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

AGENE Research Institute, Kanagawa, Japan.
Human Genetics (Impact Factor: 4.52). 08/1997; 100(1):123-30. DOI: 10.1007/s004390050477
Source: PubMed

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.

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    • "To date, more than 70 different WRN mutations have been identified (Matsumoto et al. 1997; Huang et al. 2006; Uhrhammer et al. 2006; Friedrich et al. 2010; Takada-Watanabe et al. 2012). The majority of diseasecausing mutations result in either a premature stop codon, a small indel, or splice site mutations that result in the non-sense mediated decay of mutant mRNA, and/ or deletion of the nuclear localization signals (Suzuki et al. 2001). "
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    ABSTRACT: Werner syndrome is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the WRN gene, which encodes a RecQ type helicase. To date, more than 70 disease-causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here we report two novel WRN mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.K187K), it creates a cryptic splice site resulting in a 98bp deletion at the mRNA level (r.557-654del98) followed by a frameshift (p.K187fs). These two cases shared the same haplotype across the WRN gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C>A (p.S952*) in exon 24. As the Indian population increases and the awareness of Werner syndrome grows, we anticipate that more cases will be identified with these founder mutations among South Asian Werner syndrome patients.
    05/2013; 1(1):7-14. DOI:10.1002/mgg3.1
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    • "Mutations thought to be speciWc for various ethnic-geographic groups Exon 26 deletions due to a splice site mutation, c.3139- 1G>C, in intron 25, have been widely reported in Japanese WS patients (Goto et al. 1997; Matsumoto et al. 1997; Satoh et al. 1999). These are regarded as reXecting a founder mutation. "
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    ABSTRACT: Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.
    Human Genetics 07/2010; 128(1):103-11. DOI:10.1007/s00439-010-0832-5 · 4.52 Impact Factor
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    • "Our study supports an independent role for Wrn in the modulation of weight gain and insulin resistance associated with obesity, and suggests that alleles at loci coding for Wrn should be included in the list of candidate genes determining susceptibility to diabetes. Heterozygous carriers of single mutant Wrn alleles appear to be present in the United States at a frequency range of 1:250 (Goto et al., 1997; 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). "
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    ABSTRACT: Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by mutations in the Werner (Wrn) gene. WS patients have increased incidence of a number of chronic conditions including insulin resistance and type 2 diabetes. Since ingestion of foods that are high in fat and sugar is associated with increased incidence of diabetes, we examined if Wrn mutations might affect metabolic response to a diabetogenic diet. Four-month-old mice with a null mutation for the Wrn gene were fed a diet consisting of 36% fat (lard), 33% table sugar, and 20% protein plus balanced vitamins and minerals. Wrn null mice had significantly increased body weights, increased serum insulin levels, impaired glucose tolerance, and insulin resistance during 4 months of eating the diabetogenic diet. Diffuse fatty infiltration of the liver and pancreatic islet hyperplasia was characteristic morphological features. These observations suggest that Wrn null mice have impaired glucose homeostasis and fat metabolism, and may be a useful model to investigate metabolic conditions associated with aging.
    Mechanisms of Ageing and Development 05/2008; 129(4):201-6. DOI:10.1016/j.mad.2007.12.009 · 3.51 Impact Factor
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