Werner's Syndrome (WS) is an autosomal recessive inherited condition which mimics aspects of premature aging and may provide an important model for normal senescence. Though WS is rare, some of the associated features, including vascular disease, neoplasia, and diabetes are common disorders of widespread importance. The goal of this project is to establish the chromosomal location of the WS mutation by exploiting the homozygosity mapping strategy most recently described by Lander and Botstein (1987). This method for mapping rare recessive disorders requires the use of highly polymorphic genetic markers. Presently suitable mapped markers are available for most regions of the human genome and additional markers are continually being characterized. In addition, homozygosity mapping requires a collection of affected subjects from consauginous marriages. If markers with heterozygosity values of 0.5 or greater are used, approximately 15 WS subjects from inbred pedigrees are required to have a probability of success. This strategy is highly efficient since only affected subjects are needed and additional family members or multiplex pedigrees need not be samples. Presently we have cell lines from 3 inbred Japanese WS subjects at the University of Washington. We will obtain the additional subjects through a collaborative arrangement with Dr. Fujiwara who maintains a WS registry in Japan. Approximately 50% of the WS subjects in this registry are the product of first cousin marriages. Lymphoblastoid cell lines will be prepared using Epstein Barr virus from new WS subjects and used as a source of DNA for determining restriction fragment length polymorphism genotypes. The region containing the WS defect will be identified by looking for a marker(s) which is homozygous by descent. Once a chromosomal location containing the WS mutation is found, additional markers will be typed to refine the localization with the eventual goal of identifying the WS gene.
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