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17000021
[ "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." ]
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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.
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A novel DFNA5 mutation, IVS8+4 A>G , in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family.
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21750150
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Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.
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17495183
[ "Tenomodulin", "is", "associated", "with", "obesity", "and", "diabetes", "risk:", "the", "Finnish", "diabetes", "prevention", "study." ]
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Tenomodulin is associated with obesity and diabetes risk: the Finnish diabetes prevention study.
[ 2, 5656, 13993, 3392, 1977, 2458, 1956, 5379, 1930, 4032, 2565, 30, 1920, 24016, 4032, 5455, 2161, 18, 3 ]
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16628674
[ "A", "single", "nucleotide", "polymorphism", "characterized", "by", "the", "substitution", "of", "valine", "for", "glutamate", "(", "V1188E", ")", "in", "exon", "25", "of", "the", "multidrug", "resistance", "protein", "2", "gene", "was", "found", "in", "a", "group", "of", "patients", "with", "primary", "biliary", "cirrhosis.", "This", "heterozygous", "mutation", "was", "significantly", "associated", "with", "the", "presence", "of", "pruritus." ]
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A single nucleotide polymorphism characterized by the substitution of valine for glutamate ( V1188E ) in exon 25 of the multidrug resistance protein 2 gene was found in a group of patients with primary biliary cirrhosis. This heterozygous mutation was significantly associated with the presence of pruritus.
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14708104
[ "Gonadal", "mosaicism", "in", "severe", "Pallister-Hall", "syndrome." ]
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Gonadal mosaicism in severe Pallister-Hall syndrome.
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17250663
[]
[]
[ 2, 3 ]
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20026870
[ "Angiotensin-converting", "enzyme", "insertion/deletion", "and", "angiotensin", "type", "1", "receptor", "A1166C", " ", "polymorphisms", "as", "genetic", "risk", "factors", "in", "benign", "prostatic", "hyperplasia", "and", "prostate", "cancer." ]
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Angiotensin-converting enzyme insertion/deletion and angiotensin type 1 receptor A1166C polymorphisms as genetic risk factors in benign prostatic hyperplasia and prostate cancer.
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19645056
[]
[]
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18798060
[]
[]
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17169596
[]
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22337303
[ "Seven", "strains", "of", "Epstein-Barr", "virus", "(EBV)", "are", "defined", "based", "on", "C-terminal", "sequence", "variations", "of", "the", "latent", "membrane", "protein", "1", "(LMP1).", "Some", "strains,", "especially", "those", "with", "a", "30-bp", "deletion,", "are", "thought", "to", "be", "related", "to", "tumorigenic", "activity", "and", "geographical", "localization.", "The", "aims", "of", "the", "study", "were", "to", "determine", "the", "prevalence", "of", "different", "LMP1", "strains", "and", "to", "investigate", "sequence", "variation", "in", "the", "C-terminal", "region", "of", "LMP1", "in", "Serbian", "isolates.", "This", "study", "included", "53", "EBV-DNA-positive", "plasma", "and", "tissue", "block", "samples", "from", "patients", "with", "mononucleosis", "syndrome,", "renal", "transplantation,", "and", "tumors,", "mostly", "nasopharyngeal", "carcinoma.", "The", "sequence", "of", "the", "506-bp", "fragment", "of", "LMP1", " ", "C", "terminus", "was", "used", "for", "phylogenetic", "analyses", "and", "identification", "of", "LMP1", "strains,", "deletions,", "and", "mutations.", "The", "majority", "of", "isolates", "were", "non-deleted", "(66%),", "and", "the", "rest", "had", "30-bp,", "rare", "69-bp,", "or", "yet", "unknown", "27-bp", "deletions,", "which", "were", "not", "related", "to", "malignant", "or", "non-malignant", "isolate", "origin.", "However,", "the", "majority", "of", "69-bp", "deletion", "isolates", "were", "derived", "from", "patients", "with", "nasopharyngeal", "carcinoma.", "Less", "than", "five", "33-bp", "repeats", "were", "found", "in", "the", "majority", "of", "non-deleted", "isolates", "(68.6%),", "whereas", "most", "69-bp", "deletion", "isolates", "(75%)", "had", "five", "or", "six", "repeats.", "Serbian", "isolates", "were", "assigned", "to", "four", "LMP1", "strains:", "B95-8", "(32.1%),", "China", "1", "(24.5%),", "North", "Carolina", "(NC;", "18.9%),", "and", "Mediterranean", "(Med;", "24.5%).", "In", "NC", "isolates,", "three", "new", "mutations", "unique", "for", "this", "strain", "were", "identified.", "EBV", "EBNA2", "genotypes", "1", "and", "2", "were", "both", "found,", "with", "dominance", "of", "genotype", "1", "(90.7%).", "This", "study", "demonstrated", "noticeable", "geographical-associated", "characteristics", "in", "the", "LMP1", "C", "terminus", "of", "investigated", "isolates." ]
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Seven strains of Epstein-Barr virus (EBV) are defined based on C-terminal sequence variations of the latent membrane protein 1 (LMP1). Some strains, especially those with a 30-bp deletion, are thought to be related to tumorigenic activity and geographical localization. The aims of the study were to determine the prevalence of different LMP1 strains and to investigate sequence variation in the C-terminal region of LMP1 in Serbian isolates. This study included 53 EBV-DNA-positive plasma and tissue block samples from patients with mononucleosis syndrome, renal transplantation, and tumors, mostly nasopharyngeal carcinoma. The sequence of the 506-bp fragment of LMP1 C terminus was used for phylogenetic analyses and identification of LMP1 strains, deletions, and mutations. The majority of isolates were non-deleted (66%), and the rest had 30-bp, rare 69-bp, or yet unknown 27-bp deletions, which were not related to malignant or non-malignant isolate origin. However, the majority of 69-bp deletion isolates were derived from patients with nasopharyngeal carcinoma. Less than five 33-bp repeats were found in the majority of non-deleted isolates (68.6%), whereas most 69-bp deletion isolates (75%) had five or six repeats. Serbian isolates were assigned to four LMP1 strains: B95-8 (32.1%), China 1 (24.5%), North Carolina (NC; 18.9%), and Mediterranean (Med; 24.5%). In NC isolates, three new mutations unique for this strain were identified. EBV EBNA2 genotypes 1 and 2 were both found, with dominance of genotype 1 (90.7%). This study demonstrated noticeable geographical-associated characteristics in the LMP1 C terminus of investigated isolates.
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15198485
[ "Endothelin-1", "(ET-1)", "is", "a", "potent", "vasoconstrictor", "and", "shows", "various", "pharmacological", "responses.", "Two", "single", "nucleotide", "polymorphisms", "in", "the", "ET-1", "gene", "(EDN1)", "have", "been", "reported", "to", "be", "associated", "with", "blood", "pressure", "(BP).", "One", "is", "the", "Lys198Asn", " ", "polymorphism,", "which", "showed", "a", "positive", "association", "with", "BP", "in", "overweight", "people.", "Another", "is", "the", "3A/4A", "polymorphism", "(", "-134delA", ")", "located", "in", "the", "5'-untranslated", "region.", "In", "this", "study,", "we", "investigated", "the", "expression", "of", "the", "Lys198Asn", " ", "polymorphism", "in", "ET-1", "in", "vitro,", "as", "well", "as", "the", "association", "between", "either", "of", "the", "two", "polymorphisms", "and", "the", "plasma", "ET-1", "level.", "We", "expressed", "both", "the", "major", "(Lys-type)", "and", "minor", "type", "(Asn-type)", "preproET-1", "in", "three", "different", "cell", "lines,", "and", "measured", "the", "levels", "of", "ET-1", "and", "big", "ET-1", "in", "the", "culture", "supernatant.", "There", "was", "no", "significant", "difference", "in", "the", "levels", "of", "ET-1", "or", "big", "ET-1", "between", "the", "Asn-type", "and", "Lys-type", "transfectant.", "In", "the", "association", "study,", "the", "plasma", "levels", "of", "ET-1", "in", "54", "hypertensive", "patients", "having", "an", "amino", "acid", "substitution", "from", "Lys", "to", "Asn", "at", "position", "198", "were", "not", "different", "from", "those", "of", "hypertensives", "without", "the", "substitution.", "However,", "we", "found", "a", "significant", "difference", "in", "ET-1", "levels", "between", "individuals", "with", "the", "3A/3A", "and", "3A/4A", "genotypes.", "Our", "transient", "expression", "study", "indicates", "that", "the", "Lys198Asn", " ", "polymorphism", "may", "not", "directly", "affect", "ET-1", "and", "big", "ET-1", "production.", "Another", "variant", "in", "the", "EDN1", "gene", "in", "linkage", "disequilibrium", "with", "the", "Lys198Asn", " ", "polymorphism", "may", "be", "responsible", "for", "the", "association", "with", "BP,", "or", "the", "interaction", "between", "the", "EDN1", "Lys198Asn", " ", "polymorphism", "and", "other", "factors", "such", "as", "obesity", "may", "be", "involved", "in", "the", "mechanisms", "elevating", "BP", "in", "vivo." ]
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Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism ( -134delA ) located in the 5'-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo.
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15205584
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We analyzed the factor XII (FXII) gene of a patient with congenital FXII deficiency and identified a novel amino acid substitution ( W486C ) in the catalytic domain. The proband was an asymptomatic 49-year-old Japanese female with abnormal coagulation test, discovered by chance. The FXII activity and antigen level were both under 10%, suggesting a cross-reacting material-negative FXII deficiency. Sequence analysis of the proband's FXII gene revealed a homozygous nucleotide substitution G --> C in exon 12, resulting in the amino acid substitution W486C in the catalytic domain. We constructed the mutant FXII cDNA in an expression plasmid vector and transfected it into Chinese hamster ovary cells. The recombinant wild-type FXII antigen was detected in the culture medium by immunoprecipitation assay, but the mutant FXII ( W486C ) was not observed. On the other hand, both the wild-type FXII and W486C cell lysates contained FXII antigen and FXII mRNA, as estimated by western blotting and quantitative reverse transcriptase-polymerase chain reaction. These findings suggest that the W486C substitution of FXII impairs intracellular processing of the protein and/or transport system.
