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Results for “Recurrent mutation”

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At least 163 records · Page 9Linked to original sources
PubMed1996

Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome.

Alport syndrome is a mainly X-linked hereditary disease of basement membranes that is characterized by progressive renal failure, deafness, and ocular lesions. It is associated with mutations of the COL4A5 gene located at Xq22 and encoding the alpha5 chain of type IV collagen. We have screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and have identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients. This represents a mutation-detection rate of 50%. There were no hot-spot mutations and no recurrent mutations in our population. The identified mutations were 6 nonsense mutations, 12 frameshift mutations, 17 splice-site mutations, and 29 missense mutations, 27 of the latter being glycine substitutions in the collagenous domain. Two of these occurred on the same allele in one patient and segregated with the disease in the family. We showed that some of the glycine substitutions could be associated with the lack of immunological expression of the alpha3(IV)-alpha5(IV) collagen chains in the glomerular basement membrane.

Adolescent↗
PubMedDate not supplied

Unique and recurrent WAS gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia.

Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are allelic phenotypes caused by defects of the WAS gene. Fourteen distinct mutations including seven novel gene defects in 16 WAS and four XLT patients were identified by single strand conformation polymorphism analysis and DNA sequencing of the WAS gene. Eleven (79%) of these mutations are located within exons 1 to 4 with clustering in exon 2. Carrier detection in 33 at-risk females and prenatal diagnosis at 12 weeks gestation in one family with a novel WAS mutation was performed by direct mutation analysis. A remarkably high frequency (72%) of point mutations involved CpG dinucleotides. C-->T or G-->A transitions at CpG sites were identified in all isolated WAS cases (n = 7). Allele frequencies for the dinucleotide repeat at locus DXS6940 were determined in Northern European, African and Asian populations. Mutation screening alone or in combination with analysis of polymorphic loci DXS6940 and DXS255 delineated the germline origin of a unique insertion mutation and four recurrent CpG mutations, three of which arose spontaneously during maternal gametogenesis.

Asian People↗
PubMed2003

Patterns and relative rates of nucleotide and insertion/deletion evolution at six chloroplast intergenic regions in new world species of the Lecythidaceae.

Insertions and deletions (indels) in chloroplast noncoding regions are common genetic markers to estimate population structure and gene flow, although relatively little is known about indel evolution among recently diverged lineages such as within plant families. Because indel events tend to occur nonrandomly along DNA sequences, recurrent mutations may generate homoplasy for indel haplotypes. This is a potential problem for population studies, because indel haplotypes may be shared among populations after recurrent mutation as well as gene flow. Furthermore, indel haplotypes may differ in fitness and therefore be subject to natural selection detectable as rate heterogeneity among lineages. Such selection could contribute to the spatial patterning of cpDNA haplotypes, greatly complicating the interpretation of cpDNA population structure. This study examined both nucleotide and indel cpDNA variation and divergence at six noncoding regions (psbB-psbH, atpB-rbcL, trnL-trnH, rpl20-5'rps12, trnS-trnG, and trnH-psbA) in 16 individuals from eight species in the Lecythidaceae and a Sapotaceae outgroup. We described patterns of cpDNA changes, assessed the level of indel homoplasy, and tested for rate heterogeneity among lineages and regions. Although regression analysis of branch lengths suggested some degree of indel homoplasy among the most divergent lineages, there was little evidence for indel homoplasy within the Lecythidaceae. Likelihood ratio tests applied to the entire phylogenetic tree revealed a consistent pattern rejecting a molecular clock. Tajima's 1D and 2D tests revealed two taxa with consistent rate heterogeneity, one showing relatively more and one relatively fewer changes than other taxa. In general, nucleotide changes showed more evidence of rate heterogeneity than did indel changes. The rate of evolution was highly variable among the six cpDNA regions examined, with the trnS-trnG and trnH-psbA regions showing as much as 10% and 15% divergence within the Lecythidaceae. Deviations from rate homogeneity in the two taxa were constant across cpDNA regions, consistent with lineage-specific rates of evolution rather than cpDNA region-specific natural selection. There is no evidence that indels are more likely than nucleotide changes to experience homoplasy within the Lecythidaceae. These results support a neutral interpretation of cpDNA indel and nucleotide variation in population studies within species such as Corythophora alta.

