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Results for “Recurrent mutation”

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At least 253 records · Page 14Linked to original sources
PubMed1999

Inheritance of two different alleles of the low-density lipoprotein (LDL)-receptor gene carrying the recurrent Pro664Leu mutation in a patient with homozygous familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is caused by mutations in the low-density lipoprotein (LDL)-receptor gene that result in impaired clearance of plasma LDL and increased risk of coronary heart disease. Numerous different mutations have been found in FH patients worldwide, the majority of which are infrequent in out-bred populations and account for 2% or less of patients with the disorder in large cohorts. Thus, it was surprising to find that two homozygous FH patients referred to a single hospital in the UK were both apparently homozygous for the Pro664Leu mutation. One, an Asian patient, was a true homozygote. The other, of English origin, had inherited two different alleles of the LDL-receptor gene with the same mutation from unrelated parents, as inferred from the haplotype of polymorphic markers. A third, clinically homozygous FH patient, despite being the offspring of first cousins, had inherited one 'Asian' Pro664Leu allele, but an allele with a 1-bp deletion in exon 5 from the other parent. The Pro664Leu mutation in the LDL-receptor gene has now been described in heterozygous patients of very different ethnic origin and is associated with different haplotypes, suggesting that the same base change at a CpG may have recurred as many as six times.

Alleles↗
PubMed1998

Clinical and haematological consequences of recurrent G6PD mutations and a single new mutation causing chronic nonspherocytic haemolytic anaemia.

We have determined the causative mutation in 12 cases of glucose-6-phosphate dehydrogenase deficiency associated with chronic non-spherocytic haemolytic anaemia. In 11 of them the mutation we found had been previously reported in unrelated individuals. These mutations comprise seven different missense mutations and a 24 base pair deletion. G6PD Nara, previously found in a Japanese boy. Repeated findings of the same mutations suggests that a limited number of amino acid changes can produce the CNSHA phenotype and be compatible with normal development. The one new mutation we have found, G6PD Serres, is 1082 C-->T causing a 361 Ala-->Val substitution in the dimer interface where most other severe G6PD mutations are found. Now that several patients with the same mutation have been reported we can compare the resulting clinical phenotypes. For each mutation we find a reasonably consistent clinical picture, ranging from mild (G6PD Clinic) through moderate (G6PD Nashville) to severe (G6PD Beverly Hills and G6PD Nara).

Adolescent↗
PubMed2001

Two novel and one recurrent missense mutation in the factor XIII A gene in two Dutch patients with factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive disorder, usually attributed to a defect in the FXIII A subunit, whose genetic basis has been studied in a number of cases. We describe here the genetic variations found in two unrelated patients with FXIII deficiency. Both patients, under prophylactic substitution with FXIII concentrate, showed low plasma FXIII A subunit antigen levels with undetectable A subunit antigen in the platelets and normal plasma B antigen levels, which indicate that the defects are present in the A subunit of the molecule. Both probands were heterozygous for a previously reported G-->A transversion in exon 8 of the FXIII A subunit gene (Arg326Gln substitution). Proband 1 was also heterozygous for a novel G-->T transversion in exon 7, which predicts a Val316Phe substitution. Two of her sons were heterozygous for this mutation and showed low FXIII activity and FXIII A subunit antigen levels. Val316 is a well-conserved amino acid among the transglutaminase family, located within the core domain, close to the Cys314 member of the catalytic triad. Proband 2 had a unique 2-bp (TT) insertion in one of the alleles within or adjacent to the -7 to -20 T tail of intron A. This insertion was not found in 50 healthy individuals, which supports this being the second mutation in this patient.

Adult↗
PubMed2000

Recurrent R156H mutation of KRT10 in a Japanese family with bullous congenital ichthyosiform erythroderma.

Recently, mutations of keratin 1 gene (KRT1) and keratin 10 gene (KRT10) have been reported in various patients with bullous congenital ichthyosiform erythroderma (BCIE). The substitution of arginine (R) to histidine (H) at amino acid residue 156 (R156H) of coiled 1A region is one of the most frequent mutations of KRT10. In this study, we searched for a mutation in KRT1 and KRT10 in a Japanese family with BCIE and detected mutation R156H in KRT10. Our search led to the detection of R156H. This mutation was not detected in 50 normal individuals. These results confirmed that codon 156 is a frequently mutated site, and that R156H in KRT10 is likely also to be a mutation hotspot in Japanese patients with BCIE.

