MECHANISM OF CARDIOMYOPATHY IN SARCOGLYCAN DEFICIENCY

University Of Chicago, Chicago IL

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Abstract

Mutations in sarcoglycan, a dystrophin-associated protein complex, cause cardiomyopathy and muscular dystrophy in humans. Through gene targeting, we have generated mice lacking different sarcoglycan subunits to understand better the mechanism by which the loss of these proteins produces membrane instability and cardiac muscle damage. Gamma-sarcoglycan and delta-sarcoglycan are highly related 35 KD, transmembrane proteins. Mice lacking either these sarcoglycans develop cardiomyopathy and show membrane defects characteristic of those seen in humans with mutations in these genes. Gamma-sarcoglycan is expressed exlusively in cardiac and skeletal muscle, yet mice lacking gamma-sarcoglycan appear to have smooth muscle vascular alterations similar to those seen in mice lacking delta-sarcoglycan. Thus, such defects may be a secondary consequence of the primary loss of sarcoglycan in the cariomyocyte. To investigate this, we will compare mice lacking gamma- or delta-sarcoglycan. We will rescue smooth muscle expression of delta-sarcoglycan. We will investigate the role of nitric oxide synthase since unopposed vasoconstriction has been identified as a mediator of abnormal vascular tone in the absence of dystrophin. Lastly, we will study whether cardiomyocyte degeneration produces vascular changes by studying other models of cardiomyopathy.