GENE EXPRESSION IN LIMB GIRDLE MUSCULAR DYSTROPHY

University Of Chicago, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): The muscular dystrophies are a genetically diverse group of disorders that lead to progressive muscle weakness and disability. In recent years, a number of genes have been discovered that, when mutated, lead to muscular dystrophy. In humans, mutations in the genes encoding sarcoglycan proteins produce Limb Girdle Muscular Dystrophy (LGMD). The sarcoglycan genes encode proteins each with a single transmembrane domain. Together, the sarcoglycan subunits form a subcomplex within the dystrophin glycoprotein complex (DGC). The DGC is important for stabilizing the cytoskeleton, the plasma membrane and the extracellular matrix. The loss of sarcoglycan from the plasma membrane causes degeneration to occur in both skeletal and cardiac muscle. Loss of function mutations in sarcoglycan genes causes muscle degeneration and abnormal muscle membrane permeability. Mouse models, engineered with sarcoglycan gene mutations, were found to target different aspects of sarcoglycan function. Mice lacking delta-sarcoglycan develop increased myocyte damage in response to the force of muscle contraction. In contrast, mice lacking gamma-sarcoglycan do not display increased myocyte damage in response to muscle contraction suggesting that gamma-sarcoglycan deficiency may cause membrane damage by a non-mechanical, or signaling, defect. Interestingly, skeletal and cardiac muscle degeneration is identical between mice lacking either gamma-sarcoglycan or delta-sarcoglycan. Therefore, these two different mouse models modify specific mechano signaling aspects of sarcoglycan function. We propose to conduct a microarray analysis of gene expression using gamma-sarcoglycan and delta-sarcoglycan mutant muscle to compare the changes in gene expression between these two forms of LGMD. The changes in gene expression in sarcoglycan mutant muscle will be compared to those found in dystrophin deficient muscle. Finally, we propose to analyze gene expression in cardiac tissue from gamma- and delta-sarcoglycan mutant mice. Together, these experiments will outline the temporal profile of gene expression changes that arise in these disorders.