Cardiac myosin plays a key role in cardiac contractility. Mutations in the cardiac myosin heavy chain gene is linked in some families to familial hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disease. To date, over 40 mutations in the S-1 and proximal S-2 regions of the heavy chain have been detected. Recently, mutations in the regulatory and essential light chain of cardiac myosin have also been found. Interestingly, two mutations in the essential light chain map quite close to a number of heavy chain mutations. We have studied a heavy chain mutant, R719Q, and an essential light chain mutant, M149V, which lie close to each other in space using the crystal structure of chicken fast skeletal muscle as a guide. In contrast to other mutations in the heavy chain that we have studied, these two mutations are associated with a higher rate of movement of actin filaments in an in vitro motility assay. The location of these two mutations suggests that they lie in what may be a hinge region between the heavy chain and light chain where two domains slide past one another during force transduction. The increase in rate of actin filament translocation in vitro may reflect an increase in the crossbridge cycling rate in vivo. Such an increase in crossbridge cycling rate would require a higher energy consumption, contributing to hypoxia of cardiac muscle in HCM patients, who usually have ventricular hypertrophy, which could augment the effects of hypoxia by increasing the distance for oxygen exchange between muscle cells and capillaries.
