ullrich-Turner Syndrome (UTS). Nucleotide 1833 was found in a heterozygous or a homozygous state in KS, normal males and normal females; UTS patients were always homozygous. Of the 61 males, 17 were heterozygous, while 11 were TT and 33 were CC. With these observations we can not assure whether these patients present a \"real\" polymorphism. Besides, all males were heterozygous in nucleotides 1678, 1694, 1699, 1708 and 1825, whilst females were homozygous; and in these positions, KAL1 also differs from its pseudogene. These results indicate that we are identifying the X and the Y nucleotide and these variants are not polymorphisms. Sequence variations may be pseudogene products rather than true polymorphisms, so we should always determine if the position where the variation is located differs between KAL1 and its pseudogene, because it has been suggested that the presence of various polymorphisms in affected individuals could be the cause of KS." ], "offsets": [ [ 93, 1609 ] ] } ]

[ { "id": "290", "type": "DNAMutation", "text": [ "T to C substitution at position 1833" ], "offsets": [ [ 256, 292 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "809446" } ] } ]

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[ { "id": "296", "type": "title", "text": [ "A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia." ], "offsets": [ [ 0, 121 ] ] }, { "id": "297", "type": "abstract", "text": [ "OBJECTIVE: Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth. METHODS: Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia. RESULTS: A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation. CONCLUSIONS: These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine." ], "offsets": [ [ 122, 1815 ] ] } ]

[ { "id": "294", "type": "DNAMutation", "text": [ "G-->A substitution at codon 1763" ], "offsets": [ [ 807, 839 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199473631" } ] }, { "id": "295", "type": "ProteinMutation", "text": [ "V1763M" ], "offsets": [ [ 1566, 1572 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199473631" } ] } ]

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[ { "id": "311", "type": "title", "text": [ "Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects." ], "offsets": [ [ 0, 196 ] ] }, { "id": "312", "type": "abstract", "text": [ "BACKGROUND AND AIM: Numerous mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with familial unconjugated hyperbilirubinemia. The UGT1A1 mutation appears to be considerably different among ethnic groups. To clarify the incidence of this gene mutation in the Japanese population, the presence of UGT1A1 mutation was investigated in a group of Japanese patients with Crigler-Najjar syndrome type 2 (CNS2) and Gilbert's syndrome (GS), as well as in healthy anicteric subjects. METHODS: Four patients with CNS2, 63 patients with GS, and 71 healthy subjects were enrolled in the study. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. The PCR products were directly sequenced by a dye terminating method. The UGT1A1 enzyme activity was determined in COS7 cells transfected with wild or P364L (1091 C > T) mutant DNA. RESULTS: Homozygous Y486D was observed in all four patients with CNS2. The GS patients had UGT1A1 mutations with 13 different genotypes in the promoter and coding region. Homozygous TA insertion in the TATA box (TA7) of the promoter region (TA7/7; 33%), homozygous G71R (9%), and combination of TA7/6 and heterozygous G71R (17%) were the most frequent findings in GS patients. Homozygous or heterozygous Y486D (8%) and P229Q (8%) were also observed in GS. A novel mutation, heterozygous P364L, was also identified in a GS patient. In addition to GS patients, homozygous or heterozygous TA7, G71R, and heterozygous Y486D were also observed in healthy subjects. The allele frequency of G71R and TA7 was 0.183 and 0.113 in healthy subjects, respectively. The P364L UGT1A1 enzyme activity was 64.4% lower than the wild-type enzyme activity. CONCLUSIONS: Polymorphisms in the coding region of UGT1A1 were commonly observed in Japanese patients with GS and in healthy subjects. The genetic basis of hyperbilirubinemia appears to be different between the Japanese and Caucasian populations." ], "offsets": [ [ 197, 2240 ] ] } ]

[ { "id": "299", "type": "ProteinMutation", "text": [ "P364L" ], "offsets": [ [ 1126, 1131 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34946978" } ] }, { "id": "300", "type": "DNAMutation", "text": [ "1091 C > T" ], "offsets": [ [ 1133, 1143 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34946978" } ] }, { "id": "301", "type": "ProteinMutation", "text": [ "Y486D" ], "offsets": [ [ 1177, 1182 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34993780" } ] }, { "id": "302", "type": "ProteinMutation", "text": [ "G71R" ], "offsets": [ [ 1422, 1426 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4148323" } ] }, { "id": "303", "type": "ProteinMutation", "text": [ "G71R" ], "offsets": [ [ 1475, 1479 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4148323" } ] }, { "id": "304", "type": "ProteinMutation", "text": [ "Y486D" ], "offsets": [ [ 1561, 1566 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34993780" } ] }, { "id": "305", "type": "ProteinMutation", "text": [ "P229Q" ], "offsets": [ [ 1576, 1581 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "35350960" } ] }, { "id": "306", "type": "ProteinMutation", "text": [ "P364L" ], "offsets": [ [ 1644, 1649 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34946978" } ] }, { "id": "307", "type": "ProteinMutation", "text": [ "G71R" ], "offsets": [ [ 1748, 1752 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4148323" } ] }, { "id": "308", "type": "ProteinMutation", "text": [ "Y486D" ], "offsets": [ [ 1771, 1776 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34993780" } ] }, { "id": "309", "type": "ProteinMutation", "text": [ "G71R" ], "offsets": [ [ 1841, 1845 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4148323" } ] }, { "id": "310", "type": "ProteinMutation", "text": [ "P364L" ], "offsets": [ [ 1913, 1918 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34946978" } ] } ]

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[ { "id": "315", "type": "title", "text": [ "De novo germline mutation in the serine-threonine kinase STK11/LKB1 gene associated with Peutz-Jeghers syndrome." ], "offsets": [ [ 0, 112 ] ] }, { "id": "316", "type": "abstract", "text": [ "Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease, characterized phenotypically by mucocutaneous pigmentation and hamartomatous polyposis. Affected patients are at an increased risk of developing gastrointestinal and other malignancies. Mutations in the STK11/LKB1 (LKB1) gene, which encodes for a serine-threonine kinase, have been identified as a genetic cause of PJS. Molecular analysis of the LKB1 gene in a simplex case of PJS revealed a substitution of cytosine (C) for guanine (G) at codon 246 in exon 6, resulting in the Tyr246X mutation. The nucleotide substitution leads to a premature stop codon at the 246 residue, predicting a truncated protein and presumed loss of kinase activity. Analysis of DNA from both parents of the PJS patient did not show this mutation, which is therefore a de novo mutation. We isolated DNA from microdissected gastrointestinal hamartomatous polyps in the PJS patient and investigated the loss of heterozygosity (LOH) at the LKB1 locus by real-time fluorescence polymerase chain reaction genotyping using a fluorescent resonance energy transfer technique. The results suggest a different mechanism from LOH in the formation of hamartomatous polyps." ], "offsets": [ [ 113, 1314 ] ] } ]

[ { "id": "314", "type": "ProteinMutation", "text": [ "Tyr246X" ], "offsets": [ [ 654, 661 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137853083" } ] } ]