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17595233
[ "BACKGROUND", "AND", "AIMS:", "A", "number", "of", "antibodies", "against", "microbial", "epitopes", "or", "self-antigens", "have", "been", "associated", "with", "Crohn's", "disease.", "The", "development", "of", "antibodies", "reflects", "a", "loss", "of", "tolerance", "to", "intestinal", "bacteria", "that", "underlies", "Crohn's", "disease,", "resulting", "in", "an", "exaggerated", "adaptive", "immune", "response", "to", "these", "bacteria.", "It", "was", "hypothesised", "that", "the", "development", "of", "antimicrobial", "antibodies", "is", "influenced", "by", "the", "presence", "of", "genetic", "variants", "in", "pattern", "recognition", "receptor", "genes.", "The", "aim", "of", "this", "study", "was", "therefore", "to", "investigate", "the", "influence", "of", "mutations", "in", "these", "innate", "immune", "receptor", "genes", "(nucleotide", "oligomerisation", "domain", "(NOD)", "2/caspase", "recruitment", "domain", "(CARD)", "15,", "NOD1/CARD4,", "TUCAN/CARDINAL/CARD8,", "Toll-like", "receptor", "(TLR)", "4,", "TLR2,", "TLR1", "and", "TLR6)", "on", "the", "development", "of", "antimicrobial", "and", "antiglycan", "antibodies", "in", "inflammatory", "bowel", "disease", "(IBD).", "Materials", "and", "METHODS:", "A", "cohort", "of", "1163", "unrelated", "patients", "with", "IBD", "(874", "Crohn's", "disease,", "259", "ulcerative", "colitis,", "30", "indeterminate", "colitis)", "and", "312", "controls", "were", "analysed", "for", "anti-Saccharomyces", "cerevisiae", "antibodies", "(gASCA)", "IgG,", "anti-laminaribioside", "antibodies", "(ALCA)", "IgG,", "anti-chitobioside", "antibodies", "(ACCA)", "IgA,", "anti-mannobioside", "antibodies", "(AMCA)", "IgG", "and", "outer", "membrane", "porin", "(Omp)", "IgA", "and", "were", "genotyped", "for", "variants", "in", "NOD2/CARD15,", "TUCAN/CARDINAL/CARD8,", "NOD1/CARD4,", "TLR4,", "TLR1,", "TLR2", "and", "TLR6.", "RESULTS:", "When", "compared", "with", "Crohn's", "disease", "patients", "without", "CARD15", "mutations,", "the", "presence", "of", "at", "least", "one", "CARD15", "variant", "in", "Crohn's", "disease", "patients", "more", "frequently", "led", "to", "gASCA", "positivity", "(66.1%", "versus", "51.5%,", "p", "<", "0.0001)", "and", "ALCA", "positivity", "(43.3%", "versus", "34.9%,", "p", "=", "0.018)", "and", "higher", "gASCA", "titers", "(85.7", "versus", "51.8", "ELISA", "units,", "p", "<", "0.0001),", "independent", "of", "ileal", "involvement.", "A", "gene", "dosage", "effect,", "with", "increasing", "gASCA", "and", "ALCA", "positivity", "for", "patients", "carrying", "none,", "one", "and", "two", "CARD15", "variants,", "respectively,", "was", "seen", "for", "both", "markers.", "Similarly,", "Crohn's", "disease", "patients", "carrying", "NOD1/CARD4", "indel", "had", "a", "higher", "prevalence", "of", "gASCA", "antibodies", "than", "wild-type", "patients", "(63.8%", "versus", "55.2%,", "p", "=", "0.014),", "also", "with", "a", "gene", "dosage", "effect.", "An", "opposite", "effect", "was", "observed", "for", "the", "TLR4", "D299G", " ", "and", "TLR2", "P631H", " ", "variants,", "with", "a", "lower", "prevalence", "of", "ACCA", "antibodies", "(23.4%", "versus", "35%,", "p", "=", "0.013)", "and", "Omp", "antibodies", "(20.5%", "versus", "34.6%,", "p", "=", "0.009),", "respectively.", "CONCLUSION:", "Variants", "in", "innate", "immune", "receptor", "genes", "were", "found", "to", "influence", "antibody", "formation", "against", "microbial", "epitopes.", "In", "this", "respect,", "it", "is", "intriguing", "that", "an", "opposite", "effect", "of", "CARD15", "and", "TLR4", "variants", "was", "observed.", "These", "findings", "may", "contribute", "to", "an", "understanding", "of", "the", "aetiology", "of", "the", "seroreactivity", "observed", "in", "IBD." ]
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BACKGROUND AND AIMS: A number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD). Materials and METHODS: A cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6. RESULTS: When compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively. CONCLUSION: Variants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD.
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18470323
[ "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." ]
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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.
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Spinal muscular atrophy (SMA) is an autosomal recessive disease caused, in about 95% of SMA cases, by homozygous deletion of the survival motor neuron 1 (SMN1) gene or its conversion to the highly homologous SMN2 gene. The molecular diagnosis of SMA is usually carried out by a PCR-Restriction fragment length polymorphism (RFLP) approach. However, this approach is not useful for identification of healthy deletion carriers. TaqMan technology is one of the most reliable and widely adopted techniques for the SMN1 copy number evaluation. However, several limitations of this technique have been described. Particularly, DNA extraction methods and accurate template quantification have been shown to be critical for reliable results. In this work, we set up a reliable, highly reproducible, and easy-to-perform TaqMan technology-based protocol to obtain the SMN1 gene copy number assessment. We demonstrate that PCR amplification of both target gene and reference gene in the same reaction mix, instead of separated mixes, greatly reduces reported criticisms of simplex TaqMan technology. The multiplex real-time PCR we describe allows interlaboratory samples and data exchange, without the need to equalize the DNA isolation technique. Further, the protocol described below requires fewer replica tests than the simplex methodology does, leading to reduced overall cost for the diagnostic assay.
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20577006
[ "Novel", "and", "recurrent", "TRPV4", "mutations", "and", "their", "association", "with", "distinct", "phenotypes", "within", "the", "TRPV4", "dysplasia", "family." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.
[ 2, 4008, 1930, 7457, 23067, 1006, 3527, 1930, 2310, 3279, 1956, 4493, 6568, 2651, 1920, 23067, 1006, 14095, 3416, 18, 3 ]
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19353688
[]
[]
[ 2, 3 ]
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[ 1, 1 ]
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12737948
[ "A", "\"null", "allele\"", "mutation", "is", "responsible", "for", "erythropoietic", "protoporphyria", "in", "an", "Israeli", "patient", "who", "underwent", "liver", "transplantation:", "relationships", "among", "biochemical,", "clinical,", "and", "genetic", "parameters." ]
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A "null allele" mutation is responsible for erythropoietic protoporphyria in an Israeli patient who underwent liver transplantation: relationships among biochemical, clinical, and genetic parameters.
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21159032
[ "AIM:", "The", "aim", "of", "our", "study", "was", "to", "investigate", "the", "relationship", "between", "the", "alpha2B-adrenoreceptor", "insertion/deletion", "(I/D)", "polymorphism", "and", "recurrent", "spontaneous", "abortions", "(RSA).", "METHODS:", "Genotyping", "was", "performed", "in", "48", "women", "with", "a", "history", "of", "at", "least", "three", "consecutive", "spontaneous", "abortions", "and", "96", "women", "with", "at", "least", "two", "live", "births", "and", "no", "history", "of", "pregnancy", "loss.", "Peripheral", "venous", "puncture,", "DNA", "extraction", "and", "PCR", "were", "used", "for", "the", "research", "of", "DD,", "ID", "and", "II", "genotype", "characters.", "RESULTS:", "The", "distribution", "of", "DD,", "ID", "and", "II", "genotypes", "of", "the", "alpha2B-adrenoreceptor", "gene", "was", "2", "(4.2%),", "19", "(39.6%)", "and", "27", "(56.2%)", "in", "the", "study", "group", "and", "6", "(6.5%),", "28", "(30.4%)", "and", "58", "(63%)", "in", "the", "control", "group,", "respectively.", "There", "was", "no", "significant", "difference", "between", "the", "groups.", "The", "presence", "of", "the", "D", "allele", "was", "not", "associated", "with", "RSA", "(P", "=", "0.78,", "odds", "ratio", "=", "0.88,", "95%", "CI", "=", "0.47-1.65).", "CONCLUSION:", "Our", "data", "fall", "short", "of", "showing", "any", "association", "between", "the", "presence", "of", "the", "alpha2B", "D", "allele", "and", "the", "occurrence", "of", "spontaneous", "abortions", "in", "the", "examined", "population." ]
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AIM: The aim of our study was to investigate the relationship between the alpha2B-adrenoreceptor insertion/deletion (I/D) polymorphism and recurrent spontaneous abortions (RSA). METHODS: Genotyping was performed in 48 women with a history of at least three consecutive spontaneous abortions and 96 women with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction and PCR were used for the research of DD, ID and II genotype characters. RESULTS: The distribution of DD, ID and II genotypes of the alpha2B-adrenoreceptor gene was 2 (4.2%), 19 (39.6%) and 27 (56.2%) in the study group and 6 (6.5%), 28 (30.4%) and 58 (63%) in the control group, respectively. There was no significant difference between the groups. The presence of the D allele was not associated with RSA (P = 0.78, odds ratio = 0.88, 95% CI = 0.47-1.65). CONCLUSION: Our data fall short of showing any association between the presence of the alpha2B D allele and the occurrence of spontaneous abortions in the examined population.
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15557460
[ "Genetic", "linkage", "of", "snowflake", "vitreoretinal", "degeneration", "to", "chromosome", "2q36." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36.
[ 2, 3299, 8611, 1927, 19246, 2911, 2934, 16986, 28771, 1923, 9174, 1942, 5597, 22, 1055, 5677, 18, 3 ]
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[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
16723031
[ "Polymorphisms", "in", "thymidylate", "synthase", "gene", "and", "susceptibility", "to", "breast", "cancer", "in", "a", "Chinese", "population:", "a", "case-control", "analysis." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis.
[ 2, 8321, 1922, 7330, 19743, 2010, 8921, 2359, 1930, 6461, 1942, 3739, 2539, 1922, 43, 7185, 2973, 30, 43, 3087, 17, 2285, 2333, 18, 3 ]
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[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
21159032
[]
[]
[ 2, 3 ]
[ 0, 0 ]
[ 1, 1 ]
[ -100, -100 ]
16157158
[ "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." ]
[ 0, 3, 4, 4, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
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.
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18681856
[ "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." ]
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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.
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16200390
[ "A", "genetic", "analysis", "of", "serotonergic", "biosynthetic", "and", "metabolic", "enzymes", "in", "migraine", "using", "a", "DNA", "pooling", "approach." ]
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A genetic analysis of serotonergic biosynthetic and metabolic enzymes in migraine using a DNA pooling approach.
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15122708
[]
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19309272
[]
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21629979
[ "The", "genetic", "and", "clinical", "features", "of", "glioblastoma", "with", "an", "oligodendroglial", "component", "(GBMO),", "pathologically", "defined", "as", "anaplastic", "oligo-astrocytoma", "with", "necrosis,", "remain", "unclear.", "We", "investigated", "the", "correlation", "between", "genetic", "alterations", "and", "clinical", "outcomes", "in", "19", "GBMO", "patients", "we", "have", "encountered", "since", "1997.", "Using", "single", "nucleotide", "polymorphism", "oligonucleotide", "genomic", "(SNP)", "microarrays,", "we", "analyzed", "gene", "amplification,", "loss", "of", "heterozygosity", "(LOH),", "and", "homozygous", "deletions", "in", "their", "whole", "genome.", "We", "also", "analyzed", "their", "overall", "survival", "(OS).", "Pathological", "studies", "revealed", "the", "presence", "of", "calcification", "in", "11", "and", "of", "a", "cyst", "in", "9", "of", "the", "19", "patients.", "Whole-genome", "analysis", "using", "SNP", "microarrays", "revealed", "LOH", "of", "chromosome", "10", "in", "11,", "EGFR", "amplification", "in", "8,", "9p21", "(INK4", "locus)", "deletion", "in", "12,", "PDGFR", "amplification", "in", "2,", "and", "LOH", "of", "1p19q", "in", "2", "patients.", "Median", "OS", "was", "14", " ", "months", "(average", "22.8", " ", "months).", "The", "pattern", "of", "genetic", "alterations", "was", "similar", "in", "GBMO", "and", "glioblastoma", "multiforme", "(GBM)", "patients,", "and", "the", "clinical", "outcomes", "were", "similar", "in", "GBMO", "and", "GBM", "patients." ]
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The genetic and clinical features of glioblastoma with an oligodendroglial component (GBMO), pathologically defined as anaplastic oligo-astrocytoma with necrosis, remain unclear. We investigated the correlation between genetic alterations and clinical outcomes in 19 GBMO patients we have encountered since 1997. Using single nucleotide polymorphism oligonucleotide genomic (SNP) microarrays, we analyzed gene amplification, loss of heterozygosity (LOH), and homozygous deletions in their whole genome. We also analyzed their overall survival (OS). Pathological studies revealed the presence of calcification in 11 and of a cyst in 9 of the 19 patients. Whole-genome analysis using SNP microarrays revealed LOH of chromosome 10 in 11, EGFR amplification in 8, 9p21 (INK4 locus) deletion in 12, PDGFR amplification in 2, and LOH of 1p19q in 2 patients. Median OS was 14 months (average 22.8 months). The pattern of genetic alterations was similar in GBMO and glioblastoma multiforme (GBM) patients, and the clinical outcomes were similar in GBMO and GBM patients.
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19048115
[ "Neurofibromin", "1", "(NF1)", "defects", "are", "common", "in", "human", "ovarian", "serous", "carcinomas", "and", "co-occur", "with", "TP53", "mutations." ]
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Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations.
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16046395
[]
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[ 2, 3 ]
[ 0, 0 ]
[ 1, 1 ]
[ -100, -100 ]
17634480
[]
[]
[ 2, 3 ]
[ 0, 0 ]
[ 1, 1 ]
[ -100, -100 ]
21943124
[]
[]
[ 2, 3 ]
[ 0, 0 ]
[ 1, 1 ]
[ -100, -100 ]
21499297
[ "C10ORF97", "is", "a", "novel", "tumor-suppressor", "gene", "of", "non-small-cell", "lung", "cancer", "and", "a", "functional", "variant", "of", "this", "gene", "increases", "the", "risk", "of", "non-small-cell", "lung", "cancer." ]
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C10ORF97 is a novel tumor-suppressor gene of non-small-cell lung cancer and a functional variant of this gene increases the risk of non-small-cell lung cancer.
