PUBLICATION
Functional characterization of human myosin-binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon-specific cardiac phenotypes in zebrafish model
- Authors
- Da'as, S.I., Yalcin, H.C., Nasrallah, G.K., Mohamed, I.A., Nomikos, M., Yacoub, M.H., Fakhro, K.A.
- ID
- ZDB-PUB-200118-6
- Date
- 2020
- Source
- Journal of Cellular Physiology 235(11): 7870-7888 (Journal)
- Registered Authors
- Da'as, Sahar
- Keywords
- hypertrophic cardiomyopathy, myosin-binding protein C3, splice site variants, ventricle, zebrafish
- MeSH Terms
-
- Animals
- Cardiomyopathy, Hypertrophic/genetics*
- Cardiomyopathy, Hypertrophic/pathology*
- Carrier Proteins/genetics*
- Disease Models, Animal
- Exons/genetics
- Humans
- Phenotype
- Protein Isoforms/genetics
- Zebrafish
- PubMed
- 31943169 Full text @ J. Cell. Physiol.
Citation
Da'as, S.I., Yalcin, H.C., Nasrallah, G.K., Mohamed, I.A., Nomikos, M., Yacoub, M.H., Fakhro, K.A. (2020) Functional characterization of human myosin-binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon-specific cardiac phenotypes in zebrafish model. Journal of Cellular Physiology. 235(11):7870-7888.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping