Muscular dystrophy arises from defects in many different single genes. Mutations in the genes encoding dystrophin or the sarcoglycans elicit a similar phenotype of progressive muscle weakness accompanied by dilated cardiomyopathy. The relationship between dystrophin and sarcoglycan loss is further reinforced by the assembly of these proteins into the dystrophin glycoprotein complex (DGC). The DGC plays a key role in stabilizes the plasma membrane against the forces associated with repetitive contraction. As both cardiac and skeletal muscle face repeated contraction, both heart and muscle are damaged by loss of the DGC. Mutations in ?-sarcoglycan lead to a recessive form of muscular dystrophy, similar to what occurs in Duchenne Muscular Dystrophy (DMD). There is a single mutation responsible for ?-sarcoglycan, 521?T, that has been described in LGMD patients from around the world. Despite the presence of the identical gene mutation, there is considerable phenotypic variability with this mutation. Similarly, in DMD, brothers sharing the same mutation may have a discrepant disease process. We sought to identify genes that modify the outcome of muscular dystrophy using a mouse model of ?-sarcoglycan mutations, Sgcg null. We selected this model because of the strong evidence for genetic modifiers in the corresponding human disease and because we reasoned that such modifiers could point to pathways that may be useful for therapeutic intervention. Using the Sgcg null model, we recently identified LTBP4, a TGF? binding protein, as a modifier of muscle disease.

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We mapped modifiers of muscular dystrophy by identifying two distinct background strains, D2 and 129, that lead to severe and mild forms of muscle disease, respectively. We propose to use a similar strategy to understand modifiers of cardiac function in muscular dystrophy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZNS1-SRB-S)
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University of Pennsylvania
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