Genetic modifier genes for inherited heart and muscle disease

Genetic mutations in single genes lead to inherited forms of cardiac and muscle disease. Cardiomyopathy from genetic mutations may develop in early or later life and may be associated with heart failure or be asymptomatic.The range of clinical outcome with inherited cardiomyopathy within families where there is a single genetic defect is,in part,determined by other genetic variants.We hypothesized that the interaction of single gene mutations with common genetic variants was responsible for cardiac and muscle disease.In a mouse model, we used a whole genome approach to identify genes that cause more severe heart and muscle disease. We identified a genetic locus on chromosome 7 that was significantly associated with severe disease.We identified the causative gene as Ltbp4,a gene that encodes the latent TGFbeta binding protein.We found that increased TGFbeta signaling was seen in the severely affected heart and muscle compared to the mildly affected strain.We found that increased proteolytic cleavage of LTBP4 protein was associated with increased SMAD signaling.These data support a model where increased proteolytic cleavage of LTBP4 results in increased TGFbeta release and signaling.We also identified other genetic regions that influence the severity of cardiomyopathy in this model.A genetic region on chromosome 9 was specifically associated with increased cardiac fibrosis in cardiomyopathy.Identifying modifier genes helps explain pathways important for modulating heart and muscle disease and may point to pathways that can be used therapeutically.(Supported by NIH,the Muscular Dystrophy Association and the Doris Duke Charitable Foundation.)