Homozygosity mapping of the Werner syndrome locus (WRN)
Department of Geriatric Medicine, Osaka University Medical School, Japan. Genomics
(Impact Factor: 2.28).
Werner syndrome (WS) is an autosomal recessive disorder characterized by the early onset of several age-related diseases. The locus for this disease was recently mapped to 8p12. We studied 27 WS kindreds of mixed ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of "definite" WS and affected subjects in the remaining 3 pedigrees were given the diagnosis of "probable" WS. Affected subjects from each kindred were genotyped for 13 short tandem repeat polymorphic sites. Two-point linkage analysis yielded significant evidence for linkage to D8S137, D8S339, D8S87, PLAT, D8S165, and D8S166. The locus yielding a maximum lod score at the smallest recombination fraction was D8S339, suggesting that this marker is the closest to the WS gene (WRN locus) of those tested. D8S339 gave significant lod scores (Zmax > or = 3.0) for both Japanese and non-Japanese (mostly Caucasian) families, demonstrating that a single locus is responsible for WS in both groups. Multipoint analysis of these markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. The combined evidence from 2-point analysis, multipoint analysis, and analysis of regions of homozygosity in subjects from inbred pedigrees indicates that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339.
Available from: Junko Oshima
- "We report on three pedigrees of WS of Indian/Pakistani origin. The clinical findings of the affected patients meet the clinical criteria for a definite (VELO1010) or probable (KERA1010 and YOSI1010) diagnosis of WS (Nakura et al. 1994; Yu et al. 1996; Oshima et al. 2012). The first patient from Kerala and the second patient, originally from Pakistan, shared the same mutation and same haplotype, which was distinct from the third case from Tamil Nadu. "
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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
Available from: Kevin B Jones
- "Werner syndrome (WS), also known as adult progeria, is a rare autosomal recessive condition characterized by premature aging, short stature, bilateral cataracts, and distinctive skin changes . The condition is overrepresented in Japan, presumably due to a founder effect similar to RAPADILINO syndrome. "
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ABSTRACT: Osteosarcoma is the most common primary malignancy of bone. Most cases are sporadic without a known genetic or environmental cause. Heritable genetic predisposition syndromes are associated with a small percentage of osteosarcomas. Study of these rare disorders has provided insight into the molecular pathogenesis of osteosarcoma. Screening of at-risk families and surveillance of affected individuals for these syndromes may permit earlier diagnosis and more effective treatment of osteosarcoma in these populations. This paper reviews the genetic and clinical features of the known osteosarcoma predisposition syndromes.
Sarcoma 03/2012; 2012(4):152382. DOI:10.1155/2012/152382
Available from: Martin Poot
- "Referrals were based upon the clinical interpretations of referring physicians and guided by published descriptions of the characteristic signs and symptoms, including a set of criteria developed for the research project that led to the positional cloning of the WRN locus (Nakura et al. 1994; Yu et al. 1996). These clinical criteria have been recently reviewed (Leistritz et al. 2007; Nakura et al. 1994). The study has ongoing approval from the University of Washington Institutional Review Board. "
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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 · 4.82 Impact Factor
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