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Pflugers Arch. 2014 Feb;466(2):207-13. doi: 10.1007/s00424-013-1417-7. Epub 2013 Dec 11.

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

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Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL, 60153-5500, USA,


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 affecting people of South Asian descent, with 4% of this population carrying the mutation. 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 with a novel sequence of 58 residues (cMyBP-C(C10mut)). 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-C(C10mut). This review article aims to examine the effects of cMyBP-C(C10mut) on cardiac function, emphasizing the need for the development of genetic testing and expanded therapeutic strategies.

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