Werner's syndrome (WS) is an autosomal dominant recessive disorder which is characterized by the premature occurrence of are-related diseases and the premature appearance of some of the physical features associated with normal aging. WS subjects develop a striking array of age-related degenerative and proliferative disorders early in life. These include some of the most significant age-related diseases of man such as arteriosclerosis, (atherosclerosis, arteriolosclerosis, medial calcinosis, heart valve calcification), a variety of benign and malignant neoplasms, diabetes mellitus, osteoporosis and ocular cataracts. Other features include cutaneous atrophy, short stature, graying or loss of hair, hypogonadism, altered skin pigmentation, high-pitched voice, hyperkeratosis, tight skin, a bird-like facies, cutaneous ulcers of the legs, telangiectasia, and a shortened life expectancy. Onset of at least some of the symptoms is usually noted after adolescence although shortened stature may indicate some undefined alteration in development. Recently, linkage analysis was used to assign the locus for WS (designated WRN) to 8p21. This proposal outlines an approach for identifying the WRN gene by positional cloning techniques. Preliminary work has identified 3 markers which are in linkage disequilibrium with the WRN mutation(s). This observation suggests that the these markers are with O.5-1Mb of the WRN gene. This region has been cloned in yeast artificial chromosome (YAC) clones. New polymorphic markers will be identified so that the region of disequilibrium can be further refined. Genes in the region will be identified by hybridizing cDNA libraries to YACs and by exon trapping. These genes will be sequenced as candidate genes to detect mutations. Once the WRN gene is identified, the long-range goal 'will be to find the function of the gene product and to understand its role in the aging process and its role in major human diseases including arteriosclerosis, neoplasms, diabetes mellitus, and osteoporosis.