MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease and the leading cause of sudden cardiac death in young people. HCM is caused by mutations in genes encoding contractile proteins. Cardiac myosin binding protein-C (cMyBP-C) is a thick filament contractile protein that regulates sarcomere organization and cardiac contractility. About 200 different mutations in the cMyBP-C gene (MYBPC3) have thus far been reported as causing HCM. Among them, a 25 base pair deletion in the branch point of intron 32 of MYBPC3 is widespread, particularly in South Asia, where it affects ≈4% of South Asian descendants worldwide. This polymorphic mutation results in skipping of exon 33 and a reading frame shift, which, in turn, replaces the last 65 amino acids of the C-terminal C10 domain of cMyBP-C (cMyBP-CC10mut) with a novel sequence of 58 residues. Carriers of the 25 base pair deletion mutation are at increased risk of developing cardiomyopathy and heart failure. Because of the high prevalence of this mutation in certain populations, genetic screening of at-risk groups might be beneficial. Scientifically, the functional consequences of C-terminal mutations and the precise mechanisms leading to HCM should be defined using induced pluripotent stem cells and engineered heart tissue in vitro, or mouse models in vivo. Most importantly, therapeutic strategies that include pharmacology, gene repair and gene therapy should be developed to prevent the adverse clinical effects of cMyBP-CC10mut. This review article aims to examine the effects of cMyBP-CC10mut on cardiac function, emphasizing the need for the development of genetic testing and expanded therapeutic strategies.

Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice

“…Heterozygous carriers of these mutations often have incomplete penetrance and variable onset of disease [19], suggesting that other genetic or environmental factors modify the phenotype and influence the development of disease [20]. This view has been supported by studies of models of HCM-causing mutations in MYBPC3 and other genes that have been shown to be altered by genetic modifiers [20-22] and external stress [23], contributing to dysfunction and affecting the course of disease.…”

High-Throughput Diagnostic Assay for a Highly Prevalent Cardiomyopathy-Associated MYBPC3 Variant

“…Moreover, adding this test to the existing diagnostic tool kit will allow the frequency and severity of this variant to be determined over time by studying clinical outcomes [28]. Importantly, since this MYBPC3 ΔInt32 variant is highly prevalent, large-scale clinical screening can determine if this variant is a direct cause of cardiomyopathies or is a risk allele that acts with other pathogenic variants, or environmental factors.…”

Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis

“…12, 13). Due to an ancient founder mutation, 4% of the population of India carries a truncating MYBPC3 mutation (14,15). The majority of cardiac MYBPC3 mutations are predicted to encode truncated proteins that lack portions of either the carboxyl myosin and/or titin binding domains (7,13).…”