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. Several mutations resulting in substitutions of single evolutionary conserved 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 of individuals carrying the 403 Arg-Gln beta-MHC gene mutation. Moreover, in the attempt to study the enzymatic activity of this and another mutant beta-myosin (908 Leu- Val), we have described an abnormal behavior in the in vitro actin sliding motility assay. Using the same assay, we have examined beta- myosin from skeletal and cardiac muscle of 40 patients with HCM linked to distinct point mutations in the beta-MHC gene (124 Thr-Ile, 162 Tyr- Cys, 256 Gly-Glu, 408 Arg-Gln, 606 Val-Met, 741 Gly-Arg, 870 Arg-His, 908 Leu-Val) and detected a slower rate of sliding of actin filaments compared to that of 22 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. In one family (two sisters) carrying the 741 Gly-Arg mutation in the beta-MHC gene, beta-myosin purified from soleus and pectoralis muscle had normal in vitro activity, whereas beta-myosin from cardiac biopsies showed depressed activity; interestingly, the ratio of normal/mutant MRNA is constant in both skeletal and cardiac muscle, suggesting a possible tissue-specific expression of the mutant beta-MHC gene.