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16288199
[ "PURPOSE:", "Nitric", "oxide", "has", "many", "beneficial", "functions", "in", "the", "human", "body", "at", "the", "right", "amounts,", "but", "it", "can", "also", "be", "hazardous", "if", "it", "is", "produced", "in", "amounts", "more", "than", "needed", "and", "has", "therefore", "been", "studied", "in", "relation", "to", "several", "neurological", "and", "non-neurological", "disorders.", "In", "vitro", "and", "in", "vivo", "studies", "demonstrate", "a", "connection", "between", "the", "inducible", "form", "of", "Nitric", "Oxide", "Synthase,", "iNOS,", "and", "the", "neuropathological", "disorder", "glaucoma,", "one", "of", "the", "major", "causes", "of", "blindness", "in", "the", "world.", "In", "this", "study,", "we", "sought", "to", "establish", "the", "genetic", "association", "between", "iNOS", "and", "primary", "open", "angle", "glaucoma,", "POAG,", "and", "to", "find", "the", "functional", "element(s)", "connected", "with", "the", "pathogenesis", "of", "the", "disease.", "METHODS:", "Two", "microsatellites,", "1", "insertion/deletion,", "and", "8", "single", "nucleotide", "polymorphisms", "(SNPs)", "in", "the", "regulatory", "region", "of", "iNOS", "were", "genotyped", "in", "200", "POAG", "patients", "and", "200", "age-matched", "controls.", "Also,", "the", "CCTTT-microsatellite", "was", "examined", "for", "its", "protein-binding", "capability", "in", "an", "electrophoretic", "mobility", "shift", "assay,", "EMSA.", "RESULTS:", "There", "was", "a", "significant", "difference", "in", "allele", "distribution", "of", "the", "CCTTT-microsatellite,", "between", "patients", "and", "controls.", "(CCTTT)14,", "which", "has", "been", "reported", "to", "have", "a", "higher", "activity", "in", "a", "reporter-construct,", "was", "significantly", "more", "abundant", "in", "POAG", "patients,", "while", "(CCTTT)10", "and", "(CCTTT)13", "were", "less", "common.", "In", "EMSA,", "the", "(CCTTT)14", "allele", "exhibited", "specific", "binding", "of", "nuclear", "proteins.", "CONCLUSIONS:", "These", "results,", "together", "with", "other", "studies", "on", "this", "gene", "and", "the", "CCTTT-microsatellite,", "establish,", "for", "the", "first", "time,", "a", "genetic", "association", "of", "iNOS", "with", "POAG", "and", "suggest", "a", "regulatory", "function", "for", "the", "microsatellite." ]
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PURPOSE: Nitric oxide has many beneficial functions in the human body at the right amounts, but it can also be hazardous if it is produced in amounts more than needed and has therefore been studied in relation to several neurological and non-neurological disorders. In vitro and in vivo studies demonstrate a connection between the inducible form of Nitric Oxide Synthase, iNOS, and the neuropathological disorder glaucoma, one of the major causes of blindness in the world. In this study, we sought to establish the genetic association between iNOS and primary open angle glaucoma, POAG, and to find the functional element(s) connected with the pathogenesis of the disease. METHODS: Two microsatellites, 1 insertion/deletion, and 8 single nucleotide polymorphisms (SNPs) in the regulatory region of iNOS were genotyped in 200 POAG patients and 200 age-matched controls. Also, the CCTTT-microsatellite was examined for its protein-binding capability in an electrophoretic mobility shift assay, EMSA. RESULTS: There was a significant difference in allele distribution of the CCTTT-microsatellite, between patients and controls. (CCTTT)14, which has been reported to have a higher activity in a reporter-construct, was significantly more abundant in POAG patients, while (CCTTT)10 and (CCTTT)13 were less common. In EMSA, the (CCTTT)14 allele exhibited specific binding of nuclear proteins. CONCLUSIONS: These results, together with other studies on this gene and the CCTTT-microsatellite, establish, for the first time, a genetic association of iNOS with POAG and suggest a regulatory function for the microsatellite.
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17994380
[ "Screening", "of", "Iranian", "thalassemic", "families", "for", "the", "most", "common", "deletions", "of", "the", "beta-globin", "gene", "cluster." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Screening of Iranian thalassemic families for the most common deletions of the beta-globin gene cluster.
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16120104
[ "A", "single-nucleotide", "polymorphism", "in", "the", "5'-untranslated", "region", "of", "the", "hPER2", "gene", "is", "associated", "with", "diurnal", "preference." ]
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A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference.
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17327131
[ "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." ]
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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.
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17549393
[ "A", "novel", "IRF6", "nonsense", "mutation", "(", "Y67X", ")", "in", "a", "German", "family", "with", "Van", "der", "Woude", "syndrome." ]
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A novel IRF6 nonsense mutation ( Y67X ) in a German family with Van der Woude syndrome.
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20634801
[ "Four", "independent", "regions", "within", "8q24", "near", "the", "MYC", "gene", "are", "associated", "with", "risk", "for", "prostate", "cancer", "(Pca).", "Here,", "we", "investigated", "allelic", "imbalance", "(AI)", "at", "8q24", "risk", "variants", "and", "MYC", "gene", "DNA", "copy", "number", "(CN)", "in", "27", "primary", "Pcas.", "Heterozygotes", "were", "observed", "in", "24", "of", "27", "patients", "at", "one", "or", "more", "8q24", "markers", "and", "27%", "of", "the", "loci", "exhibited", "AI", "in", "tumor", "DNA.", "The", "8q24", "risk", "alleles", "were", "preferentially", "favored", "in", "the", "tumors.", "Increased", "MYC", "gene", "CN", "was", "observed", "in", "33%", "of", "tumors,", "and", "the", "co-existence", "of", "increased", "MYC", "gene", "CN", "with", "AI", "at", "risk", "loci", "was", "observed", "in", "86%", "(P<0.004", "exact", "binomial", "test)", "of", "the", "informative", "tumors.", "No", "AI", "was", "observed", "in", "tumors,", "which", "did", "not", "reveal", "increased", "MYC", "gene", "CN.", "Higher", "Gleason", "score", "was", "associated", "with", "tumors", "exhibiting", "AI", "(P=0.04)", "and", "also", "with", "increased", "MYC", "gene", "CN", "(P=0.02).", "Our", "results", "suggest", "that", "AI", "at", "8q24", "and", "increased", "MYC", "gene", "CN", "may", "both", "be", "related", "to", "high", "Gleason", "score", "in", "Pca.", "Our", "findings", "also", "suggest", "that", "these", "two", "somatic", "alterations", "may", "be", "due", "to", "the", "same", "preferential", "chromosomal", "duplication", "event", "during", "prostate", "tumorigenesis." ]
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Four independent regions within 8q24 near the MYC gene are associated with risk for prostate cancer (Pca). Here, we investigated allelic imbalance (AI) at 8q24 risk variants and MYC gene DNA copy number (CN) in 27 primary Pcas. Heterozygotes were observed in 24 of 27 patients at one or more 8q24 markers and 27% of the loci exhibited AI in tumor DNA. The 8q24 risk alleles were preferentially favored in the tumors. Increased MYC gene CN was observed in 33% of tumors, and the co-existence of increased MYC gene CN with AI at risk loci was observed in 86% (P<0.004 exact binomial test) of the informative tumors. No AI was observed in tumors, which did not reveal increased MYC gene CN. Higher Gleason score was associated with tumors exhibiting AI (P=0.04) and also with increased MYC gene CN (P=0.02). Our results suggest that AI at 8q24 and increased MYC gene CN may both be related to high Gleason score in Pca. Our findings also suggest that these two somatic alterations may be due to the same preferential chromosomal duplication event during prostate tumorigenesis.
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14722925
[ "Mutations", "in", "the", "serine", "protease", "inhibitor", "Kazal", "type", "1", "gene", "(SPINK1)", "encoding", "pancreatic", "secretory", "trypsin", "inhibitor", "(PSTI)", "have", "recently", "been", "found", "to", "be", "associated", "with", "chronic", "pancreatitis.", "Nevertheless,", "knowledge", "of", "severe", "mutations", "is", "particularly", "scarce,", "both", "in", "terms", "of", "number", "and", "in", "the", "extent", "of", "clinical", "information.", "The", "aim", "of", "this", "study", "was", "to", "expand", "the", "known", "spectrum", "of", "such", "mutations.", "46", "unrelated", "families,", "each", "including", "at", "least", "two", "pancreatitis", "patients", "and", "carrying", "neither", "cationic", "trypsinogen", "(PRSS1)", "mutations", "nor", "the", "frequent", "SPINK1", "N34S", " ", "mutation,", "participated", "in", "this", "study.", "The", "four", "exons", "and", "their", "flanking", "sequences", "of", "the", "SPINK1", "gene", "were", "screened", "by", "denaturing", "high", "performance", "liquid", "chromatography", "analysis", "(DHPLC);", "and", "mutations", "were", "identified", "by", "direct", "sequencing.", "A", "heterozygous", "microdeletion", "mutation", "(", "c.27delC", "),", "which", "occurs", "within", "a", "symmetric", "element,", "was", "identified", "in", "two", "families.", "In", "one", "family,", "c.27delC", " ", "showed", "segregation", "with", "the", "disease", "across", "two", "generations,", "with", "a", "penetrance", "of", "up", "to", "75%.", "But", "in", "the", "other", "family,", "however,", "the", "same", "mutation", "manifested", "as", "a", "low-penetrance", "susceptibility", "factor.", "In", "addition,", "a", "novel", "heterozygous", "splicing", "mutation,", "c.87+1G>A", " ", "(", "G>A", "substitution", "at", "nucleotide", "+1", "of", "intron", "2", ")", "was", "found", "in", "one", "family", "with", "familial", "pancreatitis.", "Our", "results", "also", "helped", "to", "resolve", "the", "sharply", "differing", "views", "about", "PSTI's", "role", "in", "pancreatitis." ]
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Mutations in the serine protease inhibitor Kazal type 1 gene (SPINK1) encoding pancreatic secretory trypsin inhibitor (PSTI) have recently been found to be associated with chronic pancreatitis. Nevertheless, knowledge of severe mutations is particularly scarce, both in terms of number and in the extent of clinical information. The aim of this study was to expand the known spectrum of such mutations. 46 unrelated families, each including at least two pancreatitis patients and carrying neither cationic trypsinogen (PRSS1) mutations nor the frequent SPINK1 N34S mutation, participated in this study. The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing. A heterozygous microdeletion mutation ( c.27delC ), which occurs within a symmetric element, was identified in two families. In one family, c.27delC showed segregation with the disease across two generations, with a penetrance of up to 75%. But in the other family, however, the same mutation manifested as a low-penetrance susceptibility factor. In addition, a novel heterozygous splicing mutation, c.87+1G>A ( G>A substitution at nucleotide +1 of intron 2 ) was found in one family with familial pancreatitis. Our results also helped to resolve the sharply differing views about PSTI's role in pancreatitis.
