Mutations in thick filament binding proteins act as dynamic regulators of the thick filament activation state, contributing to the speed and force of myosin-driven muscle contraction.
This review summarizes the functional consequences of mutations in thick filament binding proteins and their role in the pathogenesis of familial hypertrophic cardiomyopathy.
In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.
Harris et al. (Thu,) conducted a review in Familial hypertrophic cardiomyopathy (HCM). Mutations affecting thick filament binding proteins was evaluated. Mutations in thick filament binding proteins act as dynamic regulators of the thick filament activation state, contributing to the speed and force of myosin-driven muscle contraction.