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BigScience Biomedical Datasets 138

[ { "id": "720", "type": "title", "text": [ "Identification of LIPH gene mutation in a consanguineous family segregating the woolly hair/hypotrichosis phenotype." ], "offsets": [ [ 0, 116 ] ] }, { "id": "721", "type": "abstract", "text": [ "OBJECTIVE: To identify the disease causing gene in a four generation consanguineous family in which eleven family members were suffering from Woolly hair/hypotrichosis phenotype. METHODS: Linkage analysis was carried out to identify the disease-causing gene in this family. Genomic DNA of all the available family members was genotyped for the microsatellite markers for all the known woolly hair/hypotrichosis loci.Automated DNA sequencing of the candidate gene was performed to identify the disease-causing mutation. RESULTS: By using homozygosity linkage analysis we have mapped the family on chromosome 3q27.3 with a two point LOD score of 4.04, Mutation screening of the LIPH gene revealed a homozygous c.659_660delTA deletion mutation segregating with the disease phenotype. CONCLUSION: The results indicate that the c.659_660delTA mutation in the LIPH gene cause autosomal recessive WH/hypotrichosis phenotype in this family. This mutation has been reported in several Pakistani and Guyanese families suggesting a founder mutation in the LIPH gene in Indo-Pak sub-continent." ], "offsets": [ [ 117, 1198 ] ] } ]

[ { "id": "718", "type": "DNAMutation", "text": [ "c.659_660delTA" ], "offsets": [ [ 825, 839 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "559648418" } ] }, { "id": "719", "type": "DNAMutation", "text": [ "c.659_660delTA" ], "offsets": [ [ 940, 954 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "559648418" } ] } ]

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[ { "id": "727", "type": "title", "text": [ "Molecular diagnosis of 46,XY DSD and identification of a novel 8 nucleotide deletion in exon 1 of the SRD5A2 gene." ], "offsets": [ [ 0, 114 ] ] }, { "id": "728", "type": "abstract", "text": [ "Phenotypic presentation of 46,XY DSD depends on the underlying defects. Defect in androgen action on the target tissues or production of active metabolite share common morphological features. Molecular study may help differentiating these abnormalities with precision. Mutational analysis of androgen receptor (AR) and SRD5A2 genes was performed in 29 patients with 46,XY DSD, by PCR-SSCP. The amplicons that showed an aberrant migration in SSCP were subjected to sequencing. Interestingly, six patients from 4 unrelated families (a pair of sibs, uncle/nephew and other two isolated) were identified with mutations in SRD5A2 gene. In five patients p.R246Q missense mutation was detected, of which four were homozygous and one was compound heterozygous: g.80_87delT CGCGAAG (p.A27fsX132) and p.R246Q. Another patient with isolated micropenis harbored a heterozygous p.G196S missense mutation. No AR gene mutation was detected. In conclusion, our study suggests that p.R246Q mutation is common amongst patients with SRD5A2 gene defect from the Northern states of India. Also, it records a novel deletion in exon 1 of SRD5A2 gene in a patient with severe hypospadias." ], "offsets": [ [ 115, 1279 ] ] } ]

[ { "id": "723", "type": "ProteinMutation", "text": [ "p.R246Q" ], "offsets": [ [ 763, 770 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9332967" } ] }, { "id": "724", "type": "ProteinMutation", "text": [ "p.R246Q" ], "offsets": [ [ 906, 913 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9332967" } ] }, { "id": "725", "type": "ProteinMutation", "text": [ "p.G196S" ], "offsets": [ [ 980, 987 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434250" } ] }, { "id": "726", "type": "ProteinMutation", "text": [ "p.R246Q" ], "offsets": [ [ 1080, 1087 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9332967" } ] } ]

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[ { "id": "732", "type": "title", "text": [ "Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta." ], "offsets": [ [ 0, 103 ] ] }, { "id": "733", "type": "abstract", "text": [ "Osteogenesis imperfecta, or \"brittle bone disease,\" is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation. The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif. This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development." ], "offsets": [ [ 104, 1124 ] ] } ]

[ { "id": "730", "type": "DNAMutation", "text": [ "c.1052delA" ], "offsets": [ [ 394, 404 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137853893" } ] }, { "id": "731", "type": "DNAMutation", "text": [ "c.1052delA" ], "offsets": [ [ 847, 857 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137853893" } ] } ]

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[ { "id": "737", "type": "title", "text": [ "Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors." ], "offsets": [ [ 0, 167 ] ] }, { "id": "738", "type": "abstract", "text": [ "AIMS: EGFR mutations now guide the clinical use of EGFR-targeted therapy in lung cancer. However, standard EGFR mutation analysis requires a minimum amount of tumor tissue, which may not be available in certain situations. In this study, we combined a mass spectrometry genotyping assay (Sequenom) with a mutant-enriched PCR (ME-PCR) to detect EGFR mutations in free plasma DNA from patients with lung cancer. METHOD: DNAs were extracted from 31 plasma samples from 31 patients and analyzed by both methods for EGFR Exon 19 deletion and EGFR L858R mutation. Results in plasma DNA samples were compared with EGFR mutation status obtained in tumor DNA (18/31 EGFR mutant). The relationship of EGFR mutation status in tumor and/or plasma samples to overall survival was assessed. RESULTS: The EGFR mutation status in plasma DNA was identical to the primary tumor in 61% of patients (19/31). By mass spectrometry genotyping, the plasma samples contained mutant DNA corresponding to 5/14 EGFR Exon 19 deletions and 3/4 EGFR L858R mutations previously diagnosed in the matched tumors. Two samples were positive in plasma DNA but negative in primary tumor tissue. Results were similar for samples studied by ME-PCR. For patients treated with erlotinib, overall survival was correlated with the presence of EGFR mutation in plasma and/or tumor tissue (p=0.002), with the two patients positive only in plasma DNA showing responses and favorable outcomes. CONCLUSION: The detection of EGFR mutations in plasma DNA samples by mass spectrometry genotyping and ME-PCR is feasible. A positive EGFR result in plasma DNA has a high predictive value for tumor EGFR status and for favorable clinical course on EGFR-targeted therapy and could therefore be useful in guiding clinical decisions in patients with insufficient or unavailable tumor specimens." ], "offsets": [ [ 168, 2003 ] ] } ]

[ { "id": "735", "type": "ProteinMutation", "text": [ "L858R" ], "offsets": [ [ 710, 715 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434568" } ] }, { "id": "736", "type": "ProteinMutation", "text": [ "L858R" ], "offsets": [ [ 1187, 1192 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121434568" } ] } ]

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[ { "id": "743", "type": "title", "text": [ "The M235T polymorphism of the angiotensinogen gene in South Indian patients of hypertrophic cardiomyopathy." ], "offsets": [ [ 0, 107 ] ] }, { "id": "744", "type": "abstract", "text": [ "INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI. RESULTS: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM. CONCLUSION: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM." ], "offsets": [ [ 108, 1521 ] ] } ]

[ { "id": "740", "type": "ProteinMutation", "text": [ "M235T" ], "offsets": [ [ 4, 9 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "699" } ] }, { "id": "741", "type": "ProteinMutation", "text": [ "methionine to threonine substitution at codon 235" ], "offsets": [ [ 862, 911 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "699" } ] }, { "id": "742", "type": "ProteinMutation", "text": [ "M235T" ], "offsets": [ [ 913, 918 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "699" } ] } ]

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[ { "id": "747", "type": "title", "text": [ "Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses." ], "offsets": [ [ 0, 135 ] ] }, { "id": "748", "type": "abstract", "text": [ "We have found a B2 repeat insertion in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6) in a mouse that developed a skin disorder with clinical and histopathological features resembling those seen in human neutrophilic dermatoses. Neutrophilic dermatoses are a group of complex heterogeneous autoinflammatory diseases that all demonstrate excessive neutrophil infiltration of the skin. Therefore, we tested the cDNA and genomic DNA sequences of PTPN6 from patients with Sweet's syndrome (SW) and pyoderma gangrenosum and found numerous novel splice variants in different combinations. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were the most common in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1.7-kbp deletion in the promoter region of the PTPN6 gene. Although full-length PTPN6 was detected in all other patients with either pyoderma gangrenosum or SW, it was always associated with splice variants: a partial deletion of exon 4 with the complete deletion of exon 5, alterations that were not detected in healthy controls. The defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses." ], "offsets": [ [ 136, 1613 ] ] } ]

[ { "id": "746", "type": "ProteinMutation", "text": [ "E441G" ], "offsets": [ [ 1064, 1069 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "200005925" } ] } ]

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[ { "id": "752", "type": "title", "text": [ "Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family." ], "offsets": [ [ 0, 117 ] ] }, { "id": "753", "type": "abstract", "text": [ "BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases." ], "offsets": [ [ 118, 1818 ] ] } ]

[ { "id": "750", "type": "ProteinMutation", "text": [ "P799L" ], "offsets": [ [ 931, 936 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121912637" } ] }, { "id": "751", "type": "ProteinMutation", "text": [ "R594H" ], "offsets": [ [ 1087, 1092 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "77975504" } ] } ]

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[ { "id": "769", "type": "title", "text": [ "Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion." ], "offsets": [ [ 0, 93 ] ] }, { "id": "770", "type": "abstract", "text": [ "BACKGROUND: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance. METHODS: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. RESULTS: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model <or= 0.009, effect sizes 8/8%, rs6232: pdominant model <or= 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom <or= 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. CONCLUSIONS: Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis." ], "offsets": [ [ 94, 2071 ] ] } ]

[ { "id": "755", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 383, 389 ] ], "normalized": [] }, { "id": "756", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 394, 400 ] ], "normalized": [] }, { "id": "757", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 613, 619 ] ], "normalized": [] }, { "id": "758", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 624, 630 ] ], "normalized": [] }, { "id": "759", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 916, 922 ] ], "normalized": [] }, { "id": "760", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 936, 942 ] ], "normalized": [] }, { "id": "761", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 1010, 1016 ] ], "normalized": [] }, { "id": "762", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1021, 1027 ] ], "normalized": [] }, { "id": "763", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 1232, 1238 ] ], "normalized": [] }, { "id": "764", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1289, 1295 ] ], "normalized": [] }, { "id": "765", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1472, 1478 ] ], "normalized": [] }, { "id": "766", "type": "SNP", "text": [ "rs6235" ], "offsets": [ [ 1736, 1742 ] ], "normalized": [] }, { "id": "767", "type": "SNP", "text": [ "rs6232" ], "offsets": [ [ 1968, 1974 ] ], "normalized": [] }, { "id": "768", "type": "ProteinMutation", "text": [ "N221D" ], "offsets": [ [ 2009, 2014 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6232" } ] } ]

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[ { "id": "776", "type": "title", "text": [ "A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome." ], "offsets": [ [ 0, 111 ] ] }, { "id": "777", "type": "abstract", "text": [ "AIMS: Disrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS. MAIN METHODS: Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. KEY FINDINGS: We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele. SIGNIFICANCE: DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases." ], "offsets": [ [ 112, 1655 ] ] } ]

[ { "id": "772", "type": "ProteinMutation", "text": [ "Ser704Cys" ], "offsets": [ [ 884, 893 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "821616" } ] }, { "id": "773", "type": "ProteinMutation", "text": [ "Ser704Cys" ], "offsets": [ [ 1029, 1038 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "821616" } ] }, { "id": "774", "type": "ProteinMutation", "text": [ "Ser704Cys" ], "offsets": [ [ 1153, 1162 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "821616" } ] }, { "id": "775", "type": "ProteinMutation", "text": [ "Ser704Cys" ], "offsets": [ [ 1512, 1521 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "821616" } ] } ]

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[ { "id": "780", "type": "title", "text": [ "The six-nucleotide deletion/insertion variant in the CASP8 promoter region is inversely associated with risk of squamous cell carcinoma of the head and neck." ], "offsets": [ [ 0, 157 ] ] }, { "id": "781", "type": "abstract", "text": [ "Caspase 8 (CASP8) is an apoptosis-related cysteine peptidase involved in the death receptor pathway and likely in the mitochondrial pathway. A CASP8 promoter region six-nucleotide deletion/insertion (-652 6N ins/del) variant and a coding region D302H polymorphism are reportedly important in cancer development, but no reported study has assessed the associations of these genetic variations with risk of head and neck cancer. In a hospital-based study of non-Hispanic whites, we genotyped CASP8 -652 6N del and 302H variants in 1,023 patients with squamous cell carcinoma of the head and neck (SCCHN) and 1,052 cancer-free controls. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression models. The CASP8 -652 6N del variant genotypes or haplotypes were inversely associated with SCCHN risk (adjusted OR, 0.70; 95% CI, 0.57-0.85 for the ins/del + del/del genotypes compared with the ins/ins genotype; adjusted OR, 0.73; 95% CI, 0.55-0.97 for the del-D haplotype compared with the ins-D haplotype). Furthermore, the number of the CASP8 -652 6N del (but not 302H) variant allele tended to correlate with increased levels of camptothecin-induced p53-mediated apoptosis in T lymphocytes from 170 cancer-free controls. We concluded that the CASP8 -652 6N del variant allele may contribute to the risk of developing SCCHN in non-Hispanic white populations. Further validation by population-based case-control studies and rigorous mechanistic studies is warranted." ], "offsets": [ [ 158, 1687 ] ] } ]