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21779184
[ "BACKGROUND:", "Prevention", "and", "control", "of", "thalassemia", "requires", "simple,", "rapid,", "and", "accurate", "screening", "tests", "for", "carrier", "couples", "who", "are", "at", "risk", "of", "conceiving", "fetuses", "with", "severe", "thalassemia.", "METHODS:", "Single-tube", "multiplex", "real-time", "PCR", "with", "SYBR", "Green1", "and", "high-resolution", "melting", "(HRM)", "analysis", "were", "used", "for", "the", "identification", "of", "a-thalassemia-1", "Southeast", "Asian", "(SEA)", "and", "Thai", "type", "deletions", "and", "b-thalassemia", "3.5-kb", "gene", "deletion.", "The", "results", "were", "compared", "with", "those", "obtained", "using", "conventional", "gap-PCR.", "DNA", "samples", "were", "derived", "from", "28", "normal", "individuals,", "11", "individuals", "with", "a-thalassemia-1", "SEA", "type", "deletion,", "2", "with", "a-thalassemia-1", "Thai", "type", "deletion,", "and", "2", "with", "heterozygous", "b-thalassemia", "3.5-kb", "gene", "deletion.", "RESULTS:", "HRM", "analysis", "indicated", "that", "the", "amplified", "fragments", "from", "a-thalassemia-1", "SEA", "type", "deletion,", "a-thalassemia-1", "Thai", "type", "deletion,", "b-thalassemia", "3.5-kb", "gene", "deletion,", "and", "the", "wild-type", "b-globin", "gene", "had", "specific", "peak", "heights", "at", "mean", "melting", "temperature", "(T(m))", "values", "of", "86.89", " ", ",", "85.66", " ", ",", "77.24", " ", ",", "and", "74.92", " ", ",", "respectively.", "The", "results", "obtained", "using", "single-tube", "multiplex", "real-time", "PCR", "with", "SYBR", "Green1", "and", "HRM", "analysis", "showed", "100%", "consistency", "with", "those", "obtained", "using", "conventional", "gap-PCR.", "CONCLUSIONS:", "Single-tube", "multiplex", "real-time", "PCR", "with", "SYBR", "Green1", "and", "HRM", "analysis", "is", "a", "potential", "alternative", "for", "routine", "clinical", "screening", "of", "the", "common", "types", "of", "a-", "and", "b-thalassemia", "large", "gene", "deletions,", "since", "it", "is", "simple,", "cost-effective,", "and", "highly", "accurate." ]
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BACKGROUND: Prevention and control of thalassemia requires simple, rapid, and accurate screening tests for carrier couples who are at risk of conceiving fetuses with severe thalassemia. METHODS: Single-tube multiplex real-time PCR with SYBR Green1 and high-resolution melting (HRM) analysis were used for the identification of a-thalassemia-1 Southeast Asian (SEA) and Thai type deletions and b-thalassemia 3.5-kb gene deletion. The results were compared with those obtained using conventional gap-PCR. DNA samples were derived from 28 normal individuals, 11 individuals with a-thalassemia-1 SEA type deletion, 2 with a-thalassemia-1 Thai type deletion, and 2 with heterozygous b-thalassemia 3.5-kb gene deletion. RESULTS: HRM analysis indicated that the amplified fragments from a-thalassemia-1 SEA type deletion, a-thalassemia-1 Thai type deletion, b-thalassemia 3.5-kb gene deletion, and the wild-type b-globin gene had specific peak heights at mean melting temperature (T(m)) values of 86.89 , 85.66 , 77.24 , and 74.92 , respectively. The results obtained using single-tube multiplex real-time PCR with SYBR Green1 and HRM analysis showed 100% consistency with those obtained using conventional gap-PCR. CONCLUSIONS: Single-tube multiplex real-time PCR with SYBR Green1 and HRM analysis is a potential alternative for routine clinical screening of the common types of a- and b-thalassemia large gene deletions, since it is simple, cost-effective, and highly accurate.
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19429807
[ "A", "novel", "ATP7A", "gross", "deletion", "mutation", "in", "a", "Korean", "patient", "with", "Menkes", "disease." ]
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A novel ATP7A gross deletion mutation in a Korean patient with Menkes disease.
[ 2, 43, 4008, 4498, 13827, 10461, 5541, 3979, 1922, 43, 13327, 2774, 1956, 3925, 15088, 2573, 18, 3 ]
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21943124
[ "BACKGROUND:", "Signalling", "by", "fibroblast", "growth", "factor", "receptor", "type", "2", "(FGFR2)", "normally", "involves", "a", "tissue-specific", "alternative", "splice", "choice", "between", "two", "exons", "(IIIb", "and", "IIIc),", "which", "generates", "two", "receptor", "isoforms", "(FGFR2b", "and", "FGFR2c", "respectively)", "with", "differing", "repertoires", "of", "FGF-binding", "specificity.", "Here", "we", "describe", "a", "unique", "chimeric", "IIIb/c", "exon", "in", "a", "patient", "with", "Apert", "syndrome,", "generated", "by", "a", "non-allelic", "homologous", "recombination", "event.", "CASE", "PRESENTATION:", "We", "present", "a", "child", "with", "Apert", "syndrome", "in", "whom", "routine", "genetic", "testing", "had", "excluded", "the", "FGFR2", "missense", "mutations", "commonly", "associated", "with", "this", "disorder.", "The", "patient", "was", "found", "to", "harbour", "a", "heterozygous", "1372", "bp", "deletion", "between", "FGFR2", "exons", "IIIb", "and", "IIIc,", "apparently", "originating", "from", "recombination", "between", "13", "bp", "of", "identical", "DNA", "sequence", "present", "in", "both", "exons.", "The", "rearrangement", "was", "not", "present", "in", "the", "unaffected", "parents.", "CONCLUSIONS:", "Based", "on", "the", "known", "pathogenesis", "of", "Apert", "syndrome,", "the", "chimeric", "FGFR2", "protein", "is", "predicted", "to", "act", "in", "a", "dominant", "gain-of-function", "manner.", "This", "is", "likely", "to", "result", "from", "its", "expression", "in", "mesenchymal", "tissues,", "where", "retention", "of", "most", "of", "the", "residues", "essential", "for", "FGFR2b", "binding", "activity", "would", "result", "in", "autocrine", "activation.", "This", "report", "adds", "to", "the", "repertoire", "of", "rare", "cases", "of", "Apert", "syndrome", "for", "which", "a", "pathogenesis", "based", "on", "atypical", "FGFR2", "rearrangements", "can", "be", "demonstrated." ]
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BACKGROUND: Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event. CASE PRESENTATION: We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents. CONCLUSIONS: Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.
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15191352
[ "Resistance", "to", "thyroid", "hormone", "syndrome", "(RTH)", "is", "a", "rare", "disorder,", "usually", "inherited", "as", "an", "autosomal", "dominant", "trait.", "Patients", "with", "RTH", "are", "usually", "euthyroid", "but", "can", "occasionally", "present", "with", "signs", "and", "symptoms", "of", "thyrotoxicosis", "or", "rarely", "with", "hypothyroidism.", "Affected", "individuals", "are", "usually", "heterozygous", "for", "mutations", "in", "the", "thyroid", "hormone", "receptor", "beta", "gene", "(TR-beta).", "We", "present", "a", "patient", "with", "RTH", "found", "to", "be", "homo-/hemizygous", "for", "a", "mutation", "in", "the", "TR-beta", "gene.", "The", "single", "nucleotide", "substitution", "I280S", " ", "(", "1123T-->G", ")", "was", "present", "either", "on", "both", "alleles", "or", "in", "a", "hemizygous", "form", "with", "complete", "deletion", "of", "the", "second", "allele.", "The", "I280S", " ", "mutation", "was", "recently", "reported", "in", "a", "heterozygous", "patient.", "The", "severe", "phenotype", "with", "seriously", "impaired", "intellectual", "development,", "hyperkinetic", "behaviour,", "tachycardia,", "hearing", "and", "visual", "impairment", "is", "probably", "due", "to", "the", "dominant", "negative", "effect", "of", "the", "I280S", " ", "mutant", "protein", "and", "the", "absence", "of", "any", "functional", "TR-beta." ]
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Resistance to thyroid hormone syndrome (RTH) is a rare disorder, usually inherited as an autosomal dominant trait. Patients with RTH are usually euthyroid but can occasionally present with signs and symptoms of thyrotoxicosis or rarely with hypothyroidism. Affected individuals are usually heterozygous for mutations in the thyroid hormone receptor beta gene (TR-beta). We present a patient with RTH found to be homo-/hemizygous for a mutation in the TR-beta gene. The single nucleotide substitution I280S ( 1123T-->G ) was present either on both alleles or in a hemizygous form with complete deletion of the second allele. The I280S mutation was recently reported in a heterozygous patient. The severe phenotype with seriously impaired intellectual development, hyperkinetic behaviour, tachycardia, hearing and visual impairment is probably due to the dominant negative effect of the I280S mutant protein and the absence of any functional TR-beta.
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16989765
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12809638
[ "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." ]
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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.
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12636044
[ "Identification", "of", "new", "polymorphisms", "in", "the", "CACNA1S", "gene." ]
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Identification of new polymorphisms in the CACNA1S gene.
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16781314
[ "We", "report", "an", "unusual", "case", "of", "an", "inherited", "disorder", "of", "the", "desmosomal", "protein", "plakophilin", "1,", "resulting", "in", "ectodermal", "dysplasia-skin", "fragility", "syndrome.", "The", "affected", "6-year-old", "boy", "had", "red", "skin", "at", "birth", "and", "subsequently", "developed", "skin", "fragility,", "progressive", "plantar", "keratoderma,", "nail", "dystrophy,", "and", "alopecia.", "Skin", "biopsy", "revealed", "widening", "of", "intercellular", "spaces", "in", "the", "epidermis", "and", "a", "reduced", "number", "of", "small,", "poorly", "formed", "desmosomes.", "Mutation", "analysis", "of", "the", "plakophilin", "1", "gene", "PKP1", "revealed", "a", "homozygous", "deletion", "of", "C", "at", "nucleotide", "888", "within", "exon", "5.", "This", "mutation", "differs", "from", "the", "PKP1", "gene", "pathology", "reported", "in", "8", "previously", "published", "individuals", "with", "this", "rare", "genodermatosis.", "However,", "all", "cases", "show", "similar", "clinical", "features,", "highlighting", "the", "importance", "of", "functional", "plakophilin", "1", "in", "maintaining", "desmosomal", "adhesion", "in", "skin,", "as", "well", "as", "the", "role", "of", "this", "protein", "in", "aspects", "of", "ectodermal", "development." ]
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We report an unusual case of an inherited disorder of the desmosomal protein plakophilin 1, resulting in ectodermal dysplasia-skin fragility syndrome. The affected 6-year-old boy had red skin at birth and subsequently developed skin fragility, progressive plantar keratoderma, nail dystrophy, and alopecia. Skin biopsy revealed widening of intercellular spaces in the epidermis and a reduced number of small, poorly formed desmosomes. Mutation analysis of the plakophilin 1 gene PKP1 revealed a homozygous deletion of C at nucleotide 888 within exon 5. This mutation differs from the PKP1 gene pathology reported in 8 previously published individuals with this rare genodermatosis. However, all cases show similar clinical features, highlighting the importance of functional plakophilin 1 in maintaining desmosomal adhesion in skin, as well as the role of this protein in aspects of ectodermal development.
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20854438
[ "BACKGROUND:", "Mal", "de", "Meleda", "(MDM)", "is", "palmoplantar", "erythrokeratoderma", "with", "an", "autosomal", "recessive", "inheritance", "and", "is", "caused", "by", "a", "mutation", "in", "the", "gene", "encoding", "SLURP-1", "(lymphocyte", "antigen", "6/urokinase-type", "plasminogen", "activator", "receptor", "related", "protein-1).", "SLURP-1", "is", "an", "allosteric", "agonist", "to", "the", "nicotinic", "acetylcholine", "receptor", "(nAchR)", "and", "it", "regulates", "epidermal", "homeostasis.", "In", "addition,", "murine", "studies", "have", "shown", "that", "nAchR", "signalling", "is", "important", "for", "the", "regulation", "of", "T-cell", "function.", "Among", "the", "family", "members,", "patients", "with", "the", "homozygous", "SLURP1", "(previously", "known", "as", "ARS", "component", "B)", "mutation", "are", "prone", "to", "melanoma", "and", "viral", "infection,", "which", "might", "link", "to", "defective", "T-cell", "function", "as", "well", "as", "a", "derangement", "of", "epidermal", "homeostasis.", "OBJECTIVES:", "To", "investigate", "the", "association", "of", "the", "SLURP1", "gene", "mutation", "with", "T-cell", "activation", "in", "a", "Taiwanese", "family", "with", "MDM.", "To", "test", "that", "SLURP-1", "is", "essential", "for", "T-cell", "activation.", "METHODS:", "Human", "peripheral", "blood", "mononuclear", "cells", "(PBMCs)", "were", "isolated", "from", "a", "Taiwanese", "MDM", "family", "bearing", "the", "G", "to", "A", "substitution", "in", "nucleotide", "256", "in", "the", "SLURP1", "gene,", "corresponding", "to", "a", "glycine", "to", "arginine", "substitution", "at", "amino", "acid", "86", "(", "G86R", ")", "in", "the", "SLURP-1", "protein.", "PBMCs", "from", "homozygotes", "and", "wild-type", "controls", "were", "stimulated", "with", "anti-CD3/anti-CD28", "antibodies", "and", "the", "level", "of", "T-cell", "activation", "was", "determined", "by", "the", "stimulation", "index.", "RESULTS:", "PBMCs", "with", "the", "heterozygous", "and", "homozygous", "SLURP-1", "G86R", " ", "mutation", "had", "defective", "T-cell", "activation.", "This", "was", "restored", "by", "the", "addition", "of", "0", " ", "5", "ug", "mL(-1)", "recombinant", "human", "SLURP-1", "protein.", "CONCLUSIONS:", "Patients", "with", "MDM", "with", "the", "homozygous", "SLURP-1", "G86R", " ", "mutation", "may", "have", "an", "impaired", "T-cell", "activation.", "The", "presence", "of", "wild-type", "SLURP-1", "is", "essential", "for", "normal", "T-cell", "activation." ]
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BACKGROUND: Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1). SLURP-1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T-cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis. OBJECTIVES: To investigate the association of the SLURP1 gene mutation with T-cell activation in a Taiwanese family with MDM. To test that SLURP-1 is essential for T-cell activation. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 ( G86R ) in the SLURP-1 protein. PBMCs from homozygotes and wild-type controls were stimulated with anti-CD3/anti-CD28 antibodies and the level of T-cell activation was determined by the stimulation index. RESULTS: PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0 5 ug mL(-1) recombinant human SLURP-1 protein. CONCLUSIONS: Patients with MDM with the homozygous SLURP-1 G86R mutation may have an impaired T-cell activation. The presence of wild-type SLURP-1 is essential for normal T-cell activation.
