Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disease representing an important cause of sudden cardiac death in otherwise healthy young individuals such as athletes. The disease has been defined as an increase in left ventricular wall thickness in the absence of another cause of cardiac hypertrophy. The phenotype has been linked, in some kindreds, to the beta-myosin heavy chain (beta-MHC) gene, localized on the long arm of chromosome 14. Over thirty mutations resulting in substitutions of single amino acids have been described. These mutations are localized in the head and head-rod junction regions of beta-myosin. The beta-MHC gene, however, has been excluded as the disease locus in other kindreds. Thus, there is allelic and nonallelic heterogeneity in HCM. We have previously reported that the mutant beta- myosin is expressed, together with the wild-type, not only in cardiac, but also in soleus muscle. We have studied the functional consequences of these mutations on the enzymatic activity of beta-myosin using an in vitro motility assay in which fluorescently-labeled actin filaments are moved by the wild-type and mutant myosins which are bound to a glass surface. We have examined beta-myosin from skeletal and cardiac muscle of patients with HCM linked to the following distinct point mutations in the beta-MHC gene: T124I, Y162C, G256E, R408Q, V606M, R719Q, G741R, R870H, L908V and detected a slower rate of sliding of actin filaments compared to that of normal controls. These results demonstrate that some beta-MHC gene mutations in patients with HCM are associated with an abnormal acto-myosin interaction which may be the basis of their disease. We have used the three-dimensional crystal structure of the head fragment of chicken skeletal muscle myosin as a guide to locate the positions of the mutations in the tertiary structure of myosin. There are four general areas where the mutations cluster: in the nucleotide binding pocket, in an actin interface, near the essential light chain binding site and near the SH1/SH2 helix.
