Abstract
Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25–base pair deletion in intron 32 of MYBPC3 (MYBPC3Δ25bp) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3Δ25bp carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3Δ25bp variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3Δ25bp pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.
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Funding
Dr. Sadayappan has received support from the National Institutes of Health grants (R01 HL130356, R01 HL105826, R01 AR067279, and RO1/R56 HL139680), the American Heart Association, Cardiovascular Genome-Phenome Study (15CVGPSD27020012), Catalyst (17CCRG33671128), Institutional Undergraduate Student (19UFEL34380251) and Transformation (19TPA34830084) awards, and the PLN Foundation (PLN crazy idea) awards, as well as from AstraZeneca, MyoKardia, Merck, and Amgen. Dr. Dhandapany is funded by an American Heart Association-Scientist Development Grant (15SDG23250005) and Wellcome Trust-Intermediate Fellowship (IA/I/16/1/502367). Drs. Kranias and Sadayappan are funded by the Leducq Foundation (Transatlantic Network 18CVD01, PLN-CURE). Dr. Becker has received support from the National Institutes of Health grants R01-HL065222 and U54-HL112307 and the American Heart Association 14FRN24110000. Dr. Kumar (Predoctoral Fellowship, 17PRE33630192), Ms. Desai (Predoctoral Fellowship, 20PRE35120272) and Dr. Song (Postdoctoral Fellowship, 19POST34380448) were supported by the American Heart Association fellowship training grants.
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Dr. Sadayappan provides consulting and collaborative research studies to the Leducq Foundation (CURE-PLAN), Red Saree Inc., Greater Cincinnati Tamil Sangam, AstraZeneca, MyoKardia, Merck, and Amgen, but such work is unrelated to the content of this manuscript. Dr. Becker serves on scientific advisory boards for following: Janssen and DSMB Committees for Ionis Pharmaceuticals, Akcea Therapeutics, and Novartis. Dr. Singh has been a post-doctoral fellow of Amgen, starting from June, 2019 and performs research at the University of Cincinnati. No other disclosures are reported.
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Arif, M., Nabavizadeh, P., Song, T. et al. Genetic, clinical, molecular, and pathogenic aspects of the South Asian–specific polymorphic MYBPC3Δ25bp variant. Biophys Rev 12, 1065–1084 (2020). https://doi.org/10.1007/s12551-020-00725-1
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DOI: https://doi.org/10.1007/s12551-020-00725-1