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20728296
[ "Interstitial", "deletion", "of", "13q14.13-q32.3", "presenting", "with", "Arima", "syndrome", "and", "bilateral", "retinoblastoma." ]
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Interstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma.
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21903317
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16418600
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12925722
[ "A", "glycine", "to", "aspartic", "acid", "substitution", "of", "COL2A1", "in", "a", "family", "with", "the", "Strudwick", "variant", "of", "spondyloepimetaphyseal", "dysplasia." ]
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A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia.
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21130517
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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.
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15086325
[ "Identification", "of", "three", "F5", "gene", "mutations", "associated", "with", "inherited", "coagulation", "factor", "V", "deficiency", "in", "two", "Chinese", "pedigrees." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees.
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18457324
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17286451
[ "OBJECTIVES:", "This", "study", "was", "conducted", "with", "two", "objectives.", "The", "first", "was", "to", "estimate", "the", "frequency", "of", "loss", "of", "heterozygosity", "(LOH)", "of", "the", "RB1", "gene", "as", "a", "mechanism", "in", "disease", "causation", "in", "tumors", "of", "patients", "from", "India.", "The", "second", "objective", "was", "to", "employ", "RB1", "molecular", "deletion", "and", "microsatellite-based", "linkage", "analysis", "as", "laboratory", "tools,", "while", "counseling", "families", "with", "a", "history", "of", "retinoblastoma", "(RB).", "METHODS:", "DNA", "was", "extracted", "from", "peripheral", "blood", "and", "tumors", "of", "54", "RB", "patients", "and", "their", "relatives.", "Eight", "fluorescent", "microsatellite", "markers,", "both", "intragenic", "and", "flanking", "the", "RB1", "gene,", "were", "used.", "After", "PCR", "amplification,", "samples", "were", "run", "on", "an", "ABI", "PRISM", "310", "genetic", "analyzer", "for", "LOH,", "deletion", "detection,", "and", "haplotype", "generation.", "RESULTS:", "LOH", "was", "found", "in", "conjunction", "with", "tumor", "formation", "in", "72.9%", "of", "RB", "patients", "(39/54", "patients;", "p=0.001;", "95%", "CI", "0.6028,", "0.8417);", "however,", "we", "could", "not", "associate", "various", "other", "clinical", "parameters", "of", "RB", "patients", "with", "the", "presence", "or", "absence", "of", "RB1", "LOH.", "Seven", "germline", "deletions", "(13%", "of", "RB", "patients)", "were", "identified,", "and", "the", "maternal", "allele", "was", "more", "frequently", "lost", "(p=0.01).", "A", "disease", "co-segregating", "haplotype", "was", "detected", "in", "two", "hereditary", "autosomal", "dominant", "cases.", "CONCLUSION:", "LOH", "of", "the", "RB1", "gene", "could", "play", "an", "important", "role", "in", "tumor", "formation.", "Large", "deletions", "involving", "RB1", "were", "observed,", "and", "a", "disease", "co-segregating", "haplotype", "was", "used", "for", "indirect", "genetic", "testing.", "This", "is", "the", "first", "report", "from", "India", "where", "molecular", "testing", "has", "been", "applied", "for", "RB", "families", "in", "conjunction", "with", "genetic", "counseling.", "In", "tertiary", "ophthalmic", "practice", "in", "India,", "there", "is", "an", "emerging", "trend", "towards", "the", "application", "of", "genetical", "knowledge", "in", "clinical", "practice." ]
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OBJECTIVES: This study was conducted with two objectives. The first was to estimate the frequency of loss of heterozygosity (LOH) of the RB1 gene as a mechanism in disease causation in tumors of patients from India. The second objective was to employ RB1 molecular deletion and microsatellite-based linkage analysis as laboratory tools, while counseling families with a history of retinoblastoma (RB). METHODS: DNA was extracted from peripheral blood and tumors of 54 RB patients and their relatives. Eight fluorescent microsatellite markers, both intragenic and flanking the RB1 gene, were used. After PCR amplification, samples were run on an ABI PRISM 310 genetic analyzer for LOH, deletion detection, and haplotype generation. RESULTS: LOH was found in conjunction with tumor formation in 72.9% of RB patients (39/54 patients; p=0.001; 95% CI 0.6028, 0.8417); however, we could not associate various other clinical parameters of RB patients with the presence or absence of RB1 LOH. Seven germline deletions (13% of RB patients) were identified, and the maternal allele was more frequently lost (p=0.01). A disease co-segregating haplotype was detected in two hereditary autosomal dominant cases. CONCLUSION: LOH of the RB1 gene could play an important role in tumor formation. Large deletions involving RB1 were observed, and a disease co-segregating haplotype was used for indirect genetic testing. This is the first report from India where molecular testing has been applied for RB families in conjunction with genetic counseling. In tertiary ophthalmic practice in India, there is an emerging trend towards the application of genetical knowledge in clinical practice.
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20630757
[ "Manifesting", "carriers", "of", "DMD", "gene", "mutations", "may", "present", "diagnostic", "challenges,", "particularly", "in", "the", "absence", "of", "a", "family", "history", "of", "dystrophinopathy.", "We", "review", "the", "clinical", "and", "genetic", "features", "in", "15", "manifesting", "carriers", "identified", "among", "860", "subjects", "within", "the", "United", "Dystrophinopathy", "Project,", "a", "large", "clinical", "dystrophinopathy", "cohort", "whose", "members", "undergo", "comprehensive", "DMD", "mutation", "analysis.", "We", "defined", "manifesting", "carriers", "as", "females", "with", "significant", "weakness,", "excluding", "those", "with", "only", "myalgias/cramps.", "DNA", "extracted", "from", "peripheral", "blood", "was", "used", "to", "study", "X-chromosome", "inactivation", "patterns.", "Among", "these", "manifesting", "carriers,", "age", "at", "symptom", "onset", "ranged", "from", "2", "to", "47", "years.", "Seven", "had", "no", "family", "history", "and", "eight", "had", "male", "relatives", "with", "Duchenne", "muscular", "dystrophy", "(DMD).", "Clinical", "severity", "among", "the", "manifesting", "carriers", "varied", "from", "a", "DMD-like", "progression", "to", "a", "very", "mild", "Becker", "muscular", "dystrophy-like", "phenotype.", "Eight", "had", "exonic", "deletions", "or", "duplications", "and", "six", "had", "point", "mutations.", "One", "patient", "had", "two", "mutations", "(an", "exonic", "deletion", "and", "a", "splice", "site", "mutation),", "consistent", "with", "a", "heterozygous", "compound", "state.", "The", "X-chromosome", "inactivation", "pattern", "was", "skewed", "toward", "non-random", "in", "four", "out", "of", "seven", "informative", "deletions", "or", "duplications", "but", "was", "random", "in", "all", "cases", "with", "nonsense", "mutations.", "We", "present", "the", "results", "of", "DMD", "mutation", "analysis", "in", "this", "manifesting", "carrier", "cohort,", "including", "the", "first", "example", "of", "a", "presumably", "compound", "heterozygous", "DMD", "mutation.", "Our", "results", "demonstrate", "that", "improved", "molecular", "diagnostic", "methods", "facilitate", "the", "identification", "of", "DMD", "mutations", "in", "manifesting", "carriers,", "and", "confirm", "the", "heterogeneity", "of", "mutational", "mechanisms", "as", "well", "as", "the", "wide", "spectrum", "of", "phenotypes." ]
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Manifesting carriers of DMD gene mutations may present diagnostic challenges, particularly in the absence of a family history of dystrophinopathy. We review the clinical and genetic features in 15 manifesting carriers identified among 860 subjects within the United Dystrophinopathy Project, a large clinical dystrophinopathy cohort whose members undergo comprehensive DMD mutation analysis. We defined manifesting carriers as females with significant weakness, excluding those with only myalgias/cramps. DNA extracted from peripheral blood was used to study X-chromosome inactivation patterns. Among these manifesting carriers, age at symptom onset ranged from 2 to 47 years. Seven had no family history and eight had male relatives with Duchenne muscular dystrophy (DMD). Clinical severity among the manifesting carriers varied from a DMD-like progression to a very mild Becker muscular dystrophy-like phenotype. Eight had exonic deletions or duplications and six had point mutations. One patient had two mutations (an exonic deletion and a splice site mutation), consistent with a heterozygous compound state. The X-chromosome inactivation pattern was skewed toward non-random in four out of seven informative deletions or duplications but was random in all cases with nonsense mutations. We present the results of DMD mutation analysis in this manifesting carrier cohort, including the first example of a presumably compound heterozygous DMD mutation. Our results demonstrate that improved molecular diagnostic methods facilitate the identification of DMD mutations in manifesting carriers, and confirm the heterogeneity of mutational mechanisms as well as the wide spectrum of phenotypes.
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14962306
[ "Identification", "of", "the", "Kna/Knb", "polymorphism", "and", "a", "method", "for", "Knops", "genotyping." ]
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Identification of the Kna/Knb polymorphism and a method for Knops genotyping.
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18470323
[]
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19592582
[ "Matriptase-2", "mutations", "in", "iron-refractory", "iron", "deficiency", "anemia", "patients", "provide", "new", "insights", "into", "protease", "activation", "mechanisms." ]
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Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.
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14708104
[ "Pallister-Hall", "syndrome", "(PHS,", "MIM", "#146510)", "is", "characterized", "by", "central", "and", "postaxial", "polydactyly,", "hypothalamic", "hamartoma", "(HH),", "bifid", "epiglottis,", "imperforate", "anus,", "renal", "abnormalities,", "and", "pulmonary", "segmentation", "anomalies.", "It", "is", "inherited", "in", "an", "autosomal", "dominant", "pattern.", "Here,", "we", "describe", "a", "family", "with", "two", "affected", "children", "manifesting", "severe", "PHS", "with", "mental", "retardation,", "behavioral", "problems,", "and", "intractable", "seizures.", "Both", "parents", "are", "healthy,", "with", "normal", "intelligence,", "and", "have", "no", "malformations", "on", "physical,", "laryngoscopic,", "and", "cranial", "MRI", "exam.", "The", "atypical", "presentation", "of", "these", "children", "and", "the", "absence", "of", "parental", "manifestations", "suggested", "an", "autosomal", "recessive", "mode", "of", "inheritance", "or", "gonadal", "mosaicism.", "Sequencing", "of", "GLI3", "revealed", "a", "two", "nucleotide", "deletion", "in", "exon", "15", "(", "c.3385_3386delTT", ")", "predicting", "a", "frameshift", "and", "premature", "stop", "at", "codon", "1129", "(", "p.F1129X", ")", "in", "the", "children", "while", "both", "parents", "have", "wild", "type", "alleles.", "Genotyping", "with", "GLI3", "intragenic", "markers", "revealed", "that", "both", "children", "inherited", "the", "abnormal", "allele", "from", "their", "mother", "thus", "supporting", "gonadal", "mosaicism", "as", "the", "underlying", "mechanism", "of", "inheritance", "(paternity", "was", "confirmed).", "This", "is", "the", "first", "reported", "case", "of", "gonadal", "mosaicism", "in", "PHS.", "The", "severe", "CNS", "manifestations", "of", "these", "children", "are", "reminiscent", "of", "children", "with", "non-syndromic", "HH", "who", "often", "have", "progressive", "mental", "retardation", "with", "behavioral", "problems", "and", "intractable", "seizures.", "We", "conclude", "that", "the", "phenotypic", "spectrum", "of", "PHS", "can", "include", "severe", "CNS", "manifestations", "and", "that", "recurrence", "risks", "for", "PHS", "should", "include", "a", "proviso", "for", "gonadal", "mosaicism,", "though", "the", "frequency", "cannot", "be", "calculated", "from", "a", "single", "case", "report.", "Published", "2003", "Wiley-Liss,", "Inc." ]
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Pallister-Hall syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 ( c.3385_3386delTT ) predicting a frameshift and premature stop at codon 1129 ( p.F1129X ) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc.