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[ { "id": "322", "type": "title", "text": [ "Polymorphisms in the CYP1B1 gene are associated with increased risk of prostate cancer." ], "offsets": [ [ 0, 87 ] ] }, { "id": "323", "type": "abstract", "text": [ "CYP1B1 has been evaluated as a candidate gene for various cancers because of its function in activating environmental procarcinogens and catalysing the conversion of oestrogens to genotoxic catechol oestrogens. To test the hypothesis that genetic polymorphisms in the CYP1B1 gene may associate with the risk for prostate cancer (CaP), we compared the allele, genotype, and haplotype frequencies of 13 single nucleotide polymorphisms (SNPs) of CYP1B1 among 159 hereditary prostate cancer (HPC) probands, 245 sporadic CaP cases, and 222 unaffected men. When each of the SNPs was analysed separately, marginally significant differences were observed for allele frequencies between sporadic cases and controls for three consecutive SNPs (-1001C/T, -263G/A, and -13C/T, P=0.04-0.07). Similarly, marginally significant differences between sporadic cases and controls in the frequency of variant allele carriers were observed for five consecutive SNPs (-1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T, P=0.02-0.08). Interestingly, when the combination of these five SNPs was analysed using a haplotype approach, a larger difference was found (P=0.009). One frequent haplotype (C-G-C-C-G of -1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T) was associated with an increased risk for CaP, while the other frequent haplotype (T-A-T-G-T) was associated with a decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for CaP." ], "offsets": [ [ 88, 1548 ] ] } ]

[ { "id": "318", "type": "DNAMutation", "text": [ "+142C/G" ], "offsets": [ [ 1061, 1068 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "10012" } ] }, { "id": "319", "type": "DNAMutation", "text": [ "+355G/T" ], "offsets": [ [ 1074, 1081 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056827" } ] }, { "id": "320", "type": "DNAMutation", "text": [ "+142C/G" ], "offsets": [ [ 1298, 1305 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "10012" } ] }, { "id": "321", "type": "DNAMutation", "text": [ "+355G/T" ], "offsets": [ [ 1311, 1318 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056827" } ] } ]

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[ { "id": "331", "type": "title", "text": [ "Genetic polymorphism of the renin-angiotensin-aldosterone system and arterial hypertension in the Italian population: the GENIPER Project." ], "offsets": [ [ 0, 138 ] ] }, { "id": "332", "type": "abstract", "text": [ "OBJECTIVE: To detect the association of single polymorphisms of the renin-angiotensin-aldosterone system (RAAS), or different combinations thereof, with hypertension. DESIGN AND METHODS: The GENIPER database is the result of a collaborative effort of 13 Italian research centres to collect genomic DNA in subjects well characterized in terms of blood pressure status. A total of 2461 subjects (normotensive = 611; hypertensive = 1850) were selected and genotyped for the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) T/C704, angiotensin receptor type 1 (AT1) A/C1166 and aldosterone synthase (ALDO) T/C-344 genetic variants. RESULTS: Allele frequencies were homogeneous over the Italian territory, with the relevant exception of the ACE I/D, the D allele being significantly less frequent in the northern region (61%) than in the rest of the country (67%; P < 0.0001). When comparing allele and genotype distributions in normotensives and hypertensives, the latter presented a small but statistically significant increase of the C allele of AGT T/C704, the A allele of AT1 A/C1166 and the T allele of ALDO T/C-344 polymorphisms (P = 0.018, P = 0.037 and P = 0.015, respectively), with similar trends all over the country. A step-wise logistic regression analysis confirmed these findings, by entering in the model as independent predictors of blood pressure status of AGT T/C704 (P = 0.013), ALDO T/C-344 (P = 0.032) and AT1 A/C1166 polymorphisms (P = 0.075), but not ACE I/D (P = 0.996). We also found some evidence of an additive effect of individual genetic variants of the RAAS, modulating at different levels the same functional pathway, on the risk of developing hypertension, but no synergistic interaction was observed. CONCLUSIONS: Our results suggest that some allelic variants of RAAS genes carry a small but identifiable risk of developing arterial hypertension." ], "offsets": [ [ 139, 2049 ] ] } ]

[ { "id": "325", "type": "DNAMutation", "text": [ "A/C1166" ], "offsets": [ [ 734, 741 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] }, { "id": "326", "type": "DNAMutation", "text": [ "T/C-344" ], "offsets": [ [ 774, 781 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799998" } ] }, { "id": "327", "type": "DNAMutation", "text": [ "A/C1166" ], "offsets": [ [ 1248, 1255 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] }, { "id": "328", "type": "DNAMutation", "text": [ "T/C-344" ], "offsets": [ [ 1281, 1288 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799998" } ] }, { "id": "329", "type": "DNAMutation", "text": [ "T/C-344" ], "offsets": [ [ 1572, 1579 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799998" } ] }, { "id": "330", "type": "DNAMutation", "text": [ "A/C1166" ], "offsets": [ [ 1600, 1607 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] } ]

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[ { "id": "335", "type": "title", "text": [ "Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections." ], "offsets": [ [ 0, 144 ] ] }, { "id": "336", "type": "abstract", "text": [ "We identified previously a patient with recurrent bacterial infections who failed to respond to gram-negative LPS in vivo, and whose leukocytes were profoundly hyporesponsive to LPS and IL-1 in vitro. We now demonstrate that this patient also exhibits deficient responses in a skin blister model of aseptic inflammation. A lack of IL-18 responsiveness, coupled with diminished LPS and/or IL-1-induced nuclear factor-kappaB and activator protein-1 translocation, p38 phosphorylation, gene expression, and dysregulated IL-1R-associated kinase (IRAK)-1 activity in vitro support the hypothesis that the defect lies within the signaling pathway common to toll-like receptor 4, IL-1R, and IL-18R. This patient expresses a \"compound heterozygous\" genotype, with a point mutation (C877T in cDNA) and a two-nucleotide, AC deletion (620-621del in cDNA) encoded by distinct alleles of the IRAK-4 gene (GenBank/EMBL/DDBJ accession nos. AF445802 and AY186092). Both mutations encode proteins with an intact death domain, but a truncated kinase domain, thereby precluding expression of full-length IRAK-4 (i.e., a recessive phenotype). When overexpressed in HEK293T cells, neither truncated form augmented endogenous IRAK-1 kinase activity, and both inhibited endogenous IRAK-1 activity modestly. Thus, IRAK-4 is pivotal in the development of a normal inflammatory response initiated by bacterial or nonbacterial insults." ], "offsets": [ [ 145, 1553 ] ] } ]

[ { "id": "334", "type": "DNAMutation", "text": [ "C877T in cDNA" ], "offsets": [ [ 919, 932 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908002" } ] } ]

