Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P
Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P