[ { "id": "779", "type": "ProteinMutation", "text": [ "D302H" ], "offsets": [ [ 403, 408 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1045485" } ] } ]

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[ { "id": "785", "type": "title", "text": [ "FGFR4 Gly388Arg polymorphism and prostate cancer risk in Scottish men." ], "offsets": [ [ 0, 70 ] ] }, { "id": "786", "type": "abstract", "text": [ "Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth receptor family, was recently reported to be more abundantly expressed in malignant than benign prostate cells. A single nucleotide polymorphism at position 388 of the FGFR4 amino-acid sequence results in the substitution of glycine (Gly) with arginine (Arg) and higher frequency of the ArgArg genotype was previously found in prostate cancer patients. DNA was extracted from the blood drawn from 399 prostate cancer patients, 150 BPH patients and 294 healthy community controls. Polymerase chain reaction was carried out and single nucleotide polymorphisms of FGFR4 were identified by restriction enzyme digestion. No overall association is detectable between the Arg allele and increased prostate cancer risk. Subgroup analysis shows a higher incidence of the heterozygous ArgGly genotype in cancer cases than in the combined group of BPH and controls (P<0.05); this difference is statistically significant between cancer and BPH patients but not between cancer cases and community controls. The single nucleotide polymorphism Gly(388)Arg in FGFR4 is not associated with increased risk of prostate cancer in Scottish men. This observation is in contrast with results from two previous studies conducted in the USA and Japan." ], "offsets": [ [ 71, 1376 ] ] } ]

[ { "id": "783", "type": "ProteinMutation", "text": [ "Gly388Arg" ], "offsets": [ [ 6, 15 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "351855" } ] }, { "id": "784", "type": "ProteinMutation", "text": [ "Gly(388)Arg" ], "offsets": [ [ 1179, 1190 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "351855" } ] } ]

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[ { "id": "791", "type": "title", "text": [ "A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant." ], "offsets": [ [ 0, 145 ] ] }, { "id": "792", "type": "abstract", "text": [ "BACKGROUND: beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish beta-mannosidase activity. In this study, we characterized the molecular defect of a new case of beta-mannosidosis, presenting with a severe neurological disorder. METHODS: Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The beta-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells. RESULTS: A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity. CONCLUSION: Correlations between MANBA mutations, residual activity of beta-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of beta-mannosidase is also discussed." ], "offsets": [ [ 146, 1866 ] ] } ]

[ { "id": "788", "type": "DNAMutation", "text": [ "c.1922G>A" ], "offsets": [ [ 1198, 1207 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "569997475" } ] }, { "id": "789", "type": "ProteinMutation", "text": [ "p.Arg641His" ], "offsets": [ [ 1209, 1220 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "569997475" } ] }, { "id": "790", "type": "DNAMutation", "text": [ "c.1922G>A" ], "offsets": [ [ 1755, 1764 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "569997475" } ] } ]

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[ { "id": "795", "type": "title", "text": [ "Screening of the LIX1 gene in Japanese and Malaysian patients with SMA and/or SMA-like disorder." ], "offsets": [ [ 0, 96 ] ] }, { "id": "796", "type": "abstract", "text": [ "BACKGROUND: The majority of spinal muscular atrophy (SMA) patients showed homozygous deletion or other mutations of SMN1. However, the genetic etiology of a significant number of SMA patients has not been clarified. Recently, mutation in the gene underlying cat SMA, limb expression 1 (LIX1), has been reported. Similarity in clinical and pathological features of cat and human SMA may give an insight into possible similarity of the genetic etiology. PATIENTS AND METHODS: In this study, we screened for a mutation in LIX1 using direct DNA sequencing in our SMA and/or SMA-like patients who retained SMN1. A total of 33 patients were enrolled in this study, of which 22 were Japanese and 11 were Malaysians. All these patients possessed at least two copies of SMN1. RESULTS: We did not identify any pathogenic mutations in the coding regions or splice sites of LIX1 in the patients. In addition, we described a polymorphism within LIX1 intron 3, c.387+107A>T. We found that A-allele is significantly more frequent in SMA patients compared to normal individuals. CONCLUSION: Molecular genetic analysis of our SMA and/or SMA-like patients suggests that LIX1 is not associated with the development of their disorders. However, the number of patients analyzed in this study was very limited, and a larger study with bigger sample size is needed to confirm this result." ], "offsets": [ [ 97, 1462 ] ] } ]

[ { "id": "794", "type": "DNAMutation", "text": [ "c.387+107A>T" ], "offsets": [ [ 1044, 1056 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "316179" } ] } ]

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[ { "id": "801", "type": "title", "text": [ "Serotonin transporter gene polymorphic element 5-HTTLPR increases the risk of sporadic Parkinson's disease in Italy." ], "offsets": [ [ 0, 116 ] ] }, { "id": "802", "type": "abstract", "text": [ "Parkinson's disease (PD) is a neurodegenerative disorder causing muscular rigidity, resting tremor and bradykinesia. We conducted an association study assessing how PD risk in Italy was influenced by the serotonin transporter gene (SLC6A4) polymorphic region 5-HTTLPR, consisting of an insertion/deletion (long allele-L/short allele-S) of 43 bp in the SLC6A4 promoter region. The SLC6A4 promoter single nucleotide polymorphism rs25531(A-->G) was evaluated too. We collected 837 independent subjects (393 PD, 444 controls). An association between the 5-HTTLPR polymorphism and risk of PD (S/S genotype OR [95% CI]: 1.7[1.2-2.5], p = 0.002) was found. The rs25531 and the haplotype 5-HTTLPR/rs25531 did not associate with risk of PD. Our data indicate that the 5-HTTLPR polymorphic element within the SLC6A4 promoter may govern the genetic risk of PD in Italians." ], "offsets": [ [ 117, 978 ] ] } ]

[ { "id": "798", "type": "SNP", "text": [ "rs25531" ], "offsets": [ [ 544, 551 ] ], "normalized": [] }, { "id": "799", "type": "SNP", "text": [ "rs25531" ], "offsets": [ [ 771, 778 ] ], "normalized": [] }, { "id": "800", "type": "SNP", "text": [ "rs25531" ], "offsets": [ [ 806, 813 ] ], "normalized": [] } ]

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[ { "id": "806", "type": "title", "text": [ "A large Swiss family with Bernard-Soulier syndrome - Correlation phenotype and genotype." ], "offsets": [ [ 0, 88 ] ] }, { "id": "807", "type": "abstract", "text": [ "Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive inherited bleeding disorder associated with thrombocytopenia, thrombocytopathy and giant platelets. BSS is caused by genetic alterations of the glycoprotein (GP) Ib/V/IX complex. We report on a large Swiss family of whom four family members suffer from BSS. Here, a homozygous missense mutation in position 1829 (A(R)G) of the GPIX gene constituting a N45S substitution is the cause for the bleeding symptoms. A total of 38 family members within two generations were analyzed regarding the N45S mutation by DNA sequencing and restriction fragment length polymorphism. The laboratory parameters which are characteristically for BSS such as platelet count, platelet volume and the expression of CD42a (GPIX), CD42b (GPIbalpha) and CD41 (GPIIb) were measured for all 38 individuals. The four homozygous patients showed bleeding symptoms, thrombocytopenia and giant platelets. In these patients, the expression of CD42a (GPIX), CD42b (GPIbalpha) was diminished. Interestingly, the intensity of the bleeding symptoms of the 4 homozygous family members seemed to vary although they carry the same mutation. The 24 heterozygous carriers did not differ significantly from their 10 wildtype family members regarding bleeding symptoms and laboratory analysis." ], "offsets": [ [ 89, 1400 ] ] } ]

[ { "id": "804", "type": "ProteinMutation", "text": [ "N45S" ], "offsets": [ [ 503, 507 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030764" } ] }, { "id": "805", "type": "ProteinMutation", "text": [ "N45S" ], "offsets": [ [ 641, 645 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5030764" } ] } ]

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[ { "id": "815", "type": "title", "text": [ "Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma." ], "offsets": [ [ 0, 189 ] ] }, { "id": "816", "type": "abstract", "text": [ "Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610-2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610-2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment." ], "offsets": [ [ 190, 2173 ] ] } ]

[ { "id": "809", "type": "ProteinMutation", "text": [ "p.T286M" ], "offsets": [ [ 478, 485 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193302860" } ] }, { "id": "810", "type": "ProteinMutation", "text": [ "p.W111X" ], "offsets": [ [ 501, 508 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852884" } ] }, { "id": "811", "type": "DNAMutation", "text": [ "c.610-2A>G" ], "offsets": [ [ 607, 617 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193302855" } ] }, { "id": "812", "type": "DNAMutation", "text": [ "c.611delG" ], "offsets": [ [ 677, 686 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193302856" } ] }, { "id": "813", "type": "DNAMutation", "text": [ "c.640_667del28" ], "offsets": [ [ 691, 705 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193302859" } ] }, { "id": "814", "type": "DNAMutation", "text": [ "c.610-2A>G" ], "offsets": [ [ 839, 849 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "193302855" } ] } ]

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[ { "id": "826", "type": "title", "text": [ "Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene Met326Ile polymorphism in women with polycystic ovary syndrome." ], "offsets": [ [ 0, 126 ] ] }, { "id": "827", "type": "abstract", "text": [ "BACKGROUND: Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Phosphatidylinositol (PI) 3-kinase is an important enzyme in the early insulin signaling cascade and plays a key role in insulin-mediated glucose transport. In its regulatory subunit, p85alpha, there is a common amino acid substitution (the Met326Ile polymorphism), and this amino acid may be crucial for the function of the p85alpha regulatory subunit and PI3-kinase. METHODS: Analysis of the Met326Ile polymorphism was carried out on DNA samples from 256 PCOS patients and 283 controls. Clinical and biochemical profiles of participants were also compared. RESULTS: The genotype distribution of the Met326Ile polymorphism in the PCOS group was not different from that of the controls (Met326Met/Met326Ile/Ile326Ile rates were 73.4%/23.4%/3.2% and 70.3%/26.1%/3.6% for the PCOS and control groups, respectively, P = 0.72). The PCOS group was divided into two subgroups according to the presence of the variant 326Ile allele. Compared with those carrying at least one variant 326Ile allele, carriers with the Met326Met genotype had higher serum 17-hydroxyprogesterone (17-OHP) {1.1 [95% confidence interval (CI) 1.1-1.3] ng/ml in those with the Met326Met genotype versus 0.8 (95% CI 0.7-1.0) ng/ml in those with Ile326Ile and Met326Ile genotypes, P = 0.0073} and free testosterone levels [1.2 (95% CI 1.1-1.4) pg/ml for Met326Met genotype versus 0.9 (95% CI 0.6-1.3) pg/ml for Ile326Ile and Met326Ile genotypes, P = 0.038]. CONCLUSIONS: Our results suggest that the PI3-kinase gene Met326Ile polymorphism may not be a major determinant for the development of PCOS, but it may modulate the concentrations of serum 17-OHP or free testosterone in PCOS patients." ], "offsets": [ [ 127, 1871 ] ] } ]

[ { "id": "818", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 63, 72 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "819", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 454, 463 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "820", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 607, 616 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "821", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 814, 823 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "822", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 910, 919 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "823", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 1439, 1448 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "824", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 1604, 1613 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] }, { "id": "825", "type": "ProteinMutation", "text": [ "Met326Ile" ], "offsets": [ [ 1695, 1704 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3730089" } ] } ]