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[ { "id": "340", "type": "title", "text": [ "Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion." ], "offsets": [ [ 0, 86 ] ] }, { "id": "341", "type": "abstract", "text": [ "The onset of type 2 diabetes (T2DM) is preceded by obesity, insulin resistance, and impaired beta-cell function. Uncoupling protein-2 (UCP2) is a widely expressed inner mitochondrial membrane protein. Common polymorphisms of the UCP2 gene have been implicated in diabetes, in obesity, and with changes in UCP2 mRNA levels. We tested the hypothesis that common UCP2 variants influence T2DM susceptibility in four parallel studies of separate populations. We typed the -866 promoter (G/A) variant, a nonsynonymous (Ala55Val or A55V) single-nucleotide polymorphism in exon 4, and a 45-nt insertion in the 3'-untranslated (3'UTR) region. Study populations included a case-control population study, a family-based association study, and a metabolic study of individuals who had been characterized for insulin sensitivity and secretion. To evaluate UCP2 mRNA levels, we examined a fourth population of subjects, who had undergone subcutaneous fat biopsy. All three variants showed a trend to an association with T2DM (P = 0.05 to 0.07) in the population but not the family-based association study. The 3' insertion/deletion (3'UTR I/D) variant was associated with body mass index (BMI, P = 0.035) among nondiabetic family members. Haplotype combinations were significantly associated with BMI (P = 0.028), triglyceride levels (P = 0.026), and fasting insulin (P = 0.029); highest values for the three traits were observed in individuals with the heterozygous combination GVI/AVD. In the metabolic study, all three variants were associated with an index of beta-cell compensation for insulin sensitivity (disposition index), particularly in interaction with family membership (P < 0.000001). Individuals homozygous for the -866 A allele had decreased adipose mRNA levels relative to GG homozygous individuals (P = 0.009), but the 3'UTR I/D variant had no impact on mRNA levels. We confirm modest effects of UCP2 variants on BMI and T2DM and show significant effects on insulin secretion in interaction with family-specific factors. However, the associated allele and the effects on gene expression are opposite to those reported previously." ], "offsets": [ [ 87, 2220 ] ] } ]

[ { "id": "338", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 600, 608 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "660339" } ] }, { "id": "339", "type": "ProteinMutation", "text": [ "A55V" ], "offsets": [ [ 612, 616 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "660339" } ] } ]

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[ { "id": "349", "type": "title", "text": [ "A novel missense mutation Asp506Gly in Exon 13 of the F11 gene in an asymptomatic Korean woman with mild factor XI deficiency." ], "offsets": [ [ 0, 126 ] ] }, { "id": "350", "type": "abstract", "text": [ "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." ], "offsets": [ [ 127, 1375 ] ] } ]

[ { "id": "343", "type": "ProteinMutation", "text": [ "Asp506Gly" ], "offsets": [ [ 26, 35 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "281875258" } ] }, { "id": "344", "type": "DNAMutation", "text": [ "c.1517A>G" ], "offsets": [ [ 1109, 1118 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "281875258" } ] }, { "id": "345", "type": "ProteinMutation", "text": [ "p.Asp506Gly" ], "offsets": [ [ 1206, 1217 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "281875258" } ] }, { "id": "346", "type": "ProteinMutation", "text": [ "Asp506Gly" ], "offsets": [ [ 1254, 1263 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "281875258" } ] }, { "id": "347", "type": "ProteinMutation", "text": [ "aspartic acid with glycine in codon 506" ], "offsets": [ [ 1165, 1204 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "281875258" } ] }, { "id": "348", "type": "DNAMutation", "text": [ "A to G substitution in nucleotide 1517" ], "offsets": [ [ 1069, 1107 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "281875258" } ] } ]

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[ { "id": "354", "type": "title", "text": [ "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." ], "offsets": [ [ 0, 199 ] ] }, { "id": "355", "type": "abstract", "text": [ "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." ], "offsets": [ [ 200, 1544 ] ] } ]

[ { "id": "352", "type": "DNAMutation", "text": [ "T10191C" ], "offsets": [ [ 909, 916 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267606890" } ] }, { "id": "353", "type": "ProteinMutation", "text": [ "p.S45P" ], "offsets": [ [ 918, 924 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267606890" } ] } ]

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[ { "id": "367", "type": "title", "text": [ "APOE genotype-function relationship: evidence of -491 A/T promoter polymorphism modifying transcription control but not type 2 diabetes risk." ], "offsets": [ [ 0, 141 ] ] }, { "id": "368", "type": "abstract", "text": [ "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." ], "offsets": [ [ 142, 2226 ] ] } ]

[ { "id": "357", "type": "DNAMutation", "text": [ "-491 A/T" ], "offsets": [ [ 49, 57 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "449647" } ] }, { "id": "358", "type": "DNAMutation", "text": [ "-491A/T" ], "offsets": [ [ 745, 752 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "449647" } ] }, { "id": "359", "type": "SNP", "text": [ "rs449647" ], "offsets": [ [ 754, 762 ] ], "normalized": [] }, { "id": "360", "type": "DNAMutation", "text": [ "-491A/T" ], "offsets": [ [ 1553, 1560 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "449647" } ] }, { "id": "361", "type": "DNAMutation", "text": [ "-491A/T" ], "offsets": [ [ 1748, 1755 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "449647" } ] }, { "id": "362", "type": "DNAMutation", "text": [ "-219G/T" ], "offsets": [ [ 1757, 1764 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "405509" } ] }, { "id": "363", "type": "SNP", "text": [ "rs405509" ], "offsets": [ [ 1766, 1774 ] ], "normalized": [] }, { "id": "364", "type": "DNAMutation", "text": [ "+113G/C" ], "offsets": [ [ 1781, 1788 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "440446" } ] }, { "id": "365", "type": "SNP", "text": [ "rs440446" ], "offsets": [ [ 1790, 1798 ] ], "normalized": [] }, { "id": "366", "type": "DNAMutation", "text": [ "-491A/T" ], "offsets": [ [ 2011, 2018 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "449647" } ] } ]

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[ { "id": "375", "type": "title", "text": [ "Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis." ], "offsets": [ [ 0, 136 ] ] }, { "id": "376", "type": "abstract", "text": [ "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." ], "offsets": [ [ 137, 1925 ] ] } ]

[ { "id": "370", "type": "DNAMutation", "text": [ "677 C>T" ], "offsets": [ [ 22, 29 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "371", "type": "DNAMutation", "text": [ "677C>T" ], "offsets": [ [ 360, 366 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "372", "type": "DNAMutation", "text": [ "677C>T" ], "offsets": [ [ 938, 944 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "373", "type": "DNAMutation", "text": [ "677C>T" ], "offsets": [ [ 1639, 1645 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "374", "type": "DNAMutation", "text": [ "677C>T" ], "offsets": [ [ 1708, 1714 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] } ]

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[ { "id": "383", "type": "title", "text": [ "SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda." ], "offsets": [ [ 0, 74 ] ] }, { "id": "384", "type": "abstract", "text": [ "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." ], "offsets": [ [ 75, 1819 ] ] } ]

[ { "id": "378", "type": "DNAMutation", "text": [ "G to A substitution in nucleotide 256" ], "offsets": [ [ 1105, 1142 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28937888" } ] }, { "id": "379", "type": "ProteinMutation", "text": [ "glycine to arginine substitution at amino acid 86" ], "offsets": [ [ 1182, 1231 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28937888" } ] }, { "id": "380", "type": "ProteinMutation", "text": [ "G86R" ], "offsets": [ [ 1233, 1237 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28937888" } ] }, { "id": "381", "type": "ProteinMutation", "text": [ "G86R" ], "offsets": [ [ 1496, 1500 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28937888" } ] }, { "id": "382", "type": "ProteinMutation", "text": [ "G86R" ], "offsets": [ [ 1689, 1693 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28937888" } ] } ]

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[ { "id": "390", "type": "title", "text": [ "Impact of 5,10-methylenetetrahydrofolate reductase gene polymorphism on neural tube defects." ], "offsets": [ [ 0, 92 ] ] }, { "id": "391", "type": "abstract", "text": [ "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." ], "offsets": [ [ 93, 2073 ] ] } ]

