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At least 1,225 records · Page 68Linked to original sources
PubMed2005

Frequency of the C34T mutation of the AMPD1 gene in world-class endurance athletes: does this mutation impair performance?

The C34T mutation in the gene encoding for the skeletal muscle-specific isoform of AMP deaminase (AMPD1) is a common mutation among Caucasians (i.e., one of five individuals) that can impair exercise capacity. The purpose of this study was twofold. First, we determined the frequency distribution of the C34T mutation in a group of top-level Caucasian (Spanish) male endurance athletes (cyclists and runners, n = 104). This group was compared with randomly selected Caucasian (Spanish) healthy (asymptomatic) nonathletes (n = 100). The second aim of this study was to compare common laboratory indexes of endurance performance (maximal oxygen uptake or ventilatory thresholds) within the group of athletes depending on their C34T AMPD1 genotype. The frequency of the mutant T allele was lower (P < 0.05) in the group of athletes (4.3%) compared with controls (8.5%). On the other hand, indexes of endurance performance did not differ (P > 0.05) between athlete carriers or noncarriers of the C34T mutation (e.g., maximal oxygen uptake 72.3 +/- 4.6 vs. 73.5 +/- 5.9 ml.kg(-1).min(-1), respectively). In conclusion, although the frequency distribution of the mutant T allele of the AMPD1 genotype is lower in Caucasian elite endurance athletes than in controls, the C34T mutation does not significantly impair endurance performance once the elite-level status has been reached in sports.

AMP Deaminase↗
PubMed2005

VSX1 mutational analysis in a series of Italian patients affected by keratoconus: detection of a novel mutation.

PURPOSE: Keratoconus is a noninflammatory corneal disorder that is clinically and genetically heterogeneous. Mutations in the VSX1 (visual system homeobox 1) gene have been identified for two distinct, inherited corneal dystrophies: posterior polymorphous corneal dystrophy and keratoconus. To evaluate the possible role of the VSX1 gene in a series of Italian patients, 80 keratoconus-affected subjects were screened for mutations. METHODS: The diagnosis of keratoconus was made on the basis of clinical examination and corneal topography. The whole coding region and the exon-intron junctions of the VSX1 gene were analyzed by direct sequencing. RESULTS: Three already-described changes, D144E, G160D, and P247R, and a novel L17P mutation were found in 7 of 80 unrelated patients (8.7%). Two undescribed intronic polymorphisms are also reported. CONCLUSIONS: Mutational analysis of the VSX1 gene in a series of Italian patients revealed one novel mutation and confirmed an important role played by this gene in a significant proportion of patients affected by keratoconus, when it is inherited as an autosomal dominant trait with variable expressivity and incomplete penetrance.

Adolescent↗
PubMed2006

Postmortem molecular screening for cardiac ryanodine receptor type 2 mutations in sudden unexplained death: R420W mutated case with characteristics of status thymico-lymphatics.

BACKGROUND: Mutations of the cardiac ryanodine receptor type 2 (RyR2) gene are known to cause effort-induced polymorphic ventricular arrhythmia, syncope and sudden death. METHODS AND RESULTS: The possible mutations in the RyR2 gene were examined in 18 autopsy cases of sudden unexplained death (SUD). Two cases were found to have the heterozygous missense mutation in exon 14 (nucleotide change C1258T, coding effect R420W). Both cases showed mild fatty infiltration of the right ventricular apex. Interestingly, 1 case showed an enlarged thymus with accompanying hypertrophy of the tonsils and mesenteric lymph nodes. In addition, a narrowing of the aorta was observed in this case. These phenotypic characteristics are consistent with status thymico-lymphaticus, which combines sudden death with an enlargement of lymphoid organs and hypoplasia of the cardiovascular system. The second case also displayed some characteristics of status thymico-lymphaticus. CONCLUSION: The R420W mutation has already been reported in families with juvenile sudden death and may be causative of sudden death in our cases. Postmortem molecular screening of the RyR2 gene could be useful for investigation for cause of death in SUD. The possible association of the RyR2 mutation with status thymico-lymphaticus is discussed.