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[ { "id": "833", "type": "title", "text": [ "Expanding clinical spectrum of non-autoimmune hyperthyroidism due to an activating germline mutation, p.M453T, in the thyrotropin receptor gene." ], "offsets": [ [ 0, 144 ] ] }, { "id": "834", "type": "abstract", "text": [ "OBJECTIVE: To describe clinical and genetic features of a Thai family with non-autoimmune hyperthyroidism (NAH) caused by an activating germline mutation in the thyrotropin receptor (TSHR) gene. PATIENTS: Three affected individuals from the same family (a father and his two children) were studied. Clinical and imaging findings were reviewed and compared. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral blood leukocytes and mutation analysis of the entire coding sequence of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS: A heterozygous germline T to C transition in exon 10 of the TSHR gene (c.1358T-->C) resulting in the substitution of methionine (ATG) by threonine (ACG) at codon 453 (p.M453T) was identified in the father and his two children. They presented with different clinical severity and variable age of onset. In addition to hyperthyroidism, ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers were consistently found in all affected individuals. CONCLUSIONS: Ventriculomegaly and bilateral shortening of the fifth metacarpal bones and the middle phalanges of the fifth fingers might be characteristic features of NAH because of an activating TSHR germline mutation. In addition, the shortening of the middle phalanges of the fifth fingers has never been previously described, expanding the phenotypic spectrum of the disease." ], "offsets": [ [ 145, 1616 ] ] } ]

[ { "id": "829", "type": "ProteinMutation", "text": [ "p.M453T" ], "offsets": [ [ 102, 109 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908864" } ] }, { "id": "830", "type": "DNAMutation", "text": [ "c.1358T-->C" ], "offsets": [ [ 803, 814 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908864" } ] }, { "id": "831", "type": "ProteinMutation", "text": [ "methionine (ATG) by threonine (ACG) at codon 453" ], "offsets": [ [ 849, 897 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908864" } ] }, { "id": "832", "type": "ProteinMutation", "text": [ "p.M453T" ], "offsets": [ [ 899, 906 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908864" } ] } ]

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[ { "id": "840", "type": "title", "text": [ "Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy." ], "offsets": [ [ 0, 132 ] ] }, { "id": "841", "type": "abstract", "text": [ "BACKGROUND: Increased susceptibility to dilated cardiomyopathy has been observed in patients carrying mutations in the SCN5A gene, but the underlying mechanism remains unclear. In this study, we identified and characterized, both in vitro and clinically, an SCN5A mutation associated with familial progressive atrioventricular block of adult onset and dilated cardiomyopathy in a Chinese family. METHODS AND RESULTS: Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the beta1 subunit, the mutated channels exhibited a -4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na(+) current reduction and a moderate increase in late Na(+) current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range. CONCLUSIONS: A1180V expresses a mild Na(+) channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na(+) influx and, hence, cellular Na(+) homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block." ], "offsets": [ [ 133, 1919 ] ] } ]

[ { "id": "836", "type": "ProteinMutation", "text": [ "A1180V" ], "offsets": [ [ 802, 808 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41310765" } ] }, { "id": "837", "type": "ProteinMutation", "text": [ "A1180V" ], "offsets": [ [ 1508, 1514 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41310765" } ] }, { "id": "838", "type": "ProteinMutation", "text": [ "A1180V" ], "offsets": [ [ 1651, 1657 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41310765" } ] }, { "id": "839", "type": "ProteinMutation", "text": [ "A1180V" ], "offsets": [ [ 1801, 1807 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41310765" } ] } ]

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[ { "id": "848", "type": "title", "text": [ "Anticipation in familial lattice corneal dystrophy type I with R124C mutation in the TGFBI (BIGH3) gene." ], "offsets": [ [ 0, 104 ] ] }, { "id": "849", "type": "abstract", "text": [ "PURPOSE: To report the clinical, ophthalmic, and genetic characteristics for lattice corneal dystrophy type I (LCDI) in a Chilean family. METHODS: Six affected family members were examined clinically including visual acuity, color cornea photography, applanation tonography, and fundoscopy. Genomic DNA was extracted from peripheral leukocytes from six affected and three unaffected members of a family with lattice corneal dystrophy type I. Exon 4 of the transforming growth factor-induced gene (TGFBI) was screened for the most frequent mutation, R124C, in the proband by sequencing. We also designed a rapid polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the same mutation, amplifying exon 4 and digesting with PstI restriction enzyme. Using this strategy, we analyzed the mutation in six affected and three healthy family members. RESULTS: Three generations of family members were positively diagnosed with lattice corneal dystrophy. Six participants demonstrated LCD1 in both eyes, most of whom were symmetric. Age at onset of symptoms was variable (3-42 years old). Moreover, in this family, the age of onset of the disease decreased in succeeding generations, which could be interpreted as anticipation. Visual acuity varied from 1.0 to 0.13. Two patients, ages 69 and 44 years old, demonstrated a degree of severity \"Bad\" according to best-corrected vision and corneal commitment. The exon 4 sequence of TGFBI of the proband exhibits the heterozygous single-nucleotide mutation, C417T, leading to amino acid substitution (R124C) in the encoded TGF-induced protein. Using PCR-RFLP, we confirmed the heterozygous mutation in six affected family members and excluded it in three healthy members. CONCLUSIONS: The R124C mutation in TGFBI cosegregated with LCD type I in the investigated family. This is the first report of a molecular analysis of LCD type I in Chilean patients. The early onset affected persons in the fourth generation raises the possibility of anticipation." ], "offsets": [ [ 105, 2134 ] ] } ]

[ { "id": "843", "type": "ProteinMutation", "text": [ "R124C" ], "offsets": [ [ 63, 68 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "844", "type": "ProteinMutation", "text": [ "R124C" ], "offsets": [ [ 654, 659 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "845", "type": "DNAMutation", "text": [ "C417T" ], "offsets": [ [ 1641, 1646 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "846", "type": "ProteinMutation", "text": [ "R124C" ], "offsets": [ [ 1684, 1689 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "847", "type": "ProteinMutation", "text": [ "R124C" ], "offsets": [ [ 1872, 1877 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] } ]

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[ { "id": "857", "type": "title", "text": [ "Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer." ], "offsets": [ [ 0, 207 ] ] }, { "id": "858", "type": "abstract", "text": [ "BACKGROUND: Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline-related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline-related CHF. METHODS: A nested case-control study was conducted within a cohort of 1979 patients enrolled in the Childhood Cancer Survivor Study who received treatment with anthracyclines and had available DNA. Thirty patients with CHF (cases) and 115 matched controls were genotyped for polymorphisms in NQO1 (NQO1*2) and CBR3 (the CBR3 valine [V] to methionine [M] substitution at position 244 [V244M]). Enzyme activity assays with recombinant CBR3 isoforms (CBR3 V244 and CBR3 M244) and the anthracycline substrate doxorubicin were used to investigate the functional impact of the CBR3 V244M polymorphism. RESULTS: Multivariate analyses adjusted for sex and primary disease recurrence were used to test for associations between the candidate genetic polymorphisms (NQO1*2 and CBR3 V244M) and the risk of CHF. Analyses indicated no association between the NQO1*2 polymorphism and the risk of anthracycline-related CHF (odds ratio [OR], 1.04; P=.97). There was a trend toward an association between the CBR3 V244M polymorphism and the risk of CHF (OR, 8.16; P=.056 for G/G vs A/A; OR, 5.44; P=.092 for G/A vs A/A). In line, recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR3 V244 [8.26+/-3.57 nmol/hour.mg] vs CBR3 M244 [3.22+/-0.67 nmol/hour.mg]; P=.01). CONCLUSIONS: The functional CBR3 V244M polymorphism may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors by modulating the intracardiac formation of cardiotoxic anthracycline alcohol metabolites. Larger confirmatory case-control studies are warranted." ], "offsets": [ [ 208, 2397 ] ] } ]

[ { "id": "851", "type": "ProteinMutation", "text": [ "valine [V] to methionine [M] substitution at position 244" ], "offsets": [ [ 1105, 1162 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056892" } ] }, { "id": "852", "type": "ProteinMutation", "text": [ "V244M" ], "offsets": [ [ 1164, 1169 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056892" } ] }, { "id": "853", "type": "ProteinMutation", "text": [ "V244M" ], "offsets": [ [ 1356, 1361 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056892" } ] }, { "id": "854", "type": "ProteinMutation", "text": [ "V244M" ], "offsets": [ [ 1551, 1556 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056892" } ] }, { "id": "855", "type": "ProteinMutation", "text": [ "V244M" ], "offsets": [ [ 1776, 1781 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056892" } ] }, { "id": "856", "type": "ProteinMutation", "text": [ "V244M" ], "offsets": [ [ 2139, 2144 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1056892" } ] } ]

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[ { "id": "862", "type": "title", "text": [ "Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas." ], "offsets": [ [ 0, 136 ] ] }, { "id": "863", "type": "abstract", "text": [ "OBJECTIVE: Pituitary adenomas occur rarely in childhood and adolescence. Pituitary adenoma predisposition (PAP) has been recently associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The aim of the study was to examine the proportion of germline AIP mutations in apparently sporadic paediatric pituitary adenomas. DESIGN: Genomic DNA was analysed for mutations in the AIP gene, by PCR amplification and direct sequencing. PATIENTS: A population-based cohort consisting of 36 apparently sporadic paediatric pituitary adenoma patients, referred to two medical centres in Italy, was included in the study. Patients were either less than 18 years at diagnosis, or showed clinical evidence of adenoma development before the age of 18 years. RESULTS: A heterozygous in-frame deletion Y248del (c.742_744delTAC) was identified in one GH-secreting adenoma patient. Loss of heterozygosity (LOH) analysis of tumour DNA revealed the loss of the wild-type allele. First degree relatives carrying the mutation were clinically unaffected. CONCLUSIONS: While mutations were absent in non-GH-secreting adenoma patients, germline AIP mutations can be found in children and adolescents with GH-secreting tumours, even in the absence of family history. The present study reports the AIP mutation analysis results on patients of a single ethnic origin. Clearly, further studies are needed to improve our knowledge on the role of AIP in paediatric pituitary adenomas." ], "offsets": [ [ 137, 1629 ] ] } ]

[ { "id": "860", "type": "ProteinMutation", "text": [ "Y248del" ], "offsets": [ [ 962, 969 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267606574" } ] }, { "id": "861", "type": "DNAMutation", "text": [ "c.742_744delTAC" ], "offsets": [ [ 971, 986 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "267606574" } ] } ]

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[ { "id": "877", "type": "title", "text": [ "Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia." ], "offsets": [ [ 0, 129 ] ] }, { "id": "878", "type": "abstract", "text": [ "PURPOSE: Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and/or microphthalmia. In this study, we evaluated 34 anophthalmic/microphthalmic patient DNA samples (two sets of siblings included) for mutations and sequence variants in SOX2 and CHX10. METHODS: Conformational sensitive gel electrophoresis (CSGE) was used for the initial SOX2 and CHX10 screening of 34 affected individuals (two sets of siblings), five unaffected family members, and 80 healthy controls. Patient samples containing heteroduplexes were selected for sequence analysis. Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples. RESULTS: Two novel heterozygous mutations and two sequence variants (one known) in SOX2 were identified in this cohort. Mutation c.310 G>T (p. Glu104X), found in one patient, was in the region encoding the high mobility group (HMG) DNA-binding domain and resulted in a change from glutamic acid to a stop codon. The second mutation, noted in two affected siblings, was a single nucleotide deletion c.549delC (p. Pro184ArgfsX19) in the region encoding the activation domain, resulting in a frameshift and premature termination of the coding sequence. The shortened protein products may result in the loss of function. In addition, a novel nucleotide substitution c.*557G>A was identified in the 3'-untranslated region in one patient. The relationship between the nucleotide change and the protein function is indeterminate. A known single nucleotide polymorphism (c. *469 C>A, SNP rs11915160) was also detected in 2 of the 34 patients. Screening of CHX10 identified two synonymous sequence variants, c.471 C>T (p.Ser157Ser, rs35435463) and c.579 G>A (p. Gln193Gln, novel SNP), and one non-synonymous sequence variant, c.871 G>A (p. Asp291Asn, novel SNP). The non-synonymous polymorphism was also present in healthy controls, suggesting non-causality. CONCLUSIONS: These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort." ], "offsets": [ [ 130, 2277 ] ] } ]

