Abstract
Animal models have played a critical role in validating human dilated cardiomyopathy (DCM) genes, particularly those that implicate novel mechanisms for heart failure. However, the disease phenotype may be delayed due to age-dependent penetrance. For this reason, we generated an adult zebrafish model, which is a simpler vertebrate model with higher throughput than rodents. Specifically, we studied the zebrafish homologue of GATAD1, a recently identified gene for adult-onset autosomal recessive DCM. We showed cardiac expression of gatad1 transcripts, by whole mount in situ hybridization in zebrafish embryos, and demonstrated nuclear and sarcomeric I-band subcellular localization of Gatad1 protein in cardiomyocytes, by injecting a Tol2 plasmid encoding fluorescently-tagged Gatad1. We next generated gatad1 knock-out fish lines by TALEN technology and a transgenic fish line that expresses the human DCM GATAD1-S102P mutation in cardiomyocytes. Under stress conditions, longitudinal studies uncovered heart failure (HF)-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines. Based on these efforts of studying a gene-based inherited cardiomyopathy model, we discuss the strengths and bottlenecks of adult zebrafish as a new vertebrate model for assessing candidate cardiomyopathy genes.
Highlights
Cardiomyopathy refers to cardiac disease that is associated with structural changes of the myocardium upon extrinsic stresses such as ischemia and hypertension, and intrinsic stresses such as genetic mutations, many of which lead to heart failure [1]
The corresponding zebrafish orthologue gatad1 is located on chromosome 19 and encodes a 242 amino acid protein
There is a single transcript listed in the Ensembl database for zebrafish gatad1 consisting of five exons (ENSDARG00000027612), which is similar to human GATAD1 (ENSG00000157259)
Summary
Cardiomyopathy refers to cardiac disease that is associated with structural changes of the myocardium upon extrinsic stresses such as ischemia and hypertension, and intrinsic stresses such as genetic mutations, many of which lead to heart failure [1]. Human genetic studies have identified mutated genes responsible for 50%–70% of HCM, 30%–50% of DCM, and a small fraction of RCM [2,3], which create opportunities to pinpoint disrupted signaling pathways and seek therapeutic strategies. Beyond hypothesis-based candidate gene approaches, the development of genomic technologies including genome-wide association studies, family-based locus mapping, whole-exome sequencing, and chromosomal microarray have facilitated discovery of novel, unsuspected susceptibility genes [4]. These strategies may yield multiple plausible candidate genes in individual families and/or require a higher burden of proof to establish causality. An efficient animal model with high throughput is needed to assess these candidate genes and to expedite the gene discovery process
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