iScienceOct 25, 2026

Truncated plakophilin-2 mutations cause heart rhythm problems like arrhythmogenic cardiomyopathy in adult zebrafish

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 26, 2026

Abstract

Zebrafish with two specific mutations in the pkp2 gene exhibit impaired cardiac function and increased risk of sudden death.

Mutations in plakophilin-2 are the most common genetic cause of arrhythmogenic cardiomyopathy (ACM).
Zebrafish serve as a complementary model for studying PKP2-related ACM due to observed similarities in cardiac issues.
Mutant zebrafish showed distinct cardiac expression patterns of PKP2 and its homologs compared to other species.
Cardiac contractility was impaired in zebrafish with pkp2 mutations, leading to arrhythmias and lipid buildup.
Transcriptomic analyses revealed changes in genes related to muscle contraction and lipid metabolism in the mutants.

Simplified

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by arrhythmias and fibrofatty myocardial remodeling, often leading to heart failure and sudden cardiac death. Mutations in plakophilin-2 (PKP2) represent the most prevalent genetic cause of ACM. Here, we establish zebrafish (Danio rerio) as a complementary vertebrate model for PKP2 mutation-based ACM. Comparative single-cell RNA-seq analyses revealed distinct cardiac expression patterns of PKP2 and its homologs across species. Using CRISPR-Cas9, we generated two truncating mutations in zebrafish pkp2, resulting in frameshifts and premature terminations (p.Glu250Glyfs∗17 and p.Glu31Glyfs∗72, respectively). Mutant zebrafish exhibited impaired cardiac contractility, arrhythmias, lipid accumulation on the ventricular surface, ultrastructural abnormalities of intercalated discs, and increased susceptibility to swimming exercise-induced sudden death. Transcriptomic analyses identified transcriptional alterations in genes involved in muscle contraction and lipid metabolism. Together, these data establish zebrafish as a useful complementary vertebrate model for studying PKP2-based ACM and gene-environment interactions underlying disease progression.

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Truncated plakophilin-2 mutations cause heart rhythm problems like arrhythmogenic cardiomyopathy in adult zebrafish

Abstract

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