Base Sequence↗
PubMed2003

Lack of association of mutations in optineurin with disease in patients with adult-onset primary open-angle glaucoma.

OBJECTIVE: To determine whether mutations in the optineurin gene contribute to susceptibility to adult-onset primary open-angle glaucoma. METHODS: The optineurin gene was screened in 86 probands with adult-onset primary open-angle glaucoma and in 80 age-matched control subjects. Exons 4 and 5, containing the recurrent mutations identified in patients with normal-tension glaucoma, were sequenced in all individuals studied, while the remaining exons were screened for DNA sequence variants with denaturing high-performance liquid chromatography. RESULTS: The recurrent mutation, Met98Lys, previously found to be associated with an increased risk of disease was found in 8 (9%) of 86 probands. We also found the Met98Lys mutation in 10% of individuals from a control population of similar age, sex, and ethnicity. Consistent segregation of the mutation with the disease was not demonstrated in any of the 8 families. No other DNA changes altering the amino acid structure of the protein were found. CONCLUSION: The mutations in the optineurin gene associated with normal-tension glaucoma are not associated with adult-onset primary open-angle glaucoma in this patient population. Clinical Relevance Genetic abnormalities that render the optic nerve susceptible to degeneration are excellent candidates for genetic factors that could contribute to adult-onset primary open-angle glaucoma. Mutations in optineurin have been associated with normal-tension glaucoma, but are not associated with disease in patients with adult-onset primary open-angle glaucoma. This result may indicate that normal-tension glaucoma is not necessarily part of the phenotypic spectrum of adult open-angle glaucoma.

Aged↗
PubMed2000

Nine independent F9 mutations in the Mexican hemophilia B population: nonrandom recurrences of point mutation events in the human germline.

The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.

Factor IX↗
PubMed2002

A coalescent-based method for detecting and estimating recombination from gene sequences.

Determining the amount of recombination in the genealogical history of a sample of genes is important to both evolutionary biology and medical population genetics. However, recurrent mutation can produce patterns of genetic diversity similar to those generated by recombination and can bias estimates of the population recombination rate. Hudson 2001 has suggested an approximate-likelihood method based on coalescent theory to estimate the population recombination rate, 4N(e)r, under an infinite-sites model of sequence evolution. Here we extend the method to the estimation of the recombination rate in genomes, such as those of many viruses and bacteria, where the rate of recurrent mutation is high. In addition, we develop a powerful permutation-based method for detecting recombination that is both more powerful than other permutation-based methods and robust to misspecification of the model of sequence evolution. We apply the method to sequence data from viruses, bacteria, and human mitochondrial DNA. The extremely high level of recombination detected in both HIV1 and HIV2 sequences demonstrates that recombination cannot be ignored in the analysis of viral population genetic data.

Animals↗
PubMed1998

Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families: evidence for common founders and independent mutations.

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5' region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed2000

Novel and recurrent EBP mutations in X-linked dominant chondrodysplasia punctata.

Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dysplasias characterized by stippled epiphyses. A subtype of CDP, X-linked dominant chondrodysplasia punctata (CDPX2), known also as Conradi-Hünermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. The cause of CDPX2 was unknown until recent identification of mutations in the gene encoding Delta(8),Delta(7) sterol isomerase emopamil-binding protein (EBP). Twelve different EBP mutations have been reported in 14 patients with CDPX2 or unclassified CDP, but with no evidence of correlation between phenotype and nature of the mutation. To characterize additional mutations and investigate possible phenotype-genotype correlation, we sequenced the entire EBP gene in 8 Japanese individuals with CDP; 5 of them presented with a CDPX2 phenotypes. We found EBP mutations in all 5 CDPX2 individuals, but none in non-CDPX2 individuals. Three of these CDPX2 individuals carried novel nonsense mutations in EBPand the other two, separate missense mutations that had been reported also in different ethnic groups. Our results, combined with previous information, suggest all EBP mutations that produce truncated proteins result in typical CDPX2, whereas the phenotypes resulted from missense mutations are not always typical for CDPX2. Patients with nonsense mutations showed abnormal sterol profiles consistent with a defect in Delta(8), Delta(7) sterol isomerase. X-inactivation patterns of the patients showed no skewing, an observation that supports the assumption that inactivation of the EBP gene occurs at random in affected individuals.