[ { "id": "386", "type": "DNAMutation", "text": [ "C-->T transition at nucleotide 677" ], "offsets": [ [ 471, 505 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "387", "type": "DNAMutation", "text": [ "677 C-->T" ], "offsets": [ [ 780, 789 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "388", "type": "DNAMutation", "text": [ "C677T" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] }, { "id": "389", "type": "DNAMutation", "text": [ "677 C-->T" ], "offsets": [ [ 1443, 1452 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801133" } ] } ]

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[ { "id": "396", "type": "title", "text": [ "Novel CRELD1 gene mutations in patients with atrioventricular septal defect." ], "offsets": [ [ 0, 76 ] ] }, { "id": "397", "type": "abstract", "text": [ "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." ], "offsets": [ [ 77, 1638 ] ] } ]

[ { "id": "393", "type": "DNAMutation", "text": [ "c.973G>A" ], "offsets": [ [ 1203, 1211 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "755981922" } ] }, { "id": "394", "type": "ProteinMutation", "text": [ "lysine for glutamic acid at amino acid 325" ], "offsets": [ [ 1263, 1305 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "755981922" } ] }, { "id": "395", "type": "ProteinMutation", "text": [ "E325K" ], "offsets": [ [ 1307, 1312 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "755981922" } ] } ]

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[ { "id": "409", "type": "title", "text": [ "Association of DNA polymorphisms within the CYP11B2/CYP11B1 locus and postoperative hypertension risk in the patients with aldosterone-producing adenomas." ], "offsets": [ [ 0, 154 ] ] }, { "id": "410", "type": "abstract", "text": [ "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." ], "offsets": [ [ 155, 2031 ] ] } ]

[ { "id": "399", "type": "SNP", "text": [ "rs1799998" ], "offsets": [ [ 791, 800 ] ], "normalized": [] }, { "id": "400", "type": "DNAMutation", "text": [ "C-344 T" ], "offsets": [ [ 802, 809 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799998" } ] }, { "id": "401", "type": "SNP", "text": [ "rs4539" ], "offsets": [ [ 833, 839 ] ], "normalized": [] }, { "id": "402", "type": "DNAMutation", "text": [ "A2718G" ], "offsets": [ [ 841, 847 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4539" } ] }, { "id": "403", "type": "SNP", "text": [ "rs6410" ], "offsets": [ [ 868, 874 ] ], "normalized": [] }, { "id": "404", "type": "DNAMutation", "text": [ "G22 5A" ], "offsets": [ [ 876, 882 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6410" } ] }, { "id": "405", "type": "SNP", "text": [ "rs6387" ], "offsets": [ [ 885, 891 ] ], "normalized": [] }, { "id": "406", "type": "DNAMutation", "text": [ "A2803G" ], "offsets": [ [ 893, 899 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6387" } ] }, { "id": "407", "type": "SNP", "text": [ "rs4539" ], "offsets": [ [ 1232, 1238 ] ], "normalized": [] }, { "id": "408", "type": "SNP", "text": [ "rs4539" ], "offsets": [ [ 1763, 1769 ] ], "normalized": [] } ]

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[ { "id": "414", "type": "title", "text": [ "Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier." ], "offsets": [ [ 0, 77 ] ] }, { "id": "415", "type": "abstract", "text": [ "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." ], "offsets": [ [ 78, 1365 ] ] } ]

[ { "id": "412", "type": "ProteinMutation", "text": [ "E831X" ], "offsets": [ [ 575, 580 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "397508387" } ] }, { "id": "413", "type": "DNAMutation", "text": [ "2623G>T" ], "offsets": [ [ 591, 598 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "397508387" } ] } ]

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[ { "id": "420", "type": "title", "text": [ "A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient." ], "offsets": [ [ 0, 90 ] ] }, { "id": "421", "type": "abstract", "text": [ "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." ], "offsets": [ [ 91, 1654 ] ] } ]

[ { "id": "417", "type": "DNAMutation", "text": [ "c.899A > T" ], "offsets": [ [ 1150, 1160 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "179363874" } ] }, { "id": "418", "type": "ProteinMutation", "text": [ "Asp to Val at the 300" ], "offsets": [ [ 1231, 1252 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "179363874" } ] }, { "id": "419", "type": "ProteinMutation", "text": [ "Asp 300 Val" ], "offsets": [ [ 1421, 1432 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "179363874" } ] } ]

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[ { "id": "431", "type": "title", "text": [ "A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population." ], "offsets": [ [ 0, 165 ] ] }, { "id": "432", "type": "abstract", "text": [ "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." ], "offsets": [ [ 166, 1709 ] ] } ]

[ { "id": "423", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 302, 308 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "424", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 471, 477 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "425", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 658, 664 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "426", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 814, 820 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "427", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 1009, 1015 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "428", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 1042, 1048 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "429", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 1481, 1487 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] }, { "id": "430", "type": "DNAMutation", "text": [ "G-395A" ], "offsets": [ [ 1603, 1609 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1207568" } ] } ]

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[ { "id": "438", "type": "title", "text": [ "COL3A1 2209G>A is a predictor of pelvic organ prolapse." ], "offsets": [ [ 0, 55 ] ] }, { "id": "439", "type": "abstract", "text": [ "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." ], "offsets": [ [ 56, 1119 ] ] } ]

[ { "id": "434", "type": "DNAMutation", "text": [ "2209G>A" ], "offsets": [ [ 7, 14 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800255" } ] }, { "id": "435", "type": "DNAMutation", "text": [ "2209G>A" ], "offsets": [ [ 842, 849 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800255" } ] }, { "id": "436", "type": "SNP", "text": [ "rs1800255" ], "offsets": [ [ 851, 860 ] ], "normalized": [] }, { "id": "437", "type": "DNAMutation", "text": [ "2209G>A" ], "offsets": [ [ 1048, 1055 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800255" } ] } ]

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[ { "id": "443", "type": "title", "text": [ "A novel ATP7A gross deletion mutation in a Korean patient with Menkes disease." ], "offsets": [ [ 0, 78 ] ] }, { "id": "444", "type": "abstract", "text": [ "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." ], "offsets": [ [ 79, 1163 ] ] } ]

[ { "id": "441", "type": "DNAMutation", "text": [ "c.3943G>A" ], "offsets": [ [ 582, 591 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "797045390" } ] }, { "id": "442", "type": "ProteinMutation", "text": [ "p.G1315R" ], "offsets": [ [ 593, 601 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "797045390" } ] } ]

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[ { "id": "448", "type": "title", "text": [ "Genetic polymorphism in chemokine CCL22 and susceptibility to Helicobacter pylori infection-related gastric carcinoma." ], "offsets": [ [ 0, 118 ] ] }, { "id": "449", "type": "abstract", "text": [ "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." ], "offsets": [ [ 119, 1956 ] ] } ]

[ { "id": "446", "type": "DNAMutation", "text": [ "16C-->A" ], "offsets": [ [ 956, 963 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4359426" } ] }, { "id": "447", "type": "SNP", "text": [ "reference SNP no. 4359426" ], "offsets": [ [ 969, 994 ] ], "normalized": [] } ]

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[ { "id": "453", "type": "title", "text": [ "A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan." ], "offsets": [ [ 0, 132 ] ] }, { "id": "454", "type": "abstract", "text": [ "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." ], "offsets": [ [ 133, 1826 ] ] } ]

[ { "id": "451", "type": "DNAMutation", "text": [ "c.6799G --> A" ], "offsets": [ [ 922, 935 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "545688154" } ] }, { "id": "452", "type": "ProteinMutation", "text": [ "p.D2267N" ], "offsets": [ [ 953, 961 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "545688154" } ] } ]

