The Interplay between Heart and Muscle Disease
One of the leading causes of congestive heart failure is cardiomyopathy, a disorder with a high heritable component. Dilated cardiomyopathy and hypertrophic cardiomyopathy are clinically distinct, but many of the same genetic defects can be associated with both forms of cardiomyopathy. Within these major forms of cardiomyopathy, it is not possible on clinical grounds to make a genetic diagnosis, yet genetic information helps predict outcome, particularly for complications such as conduction system disease, noncompaction, right ventricular involvement and extra-cardiac manifestations. Progressive skeletal muscle weakness can accompany cardiomyopathy, as it often does in the muscular dystrophies.
A common mutation in the gene encoding γ-sarcoglycan, a dystrophin associated protein, leads to a range of cardiomyopathy and muscle weakness. The variable phenotype in patients with this same Sgcg null mutation suggests the presence of genetic modifiers. Using the Sgcg mouse model of muscular dystrophy and cardiomyopathy, we interbred mice with mild and severe disease and then undertook a genomewide mapping strategy to search for modifier genes. We identified Ltbp4 as a major modifier of muscle disease. Ltbp4 encodes the latent TGFβ binding protein 4, a component of the extracellular matrix in both heart and muscle that sequesters and holds TGFβ inactive. TGFβ signaling has now emerged as a major mediator of not only fibrosis but also the stability of the sarcolemma. We also uncovered unique genetic modifiers of cardiac and diaphragm muscle fibrosis. These genetic interactions reveal the complexity of single gene disorders and highlight the value of studying a genetically well-defined cohort.
- © 2011 by American Heart Association, Inc.