Myotonic muscular dystrophy (DM) is the most common form of genetic muscular dystrophy affecting adults and children. The gene for DM is located near the centromere on chromosome 19. DM and apolipoprotein C11 (apoC11) have been closely linked using two apoC11 DNA polymorphisms to test linkage in our large, multigenerational DM pedigrees. Several new anonymous restriction fragment length polymorphisms (RFLPs) have been isolated from chromosome 19 enriched libraries and are being tested for linkage to DM. We propose to continue to identify tightly linked RFLPs and to initiate chromosome walking to define the DM gene. We propose to use enriched chromosome 19 libraries prepared in phages EMBL3 and charon 35, and the LORIST vector for the chromosome walk, initiating at the tightest available DNA probe. LORIST has the advantage over other cosmid vectors in that it maintains a higher and more constant copy number with large insert size, and can rapidly discriminate the opposing ends of the insert facilitating rapid direction specific chromosome walks. We propose to map chromosome 19 in the area of DM and to identify the DM gene using multiple strategies. Our goal is to design rational treatments of DM, perhaps taking advantage of the variable expressivity and penetrance that characterize this late-age-of-onset disorder to prevent symptoms and signs in presymptomatic heterozygotes.
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