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19435819
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Glioblastoma multiforme (GBM) is an extremely malignant brain tumor. To identify new genomic alterations in GBM, genomic DNA of tumor tissue/explants from 55 individuals and 6 GBM cell lines were examined using single nucleotide polymorphism DNA microarray (SNP-Chip). Further gene expression analysis relied on an additional 56 GBM samples. SNP-Chip results were validated using several techniques, including quantitative PCR (Q-PCR), nucleotide sequencing, and a combination of Q-PCR and detection of microsatellite markers for loss of heterozygosity with normal copy number [acquired uniparental disomy (AUPD)]. Whole genomic DNA copy number in each GBM sample was profiled by SNP-Chip. Several signaling pathways were frequently abnormal. Either the p16(INK4A)/p15(INK4B)-CDK4/6-pRb or p14(ARF)-MDM2/4-p53 pathways were abnormal in 89% (49 of 55) of cases. Simultaneous abnormalities of both pathways occurred in 84% (46 of 55) samples. The phosphoinositide 3-kinase pathway was altered in 71% (39 of 55) GBMs either by deletion of PTEN or amplification of epidermal growth factor receptor and/or vascular endothelial growth factor receptor/platelet-derived growth factor receptor alpha. Deletion of chromosome 6q26-27 often occurred (16 of 55 samples). The minimum common deleted region included PARK2, PACRG, QKI, and PDE10A genes. Further reverse transcription Q-PCR studies showed that PARK2 expression was decreased in another collection of GBMs at a frequency of 61% (34 of 56) of samples. The 1p36.23 region was deleted in 35% (19 of 55) of samples. Notably, three samples had homozygous deletion encompassing this site. Also, a novel internal deletion of a putative tumor suppressor gene, LRP1B, was discovered causing an aberrant protein. AUPDs occurred in 58% (32 of 55) of the GBM samples and five of six GBM cell lines. A common AUPD was found at chromosome 17p13.3-12 (included p53 gene) in 13 of 61 samples and cell lines. Single-strand conformational polymorphism and nucleotide sequencing showed that 9 of 13 of these samples had homozygous p53 mutations, suggesting that mitotic recombination duplicated the abnormal p53 gene, probably providing a growth advantage to these cells. A significantly shortened survival time was found in patients with 13q14 (RB) deletion or 17p13.1 (p53) deletion/AUPD. Taken together, these results suggest that this technique is a rapid, robust, and inexpensive method to profile genome-wide abnormalities in GBM.
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12750403
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The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion ( 1631delC ) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.
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18235024
[ "Cone", "dystrophy", "with", "supernormal", "rod", "response", "is", "strictly", "associated", "with", "mutations", "in", "KCNV2." ]
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Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2.
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21695597
[ "MHC", "region", "and", "risk", "of", "systemic", "lupus", "erythematosus", "in", "African", "American", "women." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
MHC region and risk of systemic lupus erythematosus in African American women.
[ 2, 8709, 3031, 1930, 2565, 1927, 5510, 13711, 22045, 1922, 7050, 5339, 3089, 18, 3 ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
[ 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 ]
[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
17635946
[ "A", "novel", "point", "mutation", "in", "helix", "11", "of", "the", "ligand-binding", "domain", "of", "the", "human", "glucocorticoid", "receptor", "gene", "causing", "generalized", "glucocorticoid", "resistance." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance.
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[ -100, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, -100 ]
17177139
[ "Resistance", "to", "thyroid", "hormone", "(RTH)", "is", "an", "inherited", "syndrome", "characterized", "by", "elevated", "serum", "thyroid", "hormones", "(TH),", "failure", "to", "suppress", "pituitary", "thyroid", "stimulating", "hormone", "(TSH)", "secretion,", "and", "variable", "peripheral", "tissue", "responsiveness", "to", "TH.", "The", "disorder", "is", "associated", "with", "diverse", "mutations", "in", "the", "thyroid", "hormone", "beta", "receptor", "(TRbeta).", "Here,", "we", "report", "a", "novel", "natural", "RTH", "mutation", "(", "E333D", ")", "located", "in", "the", "large", "carboxy-terminal", "ligand", "binding", "domain", "of", "TRbeta.", "The", "mutation", "was", "identified", "in", "a", "22-year-old", "French", "woman", "coming", "to", "medical", "attention", "because", "of", "an", "increasing", "overweight.", "Biochemical", "tests", "showed", "elevated", "free", "thyroxine", "(T4:", "20.8", "pg/ml", "(normal,", "8.5-18))", "and", "triiodothyronine", "(T3:", "5.7", "pg/ml", "(normal,", "1.4-4))", "in", "the", "serum,", "together", "with", "an", "inappropriately", "nonsuppressed", "TSH", "level", "of", "4.7", "mU/ml", "(normal,", "0.4-4).", "Her", "father", "and", "her", "brother's", "serum", "tests", "also", "showed", "biochemical", "abnormalities", "consistent", "with", "RTH.", "Direct", "sequencing", "of", "the", "TRbeta", "gene", "revealed", "a", "heterozygous", "transition", "1284A>C", " ", "in", "exon", "9", "resulting", "in", "substitution", "of", "glutamic", "acid", "333", "by", "aspartic", "acid", "residue", "(", "E333D", ").", "Further", "functional", "analyses", "of", "the", "novel", "TRbeta", "mutant", "were", "conducted.", "We", "found", "that", "the", "E333D", " ", "mutation", "neither", "significantly", "affected", "the", "affinity", "of", "the", "receptor", "for", "T3", "nor", "modified", "heterodimer", "formation", "with", "retinoid", "X", "receptor", "(RXR)", "when", "bound", "to", "DNA.", "However,", "in", "transient", "transfection", "assays,", "the", "E333D", " ", "TRbeta", "mutant", "exhibited", "impaired", "transcriptional", "regulation", "on", "two", "distinct", "positively", "regulated", "thyroid", "response", "elements", "(F2-", "and", "DR4-TREs)", "as", "well", "as", "on", "the", "negatively", "regulated", "human", "TSHalpha", "promoter.", "Moreover,", "a", "dominant", "inhibition", "of", "the", "wild-type", "TRbeta", "counterpart", "transactivation", "function", "was", "observed", "on", "both", "a", "positive", "(F2-TRE)", "and", "a", "negative", "(TSHalpha)", "promoter.", "These", "results", "strongly", "suggest", "that", "the", "E333D", " ", "TRbeta", "mutation", "is", "responsible", "for", "the", "RTH", "phenotype", "in", "the", "proposita's", "family." ]
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Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation ( E333D ) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue ( E333D ). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.
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12862311
[ "Detection", "of", "PHKA2", "gene", "mutation", "in", "four", "Japanese", "patients", "with", "hepatic", "phosphorylase", "kinase", "deficiency." ]
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Detection of PHKA2 gene mutation in four Japanese patients with hepatic phosphorylase kinase deficiency.
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17495183
[ "We", "recently", "showed", "that", "long-term", "weight", "reduction", "changes", "the", "gene", "expression", "profile", "of", "adipose", "tissue", "in", "overweight", "individuals", "with", "impaired", "glucose", "tolerance", "(IGT).", "One", "of", "the", "responding", "genes", "was", "X-chromosomal", "tenomodulin", "(TNMD),", "a", "putative", "angiogenesis", "inhibitor.", "Our", "aim", "was", "to", "study", "the", "associations", "of", "individual", "single", "nucleotide", "polymorphisms", "and", "haplotypes", "with", "adiposity,", "glucose", "metabolism,", "and", "the", "risk", "of", "type", "2", "diabetes", "(T2D).", "Seven", "single", "nucleotide", "polymorphisms", "from", "two", "different", "haploblocks", "were", "genotyped", "from", "507", "participants", "of", "the", "Finnish", "Diabetes", "Prevention", "Study", "(DPS).", "Sex-specific", "genotype", "effects", "were", "observed.", "Three", "markers", "of", "haploblock", "1", "were", "associated", "with", "features", "of", "adiposity", "in", "women", "(", "rs5966709", ",", "rs4828037", ")", "and", "men", "(", "rs11798018", ").", "Markers", "rs2073163", " ", "and", "rs1155794", " ", "from", "haploblock", "2", "were", "associated", "with", "2-hour", "plasma", "glucose", "levels", "in", "men", "during", "the", "3-year", "follow-up.", "The", "same", "two", "markers", "together", "with", "rs2073162", " ", "associated", "with", "the", "conversion", "of", "IGT", "to", "T2D", "in", "men.", "The", "risk", "of", "developing", "T2D", "was", "approximately", "2-fold", "in", "individuals", "with", "genotypes", "associated", "with", "higher", "2-hour", "plasma", "glucose", "levels;", "the", "hazard", "ratios", "were", "2.192", "(p", "=", "0.025)", "for", "rs2073162", "-A,", "2.191", "(p", "=", "0.027)", "for", "rs2073163", "-C,", "and", "1.998", "(p", "=", "0.054)", "for", "rs1155974", "-T.", "These", "results", "suggest", "that", "TNMD", "polymorphisms", "are", "associated", "with", "adiposity", "and", "also", "with", "glucose", "metabolism", "and", "conversion", "from", "IGT", "to", "T2D", "in", "men." ]
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We recently showed that long-term weight reduction changes the gene expression profile of adipose tissue in overweight individuals with impaired glucose tolerance (IGT). One of the responding genes was X-chromosomal tenomodulin (TNMD), a putative angiogenesis inhibitor. Our aim was to study the associations of individual single nucleotide polymorphisms and haplotypes with adiposity, glucose metabolism, and the risk of type 2 diabetes (T2D). Seven single nucleotide polymorphisms from two different haploblocks were genotyped from 507 participants of the Finnish Diabetes Prevention Study (DPS). Sex-specific genotype effects were observed. Three markers of haploblock 1 were associated with features of adiposity in women ( rs5966709 , rs4828037 ) and men ( rs11798018 ). Markers rs2073163 and rs1155794 from haploblock 2 were associated with 2-hour plasma glucose levels in men during the 3-year follow-up. The same two markers together with rs2073162 associated with the conversion of IGT to T2D in men. The risk of developing T2D was approximately 2-fold in individuals with genotypes associated with higher 2-hour plasma glucose levels; the hazard ratios were 2.192 (p = 0.025) for rs2073162 -A, 2.191 (p = 0.027) for rs2073163 -C, and 1.998 (p = 0.054) for rs1155974 -T. These results suggest that TNMD polymorphisms are associated with adiposity and also with glucose metabolism and conversion from IGT to T2D in men.
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15069170
[ "Four", "novel", "mutations", "in", "the", "thiazide-sensitive", "Na-Cl", "co-transporter", "gene", "in", "Japanese", "patients", "with", "Gitelman's", "syndrome." ]
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Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.
