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At least 73 records · Page 4Linked to original sources
PubMed2003

A recurrent mutation in the ARS (component B) gene encoding SLURP-1 in Turkish families with mal de Meleda: evidence of a founder effect.

Mal de Meleda is a rare form of palmoplantar keratoderma, and recently mutations in the ARS (component) B gene have been identified in families with this disease. We identified a recurrent nonsense mutation, R96X, in four families of Turkish descent. In this report, we demonstrate that these families share a common ancestral haplotype at the mal de Meleda locus, suggesting a founder effect.

Antigens, Ly↗
PubMed2001

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.

Adolescent↗
PubMed1997

Convenient, nonradioactive, heteroduplex-based methods for identifying recurrent mutations in the BRCA1 and BRCA2 genes.

The ability to identify individuals who are predisposed to specific malignant tumors is a promising molecular diagnostic by-product of over two decades of intensive research into the genetic pathogenesis of human cancer. Approximately 2% of Ashkenazi Jews carry recurrent germline mutations in either the BRCA1 or BRCA2 genes that may predispose these individuals to the development of breast and ovarian cancer. We have developed a nonisotopic method, based on the formation of heteroduplexes between polymerase chain reaction (PCR) amplified wild-type and mutant alleles, which can be used to identify the BRCA1 185delAG and the BRCA2 6174delT mutations. The same assay can also be used to verify the loss of heterozygosity in a tumor sample arising in an individual with a germline mutation. The four steps described in this report (PCR amplification, heteroduplex formation, acrylamide gel electrophoresis, and ethidium bromide staining/UV-fluorescence photography) can be readily and reproducibly performed in the course of a single day, making this a useful method for the routine identification of these mutations.

Alleles↗
PubMed2002

A recurrent mutation in the loricrin gene underlies the ichthyotic variant of Vohwinkel syndrome.

Vohwinkel syndrome (VS) is a family of genodermatoses which exhibits extensive clinical and genetic heterogeneity. Here, we studied a pedigree originating from the UK with typical features of the ichthyotic variant of VS and identified a recurrent insertion mutation in the loricrin gene resulting in a mutant polypeptide with an unusual C terminus. Functional studies in transgenic mice have shown that the accumulation of mutant loricrin in the nucleus appears to interfere with the later stages of epidermal differentiation, thereby explaining the clinical manifestations of ichthyosis, keratoderma and pseudoainhum. Our findings extend the body of evidence implicating mutations in the loricrin gene as the underlying cause of VS.

Female↗
PubMed2002

Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.

Paget disease of bone (PDB) is a common disorder characterized by focal and disorganized increases of bone turnover. Genetic factors are important in the pathogenesis of PDB. We and others recently mapped the third locus associated with the disorder, PDB3, at 5q35-qter. In the present study, by use of 24 French Canadian families and 112 unrelated subjects with PDB, the PDB3 locus was confined to approximately 300 kb. Within this interval, two disease-related haplotype signatures were observed in 11 families and 18 unrelated patients. This region encoded the ubiquitin-binding protein sequestosome 1 (SQSTM1/p62), which is a candidate gene for PDB because of its association with the NF-kappaB pathway. Screening SQSTM1/p62 for mutations led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394-440) of the protein that was not present in 291 control individuals. Our data demonstrate that two independent mutational events at the same position in SQSTM1/p62 caused PDB in a high proportion of French Canadian patients.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain.

A frame-shift 9254del5 mutation was independently identified in 12 families, eleven of them with Spanish ancestors, in a BRCA2 screening performed in 841 breast and/or ovarian cancer families and in 339 women with breast cancer diagnosed before the age of 40 at different centers in France and Spain. We sought to analyze in detail the haplotype and founder effects of the 9254del5 and to estimate the time of origin of the mutation. Eight polymorphic microsatellite markers and two BRCA2 polymorphisms were used for the haplotype analyses. The markers were located flanking the BRCA2 gene spanning a region of 6.1 cM. Our results suggest that these families shared a common ancestry with BRCA2 9254del5, which is a founder mutation originating in the Northeast Spanish, with an estimated age of 92 (95% CI 56-141) generations.

