Thick filament molecular interfaces play a critical role in pathogenesis of hypertrophic and dilated cardiomyopathy

Abstract

Hypertrophic (HCM) and dilated (DCM) cardiomyopathy variants in genes encoding the myosin heavy chain (MYH7), myosin light chains (MYL2 and MYL3), and cardiac myosin binding protein-C (cMyBP-C, MYBPC3) lead to cardiac hypertrophy or dilatation, with abnormal contractility, relaxation, and energy consumption. Here we defined the structural consequences of >200 pathogenic and benign missense variants in these genes by mapping variants onto a cryo-EM-based atomic model of the human cardiac thick filament. We identified HCM variants residing in 31 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the myosin heavy chain, essential and regulatory light chains, and cMyBP-C. Pathogenic DCM missense variants are rare, and altered only interfaces involving the myosin IHM and tails. None of the 21 variants classified as benign were within interfaces. We demonstrate earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within versus outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients. The dissimilar distribution of DCM and HCM variants could explain the different features of the two phenotypes.