Werner's Syndrome (WS) is a rare autosomal recessive disorder which resembles premature aging and may provide an important model of senescence in humans. WS results in the early development of diabetes, cataracts, atherosclerosis, neoplasms and osteoporosis. ThUs, the discovery of the gene for WS may provide important insights into the mechanism of the most common diseases associated with aging. Fibroblasts from WS patients demonstrate a markedly reduced replicative lifespan and growth rate compared to fibroblasts from age matched controls. Replicative potential normally declines in an age-related fashion, and the growth rate of fibroblasts in culture from normal elderly subjects closely resembles that of young WS patients. We hypothesize that a mutation in the WS gene on chromosome 8 results in the pathology observed in Werner's syndrome. The experiments described in this project are designed to identify and characterize the WS gene. Based on the now substantial number of disease genes which have been recently identified by a positional cloning strategy, the overall approach of this proposal is positional cloning in order to identify a pool of candidate genes from the region, followed by analysis of the candidate genes in order to isolate the causative mutation. The studies in this research project will use novel, powerful methods such as cDNA selection for the identification of expressed sequences, and single stranded conformational polymorphism analysis for mutation detection. The broad, long term objective of this proposal is to investigate the functional aspects of the Werner's syndrome gene mutation possibly by complementation assay or studies in knockout mice. These studies may offer new insights into the critical regulatory steps of aging at the cellular level.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Physician Scientist Award (K11)
Project #
5K11AG000671-04
Application #
6029716
Study Section
Special Emphasis Panel (ZAG1-BJB-9 (55))
Program Officer
Finkelstein, David B
Project Start
1995-07-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hisama, F M; Gruen, J R; Choi, J et al. (2001) Human GABA(B) receptor 1 gene: eight novel sequence variants. Hum Mutat 17:349-50
Hisama, F M; Chen, Y H; Meyn, M S et al. (2000) WRN or telomerase constructs reverse 4-nitroquinoline 1-oxide sensitivity in transformed Werner syndrome fibroblasts. Cancer Res 60:2372-6
Hisama, F M; Oshima, J; Yu, C E et al. (1998) Comparison of methods for identifying transcription units and transcription map of the Werner syndrome gene region. Genomics 52:352-7
Hisama, F M; Reyes-Mugica, M; Wargowski, D S et al. (1998) Renal tubular dysgenesis, absent nipples, and multiple malformations in three brothers: a new, lethal syndrome. Am J Med Genet 80:335-42