[ { "id": "865", "type": "DNAMutation", "text": [ "c.549delC" ], "offsets": [ [ 1212, 1221 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "587776776" } ] }, { "id": "866", "type": "ProteinMutation", "text": [ "p. Pro184ArgfsX19" ], "offsets": [ [ 1223, 1240 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "587776776" } ] }, { "id": "867", "type": "DNAMutation", "text": [ "c.*557G>A" ], "offsets": [ [ 1476, 1485 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "77677339" } ] }, { "id": "868", "type": "DNAMutation", "text": [ "c. *469 C>A" ], "offsets": [ [ 1677, 1688 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "11915160" } ] }, { "id": "869", "type": "SNP", "text": [ "rs11915160" ], "offsets": [ [ 1694, 1704 ] ], "normalized": [] }, { "id": "870", "type": "DNAMutation", "text": [ "c.471 C>T" ], "offsets": [ [ 1813, 1822 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "35435463" } ] }, { "id": "871", "type": "ProteinMutation", "text": [ "p.Ser157Ser" ], "offsets": [ [ 1824, 1835 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "35435463" } ] }, { "id": "872", "type": "SNP", "text": [ "rs35435463" ], "offsets": [ [ 1837, 1847 ] ], "normalized": [] }, { "id": "873", "type": "DNAMutation", "text": [ "c.579 G>A" ], "offsets": [ [ 1853, 1862 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "182972044" } ] }, { "id": "874", "type": "ProteinMutation", "text": [ "p. Gln193Gln" ], "offsets": [ [ 1864, 1876 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "182972044" } ] }, { "id": "875", "type": "DNAMutation", "text": [ "c.871 G>A" ], "offsets": [ [ 1931, 1940 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75395981" } ] }, { "id": "876", "type": "ProteinMutation", "text": [ "p. Asp291Asn" ], "offsets": [ [ 1942, 1954 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75395981" } ] } ]

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[ { "id": "884", "type": "title", "text": [ "Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease." ], "offsets": [ [ 0, 132 ] ] }, { "id": "885", "type": "abstract", "text": [ "BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation." ], "offsets": [ [ 133, 1794 ] ] } ]

[ { "id": "880", "type": "DNAMutation", "text": [ "c.1445T > G" ], "offsets": [ [ 559, 570 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75762896" } ] }, { "id": "881", "type": "ProteinMutation", "text": [ "phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482" ], "offsets": [ [ 646, 716 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75762896" } ] }, { "id": "882", "type": "ProteinMutation", "text": [ "p.F482C" ], "offsets": [ [ 718, 725 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75762896" } ] }, { "id": "883", "type": "ProteinMutation", "text": [ "p.F482C" ], "offsets": [ [ 1535, 1542 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75762896" } ] } ]

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[ { "id": "889", "type": "title", "text": [ "Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform." ], "offsets": [ [ 0, 151 ] ] }, { "id": "890", "type": "abstract", "text": [ "OBJECTIVE: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents. METHODS: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections. RESULTS: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis. CONCLUSION: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases." ], "offsets": [ [ 152, 2033 ] ] } ]

[ { "id": "887", "type": "ProteinMutation", "text": [ "N673S" ], "offsets": [ [ 1029, 1034 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "3917815" } ] }, { "id": "888", "type": "ProteinMutation", "text": [ "C203S" ], "offsets": [ [ 1104, 1109 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "10127175" } ] } ]

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[ { "id": "897", "type": "title", "text": [ "Skewed X inactivation in an X linked nystagmus family resulted from a novel, p.R229G, missense mutation in the FRMD7 gene." ], "offsets": [ [ 0, 122 ] ] }, { "id": "898", "type": "abstract", "text": [ "AIMS: This study aimed to identify the underlying genetic defect of a large Turkish X linked nystagmus (NYS) family. METHODS: Both Xp11 and Xq26 loci were tested by linkage analysis. The 12 exons and intron-exon junctions of the FRMD7 gene were screened by direct sequencing. X chromosome inactivation analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme, followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. RESULTS: The family contained 162 individuals, among whom 28 had NYS. Linkage analysis confirmed the Xq26 locus. A novel missense c.686C>G mutation, which causes the substitution of a conserved arginine at amino acid position 229 by glycine (p.R229G) in exon 8 of the FRMD7 gene, was observed. This change was not documented in 120 control individuals. The clinical findings in a female who was homozygous for the mutation were not different from those of affected heterozygous females. Skewed X inactivation was remarkable in the affected females of the family. CONCLUSIONS: A novel p.R229G mutation in the FRMD7 gene causes the NYS phenotype, and skewed X inactivation influences the manifestation of the disease in X linked NYS females." ], "offsets": [ [ 123, 1334 ] ] } ]

[ { "id": "892", "type": "ProteinMutation", "text": [ "p.R229G" ], "offsets": [ [ 77, 84 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852212" } ] }, { "id": "893", "type": "DNAMutation", "text": [ "c.686C>G" ], "offsets": [ [ 725, 733 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852212" } ] }, { "id": "894", "type": "ProteinMutation", "text": [ "arginine at amino acid position 229 by glycine" ], "offsets": [ [ 789, 835 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852212" } ] }, { "id": "895", "type": "ProteinMutation", "text": [ "p.R229G" ], "offsets": [ [ 837, 844 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852212" } ] }, { "id": "896", "type": "ProteinMutation", "text": [ "p.R229G" ], "offsets": [ [ 1179, 1186 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "137852212" } ] } ]

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[ { "id": "904", "type": "title", "text": [ "A novel missense mutation in the paired domain of human PAX9 causes oligodontia." ], "offsets": [ [ 0, 80 ] ] }, { "id": "905", "type": "abstract", "text": [ "PAX9 and MSX1 are transcription factors that play essential roles in craniofacial and limb development. In humans, mutations in both genes are associated with nonsyndromic and syndromic oligodontia, respectively. We screened one family with nonsyndromic oligodontia for mutations in PAX9 and MSX1. Single stranded conformational polymorphism (SSCP) analysis and sequencing revealed a novel heterozygous C139T transition in PAX9 in the affected members of the family. There were no mutations detected in the entire coding sequence of MSX1. The C139T mutation, predicted to result in the substitution of an arginine by a tryptophan (R47W) in the N-terminal subdomain, affected conserved residues in the PAX9 paired domain. To elucidate the pathogenic mechanism producing oligodontia phenotype caused by this mutation, we analyzed the binding of wild-type and mutant PAX9 paired domain protein to double-stranded DNA targets. The R47W mutation dramatically reduced DNA binding suggesting that the mutant protein with consequent haploinsufficiency results in a clinical phenotype." ], "offsets": [ [ 81, 1157 ] ] } ]

[ { "id": "900", "type": "DNAMutation", "text": [ "C139T" ], "offsets": [ [ 484, 489 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121917720" } ] }, { "id": "901", "type": "DNAMutation", "text": [ "C139T" ], "offsets": [ [ 624, 629 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121917720" } ] }, { "id": "902", "type": "ProteinMutation", "text": [ "R47W" ], "offsets": [ [ 712, 716 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121917720" } ] }, { "id": "903", "type": "ProteinMutation", "text": [ "R47W" ], "offsets": [ [ 1008, 1012 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121917720" } ] } ]

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[ { "id": "908", "type": "title", "text": [ "Angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor (AT1R) gene polymorphism and its association with preeclampsia in Chinese women." ], "offsets": [ [ 0, 174 ] ] }, { "id": "909", "type": "abstract", "text": [ "OBJECTIVE: To investigate whether polymorphisms of angiotensin converting enzyme gene (ACE) and angiotensin II receptor type 1 gene (AT1R) are associated with etiology of preeclampsia and renal impact in women with preeclampsia. METHODS: DNA was extracted from peripheral blood of 133 patients with preeclampsia and 105 healthy pregnant women. The I/D polymorphism of the ACE gene was assessed by polymerase chain reaction, and the A1166C polymorphism of the AT(1)R gene was additionally assessed by DdeI digestion. The level of proteinuria, fasting serum urea, creatinine and uric acid were investigated according to different genotypes of ACE and AT1R genes. RESULTS: The frequency of genotypes of the ACE gene and the AT1R gene was similar in preeclampsia and normal pregnancy. DD and ID genotype predominated in patients with severe proteinuria, as well as increased serum urea and uric acid. Serum creatinine was also increased, but no significant difference was found among three genotypes. The level of proteinuria, serum uric acid, urea, and creatinine did not vary between different AT1R genotypes. Compared with patients without renal dysfunction, the frequency of DD and ID genotypes of ACE gene was much higher in those with renal dysfunction, but AC and CC genotypes of AT1R gene were not. CONCLUSION: We found no association of the two gene polymorphisms with preeclampsia. However, ACE gene I/D polymorphisms were associated with the severe proteinuria and renal dysfunction seen in preeclampsia. Preeclampsia patients carrying the D allele may be susceptible to renal dysfunction." ], "offsets": [ [ 175, 1771 ] ] } ]

[ { "id": "907", "type": "DNAMutation", "text": [ "A1166C" ], "offsets": [ [ 607, 613 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5186" } ] } ]

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[ { "id": "919", "type": "title", "text": [ "An improved tetra-primer PCR approach for the detection of the FGFR3 G380R mutation responsible for achondroplasia." ], "offsets": [ [ 0, 115 ] ] }, { "id": "920", "type": "abstract", "text": [ "Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7500. In more than 98% of cases, the disease is associated with a G to A or G to C substitution at nucleotide position 1138 (p.G380R) of the fibroblast growth factor receptor 3 (FGFR3) gene. We have developed a sensitive single tube tetra-primer PCR assay to detect both the c.1138G>A and c.1138G>C mutations and can successfully distinguish DNA samples that are homozygous and heterozygous for the c.1138G>A mutation. Titration studies showed that the assay could reliably detect one copy of the mutant allele in a mix of 100 wild-type alleles. The assay has been tested in 50 healthy controls, 3 known patients with achondroplasia, and 5 amniotic fluids suspected of having achondroplasia and for whom we had previously determined the genotypes for the c.1138G>A mutation by PCR-RFLP. We have observed complete concordance between methods. Our tetra-primer PCR assay is sensitive, low-cost, and easy to use method for FGFR3 p.G380R genotyping, which could be used even in \"low-tech\" laboratories." ], "offsets": [ [ 116, 1205 ] ] } ]

[ { "id": "911", "type": "ProteinMutation", "text": [ "G380R" ], "offsets": [ [ 69, 74 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "912", "type": "DNAMutation", "text": [ "G to A or G to C substitution at nucleotide position 1138" ], "offsets": [ [ 273, 330 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "913", "type": "ProteinMutation", "text": [ "p.G380R" ], "offsets": [ [ 332, 339 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "914", "type": "DNAMutation", "text": [ "c.1138G>A" ], "offsets": [ [ 482, 491 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "915", "type": "DNAMutation", "text": [ "c.1138G>C" ], "offsets": [ [ 496, 505 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "916", "type": "DNAMutation", "text": [ "c.1138G>A" ], "offsets": [ [ 606, 615 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "917", "type": "DNAMutation", "text": [ "c.1138G>A" ], "offsets": [ [ 962, 971 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] }, { "id": "918", "type": "ProteinMutation", "text": [ "p.G380R" ], "offsets": [ [ 1133, 1140 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28931614" } ] } ]

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[ { "id": "928", "type": "title", "text": [ "Coincidence of mutations in different connexin genes in Hungarian patients." ], "offsets": [ [ 0, 75 ] ] }, { "id": "929", "type": "abstract", "text": [ "Mutations in the GJB2 gene are the most common cause of hereditary prelingual sensorineural hearing impairment in Europe. Several studies indicate that different members of the connexin protein family interact to form gap junctions in the inner ear. Mutations in different connexin genes may accumulate and, consequently lead to hearing impairment. Therefore, we screened 47 Hungarian GJB2- heterozygous (one mutation in coding exon of the GJB2 gene) patients with hearing impairment for DNA changes in two further connexin genes (GJB6 and GJB3) and in the 5' non-coding region of GJB2 including the splice sites. Eleven out of 47 GJB2-heterozygous patients analyzed carried the splice site mutation -3170G>A in the 5'UTR region of GJB2. One out of these 11 patients showed homozygous -3170G>A genotype in combination with p.R127H. Next to the GJB2 mutations we noted 2 cases of deletion in GJB6 [Delta(GJB6-D13S1830)] and 3 (2 new and 1 described) base substitutions in GJB3 [c.357C>T, c.798C>T and c.94C>T (p.R32W)] which are unlikely disease-causing. Our results suggest the importance of routine screening for the rather frequent -3170G>A mutation (in addition to c.35delG) in patients with hearing impairment." ], "offsets": [ [ 76, 1290 ] ] } ]

[ { "id": "922", "type": "ProteinMutation", "text": [ "p.R127H" ], "offsets": [ [ 899, 906 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "111033196" } ] }, { "id": "923", "type": "DNAMutation", "text": [ "c.357C>T" ], "offsets": [ [ 1053, 1061 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "41310442" } ] }, { "id": "924", "type": "DNAMutation", "text": [ "c.798C>T" ], "offsets": [ [ 1063, 1071 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "35983826" } ] }, { "id": "925", "type": "DNAMutation", "text": [ "c.94C>T" ], "offsets": [ [ 1076, 1083 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1805063" } ] }, { "id": "926", "type": "ProteinMutation", "text": [ "p.R32W" ], "offsets": [ [ 1085, 1091 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1805063" } ] }, { "id": "927", "type": "DNAMutation", "text": [ "c.35delG" ], "offsets": [ [ 1244, 1252 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "80338939" } ] } ]

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[ { "id": "934", "type": "title", "text": [ "Molecular analysis of the CYP2F1 gene: identification of a frequent non-functional allelic variant." ], "offsets": [ [ 0, 99 ] ] }, { "id": "935", "type": "abstract", "text": [ "The CYP2F1 is a human cytochrome P450 that is selectively expressed in lung tissue and involved in the metabolism of various pneumotoxicants with potential carcinogenic effects. In the present study, we report the first systematic investigation of the genetic polymorphism of this enzyme. We analyzed the nucleotidic sequence of the CYP2F1 gene in DNA samples from 90 French Caucasians consisting in 44 patients with lung cancer and 46 control individuals, using single-strand conformation polymorphism analysis of PCR products (PCR-SSCP). We identified 24 novel mutations distributed in the promoter region of the gene, as well as in the coding regions and their flanking intronic sequences. In addition to the wild-type CYP2F1*1 allele, seven allelic variant, CYP2F1*2A, *2B, *3, *4, *5A, *5B and *6, were characterized. The most frequent allelic variant, CYP2F1*2A (25.6%), harbors a combination of 9 mutations, including 2 missense mutations (Asp218Asn and Gln266His) and a 1-bp insertion (c.14_15insC) that creates a premature stop codon in exon 2, probably leading to the synthesis of a severely truncated protein with no catalytic activity. The identification of around 7% of homozygotes for the frameshift mutation in our Caucasian population suggests the existence of an interindividual variation of the CYP2F1 activity and, consequently, the possibility of interindividual differences in the toxic response to some pneumotoxicants and in the susceptibility to certain chemically induced diseases. However, our preliminary results did not show any evidence that the CYP2F1 genetic polymorphism has implications in the pathogenesis of lung cancer." ], "offsets": [ [ 100, 1755 ] ] } ]

[ { "id": "931", "type": "ProteinMutation", "text": [ "Asp218Asn" ], "offsets": [ [ 1047, 1056 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "305974" } ] }, { "id": "932", "type": "ProteinMutation", "text": [ "Gln266His" ], "offsets": [ [ 1061, 1070 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "75405062" } ] }, { "id": "933", "type": "DNAMutation", "text": [ "c.14_15insC" ], "offsets": [ [ 1094, 1105 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "11399890" } ] } ]

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[ { "id": "938", "type": "title", "text": [ "Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions." ], "offsets": [ [ 0, 106 ] ] }, { "id": "939", "type": "abstract", "text": [ "Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions." ], "offsets": [ [ 107, 1135 ] ] } ]

[ { "id": "937", "type": "ProteinMutation", "text": [ "H194Q" ], "offsets": [ [ 749, 754 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315522" } ] } ]

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[ { "id": "947", "type": "title", "text": [ "A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1." ], "offsets": [ [ 0, 150 ] ] }, { "id": "948", "type": "abstract", "text": [ "We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype." ], "offsets": [ [ 151, 1154 ] ] } ]

[ { "id": "941", "type": "ProteinMutation", "text": [ "p.D572H" ], "offsets": [ [ 678, 685 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908072" } ] }, { "id": "942", "type": "DNAMutation", "text": [ "c.G1714C" ], "offsets": [ [ 687, 695 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908072" } ] }, { "id": "943", "type": "ProteinMutation", "text": [ "p.D572N" ], "offsets": [ [ 824, 831 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908072" } ] }, { "id": "944", "type": "DNAMutation", "text": [ "c.G1714A" ], "offsets": [ [ 833, 841 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908072" } ] }, { "id": "945", "type": "ProteinMutation", "text": [ "p.D572H" ], "offsets": [ [ 1037, 1044 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908072" } ] }, { "id": "946", "type": "ProteinMutation", "text": [ "p.D572N" ], "offsets": [ [ 1080, 1087 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121908072" } ] } ]

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[ { "id": "951", "type": "title", "text": [ "Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer." ], "offsets": [ [ 0, 78 ] ] }, { "id": "952", "type": "abstract", "text": [ "CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer." ], "offsets": [ [ 79, 1296 ] ] } ]

[ { "id": "950", "type": "ProteinMutation", "text": [ "Ile462Val" ], "offsets": [ [ 401, 410 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1048943" } ] } ]

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[ { "id": "961", "type": "title", "text": [ "No independent role of the -1123 G>C and+2740 A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations." ], "offsets": [ [ 0, 172 ] ] }, { "id": "962", "type": "abstract", "text": [ "INTRODUCTION: The PTPN22 is a negative regulator of the T cell response. Its +1858C>T (R620W) polymorphism has been shown to associate with a risk for multiple autoimmune diseases, including type 1 diabetes (T1D) and juvenile idiopathic arthritis (JIA). The minor (susceptibility) allele is absent in Asian populations, but a recent study suggested an independent involvement of another polymorphism located within the promoter -1123 nucleotides relative to the translational start site. AIMS: We aimed to analyse the association of three PTPN22 polymorphisms in two distinct Caucasian populations, the Czechs (with T1D and with JIA) and Azeri (with T1D). METHODS: The single nucleotide polymorphisms (SNP) at positions -1123 (rs2488457), +1858 (rs2476601, the R620W substitution), and +2740 (rs1217412) were genotyped using TaqMan assays in 372 subjects with childhood-onset T1D, 130 subjects with JIA, and 400 control subjects of Czech origin, and in 160 subjects with T1D and 271 healthy controls of Azeri origin. RESULTS: In the Czechs, all three SNPs were in a tight linkage disequlibrium, while in the Azeri, the linkage disequlibrium was limited to between the promoter and 3'-UTR polymorphism, D'(-1123, +2740)=0.99, r(2)=0.72. Haplotype reconstruction via the expectation-maximization algorithm showed in both populations that only the haplotype containing the minor (W) allele at codon 620 was associated with T1D (OR=2.26, 95% CI 1.68-3.02 in Czechs, OR=14.8, 95% CI 2.0-651 in Azeri) or JIA (OR=2.43, 95% CI 1.66-3.56 in Czechs). The haplotypes having the wild-type (R) allele at codon 620 and minor alleles at -1123 and/or +2740 were neutral as to the risk of autoimmune conditions in both populations. CONCLUSIONS: In two different Caucasian populations, the Czechs and the Azeri, no independent contribution can be detected either of the -1123 promoter SNP or the +2740 3'-UTR SNP, and only the minor allele at PTPN22 codon 620 contributes to the risk of autoimmunity." ], "offsets": [ [ 173, 2156 ] ] } ]

[ { "id": "954", "type": "DNAMutation", "text": [ "-1123 G>C" ], "offsets": [ [ 27, 36 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2488457" } ] }, { "id": "955", "type": "DNAMutation", "text": [ "+1858C>T" ], "offsets": [ [ 250, 258 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2476601" } ] }, { "id": "956", "type": "ProteinMutation", "text": [ "R620W" ], "offsets": [ [ 260, 265 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2476601" } ] }, { "id": "957", "type": "SNP", "text": [ "rs2488457" ], "offsets": [ [ 900, 909 ] ], "normalized": [] }, { "id": "958", "type": "SNP", "text": [ "rs2476601" ], "offsets": [ [ 919, 928 ] ], "normalized": [] }, { "id": "959", "type": "ProteinMutation", "text": [ "R620W" ], "offsets": [ [ 934, 939 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "2476601" } ] }, { "id": "960", "type": "SNP", "text": [ "rs1217412" ], "offsets": [ [ 966, 975 ] ], "normalized": [] } ]

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[ { "id": "966", "type": "title", "text": [ "DNA damage and repair in gastric cancer--a correlation with the hOGG1 and RAD51 genes polymorphisms." ], "offsets": [ [ 0, 100 ] ] }, { "id": "967", "type": "abstract", "text": [ "The cell's susceptibility to mutagens and its ability to repair DNA lesions are important for cancer induction, promotion and progression. Both the mutagens' sensitivity and the efficacy of DNA repair may be affected by variation in several genes, including DNA repair genes. The hOGG1 gene encodes glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both can be involved in the repair of oxidative DNA lesions, which can contribute to stomach cancer. In the present work we determined the level of basal and oxidative DNA damage and the kinetics of removal of DNA damage induced by hydrogen peroxide in peripheral blood lymphocytes of 30 gastric cancer patients and 30 healthy individuals. The metrics from DNA damage and repair study were correlated with the genotypes of common polymorphisms of the hOGG1 and RAD51 genes: a G-->C transversion at 1245 position of the hOGG1 gene producing a Ser-->Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G-->C substitution at position 135 (5'-untranslated region) of the RAD51 gene (the G135C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis (comet assay) assisted by DNA repair enzymes: endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg), preferentially recognizing oxidized DNA bases. The genotypes of the polymorphism were determined by restriction fragment length polymorphism PCR. We observed a strong association between gastric cancer occurrence, impaired DNA repair in human lymphocytes and the G/C genotype of the G135C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and stomach cancer occurrence in subjects with high level of oxidatively damaged DNA. We did not observe any correlation between the Ser1245Cys polymorphism of the hOGG1 gene and gastric cancer, including subjects with impaired DNA repair and/or high levels of endogenous oxidative DNA lesions. Therefore, our result suggest that the G135C polymorphism of the RAD51 gene may be linked with gastric cancer by the modulation of the cellular response to oxidative stress and this polymorphism may be a useful additional marker in this disease along with the genetic or/and environmental indicators of oxidative stress." ], "offsets": [ [ 101, 2423 ] ] } ]

[ { "id": "964", "type": "ProteinMutation", "text": [ "Ser-->Cys substitution at the codon 326" ], "offsets": [ [ 1048, 1087 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1052133" } ] }, { "id": "965", "type": "ProteinMutation", "text": [ "Ser326Cys" ], "offsets": [ [ 1093, 1102 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1052133" } ] } ]

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[ { "id": "1012", "type": "title", "text": [ "Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy." ], "offsets": [ [ 0, 92 ] ] }, { "id": "1013", "type": "abstract", "text": [ "Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402-1C > G, c.2316-1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized." ], "offsets": [ [ 93, 2273 ] ] } ]

