Nature Genetics
36, 877 - 882 (2004)
Published online: 4 July 2004; | doi:10.1038/ng1389
Essential role of limiting telomeres in the pathogenesis of Werner syndromeSandy Chang1, Asha S Multani1, Noelia G Cabrera1, Maria L Naylor2, Purnima Laud1, David Lombard3, Sen Pathak1, Leonard Guarente4
& Ronald A DePinho21
Department of Molecular Genetics, M.D. Anderson Cancer Center, Box 11, 1515 Holcombe Blvd., Houston, Texas 77030, USA. 2
Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of Medicine and Genetics, Harvard Medical School, 44 Binney Street (M413), Boston, Massachusetts 02115, USA. 3
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. 4
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Correspondence should be addressed to Sandy Chang schang@mdanderson.org or Ronald A DePinho ron_depinho@dfci.harvard.eduMutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence1,
2. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome3 and the lack of a disease phenotype in Wrn-deficient mice with long telomeres4 implicate telomere attrition in the pathogenesis of Werner syndrome. Here, we show that the varied and complex cellular phenotypes of Werner syndrome are precipitated by exhaustion of telomere reserves in mice. In late-generation mice null with respect to both Wrn and Terc (encoding the telomerase RNA component), telomere dysfunction elicits a classical Werner-like premature aging syndrome typified by premature death, hair graying, alopecia, osteoporosis, type II diabetes and cataracts. This mouse model also showed accelerated replicative senescence and accumulation of DNA-damage foci in cultured cells, as well as increased chromosomal instability and cancer, particularly nonepithelial malignancies typical of Werner syndrome. These genetic data indicate that the delayed manifestation of the complex pleiotropic of Wrn deficiency relates to telomere shortening.
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