Mutation that causes hypertrophic cardiomyopathy increases force production in human β-cardiac myosin.

Myosin Mutant That Breaks Hearts Genetically linked hypertrophic cardiomyopathy [HCM; also known as familial hypertrophic cardiomyopathy (FHC)] afflicts 1 in 500 people (1). The most prominent phenotypes of HCM include increased arrhythmias and sudden cardiac arrest, even in otherwise healthy adults and children. The HCM pathologies are associated with increased thickening of the ventricular wall and decreased ventricular cavity volume, accompanied by diastolic dysfunction. More than half (60%) of all HCM cases are caused by mutations in sarcomeric proteins (2). How these mutations trigger the disease phenotype is not clear (3). Several hypotheses have been proposed, including conflicting models where HCM mutations cause either decreased or increased force generation during contraction (3). In PNAS, Sommese et al. (4) provide critical insight, determining the mechanical and kinetic basis for one of the most malignant HCM-causing mutations, R453C, in the β-cardiac myosin II heavy chain. Sommese et al. characterize the biochemical and biophysical effect of the R453C missense mutation engineered directly into the motor domain of recombinant human β-cardiac myosin, expressed and purified from a novel muscle cell-based protein expression system (5). This work opens the door for in vitro analysis of the more than 300 mutations in the cardiac myosin heavy chain that cause heart disease in humans (3). Stepping through that door is a first step toward development of targeted treatments for these devastating genetic disorders. Sommese et al. find that the malignant R453C mutation (Fig. 1) results in subtle but significant changes in the actin-activated ATPase activity, a 30% decrease in Vmax (activity at saturating actin) and a 30% decrease in Km (actin concentration needed to achieve 1/2Vmax), suggesting increased actin binding affinity during ATPase cycling. Mechanical measurements show a 50% increase in the intrinsic force generated by single myosin molecules per ATP hydrolyzed, resulting in an overall increase in force generated by an ensemble of myosins. The authors propose that these force increases cause the aberrant contractility seen in hearts with this disease.