[ { "id": "969", "type": "DNAMutation", "text": [ "c.28delC" ], "offsets": [ [ 840, 848 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833574" } ] }, { "id": "970", "type": "DNAMutation", "text": [ "c.1175delC" ], "offsets": [ [ 850, 860 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833520" } ] }, { "id": "971", "type": "DNAMutation", "text": [ "c.2186delC" ], "offsets": [ [ 862, 872 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833543" } ] }, { "id": "972", "type": "DNAMutation", "text": [ "c.2422delA" ], "offsets": [ [ 874, 884 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833558" } ] }, { "id": "973", "type": "DNAMutation", "text": [ "c.1285_1286insCAAA" ], "offsets": [ [ 949, 967 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833522" } ] }, { "id": "974", "type": "ProteinMutation", "text": [ "p.E153X" ], "offsets": [ [ 1049, 1056 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833579" } ] }, { "id": "975", "type": "ProteinMutation", "text": [ "p.R236X" ], "offsets": [ [ 1058, 1065 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833585" } ] }, { "id": "976", "type": "ProteinMutation", "text": [ "p.E270X" ], "offsets": [ [ 1067, 1074 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833588" } ] }, { "id": "977", "type": "ProteinMutation", "text": [ "p.R337X" ], "offsets": [ [ 1076, 1083 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833517" } ] }, { "id": "978", "type": "ProteinMutation", "text": [ "p.R424X" ], "offsets": [ [ 1085, 1092 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833521" } ] }, { "id": "979", "type": "DNAMutation", "text": [ "c.861+1G > T" ], "offsets": [ [ 1126, 1138 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833590" } ] }, { "id": "980", "type": "DNAMutation", "text": [ "c.1402-1C > G" ], "offsets": [ [ 1140, 1153 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833525" } ] }, { "id": "981", "type": "DNAMutation", "text": [ "c.2316-1G > A" ], "offsets": [ [ 1155, 1168 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833554" } ] }, { "id": "982", "type": "DNAMutation", "text": [ "c.2919+1G > A" ], "offsets": [ [ 1170, 1183 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833575" } ] }, { "id": "983", "type": "DNAMutation", "text": [ "c.2838+5G > A" ], "offsets": [ [ 1272, 1285 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833568" } ] }, { "id": "984", "type": "ProteinMutation", "text": [ "p.T269M" ], "offsets": [ [ 1397, 1404 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833587" } ] }, { "id": "985", "type": "ProteinMutation", "text": [ "p.R461Q" ], "offsets": [ [ 1406, 1413 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833524" } ] }, { "id": "986", "type": "ProteinMutation", "text": [ "p.G771R" ], "offsets": [ [ 1415, 1422 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833553" } ] }, { "id": "987", "type": "ProteinMutation", "text": [ "p.S132W" ], "offsets": [ [ 1495, 1502 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833576" } ] }, { "id": "988", "type": "ProteinMutation", "text": [ "p.Y138F" ], "offsets": [ [ 1504, 1511 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833577" } ] }, { "id": "989", "type": "ProteinMutation", "text": [ "p.T187K" ], "offsets": [ [ 1522, 1529 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833582" } ] }, { "id": "990", "type": "ProteinMutation", "text": [ "p.R212K" ], "offsets": [ [ 1531, 1538 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833584" } ] }, { "id": "991", "type": "ProteinMutation", "text": [ "p.T269M" ], "offsets": [ [ 1540, 1547 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833587" } ] }, { "id": "992", "type": "ProteinMutation", "text": [ "p.R373W" ], "offsets": [ [ 1549, 1556 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "150171524" } ] }, { "id": "993", "type": "ProteinMutation", "text": [ "p.I440N" ], "offsets": [ [ 1558, 1565 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833523" } ] }, { "id": "994", "type": "ProteinMutation", "text": [ "p.R461Q" ], "offsets": [ [ 1567, 1574 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833524" } ] }, { "id": "995", "type": "ProteinMutation", "text": [ "p.N533Y" ], "offsets": [ [ 1576, 1583 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833528" } ] }, { "id": "996", "type": "ProteinMutation", "text": [ "p.C644F" ], "offsets": [ [ 1585, 1592 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833535" } ] }, { "id": "997", "type": "ProteinMutation", "text": [ "p.H651R" ], "offsets": [ [ 1594, 1601 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833536" } ] }, { "id": "998", "type": "ProteinMutation", "text": [ "p.V705M" ], "offsets": [ [ 1603, 1610 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "147275962" } ] }, { "id": "999", "type": "ProteinMutation", "text": [ "p.N732K" ], "offsets": [ [ 1612, 1619 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833544" } ] }, { "id": "1000", "type": "ProteinMutation", "text": [ "p.G771R" ], "offsets": [ [ 1621, 1628 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833553" } ] }, { "id": "1001", "type": "ProteinMutation", "text": [ "p.H775R" ], "offsets": [ [ 1630, 1637 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833555" } ] }, { "id": "1002", "type": "ProteinMutation", "text": [ "p.T830M" ], "offsets": [ [ 1639, 1646 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833560" } ] }, { "id": "1003", "type": "ProteinMutation", "text": [ "p.A841P" ], "offsets": [ [ 1648, 1655 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833562" } ] }, { "id": "1004", "type": "ProteinMutation", "text": [ "p.D880V" ], "offsets": [ [ 1657, 1664 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833566" } ] }, { "id": "1005", "type": "ProteinMutation", "text": [ "p.S957P" ], "offsets": [ [ 1666, 1673 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833571" } ] }, { "id": "1006", "type": "ProteinMutation", "text": [ "p.R966G" ], "offsets": [ [ 1678, 1685 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833573" } ] }, { "id": "1007", "type": "ProteinMutation", "text": [ "p.Y138F" ], "offsets": [ [ 1857, 1864 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833577" } ] }, { "id": "1008", "type": "ProteinMutation", "text": [ "p.T269M" ], "offsets": [ [ 1866, 1873 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833587" } ] }, { "id": "1009", "type": "ProteinMutation", "text": [ "p.E153X" ], "offsets": [ [ 1878, 1885 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833579" } ] }, { "id": "1010", "type": "ProteinMutation", "text": [ "p.V705M" ], "offsets": [ [ 1965, 1972 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "147275962" } ] }, { "id": "1011", "type": "ProteinMutation", "text": [ "p.R212K" ], "offsets": [ [ 1977, 1984 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833584" } ] } ]

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[ { "id": "1016", "type": "title", "text": [ "Genetic investigation of the TSPYL1 gene in sudden infant death syndrome." ], "offsets": [ [ 0, 73 ] ] }, { "id": "1017", "type": "abstract", "text": [ "BACKGROUND: Sudden infant death syndrome (SIDS) constitutes the most frequent cause of death in the postperinatal period in Germany. Recently, a lethal phenotype characterized by sudden infant death with dysgenesis of the testes syndrome (SIDDT) was identified to be caused by loss of function mutations in the TSPYL1 gene. PURPOSE: The study's purpose was to reveal a possible role of TSPYL1 in SIDS. METHODS: DNA samples of 126 SIDS cases and 261 controls were investigated. RESULTS: We found five sequence variations, each of them causing an amino acid substitution. No Hardy Weinberg disequilibrium and no significant difference in allele frequencies between patients and controls were observed for any variation. In one female patient a p.F366L amino acid polymorphism was found heterozygous, which could not be displayed in controls. A pathogenic implication of this substitution, which is conserved in primates and rodents, cannot be ruled out completely. Because SIDDT is the result of homozygous TSPYL1 mutations, this heterozygous exchange cannot solely explain the sudden death in this child. The reported mutation associated with SIDDT (457_458insG) was not detectable in our cohort. CONCLUSION: No association of sequence variations in the TSPYL1 gene and SIDS has been found in a German cohort. Genetic analysis of TSPYL1 seems to be of limited significance in the differential diagnosis of SIDS without dysgenesis of the testes." ], "offsets": [ [ 74, 1517 ] ] } ]

[ { "id": "1015", "type": "ProteinMutation", "text": [ "p.F366L" ], "offsets": [ [ 816, 823 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "140756663" } ] } ]

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[ { "id": "1021", "type": "title", "text": [ "Indirect CFTR mutation identification by PCR/OLA anomalous electropherograms." ], "offsets": [ [ 0, 77 ] ] }, { "id": "1022", "type": "abstract", "text": [ "Mutations of CFTR gene are responsible for cystic fibrosis (CF) and other clinical conditions such as congenital absence of the vas deferens (CAVD), chronic pancreatitis (IP), and idiopathic disseminated bronchiectasis (DBE) classified as CFTR-related disorders. The PCR/OLA assay is designed to detect 31 known mutations including the 24 most common CF mutations worldwide, as identified by the CF Consortium. In order to define the CFTR genotype a series of 1812 individuals from central-southern Italy with and without CF manifestations were screened by using the PCR/OLA assay. Here we report the description of five cases of anomalous electropherograms obtained after PCR/OLA analysis, that led to the identification, in the homozygous state, of two point mutations (D110H and S589N) not included in the assay test panel, a large gene deletion (CFTRdel14b_17b), and an exonic polymorphism (c.4002A > G). Haplotype and real time PCR analysis were also performed in the subject carrying the large CFTR deletion. The study demonstrates that the PCR/OLA assay, besides being an efficient and user-friendly method to screen known mutations in the CFTR gene, may also function as a mutation/polymorphism-scanning assay, at least for certain nucleotide changes located in some critical regions of the gene." ], "offsets": [ [ 78, 1382 ] ] } ]

[ { "id": "1019", "type": "ProteinMutation", "text": [ "D110H" ], "offsets": [ [ 850, 855 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113993958" } ] }, { "id": "1020", "type": "ProteinMutation", "text": [ "S589N" ], "offsets": [ [ 860, 865 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "397508300" } ] } ]

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[ { "id": "1025", "type": "title", "text": [ "Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation." ], "offsets": [ [ 0, 89 ] ] }, { "id": "1026", "type": "abstract", "text": [ "We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal DNA markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger DNA deletions and identify the first Japanese CDG-Ic mutation." ], "offsets": [ [ 90, 925 ] ] } ]

[ { "id": "1024", "type": "DNAMutation", "text": [ "338G>A" ], "offsets": [ [ 404, 410 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "768372697" } ] } ]

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[ { "id": "1035", "type": "title", "text": [ "A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases." ], "offsets": [ [ 0, 121 ] ] }, { "id": "1036", "type": "abstract", "text": [ "Cysteinyl leukotrienes (cysLTs) play important roles in bronchial asthma, and can mediate bronchial smooth muscle constriction and increase mucous secretion, vascular permeability and cellular infiltration. We identified a novel heterozygous single-nucleotide substitution 10G>A (Glu 4 Lys) in the first exon of the leukotriene C4 synthase gene (LTC4S). This substitution was detected in 5 of 141 allergic patients, but not in 110 nonallergic subjects. There was a difference in the Glu 4 Lys frequency between the allergic patients and nonallergic subjects (Fisher's exact test, p=0.0460). The five patients with Glu 4 Lys had allergic diseases such as bronchial asthma and/or allergic dermatitis. Furthermore, a familial analysis of Glu 4 Lys revealed a link with allergic diseases. Thus, our results suggest that Glu 4 Lys in the LTC4S might be associated with allergic diseases." ], "offsets": [ [ 122, 1004 ] ] } ]

[ { "id": "1028", "type": "ProteinMutation", "text": [ "Glu 4 Lys" ], "offsets": [ [ 40, 49 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] }, { "id": "1029", "type": "DNAMutation", "text": [ "10G>A" ], "offsets": [ [ 395, 400 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] }, { "id": "1030", "type": "ProteinMutation", "text": [ "Glu 4 Lys" ], "offsets": [ [ 402, 411 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] }, { "id": "1031", "type": "ProteinMutation", "text": [ "Glu 4 Lys" ], "offsets": [ [ 605, 614 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] }, { "id": "1032", "type": "ProteinMutation", "text": [ "Glu 4 Lys" ], "offsets": [ [ 736, 745 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] }, { "id": "1033", "type": "ProteinMutation", "text": [ "Glu 4 Lys" ], "offsets": [ [ 857, 866 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] }, { "id": "1034", "type": "ProteinMutation", "text": [ "Glu 4 Lys" ], "offsets": [ [ 938, 947 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "370555009" } ] } ]

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[ { "id": "1047", "type": "title", "text": [ "A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study." ], "offsets": [ [ 0, 179 ] ] }, { "id": "1048", "type": "abstract", "text": [ "Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight." ], "offsets": [ [ 180, 1573 ] ] } ]

[ { "id": "1038", "type": "ProteinMutation", "text": [ "Cys 23-Ser 23" ], "offsets": [ [ 2, 15 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1039", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 422, 432 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1040", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 494, 504 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1041", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 600, 610 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1042", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 801, 811 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1043", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 986, 996 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1044", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 1222, 1232 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1045", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 1356, 1366 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] }, { "id": "1046", "type": "ProteinMutation", "text": [ "Cys 23 Ser" ], "offsets": [ [ 1518, 1528 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "6318" } ] } ]

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[ { "id": "1052", "type": "title", "text": [ "Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation." ], "offsets": [ [ 0, 97 ] ] }, { "id": "1053", "type": "abstract", "text": [ "BACKGROUND: Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. OBJECTIVE: To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. METHODS: Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. RESULTS: Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c.2607C>A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c.2607C>A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. CONCLUSIONS: The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy." ], "offsets": [ [ 98, 1844 ] ] } ]

[ { "id": "1050", "type": "DNAMutation", "text": [ "c.2607C>A" ], "offsets": [ [ 1083, 1092 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833565" } ] }, { "id": "1051", "type": "DNAMutation", "text": [ "c.2607C>A" ], "offsets": [ [ 1305, 1314 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "386833565" } ] } ]

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[ { "id": "1057", "type": "title", "text": [ "Parkin mutations and early-onset parkinsonism in a Taiwanese cohort." ], "offsets": [ [ 0, 68 ] ] }, { "id": "1058", "type": "abstract", "text": [ "BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic \"parkin-proven\" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific." ], "offsets": [ [ 69, 1876 ] ] } ]

[ { "id": "1055", "type": "ProteinMutation", "text": [ "G284R" ], "offsets": [ [ 951, 956 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "751037529" } ] }, { "id": "1056", "type": "ProteinMutation", "text": [ "R396G" ], "offsets": [ [ 1413, 1418 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "539917500" } ] } ]

