Since the initial identification of mutations in the dystrophin gene as the cause of Duchenne and Becker muscular dystrophies, molecular genetics has provided a plethora of new information and insights into the pathogeneses of muscle diseases. In particular, our understanding of the limb-girdle muscular dystrophies (LMGD) have been greatly enhanced. Fourteen forms of LGMD have been identified; of these, specific gene have been characterized in ten. This goal of this proposal is to identify the molecular genetic basis of a fifteenth form of LGMD which has been transmitted in an autosomal dominant fashion in a large Spanish pedigree (Spanish autosomal dominant LGMD [SAD- LGMD]). The disease locus has been mapped to a seven centimorgan region of chromosome 7q31.3-32 with a maximum two-point LOD score of 7.59 with marker D7S2519. We will attempt to reduce the size of the disease locus by fine mapping studies. Candidate genes will be screened until the disease mutation is identified. The pathogenesis of the disease will be studied by studying the expression of the gene messenger RNA and the gene product in the patients' skeletal muscle and in tissue culture using cells from patients. A mouse model of the disease will be produced to further investigate the pathogenesis. Muscle biopsies from more than 50 patients with LGMD of unknown etiology will be screened for defects of the SAD-LGMD gene product. The identification of the cause of SAD-LGMD will expand our understanding of the disease and will likely enhance our general understanding of skeletal muscle functions and structure. For the patients, achieving the proposed goals will allow more accurate prenatal diagnosis, genetic counseling, and perhaps contribute to more rational therapies in the future.
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