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.