A homozygous missense mutation in the M-domain of cardiac myosin binding protein-C is lethal in a CRISPR-gene edited mouse model

Abstract

Myosin binding protein-C (MyBP-C) is a regulatory protein that modulates striated muscle contraction. Mutations in MYBPC3, the gene encoding cardiac MyBP-C, are a leading cause of hypertrophic cardiomyopathy (HCM). The L348P substitution (L352P in humans) is an HCM-associated missense mutation that increases binding of cardiac MyBP-C's M-domain to actin (Bezold et al., J Biol Chem, 2013). We previously developed a transgenic mouse model where transgenic expression of the L348P mutant protein was 39 ± 4% of total cardiac MyBP-C (van Dijk et al., J Mol Cell Cardiol, 2018).