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Article

A Heterozygous Mutation in Cardiac Troponin T Promotes Ca2+ Dysregulation and Adult Cardiomyopathy in Zebrafish

1
Hubrecht Institute-KNAW, University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands
2
Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands
3
Department of Pediatric Cardiology, Division of Pediatrics, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editors: Mathilda Mommersteeg and Juan Manuel González-Rosa
J. Cardiovasc. Dev. Dis. 2021, 8(4), 46; https://doi.org/10.3390/jcdd8040046
Received: 8 March 2021 / Revised: 31 March 2021 / Accepted: 14 April 2021 / Published: 20 April 2021
(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)
Cardiomyopathies are a group of heterogeneous diseases that affect the muscles of the heart, leading to early morbidity and mortality in young and adults. Genetic forms of cardiomyopathy are caused predominantly by mutations in structural components of the cardiomyocyte sarcomeres, the contractile units of the heart, which includes cardiac Troponin T (TnT). Here, we generated mutations with CRISPR/Cas9 technology in the zebrafish tnnt2a gene, encoding cardiac TnT, at a mutational “hotspot” site to establish a zebrafish model for genetic cardiomyopathies. We found that a heterozygous tnnt2a mutation deleting Arginine at position 94 and Lysine at position 95 of TnT causes progressive cardiac structural changes resulting in heart failure. The cardiac remodeling is presented by an enlarged atrium, decreased ventricle size, increased myocardial stress as well as increased fibrosis. As early as five days post fertilization, larvae carrying the TnT RK94del mutation display diastolic dysfunction and impaired calcium dynamics related to increased Ca2+ sensitivity. In conclusion, adult zebrafish with a heterozygous TnT-RK94del mutation develop cardiomyopathy as seen in patients with TnT mutations and therefore represent a promising model to study disease mechanisms and to screen for putative therapeutic compounds. View Full-Text
Keywords: cardiac Troponin T; cardiomyopathy; zebrafish; structural remodeling; calcium dysregulation; contractility defects; CRISPR/Cas9 cardiac Troponin T; cardiomyopathy; zebrafish; structural remodeling; calcium dysregulation; contractility defects; CRISPR/Cas9
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MDPI and ACS Style

Kamel, S.M.; Koopman, C.D.; Kruse, F.; Willekers, S.; Chocron, S.; Bakkers, J. A Heterozygous Mutation in Cardiac Troponin T Promotes Ca2+ Dysregulation and Adult Cardiomyopathy in Zebrafish. J. Cardiovasc. Dev. Dis. 2021, 8, 46. https://doi.org/10.3390/jcdd8040046

AMA Style

Kamel SM, Koopman CD, Kruse F, Willekers S, Chocron S, Bakkers J. A Heterozygous Mutation in Cardiac Troponin T Promotes Ca2+ Dysregulation and Adult Cardiomyopathy in Zebrafish. Journal of Cardiovascular Development and Disease. 2021; 8(4):46. https://doi.org/10.3390/jcdd8040046

Chicago/Turabian Style

Kamel, Sarah M., Charlotte D. Koopman, Fabian Kruse, Sven Willekers, Sonja Chocron, and Jeroen Bakkers. 2021. "A Heterozygous Mutation in Cardiac Troponin T Promotes Ca2+ Dysregulation and Adult Cardiomyopathy in Zebrafish" Journal of Cardiovascular Development and Disease 8, no. 4: 46. https://doi.org/10.3390/jcdd8040046

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