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At least 19 recordsLinked to original sources
PubMed2025

TSC angiofibroma and ungual fibroma have different mutation signatures, with recurrent mutations in KMT2C.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome characterized by tumors affecting multiple tissues, including skin, due to inactivating TSC1/TSC2 variants. Genome-wide profiling of somatic mutations in a unique collection of angiofibroma (FAF) and ungual fibroma (UF) TSC skin tumors was performed. METHODS: Genome sequencing was performed on 9 samples, comprising 4 FAF and 5 UF, along with 6 matched normal samples from 6 individuals with TSC. RESULTS: TSC-FAF and TSC-UF skin tumors have different mutation signatures, with a predominance of UV-related single-nucleotide variant (SNV; SBS7a and SBS7b) and dinucleotide variant (DNV; DBS1) signatures in FAF, and aging-related SNV (SBS1 and SBS5) signatures in UF. We also identified a novel DNV signature for TSC-UF, with frequent TG>CA and TT>GG substitutions. Furthermore, 3 inactivating somatic mutations in KMT2C were observed in 2 of 4 TSC-FAF and 5 mutations in other cancer genes. CONCLUSION: The distinct SNV mutation signatures seen in TSC-FAF and UF indicate that they develop through distinct pathogenic mechanisms, UV-induced mutagenesis in FAF, and aging-related mutagenesis in UF. The mechanism of the novel DNV signature in UFs merits further investigation. Our observation on the occurrence of KMT2C mutations suggests that KMT2C inactivation contributes to the pathogenesis of TSC-FAF.

Humans↗
PubMed1992

Identification of three novel PKU mutations among Chinese: evidence for recombination or recurrent mutation at the PAH locus.

Three novel mutations have been identified in the phenylalanine hydroxylase (PAH) genes of Chinese classical phenylketonuria (PKU) patients. Two of these substitutions (W326X and Y356X) result in the generation of a premature stop codon, while the third (IVS-7nt2) alters an invariant dinucleotide splicing signal. These mutations together account for about 10% of all PKU alleles in the Chinese population. The W326X mutation is associated with PAH RFLP haplotype 4, the most common haplotype in Orientals, while the IVS-7nt2 mutation occurs once on a haplotype 7 chromosome. The Y356X mutation is associated with multiple haplotypes, possibly due to crossover, gene conversion, or recurrent mutation.

Asian People↗
PubMed1991

Discrimination between recurrent mutation and identity by descent: application to point mutations in exon 11 of the cystic fibrosis (CFTR) gene.

A total of 75 non-delta F508 chromosomes from 59 German cystic fibrosis patients was screened for mutations in exon 11 of the cystic fibrosis (CFTR) gene. These Caucasian patients were found to possess an identical haplotype background for two common mutations (G551D, R553X) consistent with their being identical by descent. However, a different R553X associated haplotype found in American black patients was suggestive of recurrent mutation, a postulate supported by the location of the R553X alteration in a hypermutable CpG dinucleotide. Likelihood estimates for recurrent mutation and identity by descent were compared and strongly supported the hypothesis of recurrent R553X mutation. The ability to distinguish between these two alternatives provides an indication of whether or not the search for mutations should be restricted to chromosomes with similar haplotypes.

Cystic Fibrosis↗
PubMed1990

Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations.

The codon 408 mutation (CGG----TGG, Arg----Trp) in exon 12 of the phenylalanine hydroxylase (PAH) gene occurs on haplotype 1 in French-Canadians; elsewhere this mutation (R408W) occurs on haplotype 2. A CpG dinucleotide is involved. The finding is compatible with a recurrent mutation, gene conversion, or a single recombination between haplotypes 2 and 1. A tabulation of 20 known mutations at the PAH locus reveals three instances of putative recurrent mutation.

Alleles↗
PubMed1979

Recurrent mutation and selection for increased penicillin titre in Aspergillus nidulans.

Recurrent mutation and selection has been used to increase penicillin titre in two closely related strains of Aspergillus nidulans. A selection programme was initiated from each of the two strains (programmes A and B) and continued through six cycles of mutation and selection. Near-ultraviolet light in conjuction with 8-methoxypsoralen was employed as the sole mutagen throughout programme A and ethyl methanesulphonate as the sole mutagen throughout programme B. Excluding the first cycle of A, where only 50 strains were assayed, the selection programmes were identical. In each programme, 100 survivors were assayed for penicillin titre after each mutagenic treatment and, on the basis of a single yield test, the best five strains were picked and carried forward to the next cycle. In both selection programmes, a near 300% increase in penicillin titre was achieved. This yield advance illustrates the effectiveness for strain development of experimental designs involving successive cycles of mutagenesis with a single-stage screen and the selection of the top few percent survivors in each cycle.

Aspergillus nidulans↗
PubMed1992

Protein C deficiency and thromboembolism: recurrent mutation at Arg 306 in the protein C gene.