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[ { "id": "1070", "type": "title", "text": [ "TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients." ], "offsets": [ [ 0, 89 ] ] }, { "id": "1071", "type": "abstract", "text": [ "PURPOSE: To identify mutations in the TGFBI gene in Indian patients with lattice corneal dystrophy (LCD) or granular corneal dystrophy (GCD) and to look for genotype-phenotype correlations. METHODS: Thirty-seven unrelated patients were studied, 18 with LCD and 19 with GCD. The diagnosis of LCD or GCD was made on the basis of clinical and/or histopathological evaluation. Exons and flanking intron sequences of the TGFBI gene were amplified by PCR with specific primers. PCR products were screened by the method of single-strand conformation polymorphism followed by sequencing. Mutations were confirmed by screening at least 100 unrelated normal control subjects. RESULTS: Mutations were identified in 14 of 18 patients with LCD and in all 19 patients with GCD. In LCD, three novel heterozygous mutations found were glycine-594-valine (Gly594Val) in 2 of 18 patients, valine-539-aspartic acid (Val539Asp) in 1 patient, and deletion of valine 624, valine 625 (Val624-Val625del) in 1 patient. In addition, mutation of arginine 124-to-cysteine (Arg124Cys) was found in 8 of 18 patients and histidine 626-to-arginine (His626Arg) in 2 of 18 patients. Atypical clinical features for LCD were noted in patients with the Gly594Val and Val624-Val625del mutations. In GCD, 18 patients with GCD type I had a mutation of arginine 555-to-tryptophan (Arg555Trp) and 1 patient with GCD type III (Reis-Bucklers dystrophy), had the Arg124Leu mutation. Seven novel single-nucleotide polymorphisms (SNPs) were also found, of which a change of leucine 269 to phenylalanine (Leu269Phe) was found in 12 of 18 patients with the Arg555Trp mutation. CONCLUSIONS: Arg124Cys and Arg555Trp appear to be the predominant mutations causing LCD and GCD, respectively, in the population studied. The novel mutations identified in this study are associated with distinct phenotypes." ], "offsets": [ [ 90, 1940 ] ] } ]

[ { "id": "1060", "type": "ProteinMutation", "text": [ "arginine 124-to-cysteine" ], "offsets": [ [ 1108, 1132 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "1061", "type": "ProteinMutation", "text": [ "Arg124Cys" ], "offsets": [ [ 1134, 1143 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "1062", "type": "ProteinMutation", "text": [ "arginine 555-to-tryptophan" ], "offsets": [ [ 1401, 1427 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909208" } ] }, { "id": "1063", "type": "ProteinMutation", "text": [ "Arg555Trp" ], "offsets": [ [ 1429, 1438 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909208" } ] }, { "id": "1064", "type": "ProteinMutation", "text": [ "Arg124Leu" ], "offsets": [ [ 1507, 1516 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909211" } ] }, { "id": "1065", "type": "ProteinMutation", "text": [ "leucine 269 to phenylalanine" ], "offsets": [ [ 1616, 1644 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199852470" } ] }, { "id": "1066", "type": "ProteinMutation", "text": [ "Leu269Phe" ], "offsets": [ [ 1646, 1655 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "199852470" } ] }, { "id": "1067", "type": "ProteinMutation", "text": [ "Arg555Trp" ], "offsets": [ [ 1697, 1706 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909208" } ] }, { "id": "1068", "type": "ProteinMutation", "text": [ "Arg124Cys" ], "offsets": [ [ 1730, 1739 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909210" } ] }, { "id": "1069", "type": "ProteinMutation", "text": [ "Arg555Trp" ], "offsets": [ [ 1744, 1753 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121909208" } ] } ]

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[ { "id": "1074", "type": "title", "text": [ "CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B." ], "offsets": [ [ 0, 158 ] ] }, { "id": "1075", "type": "abstract", "text": [ "We previously reported association of FCGR2B-Ile232Thr with systemic lupus erythematosus (SLE) in three Asian populations. Because polymorphism of CD72, another inhibitory receptor of B cells, was associated with murine SLE, we identified human CD72 polymorphisms, tested their association with SLE and examined genetic interaction with FCGR2B in the Japanese (160 SLE, 277 controls), Thais (87 SLE, 187 controls) and Caucasians (94 families containing SLE members). Four polymorphisms and six rare variations were detected. The former constituted two major haplotypes that contained one or two repeats of 13 nucleotides in intron 8 (designated as *1 and *2, respectively). Although association with susceptibility to SLE was not detected, the *1 allele was significantly associated with nephritis among the Japanese patients (P=0.024). RT-PCR identified a novel alternatively spliced (AS) transcript that was expressed at the protein level in COS-7 transfectants. The ratio of AS/common isoforms was strikingly increased in individuals with *2/*2 genotype when compared with *1/*1 (P=0.000038) or *1/*2 (P=0.0085) genotypes. Using the two Asian cohorts, significant association of FCGR2B-232Thr/Thr with SLE was observed only in the presence of CD72-*1/*1 genotype (OR 4.63, 95% CI 1.47-14.6, P=0.009 versus FCGR2B-232Ile/Ile plus CD72-*2/*2). Minigene assays demonstrated that the 13-nucleotide repeat and 4 bp deletion within the same haplotype of intron 8 could regulate alternative splicing. The AS isoform lacks exon 8, and is deduced to contain 49 amino acid changes in the membrane-distal portion of the extracellular domain, where considerable amino acid changes are known in CD72(c) allele associated with murine SLE. These results indicated that the presence of CD72-*2 allele decreases risk for human SLE conferred by FCGR2B-232Thr, possibly by increasing the AS isoform of CD72." ], "offsets": [ [ 159, 2050 ] ] } ]

[ { "id": "1073", "type": "ProteinMutation", "text": [ "Ile232Thr" ], "offsets": [ [ 204, 213 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1050501" } ] } ]

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[ { "id": "1079", "type": "title", "text": [ "A novel arginine substitution mutation in 1A domain and a novel 27 bp insertion mutation in 2B domain of keratin 12 gene associated with Meesmann's corneal dystrophy." ], "offsets": [ [ 0, 166 ] ] }, { "id": "1080", "type": "abstract", "text": [ "AIM: To determine the disease causing gene defects in two patients with Meesmann's corneal dystrophy. METHODS: Mutational analysis of domains 1A and 2B of the keratin 3 (K3) and keratin 12 (K12) genes from two patients with Meesmann's corneal dystrophy was performed by polymerase chain reaction amplification and direct sequencing. RESULTS: Novel mutations of the K12 gene were identified in both patients. In one patient a heterozygous point mutation (429A-->C = Arg135Ser) was found in the 1A domain of the K12 gene. This mutation was confirmed by restriction digestion. In the second patient a heterozygous 27 bp duplication was found inserted in the 2B domain at nucleotide position 1222 (1222ins27) of the K12 gene. This mutation was confirmed by gel electrophoresis. The mutations were not present in unaffected controls. CONCLUSION: Novel K12 mutations were linked to Meesmann's corneal dystrophy in two different patients. A missense mutation replacing a highly conserved arginine residue in the beginning of the helix initiation motif was found in one patient, and an insertion mutation, consisting of a duplication of 27 nucleotides, was found before the helix termination motif in the other." ], "offsets": [ [ 167, 1370 ] ] } ]

[ { "id": "1077", "type": "DNAMutation", "text": [ "429A-->C" ], "offsets": [ [ 621, 629 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61282718" } ] }, { "id": "1078", "type": "ProteinMutation", "text": [ "Arg135Ser" ], "offsets": [ [ 632, 641 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "61282718" } ] } ]

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[ { "id": "1085", "type": "title", "text": [ "POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion." ], "offsets": [ [ 0, 80 ] ] }, { "id": "1086", "type": "abstract", "text": [ "Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein." ], "offsets": [ [ 81, 802 ] ] } ]

[ { "id": "1082", "type": "ProteinMutation", "text": [ "Glu873Stop" ], "offsets": [ [ 556, 566 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121918047" } ] }, { "id": "1083", "type": "DNAMutation", "text": [ "G1681A" ], "offsets": [ [ 689, 695 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] }, { "id": "1084", "type": "ProteinMutation", "text": [ "Ala467Thr" ], "offsets": [ [ 730, 739 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "113994095" } ] } ]

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[ { "id": "1094", "type": "title", "text": [ "Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome." ], "offsets": [ [ 0, 119 ] ] }, { "id": "1095", "type": "abstract", "text": [ "BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations." ], "offsets": [ [ 120, 1857 ] ] } ]

[ { "id": "1088", "type": "DNAMutation", "text": [ "c.185C>T" ], "offsets": [ [ 930, 938 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "371443644" } ] }, { "id": "1089", "type": "ProteinMutation", "text": [ "Thr60Met" ], "offsets": [ [ 940, 948 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "371443644" } ] }, { "id": "1090", "type": "DNAMutation", "text": [ "c.1930C>T" ], "offsets": [ [ 974, 983 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "200697179" } ] }, { "id": "1091", "type": "ProteinMutation", "text": [ "Arg642Cys" ], "offsets": [ [ 985, 994 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "200697179" } ] }, { "id": "1092", "type": "DNAMutation", "text": [ "c.2552T>A" ], "offsets": [ [ 997, 1006 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "185927948" } ] }, { "id": "1093", "type": "ProteinMutation", "text": [ "Leu849His" ], "offsets": [ [ 1008, 1017 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "185927948" } ] } ]

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[ { "id": "1100", "type": "title", "text": [ "Compound heterozygous mutations in the SRD5A2 gene exon 4 in a male pseudohermaphrodite patient of Chinese origin." ], "offsets": [ [ 0, 114 ] ] }, { "id": "1101", "type": "abstract", "text": [ "The goal of this study was to perform 5-alpha-reductase type 2 gene (SRD5A2) analysis in a male pseudohermaphrodite (MPH) patient with normal testosterone (T) production and normal androgen receptor (AR) gene coding sequences. A patient of Chinese origin with ambiguous genitalia at 14 months, a 46,XY karyotype, and normal T secretion under human chorionic gonadotropin (hCG) stimulation underwent a gonadectomy at 20 months. Exons 1-8 of the AR gene and exons 1-5 of the SRD5A2 gene were sequenced from peripheral blood DNA. AR gene coding sequences were normal. SRD5A2 gene analysis revealed 2 consecutive mutations in exon 4, each located in a different allele: 1) a T nucleotide deletion, which predicts a frameshift mutation from codon 219, and 2) a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine (R227Q). Testes located in the inguinal canal showed a normal morphology for age. The patient was a compound heterozygote for SRD5A2 mutations, carrying 2 mutations in exon 4. The patient showed an R227Q mutation that has been described in an Asian population and MPH patients, along with a novel frameshift mutation, Tdel219. Testis morphology showed that, during early infancy, the 5-alpha-reductase enzyme deficiency may not have affected interstitial or tubular development." ], "offsets": [ [ 115, 1483 ] ] } ]

[ { "id": "1097", "type": "ProteinMutation", "text": [ "a missense mutation at codon 227, where the substitution of guanine (CGA) by adenine (CAA) predicts a glutamine replacement of arginine" ], "offsets": [ [ 869, 1004 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9332964" } ] }, { "id": "1098", "type": "ProteinMutation", "text": [ "R227Q" ], "offsets": [ [ 1006, 1011 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9332964" } ] }, { "id": "1099", "type": "ProteinMutation", "text": [ "R227Q" ], "offsets": [ [ 1203, 1208 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "9332964" } ] } ]

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[ { "id": "1104", "type": "title", "text": [ "Single-strand conformation polymorphism analysis of the FMR1 gene in autistic and mentally retarded children in Japan." ], "offsets": [ [ 0, 118 ] ] }, { "id": "1105", "type": "abstract", "text": [ "Fragile X syndrome is one of the most common causes of mental retardation in males, and patients with fragile X syndrome occasionally develop autism. It is usually caused by an expansion of the trinucleotide repeat in the 5'-untranslated region of the FMR1 gene, but in a small number of patients deletions and point mutations have been identified. We screened all 17 exons of the FMR1 gene for mutations in 90 autistic or mentally retarded children using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations were found in 76 male patients. However, one female patient was heterozygous for a normal allele and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This mutation was not found in 50 controls. Reverse transcription-PCR revealed that a large proportion of the mutant transcripts were spliced aberrantly, causing premature termination of the protein synthesis. Although uncommon, point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients." ], "offsets": [ [ 119, 1182 ] ] } ]