Adult↗
PubMed2000

Mutation analysis of the 5' noncoding regulatory region of the BCL-6 gene in non-Hodgkin lymphoma: evidence for recurrent mutations and intraclonal heterogeneity.

The BCL-6 proto-oncogene is involved in the genesis of non-Hodgkin lymphoma (NHL). Rearrangements due to chromosomal translocations and somatic mutations of the 5' noncoding regulatory region of the BCL-6 gene are potential mechanisms for altering its expression in NHL. To further elucidate the nature of the somatic mutations in the regulatory region of this gene, we have studied 10 healthy donors and 11 NHL biopsy samples by extensive molecular cloning and sequencing. In addition, we analyzed the BCL-6 genes of tumor and nontumor cells from 2 of the cases. The germ line sequence of this region was defined, which differs in 7 positions from that previously reported. In addition, 1 polymorphic variation at position 397(G or C) was identified. Deletions, insertions, and repeated substitution mutations were detected among the molecular isolates in 8 tumor specimens, with a mutational incidence ranging from 1.3 x 10(-3) to 1.3 x 10(-2)/bp (base pair). A total of 20 distinct substitution mutations, 1 insertion and 3 deletions were observed. One of these deletion mutations and 2 of the substitutions were observed in more than 1 tumor specimen from different individuals. In 3 tumor samples, identical mutations affecting both alleles were observed. These findings suggest the presence of mutational hot spots and hot specific events, a finding supported by our compilation of previously published data. In 6 samples, the nucleotide sequences showed evidence of intraclonal heterogeneity, consistent with a stepwise ongoing mutational process affecting the BCL-6 gene in the tumor cells. These mutations accumulating in the regulatory region of the BCL-6 gene could play a role in lymphoma progression and in the transformation of follicular lymphomas to more aggressive large cell lymphomas. (Blood. 2000;95:1400-1405)

Base Sequence↗
PubMed2004

X-linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families.

X-linked spondyloepiphyseal dysplasia tarda is a skeletal dysplasia mainly affecting the vertebrae and epiphyses and commonly associated with the early development of degenerative joint disease. Radiographically the disorder is characterized by a typical hump-shaped deformity of the vertebral bodies. SEDT is caused by mutations in SEDL located on Xp22.12-p22.31. To further elucidate the spectrum of underlying variations we performed a screening of all 6 exons of SEDL within 13 European SEDT families and identified 6 new (c.99delC, c.183_184delGA, c.236-5_236-8delATTA, c.325delT, c.345_346delTG, c.94-?_423+?del) and 9 previously reported mutations (c.1-?_93+?del, c.93+5G>A, c.157_158delAT, c.210G>A, c.236-9_236-12delTTAA, c.267_275delAAGAC, c.324-4_324-10delTCTTTCCinsAA). The recurrent splice site alteration c.93+5G>A (formerly described as IVS3+5G>A) was detected in 3 unrelated families. Two patients were carrying 2 changes in the allele. In one case, a novel variation in exon 4 (c.99delC) was associated with several nucleotide deletions in intron 4 (c.236-5_236-8delATTA), and in the second case we identified a previously reported transition c.210G>A and a novel deletion in exon 6 (c.325delT). All sequence variations identified are either deletions of complete exons or predicted to result in a premature stop codon or to lead into splicing defects and are associated with a loss of considerable parts of the sedlin protein.

Chromosomes, Human, X↗
PubMed2006

CpG methylation accounts for a recurrent mutation (c.1222C>T) in the human PAH gene.

