Nuclear membrane protein interaction in heart and muscle disease

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DESCRIPTION (provided by applicant): Defects of the nuclear membrane have emerged as an important mediator of cardiac and neuromuscular disease. Mutations in the gene encoding the intermediate filament proteins lamins A and C occur as one of the more common forms of dominantly inherited muscle disease leading to cardiomyopathy as well as muscular dystrophy. Lamins A and C are more highly expressed in terminally differentiated cell types including cardiomyocytes, skeletal myofibers and neurons. The majority of genetic mutations associated with striated muscle disease are inherited in an autosomal dominant manner where dominant negative or haploinsufficient genetic mechanisms may occur and lead to disease. Loss of lamins A and C produces cells that have impaired mechanical nuclear function. We hypothesize that the protein composition of the nuclear membrane may be specialized in cardiomyocytes and skeletal muscle, and that protein interactions within the nuclear membrane of striated muscle cells may be perturbed in response to lamin A and C gene mutations. To this end, we have characterized nesprin-11, a smaller protein generated from the nesprin-1 locus. Nesprins are nuclear membrane- associated spectrin repeat-containing proteins. In their full length form, nesprins are giant proteins that can bind to the outer nuclear membrane where they may participate in localizing the nucleus within the cell. Nesprin-11 is a smaller product that contains six spectrin repeats and is localized at the inner nuclear membrane. Nesprin-11 mRNA and protein are both highly expressed in cardiac and skeletal muscle. Moreover, nesprin-11 directly binds to lamin A in vitro, and nesprin-11 requires lamin A or lamin C for proper localization within cells. This proposal outlines experiments to elucidate protein interactions in the striated muscle nuclear membrane and the role of these interactions in cardiac and skeletal muscle disease. RELEVENCE: Mutations in genes that encode proteins of the nuclear membrane are a common cause of cardiomyopathy that affects the electrical system of the heart and muscular dystrophy. My laboratory is interesting in determining how changing the nuclear membrane leads to muscle disease.