The Werner syndrome (WS) ('Progeria of the Adult') is a rare autosomal recessive progeriod disorder. WS patients show a general appearance of premature aging, and exhibit premature onset of disorders commonly seen in the aged population including, bilateral ocular cataracts, type 2 diabetes mellitus, arteriosclerosis and osteoporosis. While they are susceptible to many neoplasms, these include a disproportionate number of cancers of mesenchymal origin and relatively rare neoplasms. Somatic cells from WS patients exhibit accelerated replicative senescence and a mutator phenotype. The Werner syndrome gene (WRN) has recently been shown to encode a helicase homologous to the RecQ of E. coli. Initially, four distinct mutations in the WRN gene were found in Japanese and Caucasian WS patients. Subsequently, more than a dozen different mutations have been identified. In this proposal, animal models of WS by targeted mutagenesis of the murine homolouge of WRN will be created. The goal is to create models of two naturally occurring human mutations, including the common Japanese exonic deletion. Life table parameters and anatomical pathology data, with emphasis upon analysis of the frequencies and the spectrum of neoplasms, will be obtained throughout the lifespan of C57B1/6 transgenic control mice. Primary cultures of somatic cells isolated from the transgenic mice will be used to determine replicative lifespan, WRN helicase activity levels and mutation frequencies at the HPRT locus. The long term goal is to elucidate the pathogenesis of WS and the role of WRN helicase in normal aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Molecular Cytology Study Section (CTY)
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Mccormick, Anna M
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University of Washington
Schools of Medicine
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Chen, Lishan; Huang, Shurong; Lee, Lin et al. (2003) WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair. Aging Cell 2:191-9
Oshima, Junko; Huang, Shurong; Pae, Chong et al. (2002) Lack of WRN results in extensive deletion at nonhomologous joining ends. Cancer Res 62:547-51
Choi, D; Whittier, P S; Oshima, J et al. (2001) Telomerase expression prevents replicative senescence but does not fully reset mRNA expression patterns in Werner syndrome cell strains. FASEB J 15:1014-20
Wang, L; Ogburn, C E; Ware, C B et al. (2000) Cellular Werner phenotypes in mice expressing a putative dominant-negative human WRN gene. Genetics 154:357-62
Castro, E; Edland, S D; Lee, L et al. (2000) Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. Am J Med Genet 95:374-80
Oshima, J (2000) Comparative aspects of the Werner syndrome gene. In Vivo 14:165-72
Balajee, A S; Machwe, A; May, A et al. (1999) The Werner syndrome protein is involved in RNA polymerase II transcription. Mol Biol Cell 10:2655-68
Wang, L; Evans, A E; Ogburn, C E et al. (1999) Werner helicase expression in human fetal and adult aortas. Exp Gerontol 34:935-41
Martin, G M; Oshima, J; Gray, M D et al. (1999) What geriatricians should know about the Werner syndrome. J Am Geriatr Soc 47:1136-44
Castro, E; Ogburn, C E; Hunt, K E et al. (1999) Polymorphisms at the Werner locus: I. Newly identified polymorphisms, ethnic variability of 1367Cys/Arg, and its stability in a population of Finnish centenarians. Am J Med Genet 82:399-403

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