Work

Stable truncating mutations in plakophilin-2 induce arrhythmogenic cardiomyopathy-like phenotypes in adult zebrafish

Year: 2026

Type: article

Abstract: 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.

Source: iScience

DOI: 10.1016/j.isci.2026.117755