Adolescent↗
PubMed2004

Mutational status of IgVH genes consistent with antigen-driven selection but not percent of mutations has prognostic impact in B-cell chronic lymphocytic leukemia.

Mutational status of immunoglobulin heavy-chain variable-region (IgVH) genes, along with CD38 expression, is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL). Configuration of IgVH genes displaying > 2% mismatch has been shown to correlate with longer survivals. In a series of 64 B-CLLs, we failed to confirm the prognostic value of the IgVH gene mutational status by using the suggested cutoff. However, the IgVH mutational status maintained its prognostic value only when evidence of antigen-driven selection could be documented. This was accomplished by applying statistical methods aimed at evaluating a significant skewing of replacement mutations from framework to complementary determining regions, as it occurs during germinal center differentiation of B cells. These data caution against wide application of the 2% somatic mutation cutoff as a prognostic determinant without demonstration of antigen-driven selection.

ADP-ribosyl Cyclase↗
PubMedDate not supplied

Mutational analysis of the CTNNB1 (beta-catenin) gene in human endometrial cancer: frequent mutations at codon 34 that cause nuclear accumulation.

Recently, CTNNB1 (beta-catenin) has been found to function as an oncoprotein that works in the Wnt signaling pathway, and mutation of this gene has been reported in various human cancers. In this study, we analyzed 44 endometrial cancers and found somatic missense mutations in five (11%) tumors. Interestingly, four (80%) of the five tumors with mutations would cause amino acid alterations at residues next to Ser 33, one of the targets for phosphorylation of glycogen synthase kinase (GSK)-3beta. The tumors with mutations showed accumulation of the CTNNB1 protein in cytoplasm and nucleus. This is the first report of frequent somatic mutation of the CTNNB1 gene at codons adjacent to those encoding to Ser/Thr residues in endometrial cancer.

Cell Nucleus↗
PubMed2000

Novel mutations, including a novel G659A missense mutation, of the FUT1 gene are responsible for the para-Bombay phenotype.

Para-Bombay phenotype, with an estimated incidence of 1 in 8000 in Taiwanese residents based on serological analysis, is caused by aberrant alpha(1,2)-fucosyltransferase function and hence diminished H-antigen synthesis. In an individual with para-Bombay phenotype, DNA sequencing revealed two missense mutations previously reported C658T mutation and a novel G659A mutation. Haplotype analysis with restriction enzyme digestion showed that the two mutations are located on opposing alleles of the H (FUT1) gene and lead to compound heterozygosity. Since no other known genetic changes were evident, it appears that the new missense mutation, G659A, is deleterious to the alpha(1,2)-fucosyltransferase function encoded by the H (FUT1) gene.

ABO Blood-Group System↗
PubMed2004

Mutation analysis of HPS1, the gene mutated in Hermansky-Pudlak syndrome, in patients with isolated platelet dense-granule deficiency.