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[ { "id": "457", "type": "title", "text": [ "Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome." ], "offsets": [ [ 0, 71 ] ] }, { "id": "458", "type": "abstract", "text": [ "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." ], "offsets": [ [ 72, 1621 ] ] } ]

[ { "id": "456", "type": "ProteinMutation", "text": [ "Arg282Trp" ], "offsets": [ [ 415, 424 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28934574" } ] } ]

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[ { "id": "464", "type": "title", "text": [ "Genetics of Meesmann corneal dystrophy: a novel mutation in the keratin 3 gene in an asymptomatic family suggests genotype-phenotype correlation." ], "offsets": [ [ 0, 145 ] ] }, { "id": "465", "type": "abstract", "text": [ "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)." ], "offsets": [ [ 146, 1991 ] ] } ]

[ { "id": "460", "type": "DNAMutation", "text": [ "1493A>T" ], "offsets": [ [ 1378, 1385 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267607431" } ] }, { "id": "461", "type": "ProteinMutation", "text": [ "E498V" ], "offsets": [ [ 1510, 1515 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267607431" } ] }, { "id": "462", "type": "ProteinMutation", "text": [ "E498V" ], "offsets": [ [ 1829, 1834 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267607431" } ] }, { "id": "463", "type": "ProteinMutation", "text": [ "glutamic acid for valine at codon 498" ], "offsets": [ [ 1471, 1508 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267607431" } ] } ]

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[ { "id": "470", "type": "title", "text": [ "Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors." ], "offsets": [ [ 0, 107 ] ] }, { "id": "471", "type": "abstract", "text": [ "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." ], "offsets": [ [ 108, 1753 ] ] } ]

[ { "id": "467", "type": "ProteinMutation", "text": [ "Ile(146)-->Leu" ], "offsets": [ [ 806, 820 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72478580" } ] }, { "id": "468", "type": "ProteinMutation", "text": [ "I146L" ], "offsets": [ [ 963, 968 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72478580" } ] }, { "id": "469", "type": "ProteinMutation", "text": [ "I146L" ], "offsets": [ [ 1354, 1359 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72478580" } ] } ]

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[ { "id": "479", "type": "title", "text": [ "Catechol-O-methyltransferase (COMT) gene variants: possible association of the Val158Met variant with opiate addiction in Hispanic women." ], "offsets": [ [ 0, 137 ] ] }, { "id": "480", "type": "abstract", "text": [ "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." ], "offsets": [ [ 138, 1463 ] ] } ]

[ { "id": "473", "type": "ProteinMutation", "text": [ "Val158Met" ], "offsets": [ [ 79, 88 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4680" } ] }, { "id": "474", "type": "DNAMutation", "text": [ "G472A" ], "offsets": [ [ 341, 346 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4680" } ] }, { "id": "475", "type": "ProteinMutation", "text": [ "Val158Met" ], "offsets": [ [ 360, 369 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4680" } ] }, { "id": "476", "type": "DNAMutation", "text": [ "G472A" ], "offsets": [ [ 679, 684 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4680" } ] }, { "id": "477", "type": "DNAMutation", "text": [ "G472A" ], "offsets": [ [ 899, 904 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4680" } ] }, { "id": "478", "type": "DNAMutation", "text": [ "G472A" ], "offsets": [ [ 973, 978 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4680" } ] } ]

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[ { "id": "484", "type": "title", "text": [ "Histamine-N-methyl transferase polymorphism and risk for migraine." ], "offsets": [ [ 0, 66 ] ] }, { "id": "485", "type": "abstract", "text": [ "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." ], "offsets": [ [ 67, 1168 ] ] } ]

[ { "id": "482", "type": "DNAMutation", "text": [ "C314T" ], "offsets": [ [ 387, 392 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "11558538" } ] }, { "id": "483", "type": "ProteinMutation", "text": [ "Thr105Ile" ], "offsets": [ [ 429, 438 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "11558538" } ] } ]

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[ { "id": "491", "type": "title", "text": [ "A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance." ], "offsets": [ [ 0, 152 ] ] }, { "id": "492", "type": "abstract", "text": [ "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." ], "offsets": [ [ 153, 2071 ] ] } ]

[ { "id": "487", "type": "DNAMutation", "text": [ "(T --> C) substitution at position 2209" ], "offsets": [ [ 793, 832 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909727" } ] }, { "id": "488", "type": "ProteinMutation", "text": [ "phenylalanine (F) to leucine (L) substitution at amino acid position 737" ], "offsets": [ [ 882, 954 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909727" } ] }, { "id": "489", "type": "ProteinMutation", "text": [ "F737L" ], "offsets": [ [ 1082, 1087 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909727" } ] }, { "id": "490", "type": "ProteinMutation", "text": [ "F737L" ], "offsets": [ [ 1697, 1702 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909727" } ] } ]

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[ { "id": "498", "type": "title", "text": [ "A novel \"pearl box\" cataract associated with a mutation in the connexin 46 (GJA3) gene." ], "offsets": [ [ 0, 87 ] ] }, { "id": "499", "type": "abstract", "text": [ "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." ], "offsets": [ [ 88, 1508 ] ] } ]

[ { "id": "494", "type": "DNAMutation", "text": [ "C260T" ], "offsets": [ [ 743, 748 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "864309687" } ] }, { "id": "495", "type": "DNAMutation", "text": [ "C260T" ], "offsets": [ [ 934, 939 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "864309687" } ] }, { "id": "496", "type": "ProteinMutation", "text": [ "threonine at position 87 by methionine" ], "offsets": [ [ 1053, 1091 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "864309687" } ] }, { "id": "497", "type": "ProteinMutation", "text": [ "T87M" ], "offsets": [ [ 1093, 1097 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "864309687" } ] } ]

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[ { "id": "502", "type": "title", "text": [ "Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease." ], "offsets": [ [ 0, 138 ] ] }, { "id": "503", "type": "abstract", "text": [ "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." ], "offsets": [ [ 139, 2770 ] ] } ]

[ { "id": "501", "type": "ProteinMutation", "text": [ "D299G" ], "offsets": [ [ 2271, 2276 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4986790" } ] } ]

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[ { "id": "509", "type": "title", "text": [ "The G51S purine nucleoside phosphorylase polymorphism is associated with cognitive decline in Alzheimer's disease patients." ], "offsets": [ [ 0, 123 ] ] }, { "id": "510", "type": "abstract", "text": [ "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." ], "offsets": [ [ 124, 1627 ] ] } ]

[ { "id": "505", "type": "ProteinMutation", "text": [ "G51S" ], "offsets": [ [ 4, 8 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049564" } ] }, { "id": "506", "type": "ProteinMutation", "text": [ "serine to glycine at position 51" ], "offsets": [ [ 832, 864 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049564" } ] }, { "id": "507", "type": "ProteinMutation", "text": [ "G51S" ], "offsets": [ [ 866, 870 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049564" } ] }, { "id": "508", "type": "ProteinMutation", "text": [ "G51S" ], "offsets": [ [ 1428, 1432 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049564" } ] } ]

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[ { "id": "516", "type": "title", "text": [ "Monocyte chemotactic protein-1 single nucleotide polymorphisms do not confer susceptibility for the development of adult onset polymyositis/dermatomyositis in UK Caucasians." ], "offsets": [ [ 0, 173 ] ] }, { "id": "517", "type": "abstract", "text": [ "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." ], "offsets": [ [ 174, 1759 ] ] } ]

