Essential role of limiting telomeres in the pathogenesis of Werner syndrome.
Mutational inactivation of the gene WRN causes Werner syndrome, an autosomal recessive disease characterized by premature aging, elevated genomic instability and increased cancer incidence. The capacity of enforced telomerase expression to rescue premature senescence of cultured cells from individuals with Werner syndrome and the lack of a disease phenotype in Wrn-deficient mice with long telomeres 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.
Chang
Sandy
S
Department of Molecular Genetics, M.D. Anderson Cancer Center, Box 11, 1515 Holcombe Blvd., Houston, Texas 77030, USA. schang@mdanderson.org
Multani
Asha S
AS
Cabrera
Noelia G
NG
Naylor
Maria L
ML
Laud
Purnima
P
Lombard
David
D
Pathak
Sen
S
Guarente
Leonard
L
DePinho
Ronald A
RA
D019588:Aging, Premature / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence; D043171:Chromosomal Instability; D004249:DNA Damage; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D008017:Life Expectancy; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000235:genetics; D016615:Telomere / Q000473:pathology / Q000502:physiology*; D014898:Werner Syndrome / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics