Cardiac and skeletal muscle expression of mutant β‐myosin heavy chains, degree of functional impairment and phenotypic heterogeneity in hypertrophic cardiomyopathy

Several mutations in distinct genes, all coding for sarcomeric proteins, have been reported in unrelated kindreds with familial hypertrophic cardiomyopathy (FHC). We have identified nine individuals from three families harboring two distinct mutations in one copy of the β‐myosin heavy chain (β‐MHC) gene. In this study, the expression of the mutant β‐myosin protein isoform, isolated from slow‐twitch fibers of skeletal muscle, was demonstrated by Northern and Western blot analysis; this myosin showed a decreased in vitro motility activity and produced a lower actin‐activated ATPase activity. Isometric tension, measured in single slow‐twitch fibers isolated from the affected individuals, also showed a significant decrease. The degree of impairment of β‐myosin function, as well as the loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strong correlation was also demonstrated between mutant β‐myosin content and clinical features of FHC. On the other hand, we were unable to detect any correlation between mutant β‐myosin expression and degree of cardiac hypertrophy, thereby strengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, might not necessarily be related to the clinical evolution of this disease. These findings lend support to the notion that additional factors rather than the mutated gene may play a pathogenetic role in cardiac wall thickening, whereas the prognosis appears to be strongly related to the amount of mutant protein. J. Cell. Physiol. 227: 3471–3476, 2012. © 2012 Wiley Periodicals, Inc.