A CGA----TGA transition in the protein C gene, resulting in an Arg306----Term substitution, was detected in a Swedish kindred with thrombotic disease whose members exhibit plasma protein C activity/antigen levels consistent with type I protein C deficiency. Although an identical lesion has been reported previously in several Dutch families, RFLP typing indicated that the Dutch and Swedish mutations were unlikely to be identical by descent and probably arose by recurrent mutation.

Amino Acid Sequence↗
PubMed1990

Recurrent mutations and three novel rearrangements in the factor VIII gene of hemophilia A patients of Italian descent.

Hemophilia A (HA), a common inherited bleeding disorder in humans, is due to the deficiency or absence of the factor VIII (FVIII) activity. The cloning of the FVIII gene has made molecular probes available for the characterization of the basic defect in this disease. In this study we describe six different mutations in the FVIII gene detected by DNA analysis of 100 HA patients of Italian descent. In two of them, with a severe clinical picture, we identified two novel deletions, one in the middle of the FVIII gene from exons 7 to 22 and the other encompassing the entire factor VIII gene. Both of these patients produced antibodies to factor VIII. In a patient with mild HA we detected a duplication of exon 13, which is a rearrangement not yet described within the FVIII gene. A possible explanation for the mild phenotype in this patient is that the molecular defect results in the production of an unstable FVIII protein with residual 10% FVIII activity. Screening by Taq I restriction endonuclease detected three mutations that were further characterized by direct sequencing on amplified DNA: a C-T substitution at codon 1960, in exon 18, converting the codon for arginine to a non-sense codon; and a G-A substitution at codon 2228 and 2326, in exons 24 and 26 respectively, resulting in the substitution of glutamine for arginine. All three of these mutations have been previously described. The non-sense mutation and the codon 2228 G-A mutation was found in patients with severe HA, while the codon 2326 G-A mutation was associated with a quite severe condition. These results confirm that the molecular bases of HA are very heterogeneous and provide further evidence that recurrent mutations are not uncommon in this system.

Base Sequence↗
PubMed1990

Recurrent mutation in the human phenylalanine hydroxylase gene.

We report the identification of a missense mutation of Glu280 to Lys280 in the phenylalanine hydroxylase (PAH) gene of a phenylketonuria (PKU) patient in Denmark. The mutation is associated with haplotype 1 of the PAH gene in this population. This mutation has previously been found in North Africa, where it is in linkage disequilibrium with haplotype 38. While it is conceivable that this mutation could have been transferred from one haplotype background to another by a double crossover or gene conversion event, the fact that the mutation is exclusively associated with the two different haplotypes in the two distinct populations supports the hypothesis that these two PKU alleles are the result of recurrent mutations in the human PAH gene. Furthermore, since the site of mutation involves a CpG dinucleotide, they may represent hot spots for mutation in the human PAH locus.

Alleles↗
PubMed1990

Recurrent mutation of immunoglobulin and c-myc genes and differential expression of cell surface antigens occur in variant cell lines derived from a Burkitt lymphoma.

The phenotypic and molecular genetic characteristics of 4 variant sublines of the Burkitt lymphoma cell line Namalwa have been examined. The sublines are DNA-fingerprint-identical and derived from a monoclonal tumour, as shown by a rearrangement of the T-cell-receptor beta-chain gene common to the 4 sublines. There is non-co-ordinate expression of MHC class-I MHC class-II, surface immunoglobulin and a number of antigens recognized by CD MAbs on the different sublines. These different phenotypes of the cells are reminiscent of B cells arrested in varying states of cellular maturity. On Southern blots there are different patterns of restriction fragments hybridizing with Ig heavy- and light-chain gene probes among the sublines, indicating that multiple rearrangements or mutations of Ig genes have occurred in the cells. Different patterns of hybridizing fragments among the sublines were also found by using c-myc probes, implying the existence of different mutations of the c-myc locus. The c-myc mutation found in one of the sublines mapped to the 5' flanking sequence and in another 3' to the c-myc locus. Using the J17BS8 probe, which detects a restriction fragment length polymorphism in the 3' flanking region of the c-myc gene, a 4-fold variation in the gene copy number among the subline was found and one of the sublines was shown to be hemizygous for c-myc. Examination of DNA from early cultures of Namalwa cells showed that the alternations in Ig and c-myc structure had occurred on prolonged culture of the cells.

Antibodies, Monoclonal↗
PubMed1991

Recurrent mutation at aa 792 in the LDL receptor gene in a French patient.