[ { "id": "1103", "type": "DNAMutation", "text": [ "A to C substitution at nucleotide 879" ], "offsets": [ [ 802, 839 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "782013865" } ] } ]

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[ { "id": "1113", "type": "title", "text": [ "The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease." ], "offsets": [ [ 0, 90 ] ] }, { "id": "1114", "type": "abstract", "text": [ "Toll-like receptor 2 (TLR2), a member of the Toll-like receptor family, plays an important role in recognition of, and subsequent immune response activation against, mycobacteria. The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. The aim of the present study was to investigate the Arg753Gln single nucleotide polymorphism of the TLR2 gene in tuberculosis (TB) patients compared to healthy controls. A retrospective case/control study was carried out. The Arg753Gln polymorphism of the TLR2 gene was studied in 151 TB patients compared to 116 ethnically and age-matched healthy control subjects. The TLR2 polymorphism (adenine (A) allele) was observed in 17.9 and 7.7% of TB patients and controls, respectively. When the ratios of the three genotypes were compared between the two groups, the AA genotype was found to be more significantly associated with TB. Allele frequencies for guanine (G) and A were found to be 0.95 and 0.05 in the control group and 0.86 and 0.14 in the TB patient group, respectively. The risk of developing TB disease was increased 6.04- and 1.60-fold for carriers of the AA and GA genotypes, respectively. In conclusion, the present data suggest that the arginine to glutamine substitution at residue 753 polymorphism of the Toll-like receptor 2 gene influences the risk of developing tuberculosis." ], "offsets": [ [ 91, 1599 ] ] } ]

[ { "id": "1107", "type": "ProteinMutation", "text": [ "Arg753GLn" ], "offsets": [ [ 4, 13 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5743708" } ] }, { "id": "1108", "type": "ProteinMutation", "text": [ "Arg753Gln" ], "offsets": [ [ 356, 365 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5743708" } ] }, { "id": "1109", "type": "ProteinMutation", "text": [ "Arg753Gln" ], "offsets": [ [ 556, 565 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5743708" } ] }, { "id": "1110", "type": "ProteinMutation", "text": [ "Arg753Gln" ], "offsets": [ [ 730, 739 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5743708" } ] }, { "id": "1111", "type": "ProteinMutation", "text": [ "arginine to glutamine substitution at residue 753" ], "offsets": [ [ 305, 354 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5743708" } ] }, { "id": "1112", "type": "ProteinMutation", "text": [ "arginine to glutamine substitution at residue 753" ], "offsets": [ [ 1456, 1505 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "5743708" } ] } ]

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[ { "id": "1120", "type": "title", "text": [ "Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients: a proposed mechanism for the thiamin-responsive phenotype." ], "offsets": [ [ 0, 169 ] ] }, { "id": "1121", "type": "abstract", "text": [ "Maple syrup urine disease (MSUD) results from mutations affecting different subunits of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex. In this study, we identified seven novel mutations in MSUD patients from Israel. These include C219W-alpha (TGC to TGG) in the E1alpha subunit; H156Y-beta (CAT to TAT), V69G-beta (GTT to GGT), IVS 9 del[-7:-4], and 1109 ins 8bp (exon 10) in the E1beta subunit; and H391R (CAC to CGC) and S133stop (TCA to TGA) affecting the E2 subunit of the branched-chain alpha-ketoacid dehydrogenase complex. Recombinant E1 proteins carrying the C219W-alpha or H156Y-beta mutation show no catalytic activity with defective subunit assembly and reduced binding affinity for cofactor thiamin diphosphate. The mutant E1 harboring the V69G-beta substitution cannot be expressed, suggesting aberrant folding caused by this mutation. These E1 mutations are ubiquitously associated with the classic phenotype in homozygous-affected patients. The H391R substitution in the E2 subunit abolishes the key catalytic residue that functions as a general base in the acyltransfer reaction, resulting in a completely inactive E2 component. However, wild-type E1 activity is enhanced by E1 binding to this full-length mutant E2 in vitro. We propose that the augmented E1 activity is responsible for robust thiamin responsiveness in homozygous patients carrying the H391R E2 mutation and that the presence of a full-length mutant E2 is diagnostic of this MSUD phenotype. The present results offer a structural and biochemical basis for these novel mutations and will facilitate DNA-based diagnosis for MSUD in the Israeli population." ], "offsets": [ [ 170, 1830 ] ] } ]

[ { "id": "1116", "type": "ProteinMutation", "text": [ "H156Y" ], "offsets": [ [ 473, 478 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121965004" } ] }, { "id": "1117", "type": "ProteinMutation", "text": [ "V69G" ], "offsets": [ [ 498, 502 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121965005" } ] }, { "id": "1118", "type": "ProteinMutation", "text": [ "H156Y" ], "offsets": [ [ 776, 781 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121965004" } ] }, { "id": "1119", "type": "ProteinMutation", "text": [ "V69G" ], "offsets": [ [ 946, 950 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "121965005" } ] } ]

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[ { "id": "1128", "type": "title", "text": [ "Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden." ], "offsets": [ [ 0, 182 ] ] }, { "id": "1129", "type": "abstract", "text": [ "Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T(4)) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5'- and 3'-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population." ], "offsets": [ [ 183, 1635 ] ] } ]

[ { "id": "1123", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 153, 157 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28933979" } ] }, { "id": "1124", "type": "ProteinMutation", "text": [ "Val30Met" ], "offsets": [ [ 761, 769 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28933979" } ] }, { "id": "1125", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 981, 985 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28933979" } ] }, { "id": "1126", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 1228, 1232 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28933979" } ] }, { "id": "1127", "type": "ProteinMutation", "text": [ "V30M" ], "offsets": [ [ 1597, 1601 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "28933979" } ] } ]

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[ { "id": "1132", "type": "title", "text": [ "A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia." ], "offsets": [ [ 0, 125 ] ] }, { "id": "1133", "type": "abstract", "text": [ "BACKGROUND: Spondyloepimetaphyseal dysplasia (SEMD) is one of a clinically heterogeneous group of skeletal disorders, characterized by defective growth and modelling of the spine and long bones. Common clinical features include disproportionate short stature, malformed vertebrae and abnormal epiphyses or metaphyses. Some cases have been associated with mutations in the COL2A1 gene. AIM: To determine whether the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis, might be caused by a novel COL2A1 mutation. DESIGN: Genetic testing and clinical examination of family members. METHODS: Direct sequencing of PCR-amplified genomic DNA from the COL2A1 gene. RESULTS: A point mutation within exon 20 of the COL2A1 gene was identified that substituted a glycine for an aspartic acid residue at codon 262. DISCUSSION: All previously reported autosomal dominant mutations causing SEMD have substituted an obligate glycine within the triple helix, in particular at codons 292, 304 and 709 in the three reported Strudwick-type patients. Additionally, a recurrent glycine substitution at codon 154 has been identified in two unrelated Finnish cases with radiological features consistent with the Strudwick subtype. Our sixth helical glycine substitution extends the mutational spectrum and genotype/phenotype correlations of Strudwick-type SEMD." ], "offsets": [ [ 126, 1613 ] ] } ]

[ { "id": "1131", "type": "ProteinMutation", "text": [ "glycine for an aspartic acid residue at codon 262" ], "offsets": [ [ 1027, 1076 ] ], "normalized": [] } ]

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[ { "id": "1137", "type": "title", "text": [ "Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missense mutation (C488R) and an MLD mutation (R84Q) in cis with a pseudodeficiency allele." ], "offsets": [ [ 0, 218 ] ] }, { "id": "1138", "type": "abstract", "text": [ "We describe three novel mutations in the human arylsulfatase A gene in three patients with MLD, an autosomal recessive lysosomal storage disorder. An insertion, 2590_2591insCCCC in exon 8 and a deletion, 752_758delGCCGGCC, in exon 3 will both result in frameshifts. A mutation in exon 8, 2566T-->C, results in a missense mutation C488R, disrupting an unusual cysteine-knot at the C-terminal end of the protein. All three mutations are heterozygous with previously documented mutations. A previously reported mutation, R84Q was identified on a pseudodeficiency allele. These mutations are part of a heterogeneous spectrum of mutations found in a collection of DNA samples from MLD patients from across Canada and the USA." ], "offsets": [ [ 219, 939 ] ] } ]

[ { "id": "1135", "type": "ProteinMutation", "text": [ "R84Q" ], "offsets": [ [ 174, 178 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315458" } ] }, { "id": "1136", "type": "ProteinMutation", "text": [ "R84Q" ], "offsets": [ [ 737, 741 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "74315458" } ] } ]

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[ { "id": "1142", "type": "title", "text": [ "NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy." ], "offsets": [ [ 0, 70 ] ] }, { "id": "1143", "type": "abstract", "text": [ "SETTING: Nrampl encoded by the NRAMP1 gene influences the phagolysosomal function of alveolar macrophage against Mycobacterium tuberculosis. Genetic polymorphisms of NRAMP1 affect innate host resistance through the defective production and function of Nrampl. OBJECTIVE: To investigate this relationship, the NRAMP1 polymorphisms in patients with tuberculous pleurisy were determined. DESIGN: Pleural biopsy proven 56 patients were designated to the pleurisy group and 45 healthy adults were designated to the healthy control group. Three NRAMP1 polymorphisms such as single nucleotide change in intron 4(469 + 14G/C, INT4), a non-conservative single-base substitution at codon 543(D543N) and TGTG deletion in the 3' untranslated region (1729 + 55del4, 3'UTR) were determined. RESULTS: The frequencies of mutant genotypes of INT4 and 3'UTR were significantly high in the pleurisy group (P = 0.01, P = 0.02), but the frequencies of D543N were not significantly different between the two groups. Odds ratios (OR), which are a comparison of the wild with the mutant genotype, were 8.02 (95%CI 2.42 approximately 26.57) for INT4 and 5.73 (95%CI 1.14 approximately 28.92) for 3'UTR which were statistically significant. In the combined analysis of the INT4 and 3'UTR, the ORs were 6.00 (95%CI 1.46 approximately 24.64) for GC/++ genotype and 14.00 (95%CI 1.61 approximately 121.75) for GC/+del when compared with GG/++; these differences were statistically significant. CONCLUSION: The NRAMP1 genetic polymorphisms, especially INT4 and 3'UTR, were closely related to tuberculous pleurisy." ], "offsets": [ [ 71, 1654 ] ] } ]

[ { "id": "1140", "type": "ProteinMutation", "text": [ "D543N" ], "offsets": [ [ 753, 758 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "17235409" } ] }, { "id": "1141", "type": "ProteinMutation", "text": [ "D543N" ], "offsets": [ [ 1002, 1007 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "17235409" } ] } ]

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[ { "id": "1146", "type": "title", "text": [ "Analysis of the G/C polymorphism in the 5'-untranslated region of the RAD51 gene in breast cancer." ], "offsets": [ [ 0, 98 ] ] }, { "id": "1147", "type": "abstract", "text": [ "The breast cancer suppressor proteins BRCA1 and BRCA2 interact with RAD51, a protein essential for maintaining genomic stability by playing a central role in homology-dependent recombinational repair of the DNA double-strand breaks. Therefore, genetic variability in the RAD51 gene may contribute to the appearance and/or progression of breast cancer. A single nucleotide polymorphism in the 5'- untranslated region of RAD51 (a G to C substitution at position 135, the G/C polymorphism) is reported to modulate breast cancer risk. We investigated the distribution of genotypes and frequency of alleles of the G/C polymorphism in breast cancer. Tumor tissues were obtained from postmenopausal women with node-negative and node-positive breast carcinoma with uniform tumor size. Blood samples from age matched healthy women served as control. The G/C polymorphism was determined by PCR-based MvaI restriction fragment length polymorphism. The distribution of the genotypes of the G/C polymorphism did not differ significantly (P > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no differences in the genotype distribution and allele frequencies between node-positive and node-negative patients. There were no significant differences between distributions of the genotypes in subgroups assigned to histological grades according to Scarf-Bloom-Richardson criteria and the distribution predicted by Hardy-Weinberg equilibrium (P > 0.05). Our study implies that the G/C polymorphism of the RAD51 gene may not be directly involved in the development and/or progression of breast cancer and so it may not be useful as an independent marker in this disease." ], "offsets": [ [ 99, 1774 ] ] } ]

[ { "id": "1145", "type": "DNAMutation", "text": [ "G to C substitution at position 135" ], "offsets": [ [ 527, 562 ] ], "normalized": [ { "db_name": "dbsnp", "db_id": "1801320" } ] } ]

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