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

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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 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-CC10mut). 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.

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Abbreviations

HCM:

Hypertrophic cardiomyopathy

LV:

Left ventricle

LVH:

Left ventricular hypertrophy

MYH7 :

Myosin heavy chain gene

MYBPC3 :

Cardiac myosin binding protein-C gene

cMyBP-C:

Cardiac myosin binding protein-C

MYBPC3 Δ25bp :

25 base pair deletion mutation in MYBPC3

cMyBP-CC10mut :

Protein product of MYBPC3 Δ25bp gene

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Acknowledgments

The authors were supported by the National Institutes of Health grants R01HL105826 and K02HL114749 (SS), as well as the American Heart Association Midwest Postdoctoral Fellowship 13POST17220009 (DWDK) entitled “Pathophysiology of Hypertrophic Cardiomyopathy-associated Cardiac Myosin Binding Protein-C Mutation” (July 2013 to June 2015).

Disclosures

A full patent application is pending (application serial no. 13/464,466, pub. no. USA 2012/0282618 A1, and date May 4, 2012) for diagnosing the presence of 25 bp deletion mutation in MYBPC3.

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

    Diederik W. D. Kuster & Sakthivel Sadayappan

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Correspondence to Sakthivel Sadayappan.

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Kuster, D.W.D., Sadayappan, S. MYBPC3's alternate ending: consequences and therapeutic implications of a highly prevalent 25 bp deletion mutation. Pflugers Arch - Eur J Physiol 466, 207–213 (2014). https://doi.org/10.1007/s00424-013-1417-7

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