Amino Acid Substitution↗
PubMed2005

Targeted somatic mutation of the BCL6 proto-oncogene and its impact on lymphomagenesis.

Cloning translocation breakpoints which cluster suspiciously to specific chromosomal loci has proved fruitful, leading to the identification of genes implicated in the onset of hematological malignancy. One of the most notable is BCL6, located on chromosome 3q27. The BCL6 is now known to encode a nuclear transcriptional repressor, with pivotal roles in germinal center (GC) formation and regulation of lymphocyte function, differentiation and survival. Unusually, the BCL6 gene locus is also actively targeted by the somatic mutation (SM) mechanism, at a rate indicative of specific, regulated events in both normal and malignant B-cells. These mutations occur in approximately 30% of normal centrocytes and centroblasts, but not in naive or pre-GC B-cells. They are also observed in approximately 70% of diffuse large B-cells lymphomas, approximately 30% of follicular lymphomas (FL) and at various frequencies in many lymphoma subtypes. Mutations are generated in the 5' proximity of the BCL6 promoter, including the first intron and are mainly single nucleotide substitutions, but with insertions and deletions also observed. Mutations in BCL6 occur independently of translocations, although mutational levels can be dramatically influenced by aberrantly translocated chromosomal elements, which map in the vicinity of the gene. Indeed, SMs are directly implicated in the generation of chromosomal translocations, as suggested by the overlap of the breakpoint cluster region and the mutational cluster domain. The prognostic value of the overall level of BCL6 mutations in specific lymphoma populations is, in the main, not as yet fully resolved. The accumulation of mutations in BCL6 during high grade transformation of FL, a mutational clustering and specific recurrent mutations suggest that some mutations may be selected for by their effect on the survival of the tumoral clone. In fact, it is now clear that SM can target and disrupt regulatory motifs in BCL6 to result in upregulated gene expression. Exogenous factors can also perturbate SM in BCL6. Viral infection elevates BCL6 mutational activity, suggesting a potential link with onset of virus-associated lymphoma. These findings to date reveal several mechanisms which can influence specific mutations targeting BCL6, and which may contribute to lymphomagenesis by dysregulating control of BCL6 expression.

Animals↗
PubMed1994

Spectrum of small length germline mutations in the RB1 gene.

A screening method based on multiplexed automated fragment length analysis of polymerase chain reaction products was used to identify germline mutations in the RB1 gene. By screening 106 unrelated patients with hereditary retinoblastoma, 20 small deletions (1-18 bp) and seven insertions (1-5 bp) were identified. When collating our data with reported mutations, recurrence of small length mutations was observed at nine sites within the RB1 gene. Most of these contained monotonic runs or direct repeats embedded in homocopolymer tracts. While the majority of mutations resulted in premature truncation, two mutations caused an in-frame loss of F755 and G540 to E545, respectively. A genotype-phenotype comparison of patients carrying different small length mutations did not reveal any consistent relation. Particularly, the two patients with in-frame mutations showed a high number of tumours consistent with regular-penetrance retinoblastoma.

Base Sequence↗
PubMedDate not supplied

Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene.

PURPOSE: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder resulting from a deficiency of the lysosomal glycosidase, alpha-L-iduronidase (IDUA). Patients with MPS I present with variable clinical manifestations ranging from severe to mild. To facilitate studies of phenotype-genotype correlation, the authors performed molecular studies to detect mutations in MPS I patients and characterize single nucleotide polymorphism (SNP) in the gene. METHODS: Twenty-two unrelated MPS I patients were subjects for mutation detection using reverse transcriptional polymerase chain reaction (RT-PCR) and genomic PCR sequencing. Polymorphism analyses were performed on controls by restriction enzyme assays of PCR amplicons flanking nine intragenic single nucleotide polymorphic alleles. RESULTS: Eleven different mutations including two common mutations (Q70X, W402X), five recurrent mutations (D315Y, P533R, R621X, R628X, S633L), and four novel mutations (R162I, G208D, 1352delG, 1952del25bp) were identified from MPS I patients. Multiple SNP alleles coexisting with the disease-causing mutations were detected. Allelic frequencies for nine SNP alleles including A8, A20, Q33H, L118, N181, A314, A361T, T388, and T410 were determined. CONCLUSIONS: The results provide further evidence for the mutational heterogeneity among MPS I patients and point out possible common haplotype structures in the gene.