The human PAH gene (GenBank: U49897.1 (cDNA), AF404777 (gDNA)) harbors alleles that either cause or are associated with hyperphenylalaninemia and phenylketonuria (http://www.pahdb.mcgill.ca). Mutation analysis has identified approximately 500 alleles of which approximately 30 produce polymorphic core haplotypes. The c.1222C>T allele (p.R408W) is the most prevalent and widely encountered PKU-causing allele. Because it occurs on multiple locus-specific polymorphic haplotypes, it is probably not identical by descent in different populations. This mutation involves a CpG dinucleotide in a so-called "hypermutable" codon suggesting that c.1222C>T could be a recurrent allele following spontaneous methylation-mediated deamination of 5 mC. This concept is widely assumed and accepted but the 5mC status of hypermutable codons has seldom been confirmed. We show that the PAH c.1222C nucleotide is indeed methylated (c.1222 mC) in somatic genomes (leukocyte and brain) of H. sapiens. Examination of a representative region in exon 12 (and also in exon 7) in the PAH gene shows that 5 mC is restricted to cytosines in CpG dinucleotides in the hypermutable codons. The methylation pattern seen in human PAH exon 12 was also observed in the corresponding codon in three nonhuman primates. The finding offers at least one explanation for the high relative frequency of the c.1222C>T (p.R408W) allele in the human population.

Alleles↗
PubMed1993

Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations.

The investigation of 114 unrelated patients, representing about half the sample of the German haemophilia B population, enabled us to delineate the causative mutation in 103 (90.4%) haemophilic factor IX genes. Of these 103 cases 84 (81.6%) turned out to be unique molecular events, the remainder being repeats. Haplotype analysis revealed that the great majority, if not all, of these recurrent observations occurred independently. This conclusion is supported by our finding that three de novo mutations could be demonstrated at two sites of frequent mutation. A further 20 de novo events could be established in an unselected sample of 37 families with sporadic haemophilia B and 37 families with a history of the disease. Altogether, the germ line of origin could be determined in 21 of these 23 cases, thereby indicating a ratio of male to female mutation rates close to 2. On the basis of the data available, it is becoming clear that rearrangements in the factor IX gene (35.4% of de novo cases) are responsible for haemophilia B at a higher frequency than has been observed today (12.3%). More than two-thirds of the de novo cases cause the severe form of the disease, thereby reflecting the deficit of these haemophilic genes in the actual gene pool because of excess mortality in the past. In addition 40% (12/30) of the de novo single-base mutations were transitions at CpG dinucleotides. Compared with the expected at-random frequency, this observation indicates an 83-fold enhancement of mutation at CpG.

DNA Mutational Analysis↗
PubMed2004

Differences in recurrent COL7A1 mutations in dystrophic epidermolysis bullosa: ethnic-specific and worldwide recurrent mutations.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the gene encoding type VII collagen (COL7A1). Although most COL7A1 mutations are unique to individual families, small numbers of mutations are recurrent. The recurrent mutations R578X, 7786delG, and R2814X seem to be exclusive to a specific ethnic group, the British population. The mutations 5818delC, 6573+1G-->C, and E2857X are present only in individuals of Japanese ethnic origin. On the other hand, the mutations 425A-->G and G2043R have been found in several different ethnic groups. The purpose of this study was to clarify whether these recurrent mutations are also found in patients of other ethnic groups with DEB, mainly Asian patients. We demonstrated the absence of the recurrent mutations R578X, 7786delG, and R2814X in 42 non-British patients with DEB and detected the mutations 425A-->G in a French patient and G2043R in Japanese and Chinese patients with DEB. The mutations 5818delC, 6573+1G-->C, and E2857X were detected in 11 Japanese patients (13 alleles) with DEB. Our results confirm that R578X, 7786delG, and R2814X mutations are specifically limited to British patients, and the mutations 5818delC, 6573+1G-->C, and E2857X are frequent in Japanese patients. On the other hand, the mutations 425A-->G and G2043R can be found in different ethnic groups. In conclusion, our results further support the notion that recurrent mutations can be classified into two types, ethnic-specific mutation and worldwide mutation.

Alanine↗