The purpose of this project is to determine the chromosomal locations of the genes responsible for hypertrophic cardiomyopathy (HCM). It is the most important cause of sudden death in apparently health young individuals. Its clinical manifestations are highly variable including cardiac morphologic abnormalities only, left ventricular outflow obstruction, palpitations, chest pain, cardiac failure, and sudden death. Linkage analysis has identified the cardiac myosin heavy chain gene as the disease gene in between 30% -50% of affected kindreds. We have identified 7 distinct mutations in the head or head-rod junction region of the molecule in 7 affected kindreds. Careful clinical examination of these kindreds has suggested mutation specific natural histories of the disease. For example one kindred with a mutation at amino acid residue 403 has a high frequency of sudden death, an early onset of disease, and 100% penetrance. Another kindred with a mutation at residue 908, has a low frequency of sudden death, late onset of disease, and 60% disease penetrance. Our studies have shown that the cardiac beta myosin heavy chain gene is also expressed in slow skeletal muscle. This has allowed us to study the pathophysiology and structure of the mutant protein from biopsy samples of patients with identified mutations. These studies have shown (1) that myosin with either the 403 or 908 mutations have abnormal function in an in vitro myosin motility assay, (2) the isometric force generated by single myofibers from patients with the 403 mutation is decreased, and that (3) skeletal muscle from patients with distinct mutations in the beta myosin heavy chain gene show the signs of central core disease, a rare nonprogressive myopathy characterized by loss of mitochondria in type I fibers. Our cloning of the cDNA has detected a new isoform of the gene with putative translational control elements in the 5' untranslated region. Investigation of these elements will lead to new understanding of myosin regulation and its relation to HCM.