BACKGROUND AND OBJECTIVES: Isolated platelet dense granule (PDG) deficiency is a heterogeneous disorder frequently found among patients with mild to moderate bleeding diatheses. However, the molecular basis of this disorder is unknown. Genes involved in other rare bleeding disorders with associated reduction in the numbers of platelet dense-granules may play a role in isolated PDG deficiency. Among such genes, HPS1 is known to play a key role in the genesis of PDG and as many as 18 different HPS1 mutations have been identified in patients with Hermansky-Pudlak syndrome. Recently, we have identified subjects with one HPS1 heterozygous mutation displaying significant reductions in PDG without the clinical phenotype of Hermansky-Pudlak syndrome. This suggested that HPS1 mutations could be involved in isolated PDG deficiency. DESIGN AND METHODS: We sequenced all coding exons, and flanking intron regions of HPS1 in 16 patients with mild to severe PDG deficiency, most of whom had mild bleeding episodes. Nine patients reported a familial history of bleeding diathesis with PDG deficiency. We also evaluated the prevalence of HPS1 variations in 215 controls. Transmission electron microscopy was used to evaluate the number and morphology of PDG from patients and selected controls. RESULTS: No patient with PDG deficiency carried severe mutations of the HPS1 gene. We identified 6 previously described and 5 new polymorphisms in the HPS1 gene. Platelet electron microscopy in controls carrying these polymorphisms revealed that they did not significantly modify the number or morphology of PDG. INTERPRETATION AND CONCLUSIONS: Mutations affecting the HPS1 gene play a minor role in isolated PDG deficiency. These results support a molecular heterogeneity responsible for the number and morphology of PDG.

Adult↗
PubMed2004

[Single nucleotide polymorphisms and point mutations of ataxia telangiectasia mutated gene in Chinese of Han ethnicity].

OBJECTIVE: To explore the single nucleotide polymorphisms (SNPs) and point mutations of ataxia telangiectasia mutated (ATM) gene in Chinese of Han ethnicity. METHODS: The target fragments of the exon 39, exon 61 and exon 63 of ATM gene were first amplified using PCR technique, then screened for the SNPs and point mutations using single strand conformation polymorphism (SSCP) technique, finally the representative bands were sequenced for the verification of the new single nucleotide polymorphisms and point mutations using the automatic DNA sequencing technique. RESULTS: Six new SNPs were found in the exon 39, intron 61 and intron 63 of ATM gene. They are respectively the A/T polymorphisms at nucleotide 5689 and 5691 in exon 39, the T/G polymorphisms at nucleotide +69 and +99, the A/G polymorphism at nucleotide +94 in intron 61, the G/C polymorphism at nucleotide +17 in intron 63. Five new point mutations were found in the exon 61, intron 62 and exon 63 of ATM gene. They are respectively the T/G transversion at nucleotide 8618 in exon 61, the T/G transversion at nucleotide -13 in intron 62, the T/G transversion at nucleotide 8793, the G/A transitions at nucleotide 8816 and 8848 in exon 63. The known three SNPs, the G/A polymorphism at nucleotide 5557 in exon 39, the T/C polymorphism at nucleotide +104 in intron 61 and the T/C polymorphism at nucleotide -55 in intron 62, were verified in Chinese of Han ethnicity. CONCLUSION: There are great differences in the SNPs of ATM gene between Chinese of Han ethnicity and Caucasian.

Asian People↗
PubMed2005

[A frame shift mutation, Arg346fs mutation, is identified in cardiac myosin-binding protein C gene in a Chinese family with hypertrophic cardiomyopathy].

OBJECTIVE: To explore the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM). METHODS: The peripheral venous blood samples were collected from 5 HCM families without consanguinity, including 5 probands, 2 males and 3 females, 28 sporadic HCM patients, 18 males and 10 females, and 80 healthy controls. The exons in the functional regions of cardiac myosin-binding protein C (MYBPC3) were amplified with PCR and the amplified products were sequenced. RESULTS: A frame shift mutation-Arg346fs mutation in exon 13, the first mutation identified in Chinese-was discovered in one family with HCM. However, the members of the same HCM family with the Arg346fs mutation showed differences in phenotype and prognosis. CONCLUSION: Cardiac myosin-binding protein C (MYBPC3) may be one of the main disease-causing genes. The heterogeneity of phenotype suggests that multiple factors may be involved in the pathogenesis.

Adolescent↗
PubMed1993

von Willebrand disease: a database of point mutations, insertions, and deletions. For the Consortium on von Willebrand Factor Mutations and Polymorphisms, and the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.

