Cardiac complications are concomitant with many forms of inherited neuromuscular disease. Many of the gene mutations that cause muscle weakness also lead to cardiomyopathy and heart failure. In addition to dilated and hypertrophic cardiomyopathy, many subtypes of muscular dystrophy and myopathy are accompanied by an increased frequency of cardiac arrhythmias that can be life-threatening. Proper genetic diagnosis of muscle disease is essential to managing and reducing risks for cardiac complications. The primary genetic diagnosis dictates the skeletal and cardiac outcomes in inherited muscle disease. However, genetic modifiers also contribute significantly to manifestations, including cardiac manifestations in muscular dystrophy. We have been pursuing genetic modifiers through a genetic intercross strategy using a mouse model of Limb girdle muscular dystrophy 2C, which is linked to mutation in gamma sarcoglycan, a dystrophin associated protein. We previously identified the gene Ltbp4, encoding latent TGFbeta binding protein 4, as a modifier of limb skeletal muscle damage and fibrosis. Nonsynonymous SNPs in human LTBP4 correlate with duration of ambulation in DMD, indicating that LTBP4 is a modifier in human disease in addition to mouse muscular dystrophy. In a separate mapping experiment, we identified Anxa6, encoding the membrane associated, calcium binding protein annexin A6, as modifier of right ventricular mass and abdominal muscle damage in a mouse model of muscular dystrophy. These data highlight the repair pathway in striated muscle and emphasize cardiorespiratory interrelationships and their importance in muscular dystrophy.
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