Adolescent↗
PubMed2002

Spontaneous mutations in the prion protein gene causing transmissible spongiform encephalopathy.

We analyzed the prion protein gene (PRNP) region in patients with transmissible spongiform encephalopathy associated with the PRNP D178N mutation. The results suggest that the D178N chromosomes had independent origins in each affected pedigree or apparently sporadic case. A de novo spontaneous PRNP mutation was observed. We provide evidence that hereditary and apparently sporadic transmissible spongiform encephalopathy cases associated with the D178N mutation result from multiple recurrent mutational events.

Adult↗
PubMed2001

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene.

Haemophilia A is a X-linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are "private", because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype-phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated.

DNA↗
PubMed2002

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene.

Haemophilia A is a X-linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are "private", because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype-phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated.

Adult↗
PubMed1990

Recurrent nonsense mutations at arginine residues cause severe hemophilia B in unrelated hemophiliacs.

Direct sequencing of the regions of the factor IX gene of likely functional significance was performed in four patients with severe hemophilia B. In two of the individuals, a transition at the dinucleotide CpG caused a nonsense mutation at arginine 333. In the other two individuals, a transition at CpG caused a nonsense mutation at arginine 29. Since these patients are all unrelated, as shown by differing alleles of the TaqI polymorphism in intron four or extensive nonoverlapping pedigrees, the mutations arose independently. In addition, the origin of one arginine 333 mutation in one family has been traced to the germline of the maternal grandfather. The frequent occurrence of mutations at arginine codons that contain the sequence CGN can be explained by the dramatic elevation of transitions at CpG. As a result, approximately one in four individuals with hemophilia B is expected to have a mutation at arginine and nonsense mutations at one of six arginine residues should be common causes of severe hemophilia.

Arginine↗
PubMed1991

Recurrent nonsense mutation in exon 7 of the phenylalanine hydroxylase gene.

A new mutation (CGA to TGA) in codon 261 of exon 7 of the phenylalanine hydroxylase gene transforms Arg261 to a stop codon in two unrelated patients of German and Turkish origin. The different ethnic backgrounds and the different polymorphic characteristics of the two mutant alleles suggest an independent origin of the mutation. This is the second defect detected in codon 261 of the phenylalanine hydroxylase gene, a codon that thus appears to be a mutation hot spot.

Arginine↗
PubMed2003

Five novel and four recurrent point mutations in the antithrombin gene causing venous thrombosis.

We analyzed the antithrombin (AT) gene in 9 unrelated Japanese patients with thrombotic disease. All 7 exons, the splice junctions, and the 5'-flanking region of the AT gene were amplified by polymerase chain reaction and sequenced directly. Nine different point mutations, all in the heterozygous state, were identified. Five novel (M-32T, M89K, L146H, Q159X, and L409P) and 2 previously reported (R132X and R359X) point mutations were identified in patients with type 1 deficiency. Two different missense mutations, R393C and R393H, located in the protease reactive site were detected in patients with type 2 deficiency. No other sequence abnormalities in the AT gene were detected by direct sequencing. None of the mutations was present in 100 alleles from 50 unrelated Japanese control subjects Although type 1 deficiency was diagnosed in patient 7 on the basis of approximately 50% AT antigen and activity levels, the data indicated that the novel L409P mutation is a type 2 pleiotropic effects (PE) deficiency because its location in the C-terminal portion of the reactive site is similar to the locations of reported PE type mutations, and it is highly conserved among other serpins.

Adolescent↗
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↗