[ { "id": "512", "type": "SNP", "text": [ "rs2857657" ], "offsets": [ [ 924, 933 ] ], "normalized": [] }, { "id": "513", "type": "SNP", "text": [ "rs4586" ], "offsets": [ [ 949, 955 ] ], "normalized": [] }, { "id": "514", "type": "SNP", "text": [ "rs13900" ], "offsets": [ [ 995, 1002 ] ], "normalized": [] }, { "id": "515", "type": "SNP", "text": [ "rs3917887" ], "offsets": [ [ 1067, 1076 ] ], "normalized": [] } ]

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[ { "id": "523", "type": "title", "text": [ "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." ], "offsets": [ [ 0, 168 ] ] }, { "id": "524", "type": "abstract", "text": [ "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." ], "offsets": [ [ 169, 1570 ] ] } ]

[ { "id": "519", "type": "DNAMutation", "text": [ "c.32C>T" ], "offsets": [ [ 482, 489 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030878" } ] }, { "id": "520", "type": "ProteinMutation", "text": [ "p.I11T" ], "offsets": [ [ 530, 536 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030878" } ] }, { "id": "521", "type": "ProteinMutation", "text": [ "p.I11T" ], "offsets": [ [ 1036, 1042 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030878" } ] }, { "id": "522", "type": "ProteinMutation", "text": [ "p.I11T" ], "offsets": [ [ 1131, 1137 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030878" } ] } ]

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[ { "id": "529", "type": "title", "text": [ "Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients." ], "offsets": [ [ 0, 90 ] ] }, { "id": "530", "type": "abstract", "text": [ "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." ], "offsets": [ [ 91, 1187 ] ] } ]

[ { "id": "526", "type": "DNAMutation", "text": [ "c.646G > C" ], "offsets": [ [ 872, 882 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801968" } ] }, { "id": "527", "type": "ProteinMutation", "text": [ "Asp216His" ], "offsets": [ [ 884, 893 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801968" } ] }, { "id": "528", "type": "DNAMutation", "text": [ "904-906delGAG" ], "offsets": [ [ 1027, 1040 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80358233" } ] } ]

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[ { "id": "543", "type": "title", "text": [ "A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes." ], "offsets": [ [ 0, 141 ] ] }, { "id": "544", "type": "abstract", "text": [ "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." ], "offsets": [ [ 142, 1824 ] ] } ]

[ { "id": "532", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 27, 32 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "13306592" } ] }, { "id": "533", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 187, 192 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41511344" } ] }, { "id": "534", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 611, 616 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41511344" } ] }, { "id": "535", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 671, 676 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41511344" } ] }, { "id": "536", "type": "ProteinMutation", "text": [ "S810L" ], "offsets": [ [ 734, 739 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41511344" } ] }, { "id": "537", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 872, 877 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "13306592" } ] }, { "id": "538", "type": "ProteinMutation", "text": [ "L809L" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "145670736" } ] }, { "id": "539", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1022, 1027 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "13306592" } ] }, { "id": "540", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1123, 1128 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "13306592" } ] }, { "id": "541", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1315, 1320 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "13306592" } ] }, { "id": "542", "type": "ProteinMutation", "text": [ "F826Y" ], "offsets": [ [ 1628, 1633 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "13306592" } ] } ]

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[ { "id": "550", "type": "title", "text": [ "Genetic homogeneity for inherited congenital microcoria loci in an Asian Indian pedigree." ], "offsets": [ [ 0, 89 ] ] }, { "id": "551", "type": "abstract", "text": [ "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." ], "offsets": [ [ 90, 2653 ] ] } ]

[ { "id": "546", "type": "DNAMutation", "text": [ "144 G>A" ], "offsets": [ [ 1433, 1440 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315339" } ] }, { "id": "547", "type": "ProteinMutation", "text": [ "Q48H" ], "offsets": [ [ 1457, 1461 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315339" } ] }, { "id": "548", "type": "ProteinMutation", "text": [ "Q48H" ], "offsets": [ [ 2294, 2298 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315339" } ] }, { "id": "549", "type": "ProteinMutation", "text": [ "Q48H" ], "offsets": [ [ 2611, 2615 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315339" } ] } ]

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[ { "id": "560", "type": "title", "text": [ "Segregation of a M404V mutation of the p62/sequestosome 1 (p62/SQSTM1) gene with polyostotic Paget's disease of bone in an Italian family." ], "offsets": [ [ 0, 138 ] ] }, { "id": "561", "type": "abstract", "text": [ "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." ], "offsets": [ [ 139, 1967 ] ] } ]

[ { "id": "553", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 17, 22 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] }, { "id": "554", "type": "ProteinMutation", "text": [ "methionine-->valine substitution at codon 404" ], "offsets": [ [ 298, 343 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] }, { "id": "555", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 345, 350 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] }, { "id": "556", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 646, 651 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] }, { "id": "557", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 991, 996 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] }, { "id": "558", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 1317, 1322 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] }, { "id": "559", "type": "ProteinMutation", "text": [ "M404V" ], "offsets": [ [ 1572, 1577 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "771966860" } ] } ]

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[ { "id": "566", "type": "title", "text": [ "Genetic variation in UCP2 (uncoupling protein-2) is associated with energy metabolism in Pima Indians." ], "offsets": [ [ 0, 102 ] ] }, { "id": "567", "type": "abstract", "text": [ "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." ], "offsets": [ [ 103, 1945 ] ] } ]

[ { "id": "563", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 752, 760 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "660339" } ] }, { "id": "564", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 983, 991 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "660339" } ] }, { "id": "565", "type": "ProteinMutation", "text": [ "Ala55Val" ], "offsets": [ [ 1193, 1201 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "660339" } ] } ]

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[ { "id": "572", "type": "title", "text": [ "Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies." ], "offsets": [ [ 0, 136 ] ] }, { "id": "573", "type": "abstract", "text": [ "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." ], "offsets": [ [ 137, 1802 ] ] } ]

[ { "id": "569", "type": "DNAMutation", "text": [ "643C>T" ], "offsets": [ [ 588, 594 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34767364" } ] }, { "id": "570", "type": "ProteinMutation", "text": [ "R215W" ], "offsets": [ [ 596, 601 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34767364" } ] }, { "id": "571", "type": "ProteinMutation", "text": [ "R215W" ], "offsets": [ [ 1096, 1101 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "34767364" } ] } ]

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[ { "id": "579", "type": "title", "text": [ "Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G." ], "offsets": [ [ 0, 89 ] ] }, { "id": "580", "type": "abstract", "text": [ "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." ], "offsets": [ [ 90, 1559 ] ] } ]

[ { "id": "575", "type": "DNAMutation", "text": [ "A118G" ], "offsets": [ [ 83, 88 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799971" } ] }, { "id": "576", "type": "DNAMutation", "text": [ "A118G" ], "offsets": [ [ 356, 361 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799971" } ] }, { "id": "577", "type": "ProteinMutation", "text": [ "N40D" ], "offsets": [ [ 377, 381 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799971" } ] }, { "id": "578", "type": "DNAMutation", "text": [ "A118G" ], "offsets": [ [ 553, 558 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799971" } ] } ]

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[ { "id": "586", "type": "title", "text": [ "DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers." ], "offsets": [ [ 0, 108 ] ] }, { "id": "587", "type": "abstract", "text": [ "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." ], "offsets": [ [ 109, 1566 ] ] } ]