The current system for the diagnosis and classification of von Willebrand disease (vWD) is quite complex, with more than 20 distinct variants described. Over the past few years considerable progress has been made toward an understanding of vWD at the molecular level. A small cluster of mutations within the vWF A1 homologous repeat appears responsible for over 90% of type IIB vWD. A similar cluster of mutations in the vWF A2 homologous repeat accounts for the majority of type IIA vWD. By RFLP analysis, several type II vWD mutations have been shown to be recurrent on distinct haplotype backgrounds, suggesting independent genetic origins (see accompanying manuscript for a complete list of known polymorphisms). Several mutations at the N-terminus of the mature vWF subunit have been identified in association with abnormal factor VIII binding. Homozygotes for this abnormal vWF present with a hemophilia-like phenotype that is autosomal recessive in inheritance. In a small subset of patients with type III vWD large gene deletions have been identified on one or both vWF alleles. Carriers heterozygous for a deleted locus and one normal vWF gene are generally asymptomatic. Nonsense mutations and other defects resulting in loss of vWF mRNA expression from one allele have also been associated with a recessive type III vWD phenotype. No distinct molecular defect responsible for classic type I vWD has yet been defined.

DNA Mutational Analysis↗
PubMed1996

UHG-based mutation screening in type 2B von Willebrand's disease: detection of a candidate mutation Ser547Phe.

We have recently described a novel mutation screening technique for the diagnosis of type 2B von Willebrand's disease (vWD). Analysis involves the use of a synthetic universal heteroduplex generator (UHG). To test the validity of the technique, we have applied UHG screening to seven type 2B vWD patients of previously unknown genotype. Characteristic heteroduplex patterns for Arg543Trp and Val553Met mutations were found in three patients and one patient, respectively. A fifth patient gave a novel pattern and direct sequencing revealed a hitherto unreported candidate mutation (Ser547Phe) 8 bases downstream of an "identifier" deletion in the UHG molecule. The two remaining patients gave normal heteroduplex patterns; an Arg578Gln mutation was identified by PstI digestion in one individual and no mutation could be identified in the sequence covered by the UHG in the final patient. Using a combination of UHG technology and restriction analysis, over 85% of type 2B vWD patients can be rapidly diagnosed by genotype.

Amino Acid Sequence↗
PubMed1996

Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom.

Mutations in the gene for the low density lipoprotein (LDL) receptor have been identified in 15 patients with homozygous familial hypercholesterolemia (FH). Five patients are homozygous at the LDL-receptor locus; their mutant alleles include Glu387Lys and Pro664Leu in patients of Asian-Indian descent, Cys292Stop in a Greek Cypriot, Cys281Trp in a Turkish patient, and Gln 540Stop in a West Indian. The other 10 patients (9 of apparently British ancestry) are compound heterozygotes. Mutations have been identified in 18 of 20 possible alleles, including Glu80Lys (2 patients), Pro664Leu (3 patients), Asp69Gly, Cys176Arg, Cys227Tyr, Ser265Arg, Asp280Ala, Asp283Glu, Arg329Pro, Asp461Asn, Leu578Ser, a single bp deletion in exon 15, a 21 bp duplication of codons 200-206 and two large deletions. The seven mutations underlined above have not been described previously. The two uncharacterized mutant alleles fail to produce detectable amounts of mRNA. LDL-receptor activity in cultured cells from 13 of the 15 homozygous patients varied from undetectable to about 30% of normal, but there was no correlation between LDL-receptor activity and the untreated plasma cholesterol concentration in these patients. When genomic DNA from 295 patients with a clinical diagnosis of FH was screened for 29 mutations found in these and other FH patients of British ancestry, most were identified in only one or a few individuals. Four patients heterozygous for the Asp461Asn allele showed a wide range of clinical manifestations. These observations confirm the striking heterogeneity underlying FH in most populations and demonstrate the variability in phenotype between patients with the same mutation.

Adolescent↗
PubMed1999

Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region.

