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Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy

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Abstract

Mutations in cardiac myosin binding protein C (MYBPC3) represent the most frequent cause of familial hypertrophic cardiomyopathy (HCM), making up approximately 50% of identified HCM mutations. MYBPC3 is distinct among other sarcomere genes associated with HCM in that truncating mutations make up the vast majority, whereas nontruncating mutations predominant in other sarcomere genes. Several studies using myocardial tissue from HCM patients have found reduced abundance of wild-type MYBPC3 compared to control hearts, suggesting haploinsufficiency of full-length MYBPC3. Further, decreased mutant versus wild-type mRNA and lack of truncated mutant MYBPC3 protein has been demonstrated, highlighting the presence of allelic imbalance. In this review, we will begin by introducing allelic imbalance and haploinsufficiency, highlighting the broad role each plays within the spectrum of human disease. We will subsequently focus on the roles allelic imbalance and haploinsufficiency play within MYBPC3-linked HCM. Finally, we will explore the implications of these findings on future directions of HCM research. An improved understanding of allelic imbalance and haploinsufficiency may help us better understand genotype-phenotype relationships in HCM and develop novel targeted therapies, providing exciting future research opportunities.

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Funding

This work was supported by the National Heart, Lung, and Blood Institute predoctoral fellowship grant HL131327-01 (to A.A. Glazier); The Children’s Cardiomyopathy Foundation (to S.M. Day); the Taubman Medical Institute (to S.M. Day); The Lefkofsky Foundation (to S.M. Day); and the University of Michigan Protein Folding Diseases Initiative (to S.M. Day).

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Authors and Affiliations

  1. Department of Molecular and Integrative Physiology, University of Michigan, 7220 MSRB III, 1150 W Medical Center Drive, SPC 0644, Ann Arbor, MI, 48109-5853, USA

    Amelia A. Glazier & Sharlene M. Day

  2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Andrea Thompson & Sharlene M. Day

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  1. Amelia A. Glazier
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  2. Andrea Thompson
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  3. Sharlene M. Day
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Correspondence to Sharlene M. Day.

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This article is part of the special issue on Sarcomeric Mutations in Pflügers Archiv – European Journal of Physiology

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Glazier, A.A., Thompson, A. & Day, S.M. Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy. Pflugers Arch - Eur J Physiol 471, 781–793 (2019). https://doi.org/10.1007/s00424-018-2226-9

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  • DOI: https://doi.org/10.1007/s00424-018-2226-9

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