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17868390
[ "We", "report", "here", "the", "clinical,", "genetic,", "and", "molecular", "characteristics", "of", "a", "large", "Chinese", "family", "exhibiting", "non-syndromic,", "late-onset", "autosomal", "dominant", "sensorineural", "hearing", "loss.", "Clinical", "evaluation", "revealed", "variable", "phenotypes", "of", "hearing", "loss", "in", "terms", "of", "severity", "and", "age-at-onset", "of", "disease", "in", "these", "subjects.", "Genome-wide", "linkage", "analysis", "mapped", "the", "disease", "gene", "to", "the", "DFNA5", "locus", "with", "a", "maximum", "two-point", "log", "odds", "score", "of", "5.39", "at", "[theta]", "=", "0", "for", "marker", "D7S2457.", "DNA", "sequencing", "of", "DFNA5", "revealed", "a", "novel", "heterozygous", "IVS8+4", "A>G", " ", "substitution", "in", "the", "splice", "donor", "site", "of", "intron", "8.", "Reverse", "transcriptase-polymerase", "chain", "reaction", "(RT-PCR)", "showed", "skipping", "of", "exon", "8", "in", "the", "mutant", "transcript.", "This", "mutation", "faithfully", "cosegregated", "with", "hearing", "loss", "in", "the", "family.", "In", "addition,", "the", "mutation", "was", "absent", "in", "100", "unrelated", "control", "DNA", "samples", "of", "Chinese", "origin.", "The", "IVS8+4", "A>G", " ", "mutation", "is", "predicted", "to", "create", "a", "shift", "in", "the", "reading", "frame", "and", "introduce", "a", "stop", "codon", "at", "position", "372,", "thereby", "resulting", "in", "a", "prematurely", "truncated", "DFNA5", "protein.", "Up", "to", "date,", "a", "total", "of", "four", "mutations", "in", "DFNA5", "have", "been", "reported", "to", "lead", "to", "hearing", "impairment,", "all", "of", "them", "result", "in", "skipping", "of", "exon", "8", "at", "the", "mRNA", "level.", "Our", "findings", "provide", "further", "support", "for", "the", "hypothesis", "that", "DFNA5-associated", "hearing", "loss", "is", "caused", "by", "a", "very", "specific", "gain-of-function", "mutation." ]
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We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.
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18202102
[]
[]
[ 2, 3 ]
[ 0, 0 ]
[ 1, 1 ]
[ -100, -100 ]
18266724
[ "Histamine-N-methyl", "transferase", "polymorphism", "and", "risk", "for", "migraine." ]
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Histamine-N-methyl transferase polymorphism and risk for migraine.
[ 2, 14622, 17, 56, 17, 4963, 13763, 8218, 1930, 2565, 1958, 13258, 18, 3 ]
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19808398
[]
[]
[ 2, 3 ]
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[ 1, 1 ]
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19448408
[ "BACKGROUND", "AND", "OBJECTIVE:", "Glutathione", "S-transferase", "M1", "(GSTM1)", "deficiency", "may", "increase", "the", "risk", "of", "nasopharyngeal", "carcinoma", "(NPC).", "This", "study", "was", "to", "evaluate", "the", "correlation", "of", "the", "single", "nucleotide", "polymorphism", "(SNP)", "in", "the", "coding", "region", "of", "GSTM1", "gene", "to", "NPC", "susceptibility", "in", "southern", "China", "population.", "METHODS:", "In", "total", "239", "NPC", "patients", "and", "286", "age-matched", "healthy", "controls", "were", "entered", "into", "the", "study.", "Among", "them,", "225", "out", "of", "239", "NPC", "patients", "and", "273", "out", "of", "286", "controls", "were", "used", "for", "statistical", "analysis.", "SNP", "screening", "of", "all", "exons,", "relevant", "intron-exon", "boundaries,", "and", "the", "promoter", "region", "of", "GSTM1,", "in", "total", "4739bp,", "was", "performed", "by", "PCR", "direct", "sequencing.", "The", "loci", "T1270533G", " ", "and", "C1256088C", "were", "selected", "for", "the", "case-control", "study", "using", "the", "tetra-Primer", "ARMS-PCR,", "as", "well", "as", "the", "sequencing", "method.", "RESULTS:", "In", "total", "29", "SNPs", "of", "GSTM1", "were", "identified", "by", "sequencing.", "Missense", "mutation", "occurred", "in", "the", "polymorphic", "loci", "of", "T1270533G", " ", "and", "C1256088C.", "However,", "no", "evident", "relationships", "between", "the", "variants", "of", "T1270533G", " ", "and", "clinical", "phenotypes", "of", "NPC", "were", "observed", "in", "the", "NPC", "group", "and", "healthy", "control", "group", "(OR", "=", "0.170,", "95%CI", "=", "0.95-0.306", "for", "homozygote", "TT).", "The", "deletion", "frequency", "of", "C1256088C", "was", "45%", "(45/100)", "for", "NPC", "patients", "and", "42%", "(42/100)", "for", "controls.", "CONCLUSIONS:", "The", "polymorphism", "of", "T1270533G", " ", "does", "not", "affect", "the", "detoxification", "function", "of", "GSTM1.", "The", "T1270533G", " ", "locus", "has", "no", "apparent", "association", "with", "genetic", "susceptibility", "to", "NPC", "in", "the", "southern", "China", "population.", "The", "loss", "rate", "of", "C1256088C", "is", "high", "in", "this", "study." ]
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BACKGROUND AND OBJECTIVE: Glutathione S-transferase M1 (GSTM1) deficiency may increase the risk of nasopharyngeal carcinoma (NPC). This study was to evaluate the correlation of the single nucleotide polymorphism (SNP) in the coding region of GSTM1 gene to NPC susceptibility in southern China population. METHODS: In total 239 NPC patients and 286 age-matched healthy controls were entered into the study. Among them, 225 out of 239 NPC patients and 273 out of 286 controls were used for statistical analysis. SNP screening of all exons, relevant intron-exon boundaries, and the promoter region of GSTM1, in total 4739bp, was performed by PCR direct sequencing. The loci T1270533G and C1256088C were selected for the case-control study using the tetra-Primer ARMS-PCR, as well as the sequencing method. RESULTS: In total 29 SNPs of GSTM1 were identified by sequencing. Missense mutation occurred in the polymorphic loci of T1270533G and C1256088C. However, no evident relationships between the variants of T1270533G and clinical phenotypes of NPC were observed in the NPC group and healthy control group (OR = 0.170, 95%CI = 0.95-0.306 for homozygote TT). The deletion frequency of C1256088C was 45% (45/100) for NPC patients and 42% (42/100) for controls. CONCLUSIONS: The polymorphism of T1270533G does not affect the detoxification function of GSTM1. The T1270533G locus has no apparent association with genetic susceptibility to NPC in the southern China population. The loss rate of C1256088C is high in this study.
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15642853
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17065479
[ "Homozygous", "deletion", "related", "to", "Alu", "repeats", "in", "RLBP1", "causes", "retinitis", "punctata", "albescens." ]
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Homozygous deletion related to Alu repeats in RLBP1 causes retinitis punctata albescens.
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21640722
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Deficiencies of DNA polymerase eta-an enzyme mediating replication past UV-induced DNA damage-predispose individuals to xeroderma pigmentosum variant (XPV) and result in a high incidence of skin cancers. We designed, developed and assessed several complementary molecular approaches to detect a genetically inherited deletion within DNA polymerase eta. RNA was reverse transcribed from XPV fibroblasts and from normal human cells, and standard polymerase chain reaction (PCR) was conducted on the cDNA targeting a region with a 13 base pair deletion within the polymerase eta gene. PCR products were subjected to restriction fragment length polymorphism (RFLP) analysis and cycle DNA sequencing. The deletion was found to eliminate a BsrGI restriction site and affected the number of resultant fragments visualized after gel electrophoresis. Cycle sequencing of polymerase eta-specific amplicons from XPV and normal cells provided a second approach for detecting the mutation. Additionally, the use of a fluorescent nucleic acid dye-EvaGreen-in real-time PCR and melt curve analysis distinguished normal and XPV patient-derived amplicons as well as heteroduplexes that represent heterozygotic carriers without the need for high resolution melt analysis-compatible software. Our approaches are easily adaptable by diagnostic laboratories that screen for or verify genetically inherited disorders and identify carriers of a defective gene.
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18779591
[ "Identification", "of", "a", "gain-of-function", "mutation", "of", "the", "prolactin", "receptor", "in", "women", "with", "benign", "breast", "tumors." ]
[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]
Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors.
[ 2, 4824, 1927, 43, 5938, 17, 1927, 17, 2347, 3979, 1927, 1920, 18386, 3148, 1922, 3089, 1956, 8867, 3739, 3861, 18, 3 ]
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20708777
[]
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[ 2, 3 ]
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19404517
[ "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." ]
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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.
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19681861
[ "BACKGROUND:", "Dystrophic", "epidermolysis", "bullosa", "(DEB)", "is", "a", "severe", "genetic", "skin", "blistering", "disorder", "caused", "by", "mutations", "in", "the", "gene", "COL7A1,", "encoding", "collagen", "VII.", "Recently,", "the", "MMP1", "promoter", "single", "nucleotide", "polymorphism", "(SNP)", "rs1799750", ",", "designated", "as", "1G", "2G,", "was", "shown", "to", "be", "involved", "in", "modulation", "of", "disease", "severity", "in", "patients", "with", "recessive", "DEB", "(RDEB),", "and", "was", "proposed", "as", "a", "genetic", "modifier.", "OBJECTIVES:", "To", "identify", "the", "molecular", "basis", "of", "DEB", "in", "103", "individuals", "and", "to", "replicate", "the", "results", "of", "the", "MMP1", "promoter", "SNP", "analysis", "in", "an", "independent", "patient", "group,", "as", "verification", "is", "necessary", "in", "such", "a", "rare", "and", "heterogeneous", "disorder.", "METHODS:", "To", "determine", "the", "molecular", "basis", "of", "the", "disease,", "we", "performed", "COL7A1", "mutation", "screening,", "reverse", "transcription-polymerase", "chain", "reaction", "(PCR)", "and", "real-time", "quantitative", "PCR.", "The", "status", "of", "the", "MMP1", "SNP", "was", "analysed", "by", "PCR", "and", "restriction", "enzyme", "digestion", "and", "verified", "by", "sequencing.", "RESULTS:", "We", "disclosed", "42", "novel", "COL7A1", "mutations,", "including", "the", "first", "large", "genomic", "deletion", "of", "4", "kb", "affecting", "only", "the", "COL7A1", "gene,", "and", "three", "apparently", "silent", "mutations", "affecting", "splicing.", "Even", "though", "the", "frequency", "of", "the", "high-risk", "allele", "was", "increased", "in", "patients", "with", "RDEB,", "no", "statistically", "significant", "correlation", "between", "disease", "severity", "and", "genotype", "could", "be", "made.", "Also,", "no", "correlation", "was", "observed", "with", "development", "of", "squamous", "cell", "carcinoma,", "a", "severe", "complication", "of", "DEB.", "CONCLUSIONS:", "Taken", "together,", "the", "results", "suggest", "that", "the", "MMP1", "SNP", "is", "not", "the", "sole", "disease", "modifier", "in", "different", "forms", "of", "DEB,", "and", "other", "genetic", "and", "environmental", "factors", "contribute", "to", "the", "clinical", "phenotype." ]
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BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a severe genetic skin blistering disorder caused by mutations in the gene COL7A1, encoding collagen VII. Recently, the MMP1 promoter single nucleotide polymorphism (SNP) rs1799750 , designated as 1G 2G, was shown to be involved in modulation of disease severity in patients with recessive DEB (RDEB), and was proposed as a genetic modifier. OBJECTIVES: To identify the molecular basis of DEB in 103 individuals and to replicate the results of the MMP1 promoter SNP analysis in an independent patient group, as verification is necessary in such a rare and heterogeneous disorder. METHODS: To determine the molecular basis of the disease, we performed COL7A1 mutation screening, reverse transcription-polymerase chain reaction (PCR) and real-time quantitative PCR. The status of the MMP1 SNP was analysed by PCR and restriction enzyme digestion and verified by sequencing. RESULTS: We disclosed 42 novel COL7A1 mutations, including the first large genomic deletion of 4 kb affecting only the COL7A1 gene, and three apparently silent mutations affecting splicing. Even though the frequency of the high-risk allele was increased in patients with RDEB, no statistically significant correlation between disease severity and genotype could be made. Also, no correlation was observed with development of squamous cell carcinoma, a severe complication of DEB. CONCLUSIONS: Taken together, the results suggest that the MMP1 SNP is not the sole disease modifier in different forms of DEB, and other genetic and environmental factors contribute to the clinical phenotype.