Black People↗
PubMed1989

A recurrent missense mutation (Arg----Gln) and a partial deletion in factor VIII gene causing severe haemophilia A.

The presence of gene lesions in coagulation factor VIII (FVIII) gene was investigated in 70 Italian patients severely affected by haemophilia A. cDNA probes specific for exons 14-26 of the FVIII gene were used. In two related patients a gene deletion removes exon 26, a gene lesion similar to that described previously in a British haemophiliac. In exon 24 a C to T transition in the reverse complement strand causes a missense mutation in the coding strand (CGA----CAA, 2209 Arg----Gln). The mutation is located in a very conserved FVIII homology region and severely reduces FVIII activity. By restriction analysis and hybridizations with oligonucleotide probes this gene alteration was found in two unrelated haemophiliacs and in their relatives.

Chromosome Deletion↗
PubMed1999

A recurrent frameshift mutation in exon 19 of the type VII collagen gene (COL7A1) in Mexican patients with recessive dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disorder caused by mutations in the type VII collagen gene (COL7A1). In this study, we determined the molecular basis of autosomal recessive DEB in a 19-year-old Hispanic Mexican woman by PCR amplification of genomic DNA, heteroduplex analysis, and automated sequencing of heteroduplex bandshifts. This approach revealed a homozygous frameshift mutation, 2470insG, in exon 19 of COL7A1 and resulted in attenuated basement membrane zone expression of type VII collagen, a reduced number of anchoring fibrils at the dermal-epidermal junction, and a sub-lamina densa level of blister formation. Clinically, the patient had widespread trauma-induced skin fragility and complete loss of the nails, but had less pseudosyndactyly of the fingers and toes and milder mucosal involvement compared to most patients with the generalized form of this genodermatosis. We also screened 7 other Hispanic-Mexican patients with recessive DEB, none of whom were known to be related to this individual, for the mutation 2470insG using heteroduplex analysis and direct sequencing and detected this mutation on 7/14 alleles. Haplotype analysis using intragenic COL7A1 and flanking polymorphisms and microsatellite markers revealed that all the mutant alleles had arisen on similar allelic backgrounds, consistent with propagation of a common Hispanic Mexican ancestral haplotype. In view of the high allelic frequency of the mutation 2470insG in the patients studied, we recommend initial screening for this mutation when attempting to identify the molecular pathology of recessive DEB in Hispanic Mexican patients.

Adult↗
PubMed2000

Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder.

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal alpha1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proalpha1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.

Achondroplasia↗
PubMed2003

Recurrent E413K mutation of hHb6 in a Japanese family with monilethrix.

Monilethrix is an autosomal dominant hair disorder characterized by a beaded appearance of the hair due to periodic thinning of the shaft. This disorder has been reported to be caused by mutations in the helix termination motif of two type II cortex keratins, hHb1 and hHb6. Here we describe a Japanese monilethrix family that has the most frequent mutation, the E413K mutation in hHb6, so far found in 26 families. Genotype/phenotype correlation was not obvious in our case or in the previously reported cases.

Child, Preschool↗
PubMed2005

Molecular mechanisms of antithrombin deficiency in two Chinese families. One novel and one recurrent point mutation in the antithrombin gene causing venous thrombosis.

We investigated the molecular mechanisms responsible for type I congenital antithrombin (AT) deficiency in two unrelated Chinese pedigrees manifesting multiple site venous thrombosis. Phenotype analysis showed both probands had almost 50% of normal AT levels. Direct sequencing of amplified DNA revealed 2757C > T in proband 1 and 13328G > A in proband 2, predicting a heterozygous Thr98Ile (T981) and Ala404Thr (A404T), respectively. No proband had 20210A allele or factor V Leiden mutation. Transient expression of complementary DNA coding for the mutations in COS-7 cells showed impaired secretion of the mutant molecules. Real-time quantitative PCR indicated that the mutant AT mRNA was transcribed at a similar or even higher level as that of wild-type (wt). Pulse-chase labeling studies suggested both AT variants did not accumulate, but degraded intracellularly. Immunohistochemical staining of the transfected cells revealed that CHO cells expressing the AT-198 mutant were stained diffusely without perinuclear enhancement and cells expressing AT-T404 mutant mainly in the whole cytoplasm with weaker perinuclear enhancement. We conclude that the impaired secretion of the mutant AT molecules, due to intracellular degradation, is the molecular pathogenesis of AT deficiency caused by T981 and A404T mutation for the two families, respectively.

Animals↗