[ { "id": "582", "type": "ProteinMutation", "text": [ "R194W" ], "offsets": [ [ 439, 444 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1799782" } ] }, { "id": "583", "type": "ProteinMutation", "text": [ "R399Q" ], "offsets": [ [ 446, 451 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "25487" } ] }, { "id": "584", "type": "ProteinMutation", "text": [ "T241M" ], "offsets": [ [ 532, 537 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "861539" } ] }, { "id": "585", "type": "ProteinMutation", "text": [ "I134T" ], "offsets": [ [ 593, 598 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28360135" } ] } ]

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[ { "id": "591", "type": "title", "text": [ "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." ], "offsets": [ [ 0, 167 ] ] }, { "id": "592", "type": "abstract", "text": [ "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." ], "offsets": [ [ 168, 1419 ] ] } ]

[ { "id": "589", "type": "ProteinMutation", "text": [ "Asn45Ser" ], "offsets": [ [ 69, 77 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030764" } ] }, { "id": "590", "type": "ProteinMutation", "text": [ "Asn45Ser" ], "offsets": [ [ 1215, 1223 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030764" } ] } ]

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[ { "id": "595", "type": "title", "text": [ "Genetic variation in apolipoprotein D and Alzheimer's disease." ], "offsets": [ [ 0, 62 ] ] }, { "id": "596", "type": "abstract", "text": [ "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." ], "offsets": [ [ 63, 1433 ] ] } ]

[ { "id": "594", "type": "ProteinMutation", "text": [ "Phe-->Ser at codon 15" ], "offsets": [ [ 515, 536 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5952" } ] } ]

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[ { "id": "599", "type": "title", "text": [ "Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity." ], "offsets": [ [ 0, 116 ] ] }, { "id": "600", "type": "abstract", "text": [ "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." ], "offsets": [ [ 117, 2512 ] ] } ]

[ { "id": "598", "type": "ProteinMutation", "text": [ "Ala7Val" ], "offsets": [ [ 1495, 1502 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "373513519" } ] } ]

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[ { "id": "611", "type": "title", "text": [ "Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene." ], "offsets": [ [ 0, 88 ] ] }, { "id": "612", "type": "abstract", "text": [ "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." ], "offsets": [ [ 89, 1722 ] ] } ]

[ { "id": "602", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 18, 27 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] }, { "id": "603", "type": "DNAMutation", "text": [ "-134delA" ], "offsets": [ [ 32, 40 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800997" } ] }, { "id": "604", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 315, 324 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] }, { "id": "605", "type": "DNAMutation", "text": [ "-134delA" ], "offsets": [ [ 440, 448 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1800997" } ] }, { "id": "606", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 542, 551 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] }, { "id": "607", "type": "ProteinMutation", "text": [ "Lys to Asn at position 198" ], "offsets": [ [ 1094, 1120 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] }, { "id": "608", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 1358, 1367 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] }, { "id": "609", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 1503, 1512 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] }, { "id": "610", "type": "ProteinMutation", "text": [ "Lys198Asn" ], "offsets": [ [ 1610, 1619 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5370" } ] } ]

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[ { "id": "619", "type": "title", "text": [ "A first Taiwanese Chinese family of type 2B von Willebrand disease with R1306W mutation." ], "offsets": [ [ 0, 88 ] ] }, { "id": "620", "type": "abstract", "text": [ "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." ], "offsets": [ [ 89, 1564 ] ] } ]

[ { "id": "614", "type": "ProteinMutation", "text": [ "R1306W" ], "offsets": [ [ 72, 78 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61749384" } ] }, { "id": "615", "type": "DNAMutation", "text": [ "C to T transition at nucleotide 3916" ], "offsets": [ [ 1161, 1197 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61749384" } ] }, { "id": "616", "type": "ProteinMutation", "text": [ "Arg 1306 Trp" ], "offsets": [ [ 1211, 1223 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61749384" } ] }, { "id": "617", "type": "ProteinMutation", "text": [ "R1306W" ], "offsets": [ [ 1225, 1231 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61749384" } ] }, { "id": "618", "type": "ProteinMutation", "text": [ "R1306W" ], "offsets": [ [ 1522, 1528 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61749384" } ] } ]

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[ { "id": "624", "type": "title", "text": [ "Molecular analysis of acute intermittent porphyria: mutation screening in 20 patients in Germany reveals 11 novel mutations." ], "offsets": [ [ 0, 124 ] ] }, { "id": "625", "type": "abstract", "text": [ "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." ], "offsets": [ [ 125, 1484 ] ] } ]

[ { "id": "622", "type": "DNAMutation", "text": [ "498 + 15 G-->T" ], "offsets": [ [ 932, 946 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "372555494" } ] }, { "id": "623", "type": "DNAMutation", "text": [ "962 G-A" ], "offsets": [ [ 1036, 1043 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "150428209" } ] } ]

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[ { "id": "628", "type": "title", "text": [ "Identification of the Kna/Knb polymorphism and a method for Knops genotyping." ], "offsets": [ [ 0, 77 ] ] }, { "id": "629", "type": "abstract", "text": [ "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." ], "offsets": [ [ 78, 1410 ] ] } ]

[ { "id": "627", "type": "ProteinMutation", "text": [ "V1561M" ], "offsets": [ [ 1004, 1010 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41274768" } ] } ]

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[ { "id": "634", "type": "title", "text": [ "Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis." ], "offsets": [ [ 0, 133 ] ] }, { "id": "635", "type": "abstract", "text": [ "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." ], "offsets": [ [ 134, 1542 ] ] } ]

[ { "id": "631", "type": "ProteinMutation", "text": [ "N34S" ], "offsets": [ [ 694, 698 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "17107315" } ] }, { "id": "632", "type": "DNAMutation", "text": [ "c.27delC" ], "offsets": [ [ 976, 984 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193922659" } ] }, { "id": "633", "type": "DNAMutation", "text": [ "c.27delC" ], "offsets": [ [ 1075, 1083 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193922659" } ] } ]

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[ { "id": "639", "type": "title", "text": [ "Association of microsomal epoxide hydrolase polymorphisms and lung cancer risk." ], "offsets": [ [ 0, 79 ] ] }, { "id": "640", "type": "abstract", "text": [ "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." ], "offsets": [ [ 80, 1727 ] ] } ]

[ { "id": "637", "type": "ProteinMutation", "text": [ "histidine to tyrosine at residue 113" ], "offsets": [ [ 347, 383 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1051740" } ] }, { "id": "638", "type": "ProteinMutation", "text": [ "arginine to histidine at residue 139" ], "offsets": [ [ 389, 425 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2234922" } ] } ]

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[ { "id": "644", "type": "title", "text": [ "Detection of PHKA2 gene mutation in four Japanese patients with hepatic phosphorylase kinase deficiency." ], "offsets": [ [ 0, 104 ] ] }, { "id": "645", "type": "abstract", "text": [ "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." ], "offsets": [ [ 105, 1171 ] ] } ]

[ { "id": "642", "type": "ProteinMutation", "text": [ "R497X" ], "offsets": [ [ 573, 578 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "750186480" } ] }, { "id": "643", "type": "ProteinMutation", "text": [ "R295C" ], "offsets": [ [ 625, 630 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "797045008" } ] } ]