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12791036
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19012332
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We present a girl who developed adrenocortical adenoma at the age of 1 year and osteosarcoma at the age of 5 years. There was no history of cancer in her parents and their relatives. However, both tumors were typical for the Li-Fraumeni syndrome (LFS), and the patient met criteria for germline TP53 mutation testing. A mutation in codon 282 ( Arg282Trp ) was identified in her blood lymphocyte genomic DNA. The substitution was found in neither of her parents, which indicated a possibility of a de novo mutation. Unexpectedly, sequencing of the DNA of the patient repeatedly showed allelic imbalance in favor of the normal allele. This observation prompted us to investigate the putative somatic mosaicism in the patient consisting of normal cells and cells heterozygous for the mutation. The imbalance was also examined in two other non-invasively sampled tissues, buccal cells, and cells from the urine sediment, and sequencing was confirmed with two other independent methods. While the findings in blood and the urine sediment were similar, in buccal cells both alleles were present in equal amounts. The allele ratio in lymphocytes was consistent with a mosaic where about 2/3 of cells carried two normal alleles and only 1/3 was heterozygous for the mutation. Despite the mosaicism the girl developed two early childhood tumors of mesodermal origin, and her phenotype was thus not milder than that of other germline TP53 mutation carriers. To our knowledge this is the first description of somatic mosaicism for a de novo TP53 mutation in LFS.
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18798060
[ "Interstitial", "collagenase-1", "degrades", "a", "variety", "of", "extracellular", "matrix", "components.", "A", "single", "guanine", "insertion", "polymorphism", "in", "the", "promoter", "has", "been", "found", "that", "influences", "on", "the", "transcription", "and", "expression", "level", "of", "the", "gene.", "It", "is", "suggested", "that", "this", "polymorphism", "may", "enhance", "susceptibility", "to", "some", "types", "of", "cancer.", "Therefore,", "this", "case-control", "study", "evaluated", "the", "association", "of", "this", "genotype", "polymorphism", "with", "susceptibility", "to", "initiation", "and", "invasion", "of", "colorectal", "cancer.", "For", "this", "reason,", "whole", "blood", "samples", "were", "obtained", "from", "150", "CRC", "patients", "and", "100", "control", "subjects", "in", "Tehran.", "Genomic", "DNA", "was", "extracted", "and", "genotyped", "by", "PCR-RFLP", "method.", "We", "showed", "that", "2G", "allele", "and", "2G/2G", "genotype", "had", "higher", "frequencies", "in", "patients", "(60%", "and", "39%,", "respectively)", "than", "in", "controls", "(47%", "and", "23%,", "respectively).", "The", "CRC", "patients", "were", "divided", "into", "two", "groups:", "with", "metastasis", "(M+)", "and", "without", "metastasis", "(M-)", "groups.", "The", "2G", "allele", "was", "more", "frequent", "in", "M+", "group", "compared", "with", "control", "group.", "However,", "no", "significantly", "difference", "was", "observed", "between", "M-group", "and", "control", "(chi(2)", "=", "0.48,", "P", "=", "0.78", "for", "2G/2G", "genotype).", "Further", "stratification", "analyses", "showed", "that", "only", "gender", "(OR", "=", "2.58,", "95%", "CI", "=", "0.89-7.52", "for", "women", "and", "OR", "=", "4.12,", "95%", "CI", "=", "1.62-10.42", "for", "men)", "and", "smoking", "(OR", "=", "3.03,", "95%", "CI", "=", "1.28-7.16", "for", "non-smokers", "and", "OR", "=", "4.09,", "95%", "CI", "=", "1.18-4.15", "for", "smoker)", "may", "modify", "the", "risk", "of", "colorectal", "invasion", "related", "to", "2G/2G", "genotype.", "Furthermore,", "individual", "with", "2G/2G", "genotype", "seems", "to", "spread", "metastasis,", "3", "years", "earlier", "than", "those", "who", "were", "1G/1G", "and", "1G/2G.", "In", "conclusion,", "to", "our", "knowledge,", "the", "present", "epidemiological", "study", "for", "the", "first", "time", "indicates", "the", "relationship", "of", "2G/2G", "genotype", "polymorphism", "with", "invasion", "risk", "of", "colorectal", "cancer", "in", "subgroups", "of", "gender", "and", "smoking,", "especially", "in", "smoker", "men." ]
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Interstitial collagenase-1 degrades a variety of extracellular matrix components. A single guanine insertion polymorphism in the promoter has been found that influences on the transcription and expression level of the gene. It is suggested that this polymorphism may enhance susceptibility to some types of cancer. Therefore, this case-control study evaluated the association of this genotype polymorphism with susceptibility to initiation and invasion of colorectal cancer. For this reason, whole blood samples were obtained from 150 CRC patients and 100 control subjects in Tehran. Genomic DNA was extracted and genotyped by PCR-RFLP method. We showed that 2G allele and 2G/2G genotype had higher frequencies in patients (60% and 39%, respectively) than in controls (47% and 23%, respectively). The CRC patients were divided into two groups: with metastasis (M+) and without metastasis (M-) groups. The 2G allele was more frequent in M+ group compared with control group. However, no significantly difference was observed between M-group and control (chi(2) = 0.48, P = 0.78 for 2G/2G genotype). Further stratification analyses showed that only gender (OR = 2.58, 95% CI = 0.89-7.52 for women and OR = 4.12, 95% CI = 1.62-10.42 for men) and smoking (OR = 3.03, 95% CI = 1.28-7.16 for non-smokers and OR = 4.09, 95% CI = 1.18-4.15 for smoker) may modify the risk of colorectal invasion related to 2G/2G genotype. Furthermore, individual with 2G/2G genotype seems to spread metastasis, 3 years earlier than those who were 1G/1G and 1G/2G. In conclusion, to our knowledge, the present epidemiological study for the first time indicates the relationship of 2G/2G genotype polymorphism with invasion risk of colorectal cancer in subgroups of gender and smoking, especially in smoker men.
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15069170
[ "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." ]
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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.
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21976404
[ "OBJECTIVES:", "To", "investigate", "the", "association", "of", "angiotensin-converting", "enzyme", "(ACE)", "gene", "polymorphism", "and", "serum", "ACE", "level", "among", "Egyptian", "SLE", "patients", "and", "its", "relation", "to", "disease", "activity", "parameters.", "SUBJECTS", "AND", "METHODS:", "We", "enrolled", "50", "Egyptian", "female", "systemic", "lupus", "erythematosus", "(SLE)", "patients", "and", "29", "healthy", "controls.", "Measurement", "of", "serum", "ACE", "level", "was", "done", "using", "ELISA,", "and", "the", "ACE", "genotype", "was", "determined", "by", "polymerase", "chain", "reaction", "using", "genomic", "DNA", "from", "peripheral", "blood.", "RESULTS:", "A", "significant", "difference", "was", "found", "in", "ACE", "genotypes", "between", "SLE", "patients", "and", "controls", "(", " ", "(2", " ", ")=", " ", "7.84,", "p", " ", "=", " ", "0.02).", "The", "frequency", "of", "ACE", "DD", "versus", "(DI", "and", "II)", "genotypes", "was", "significantly", "higher", "in", "SLE", "patients", "compared", "with", "controls", "(", " ", "(2", " ", ")=", " ", "5.57,", "p", "=", "0.018", "and", "OR", "for", "risk", "of", "SLE", "was", "3.1", "with", "95%", "confidence", "interval:", "1.198.06).", "Mean", "serum", "ACE", "level", "was", "significantly", "higher", "in", "the", "SLE", "group", "compared", "with", "controls", "(p", " ", "=", " ", "0.006).", "Subjects", "with", "DD", "genotype", "had", "a", "significantly", "higher", "mean", "level", "than", "those", "with", "DI", "(p", " ", "=", " ", "0.015)", "and", "II", "genotypes", "(p", " ", "=", " ", "0.02).", "Lupus", "nephritis", "patients", "had", "a", "significantly", "higher", "frequency", "of", "DD", "versus", "DI", "and", "II", "genotypes", "compared", "with", "lupus", "patients", "without", "nephritis", "(Fisher's", "exact", "test,", "p", " ", "=", " ", "0.025)", "and", "controls", "(", " ", "(2)", "=8.74,", "p", " ", "=", " ", "0.003).", "SLE", "patients", "with", "vasculopathy", "had", "a", "significantly", "higher", "frequency", "of", "DD", "versus", "DI/II", "genotypes", "compared", "with", "SLE", "patients", "without", "vasculopathy", "(Fisher's", "exact", "test,", "p", " ", "=", " ", "0.04)", "and", "controls", "(", " ", "(2", " ", ")=", " ", "9.84", "and", "p", " ", "=", " ", "0.002).", "Mean", "serum", "ACE", "level", "was", "significantly", "higher", "in", "the", "lupus", "nephritis", "and", "SLE", "patients", "with", "vasculopathy", "compared", "with", "controls", "(p", " ", "=", " ", "0.008,", "p", " ", "=", " ", "0.001,", "respectively).", "Significant", "positive", "correlations", "were", "found", "between", "serum", "ACE", "level", "and", "serum", "creatinine", "and", "24", " ", "h", "proteinuria", "(p", " ", "=", " ", "0.03,", "0.009,", "respectively).", "SLE", "patients", "with", "DD", "genotype", "had", "a", "statistically", "significant", "higher", "mean", "SLEDAI", "score", "than", "those", "with", "(DI/II)", "genotypes", "(p", " ", "=", " ", "0.02).", "Significant", "positive", "correlation", "was", "found", "between", "serum", "ACE", "levels", "and", "SLEDAI", "scores", "(p", " ", "=", " ", "0.04).", "CONCLUSION:", "ACE", "genotype", "and", "subsequently", "serum", "ACE", "level", "could", "be", "associated", "with", "the", "disease", "activity", "of", "Egyptian", "SLE", "patients;", "in", "addition,", "ACE", "deletion", "polymorphism", "might", "be", "used", "as", "one", "of", "the", "predictive", "factors", "for", "the", "activity", "of", "SLE.", "Further", "studies", "on", "a", "larger", "number", "of", "patients", "should", "be", "done", "to", "determine", "the", "exact", "prevalence", "of", "ACE", "gene", "polymorphism", "among", "Egyptian", "SLE", "patients." ]
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OBJECTIVES: To investigate the association of angiotensin-converting enzyme (ACE) gene polymorphism and serum ACE level among Egyptian SLE patients and its relation to disease activity parameters. SUBJECTS AND METHODS: We enrolled 50 Egyptian female systemic lupus erythematosus (SLE) patients and 29 healthy controls. Measurement of serum ACE level was done using ELISA, and the ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. RESULTS: A significant difference was found in ACE genotypes between SLE patients and controls ( (2 )= 7.84, p = 0.02). The frequency of ACE DD versus (DI and II) genotypes was significantly higher in SLE patients compared with controls ( (2 )= 5.57, p = 0.018 and OR for risk of SLE was 3.1 with 95% confidence interval: 1.198.06). Mean serum ACE level was significantly higher in the SLE group compared with controls (p = 0.006). Subjects with DD genotype had a significantly higher mean level than those with DI (p = 0.015) and II genotypes (p = 0.02). Lupus nephritis patients had a significantly higher frequency of DD versus DI and II genotypes compared with lupus patients without nephritis (Fisher's exact test, p = 0.025) and controls ( (2) =8.74, p = 0.003). SLE patients with vasculopathy had a significantly higher frequency of DD versus DI/II genotypes compared with SLE patients without vasculopathy (Fisher's exact test, p = 0.04) and controls ( (2 )= 9.84 and p = 0.002). Mean serum ACE level was significantly higher in the lupus nephritis and SLE patients with vasculopathy compared with controls (p = 0.008, p = 0.001, respectively). Significant positive correlations were found between serum ACE level and serum creatinine and 24 h proteinuria (p = 0.03, 0.009, respectively). SLE patients with DD genotype had a statistically significant higher mean SLEDAI score than those with (DI/II) genotypes (p = 0.02). Significant positive correlation was found between serum ACE levels and SLEDAI scores (p = 0.04). CONCLUSION: ACE genotype and subsequently serum ACE level could be associated with the disease activity of Egyptian SLE patients; in addition, ACE deletion polymorphism might be used as one of the predictive factors for the activity of SLE. Further studies on a larger number of patients should be done to determine the exact prevalence of ACE gene polymorphism among Egyptian SLE patients.
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