Studies in mouse, chicken and Xenopus have shown that Slug is selectively expressed in the dorsal part of the developing neural tube. Ablation and antisense experiments in chicken suggest that Slug may be an important factor during neural tube closure. We therefore investigated the role of Slug as a possible candidate contributing to the aetiology of neural tube defects (NTD) in humans. We characterised the genomic structure of human SLUG including determination of the exon-intron boundaries. The coding sequence of SLUG was screened for mutations in 150 patients with NTD using single strand conformation analysis (SSCA). In one patient, we identified a missense mutation 1548C-->A in exon 2 causing an exchange of a conserved amino acid (D119E) in the Slug subfamily-defining region preceding the first zinc finger. This is the first description of a human mutation in the SLUG gene. In accordance with the findings in model organisms, the SLUG mutation may be causally related to the development of NTD in our patient and could be considered as a predisposing factor.

Adult↗
PubMed1996

Segregation of the fragile X mutation from a male with a full mutation: unusual somatic instability in the FMR-1 locus.

Fragile X syndrome is associated with an unstable CGG-repeat in the FMR-1 gene. There are few reports of affected males transmitting the FMR-1 gene to offspring. We report on a family in which the propositus and his twin sister each had a full mutation with abnormal methylation. Their mother had an FMR-1 allele in the normal range and a large premutation, with normal methylation. The maternal grandmother had two normal FMR-1 alleles. The maternal grandfather had an unusual somatic FMR-1 pattern, with allele size ranging from premutation to full mutation. No allele was detectable by PCR analysis. Multiple Southern blot analyses identified a hybridization pattern that originated at a distinct premutation band and extended into the full mutation range. Methylation studies revealed a mosaic pattern with both unmethylated premutations and methylated full mutations. This individual declined formal evaluation but did not finish high school and has difficulty in reading and writing. The size of the premutation FMR-1 allele passed to his daughter is larger than his most prominent premutation allele. This is most likely due to gonadal mosaicism similar to that in his peripheral lymphocytes. Alternatively, this expansion event may have occurred during his daughter's early embryonic development and this large premutation allele is mitotically unstable. This pattern of FMR-1 alleles in a presumably mildly affected male is highly unusual. These findings are consistent with the absence of transmission of a full fragile X mutation through an expressing male. Studies of tissue specific FMR-1 allele expansion and FMR-1 protein expression on this individual should help to determine the correlation of the molecular findings with the phenotypic effects.

Alleles↗
PubMed1998

Search for mutations in a segment of the exon 28 of the human von Willebrand factor gene: new mutations, R1315C and R1341W, associated with type 2M and 2B variants.

von Willebrand Disease (vWD) is the most frequently inherited bleeding disorder in humans, and is caused by a qualitative and/or quantitative abnormality of the von Willebrand factor (vWF). A large number of defects that cause qualitative variants have been located in the A1 domain of the vWF, which contains sites for interaction with platelet glycoprotein Ib (GPIb). We have developed a new approach to detect mutations based on DdeI digestion and single-strand conformation polymorphism analysis. A segment of 487 nucleotides, extending from intron 27 to codon 1368 of the pre-pro vWF was amplified from genomic DNA. The cleavage with DdeI yields two fragments of appropriate size for this kind of analysis and confirms that the gene, rather than the pseudogene, is being investigated. Six families with type 2B vWD, one type 2M vWD family, and one another type 2A vWD family were studied. After sequencing the fragments with an altered electrophoretic pattern, we found four mutations previously described--R1308C, V1316M, P1337L, and R1306W--in patients with 2B vWD. The last one arose de novo in the patient. In addition, two new candidate mutations were observed: R1315C and R1341W. The first one was associated to type 2M vWD, whereas the one second cosegregated with type 2B vWD. The fact that these new mutations were not found in 100 normal alleles screened further supports their causal relationship with the disease. These mutations, which induce either a gain or a loss of function, further show an important regulatory role of this region in the binding of vWF to GPIb and its implications in causing disease.

