Abstract
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.
Highlights
Cardiomyopathies are a heterogeneous group of diseases that affect the myocardium, causing sudden cardiac death and early mortality in children and adults [1]
Targeting Exon 9 of tnnt2a via CRISPR/Cas9 Promotes Changes in Heart Morphology of Zebrafish tnnt2a is located on chromosome 23 and consists of 15 exons
In one of the lines, we identified a deletion of five nucleotides causing a frameshift followed by a stop codon resulting in a truncated protein lacking most of the Tm binding region and the entire Troponin C (TnC)-Troponin I (TnI) binding region
Summary
Cardiomyopathies are a heterogeneous group of diseases that affect the myocardium, causing sudden cardiac death and early mortality in children and adults [1]. In recent years, it is becoming more prominent that these cardiomyopathy types can come as a spectrum of disease with overlapping features [4,5] These features can include the progression of fibrosis, changes in the ventricle wall structure, disruption in the contractility and intracellular calcium (Ca2+ ), and dysregulation in the electrical functions of the heart. These diseases can have various underlying factors, many progress as a result of mutations in proteins of the sarcomere, the contractile unit of the striated muscles.
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