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[ { "id": "652", "type": "title", "text": [ "Mutation analysis of SLC7A9 in cystinuria patients in Sweden." ], "offsets": [ [ 0, 61 ] ] }, { "id": "653", "type": "abstract", "text": [ "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." ], "offsets": [ [ 62, 1953 ] ] } ]

[ { "id": "647", "type": "ProteinMutation", "text": [ "P261L" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908486" } ] }, { "id": "648", "type": "ProteinMutation", "text": [ "V330M" ], "offsets": [ [ 1020, 1025 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "201618022" } ] }, { "id": "649", "type": "ProteinMutation", "text": [ "A182T" ], "offsets": [ [ 1116, 1121 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "79389353" } ] }, { "id": "650", "type": "ProteinMutation", "text": [ "V330M" ], "offsets": [ [ 1178, 1183 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "201618022" } ] }, { "id": "651", "type": "ProteinMutation", "text": [ "P261L" ], "offsets": [ [ 1411, 1416 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908486" } ] } ]

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[ { "id": "657", "type": "title", "text": [ "A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village." ], "offsets": [ [ 0, 138 ] ] }, { "id": "658", "type": "abstract", "text": [ "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." ], "offsets": [ [ 139, 1393 ] ] } ]

[ { "id": "655", "type": "DNAMutation", "text": [ "c.615delC" ], "offsets": [ [ 782, 791 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "760040233" } ] }, { "id": "656", "type": "ProteinMutation", "text": [ "R238X" ], "offsets": [ [ 800, 805 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "104894675" } ] } ]

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[ { "id": "661", "type": "title", "text": [ "Haplotypes extending across ACE are associated with Alzheimer's disease." ], "offsets": [ [ 0, 72 ] ] }, { "id": "662", "type": "abstract", "text": [ "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." ], "offsets": [ [ 73, 1530 ] ] } ]

[ { "id": "660", "type": "DNAMutation", "text": [ "A-262T" ], "offsets": [ [ 1096, 1102 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "4291" } ] } ]

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[ { "id": "665", "type": "title", "text": [ "Identification of new polymorphisms in the CACNA1S gene." ], "offsets": [ [ 0, 56 ] ] }, { "id": "666", "type": "abstract", "text": [ "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." ], "offsets": [ [ 57, 740 ] ] } ]

[ { "id": "664", "type": "DNAMutation", "text": [ "c2403T --> C" ], "offsets": [ [ 334, 346 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "7415038" } ] } ]

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[ { "id": "669", "type": "title", "text": [ "The association between GJB2 mutation and GJB6 gene in non syndromic hearing loss school children." ], "offsets": [ [ 0, 98 ] ] }, { "id": "670", "type": "abstract", "text": [ "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." ], "offsets": [ [ 99, 1858 ] ] } ]

[ { "id": "668", "type": "ProteinMutation", "text": [ "R32Q" ], "offsets": [ [ 1494, 1498 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "766604251" } ] } ]

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[ { "id": "678", "type": "title", "text": [ "Roles of G1359A polymorphism of the cannabinoid receptor gene (CNR1) on weight loss and adipocytokines after a hypocaloric diet." ], "offsets": [ [ 0, 128 ] ] }, { "id": "679", "type": "abstract", "text": [ "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." ], "offsets": [ [ 129, 1771 ] ] } ]

[ { "id": "672", "type": "DNAMutation", "text": [ "G1359A" ], "offsets": [ [ 9, 15 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049353" } ] }, { "id": "673", "type": "DNAMutation", "text": [ "1359 G/A" ], "offsets": [ [ 178, 186 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049353" } ] }, { "id": "674", "type": "DNAMutation", "text": [ "G to A at nucleotide position 1359" ], "offsets": [ [ 241, 275 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049353" } ] }, { "id": "675", "type": "DNAMutation", "text": [ "G1359A" ], "offsets": [ [ 495, 501 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049353" } ] }, { "id": "676", "type": "DNAMutation", "text": [ "G1359A" ], "offsets": [ [ 947, 953 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049353" } ] }, { "id": "677", "type": "DNAMutation", "text": [ "G1359A" ], "offsets": [ [ 1137, 1143 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1049353" } ] } ]

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[ { "id": "683", "type": "title", "text": [ "OPA1 mutations in Japanese patients suspected to have autosomal dominant optic atrophy." ], "offsets": [ [ 0, 87 ] ] }, { "id": "684", "type": "abstract", "text": [ "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." ], "offsets": [ [ 88, 1361 ] ] } ]

[ { "id": "681", "type": "DNAMutation", "text": [ "c.2708_2711delTTAG" ], "offsets": [ [ 766, 784 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80356530" } ] }, { "id": "682", "type": "ProteinMutation", "text": [ "p.V903GfsX905" ], "offsets": [ [ 786, 799 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80356530" } ] } ]

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[ { "id": "689", "type": "title", "text": [ "Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia." ], "offsets": [ [ 0, 83 ] ] }, { "id": "690", "type": "abstract", "text": [ "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." ], "offsets": [ [ 84, 1405 ] ] } ]

[ { "id": "686", "type": "SNP", "text": [ "rs763780" ], "offsets": [ [ 303, 311 ] ], "normalized": [] }, { "id": "687", "type": "DNAMutation", "text": [ "7488T/C" ], "offsets": [ [ 313, 320 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "763780" } ] }, { "id": "688", "type": "ProteinMutation", "text": [ "His-to-Arg substitution at amino acid 161" ], "offsets": [ [ 338, 379 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "763780" } ] } ]

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[ { "id": "707", "type": "title", "text": [ "The TREX1 exonuclease R114H mutation in Aicardi-Gouti res syndrome and lupus reveals dimeric structure requirements for DNA degradation activity." ], "offsets": [ [ 0, 146 ] ] }, { "id": "708", "type": "abstract", "text": [ "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." ], "offsets": [ [ 147, 1958 ] ] } ]

[ { "id": "692", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 22, 27 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "693", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 438, 443 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "694", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 610, 615 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "695", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 759, 764 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "696", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 848, 853 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "697", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 854, 859 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "698", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1101, 1106 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "699", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1126, 1131 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "700", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1213, 1218 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "701", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1219, 1224 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "702", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1350, 1355 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "703", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1375, 1380 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "704", "type": "ProteinMutation", "text": [ "R114H" ], "offsets": [ [ 1573, 1578 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "705", "type": "ProteinMutation", "text": [ "R114A" ], "offsets": [ [ 1695, 1700 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] }, { "id": "706", "type": "ProteinMutation", "text": [ "R114K" ], "offsets": [ [ 1705, 1710 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "72556554" } ] } ]

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[ { "id": "715", "type": "title", "text": [ "Genetic polymorphism of the glutathione-S-transferase P1 gene (GSTP1) and susceptibility to prostate cancer in the Kashmiri population." ], "offsets": [ [ 0, 135 ] ] }, { "id": "716", "type": "abstract", "text": [ "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." ], "offsets": [ [ 136, 1361 ] ] } ]

[ { "id": "710", "type": "DNAMutation", "text": [ "A > G at nucleotide 313" ], "offsets": [ [ 289, 312 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1695" } ] }, { "id": "711", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 359, 368 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1695" } ] }, { "id": "712", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 475, 484 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1695" } ] }, { "id": "713", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 689, 698 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1695" } ] }, { "id": "714", "type": "ProteinMutation", "text": [ "Ile105Val" ], "offsets": [ [ 871, 880 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1695" } ] } ]

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