Amino Acid Substitution↗
PubMed1999

BAT-26 identifies sporadic colorectal cancers with mutator phenotype: a correlative study with clinico-pathological features and mutations in mismatch repair genes.

Microsatellite instability (MSI) is present in most colorectal cancers (CRC) associated with hereditary nonpolyposis colorectal cancer (HNPCC). MSI testing in so-called sporadic forms of CRC may become a useful tool in identifying new HNPCC kindred. The aim of this study was to analyse the utility of BAT-26 as a marker to identify CRCs with MSI and to investigate whether sporadic CRCs with MSI have a phenotypic expression similar to HNPCC cases. MSI was detected using two methods, an association of 7 poly(CA) repeats and a poly(A) repeat alone, BAT-26, in a series of 62 patients with apparently sporadic forms of CRC. Germ-line and somatic mutations in the hMSH2, hMLH1, and hMSH6 genes were analysed in patients with MSI+ tumours. Patients with MSI+ at poly(CA) loci and at BAT-26 were younger (p=0.024 and p=0.002), had tumours more frequently right sided (p=0.017 and p=0.0001) and more often mucinous (p=0.037 and p=0.005, respectively) than patients with MSI negative tumours. Mutation analysis allowed the identification of two patients carrying germ-line mutations in the hMLH1 gene (both were BAT-26+) and two other patients who had somatic mutation in the hMSH2 and in hMLH1 genes. In conclusion, the detection of MSI using poly(CA) repeats or BAT-26 alone allowed the identification of a subset of patients with clinico-pathological characteristics similar to those associated to HNPCC. BAT-26 has the advantage of being a simple and less expensive method that might be used as a screening procedure before mutation analysis.

Adult↗
PubMed1996

A sensitive mutation screening strategy for Fabry disease: detection of nine mutations in the alpha-galactosidase A gene.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of alpha-galactosidase A (alpha-gal; EC 3.2.1.22). In the past, it has been difficult to give an unequivocal diagnosis of carrier status in Fabry disease because of the overlap between normal and heterozygote enzyme levels. To facilitate rapid and accurate carrier and hemizygote detection, a mutation detection strategy was devised to determine the lesion in our Fabry disease patients. The seven alpha-gal exons and adjacent intron boundaries from a representative member of each kindred were PCR amplified and analysed for the presence of sequence alterations by single-stranded conformation polymorphism (SSCP) analysis followed by PCR sequencing. Here we report the use of this strategy in the detection and analysis of the causative mutations in 9 patients with classic severe Fabry disease. Three deletions of 1-, 2-, and 3-bp (987delC, 717delAA, and delta E358), five amino acid substitutions (C52R, G128E, P205T, M284T, and N298K) and a mutation that affects the initiating methionine (M1I) were found in these patients. Counting a previously reported mutation, this strategy has now successfully detected all the Fabry disease mutations present in the 10 kindreds that have been analysed.

Adult↗
PubMed1997

Mutation screening of all 65 exons of the fibrillin-1 gene in 60 patients with Marfan syndrome: report of 12 novel mutations.

Mutations in the fibrillin-1 gene on chromosome 15q21.1 have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. In this study we screened all 65 exons of the fibrillin-1 gene in 20 Marfan syndrome families where at least two affected individuals were characterised and available for analysis, another 30 families with only one affected member available for analysis, and in 10 sporadic cases. In large well-characterised families with more than four affected individuals, the detection rate for mutations rose to 78% (7/9), in families with either two or three affected members 27% (3/11). In families where only one affected family member was available, the mutation detection rate was 17% (5/30), and in sporadic cases it was 20% (2/10). In addition, we found eight neutral polymorphisms. Twelve of the 17 disease-causing mutations identified have not been previously described, thus raising the total number of different fibrillin-1 mutations reported to 85 in 94 unrelated cases.

Amino Acid Sequence↗