Mutation and haplotype analyses of the Werner's syndrome gene based on its genomic structure: genetic epidemiology in the Japanese population

Abstract

The correlation between mutations in the Werner's syndrome (WRN) gene and the haplotypes of surrounding markers was studied in Japanese patients. We have elucidated the genomic structure of WRN helicase, and found five additional mutations, designated mutations 6-10. Mutations 4 and 6 were found to be the two major mutations in this population; these mutations comprised 50.8% and 17.5%, respectively, of the total in a sample of 126 apparently unrelated chromosomes. Almost all the patients homozygous for mutation 4 shared a haplotype around the WRN gene, consistent with the view that they are derived from a single ancestor. This important advantage demonstrated in the identification of the WRN gene suggests that the Japanese present a unique population for the cloning of other disease genes. The conserved haplotype was observed across 19 loci, extending a distance estimated to be more than 1.4 Mbp around the WRN gene. This haplotype is rare among random Japanese individuals. Unexpectedly, all the nine patients homozygous for mutation 6 shared a haplotype that was identical to this haplotype at 18 of these 19 markers. These results suggest that mutations 4 and 6 arose independently in almost identical rare haplotypes. The remaining mutations (1, 5, 7, 8, 9, and 10) occurred rarely, and were each associated with different haplotypes.

Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein – Barr virus

“…Recently, Yu et al (1996) identi®ed a gene mutated in WRN patients that encodes a protein signi®cantly similar to RecQ-type DNA helicases. They described 15 mutations, and we found four additional mutations in this gene Matsumoto et al, 1997;Oshima et al, 1996;Yu et al, 1996). At least 83% of chromosomes of WRN patients had one of these mutations, while the remaining 17% of chromosomes were considered to have unrecognized mutations.…”

“…Third, hypermutable ligation of plasmid DNA ends has been reported in these cell strains of patients (Runger et al, 1994). Fourth, the WRN gene was shown to be expressed in these cell strains as shown by Northern blot and RT ± PCR analyses Matsumoto et al, 1997). We lack, however, some fundamental knowledge about EBV-transformed B-lymphoblastoid cell strains to use them to investigate the molecular mechanisms of WRN pathogenesis: for example, whether the Blymphoblastoid cell strains are mortal or immortal is unknown.…”

WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex

“…Primary cultures of ®broblasts (A/WS10801 and A/WS15501) taken from the subcutaneous tissue of WS patients has been previously described (Matsumoto et al, 1997a). The WRN mutation in WS patients is the homozygous g to c base substitution at the splice donor site of exon 26, which results in the skipping of this exon (Yu et al, 1996).…”

Hyperinsulinemia and insulin resistance in Wrn null mice fed a diabetogenic diet

“…Heterozygous carriers of single mutant Wrn alleles appear to be present in the United States at a frequency range of 1:250 Matsumoto et al, 1997). In addition, single nucleotide polymorphisms occurring in the Wrn gene product have been reported to be associated with increased incidence of diabetes (Hirai et al, 2005).…”