The long term objective of this proposal is to understand the molecular basis of inherited cardiomyopathies, particular those associated with mutations in components of the dystroglycan-glycoprotein complex. The dystroglycan-glycoprotein complex provides a link from the cytoskeleton to the extracellular matrix. Mutations in components of this complex, such as delta sarcoglycan, cause recessive forms of muscular dystrophy. Interestingly, heterozygous mutations in the same delta sarcoglycan can also cause dilated cardiomyopathy without muscular dystrophy. The basis for the tissue specificity of these mutations and the mechanism behind sarcoglycan associated dilated cardiomyopathy is unclear. Furthermore, muscular dystrophy patients with mutations in enzymes that glycosylate dystroglycan and whose activity is necessary for dystroglycan to bind extracellular ligands, also have a high prevalence of cardiomyopathy. This proposal tests the hypothesis that the link between the cytoskeleton and the extracellular matrix 'through dystroglycan, specifically in cardiac myocytes, is critical 'to the development of cardiomyopathy. The proposed research will test the dominant-negative and tissue specific effects of delta sarcoglycan mutations on the attachment of alpha-dystroglycan to the transmembrane complex using isolated muscle cell gene transfer. In addition, the tissue specific role of dystroglycan glycosylation in the link to the extracellular matrix and the development of cardiomyopathy will be tested in the myodystrophy mouse. Finally, tissue specific gene targeted mice will be generated to determine if the link from cytoskeleton to matrix through dystroglycan, is necessary and sufficient in a tissue specific manner, to cause and explain the development of DGC associated cardiomyopathy.
