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AuthorDa'as, Sahar I.
AuthorYalcin, Huseyin C.
AuthorNasrallah, Gheyath K.
AuthorMohamed, Iman A.
AuthorNomikos, Michail
AuthorYacoub, Magdi H.
AuthorFakhro, Khalid A.
Available date2020-10-15T05:03:06Z
Publication Date2020
Publication NameJournal of Cellular Physiology
Identifierhttp://dx.doi.org/10.1002/jcp.29441
CitationDa'as, SI, Yalcin, HC, Nasrallah, GK, et al. Functional characterization of human myosin‐binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon‐specific cardiac phenotypes in zebrafish model. J Cell Physiol. 2020; 235: 7870– 7888. https://doi.org/10.1002/jcp.29441
ISSN0021-9541
URIhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85077972133&origin=inward
URIhttp://hdl.handle.net/10576/16450
Abstract© 2020 Wiley Periodicals, Inc. Myosin-binding protein C 3 (MYBPC3) variants are the most common cause of hypertrophic cardiomyopathy (HCM). HCM is a complex cardiac disorder due to its significant genetic and clinical heterogeneity. MYBPC3 variants genotype–phenotype associations remain poorly understood. We investigated the impact of two novel human MYBPC3 splice-site variants: V1: c.654+2_654+4dupTGG targeting exon 5 using morpholino MOe5i5; and V2: c.772+1G'A targeting exon 6 using MOe6i6; located within C1 domain of cMyBP-C protein, known to be critical in regulating sarcomere structure and contractility. Zebrafish MOe5i5 and MOe6i6 morphants recapitulated typical characteristics of human HCM with cardiac phenotypes of varying severity, including reduced cardiomyocyte count, thickened ventricular myocardial wall, a drastic reduction in heart rate, stroke volume, and cardiac output. Analysis of all cardiac morphological and functional parameters demonstrated that V2 cardiac phenotype was more severe than V1. Coinjection with synthetic human MYBPC3 messenger RNA (mRNA) partially rescued disparate cardiac phenotypes in each zebrafish morphant. While human MYBPC3 mRNA partially restored the decreased heart rate in V1 morphants and displayed increased percentages of ejection fraction, fractional shortening, and area change, it failed to revert the V1 ventricular myocardial thickness. These results suggest a possible V1 impact on cardiac contractility. In contrast, attempts to rescue V2 morphants only restored the ventricular myocardial wall hypertrophy phenotype but had no significant effect on impaired heart rate, suggesting a potential V2 impact on the cardiac structure. Our study provides evidence of an association between MYBPC3 exon-specific cardiac phenotypes in the zebrafish model providing important insights into how these genetic variants contribute to HCM disease.
Languageen
PublisherWiley
Subjecthypertrophic cardiomyopathy
myosin-binding protein C3
splice site variants
ventricle
zebrafish
TitleFunctional characterization of human myosin-binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon-specific cardiac phenotypes in zebrafish model
TypeArticle
Pagination7870-7888
Issue Number11
Volume Number235
ESSN1097-4652
dc.accessType Full Text


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