Stable truncating mutations in plakophilin-2 induce arrhythmogenic cardiomyopathy-like phenotypes in adult zebrafish
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.
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BibTeX
@article{liu2026stable,
title = {{Stable truncating mutations in plakophilin-2 induce arrhythmogenic cardiomyopathy-like phenotypes in adult zebrafish}},
author = {Yuting Liu and Yujuan Niu and Yajie Jiang and Taiwei Ma and Peng Yang and Wenyu Ma and Shuai Liu and Yuehang Xu and Hui Xin and Hong Zhang and Chuanhong Wu and Zhiqiang Li and Yuanchao Sun and Yonghe Ding},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117755},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03136-6},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Stable truncating mutations in plakophilin-2 induce arrhythmogenic cardiomyopathy-like phenotypes in adult zebrafish
AU - Yuting Liu
AU - Yujuan Niu
AU - Yajie Jiang
AU - Taiwei Ma
AU - Peng Yang
AU - Wenyu Ma
AU - Shuai Liu
AU - Yuehang Xu
AU - Hui Xin
AU - Hong Zhang
AU - Chuanhong Wu
AU - Zhiqiang Li
AU - Yuanchao Sun
AU - Yonghe Ding
PY - 2026
DA - 2026/10/14
JO - iScience
DO - 10.1016/j.isci.2026.117755
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03136-6
AB - 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.
SN - 2589-0042
ER -