Many mutations in the low density lipoprotein receptor gene (LDLR) have been characterized at the molecular level in individuals with familial hypercholesterolemia. Most of the mutations that have been reported are large deletions or insertions in the gene, it being much more difficult to identify point mutations. In this study, 139 unrelated French familial hypercholesterolemia subjects were screened for the presence of three different previously described LDLR point mutations, employing the polymerase chain reaction and allele-specific oligonucleotide hybridization. Only one subject carried a point mutation at amino acid position 792, which substituted a Trp codon for a Stop codon. The same mutation has previously been described in a subject originating from Saudi Arabia. Haplotype analysis of LDLR associated with each mutation was performed. The haplotypes were totally different, suggesting that this mutation has occurred more than once.

Base Sequence↗
PubMed1985

Recurrent mutation pressure does not explain the prevalence of the marker (X) syndrome.

In order to test the hypothesis that the high prevalence of the mar(X) syndrome is caused by a high mutation rate in male germ cells only, the fraction of new mutants among mothers of probands in 112 informative families has been examined by segregation analysis among their brothers and sisters. The estimated fraction of new mutants among these mothers is much lower than expected if a stable equilibrium existed between an unusually high mutation rate and a selective disadvantage of mentally retarded, male and female mar(X) carriers. Hence, the above-mentioned hypothesis could not be confirmed.

Female↗
PubMedDate not supplied

Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots.

Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations. The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.

Base Composition↗
PubMed1992

Immunologic memory to phosphocholine keyhole limpet hemocyanin. Recurrent mutations in the lambda 1 light chain increase affinity for antigen.

Anti-phosphocholine (PC)-keyhole limpet hemacyanin hybridomas representative of a memory response that express the lambda 1 L chain isotype have a high reactivity to PC-protein. A common feature of these hybridomas possessing high affinity for PC-protein is the occurrence of somatic mutations resulting in replacement changes in three CDR2 positions of the lambda 1 L chain. The influence of each of these three positions on the Ag binding properties of these antibodies was examined by site-specific mutagenesis and expression of recombinant antibody molecules by transfected cells. Affinity measurements and fine specificity profile determinations demonstrated the importance of the three lambda 1 CDR2 positions in Ag binding. Compared to antibodies expressing germline lambda 1, including one with an additional junctional serine that is not encoded by V or J, those antibodies possessing critical changes in CDR2 would have a strong selective advantage based on affinity differences for Ag. Sequence analysis of a group of clonally related hybridomas expressing mutated lambda 1 genes allowed construction of a hypothetical genealogic tree that suggests selection based on changes in CDR2 of lambda 1 in the absence of H chain mutations. The results are consistent with stepwise acquisition of mutations and selection based on affinity constraints.

Animals↗
PubMed1991

Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen.

Most individuals with osteogenesis imperfecta (OI) are heterozygous for dominant mutations in one of the genes that encode the chains of type I collagen. Each of the more than 30 mutations characterized to date has been unique to the affected member(s) of the family. We have determined that two individuals with a progressive deforming variety of OI, OI type III, have the same new dominant mutation [alpha 1(I)gly154 to arg] and that two unrelated infants with perinatal lethal OI, OI type II, share a second new dominant mutation [alpha 1(I)gly1003 to ser]. These mutations occurred at CpG dinucleotides, in a manner consistent with deamination of a methylated cytosine residue, and raise the possibility that CpG dinucleotides are common sites of recurrent mutations in collagen genes. Further, these findings confirm that the OI type-III phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene of type-I collagen.

Adult↗
PubMed2026

TERT promoter mutations and recurrence patterns in differentiated thyroid carcinoma.

Telomerase reverse transcriptase promoter mutations (TERT) are known prognostic factors associated with poor outcomes in differentiated thyroid carcinoma (DTC). We analyzed differences in DTC recurrence patterns over time according to TERT. A retrospective review was conducted on DTC patients who achieved remission after total thyroidectomy and/or radioactive iodine treatment at Samsung Medical Center between 1994 and 2004. The sites and patterns by time of recurrence in the patients were reviewed. In total, 367 patients with a median follow-up of 14 years (interquartile range, 12-17 years) were included. Recurrence occurred in 91 patients, wherein 56 had lymph node recurrence and 35 had either local or distant recurrence. TE RT and tumor size <2 cm were independent factors for recurrence in the Cox proportional hazards analysis. In cases of TERT-wild type (WT), the recurrence rate decreased significantly over time after diagnosis, whereas in TERT-mutant type (MT), a consistently high recurrence rate was observed. In the Kaplan-Meier analysis, TERT-MT exhibited a significantly poorer disease-free survival, with continuous recurrence over time, whereas in TERT-WT, the curve showed a gradual decline. Further analysis of the overall survival among the 91 patients revealed that TERT-MT was significantly associated with a higher risk of mortality, whereas TERT-WT exhibited a slowly decreasing curve. In conclusion, TERT-MT was a significant adverse prognostic factor wherein continuous recurrence necessitates long-term follow-up. For TERT-WT, the recurrence rate decreased compared to TERT-MT, and even in cases of recurrence, the treatment outcomes are favorable.

Humans↗