biostudies-literatureShen JNatural Science Foundation of Zhejiang ProvinceNoncommunicable Chronic Diseases-National Science and Technology Major Project"LingYan" Research and Development ProjectKey Research and Development Program of Zhejiang ProvinceNational Natural Science Foundation of ChinaOutstanding Youth Foundations of Natural Science Foundation of Hebei ProvinceKey Project of Jiangxi Provincial Natural Science FoundationNational Key Research and Development Program of Chinae12058https://www.ebi.ac.uk/biostudies/studies/S-EPMC12677635biostudies-literatureUnknown12(45)Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited cardiomyopathy featured by life-threatening arrhythmias. While TMEM43 has been identified as an ARVC-associated gene, molecular links between TMEM43 mutations and electrophysiological abnormalities in ARVC remain largely elusive. Here, using induced-pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and knock-in mice as models, it is demonstrated that a novel TMEM43 mutation (TMEM43-P386S) causes Ca²⁺ dysregulation that leads to arrhythmic phenotypes in ARVC, which can be prevented by flecainide. Mechanistically, TMEM43 interacts with lamin B2, and the TMEM43-P386S mutation induces lamin B2 mislocalization and abnormal nuclear envelope structure in ARVC iPSC-CMs, resulting in decreased chromatin opening of promoters associated with downregulated genes, including ryanodine receptor 2 (RYR2). RYR2s are downregulated and grouped into smaller clusters in ARVC iPSC-CMs, as revealed by Tau-STED super-resolution imaging, contributing to enhanced RYR2-mediated sarcoplasmic reticulum Ca²⁺ leak. These findings represent a novel mechanism underlying arrhythmogenesis in TMEM43-related ARVC and point to RYR2 stabilization as a potential therapeutic strategy.Advanced science (Weinheim, Baden-Wurttemberg, Germany)Decreased RYR2 Cluster Size and Abnormal SR Ca<sup>2+</sup> Release Contribute to Arrhythmogenesis in TMEM43-Related ARVC.PMC126776358167037020224ACB206004824003722024ZD0521502823600732024ZD0521500819702692019C03022LD21H0200012017YFA01037002024C0315581870175819220068194100382370354H2017206381Xu LGong TPan ZShen JQiu HYang BWang HSu JSun YWang JYang FLi XFan HZhou DWang WJiang CWang XChen XDang YZhuang LLiang PZhu TTang YfalseDecreased RYR2 Cluster Size and Abnormal SR Ca<sup>2+</sup> Release Contribute to Arrhythmogenesis in TMEM43-Related ARVC.Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited cardiomyopathy featured by life-threatening arrhythmias. While TMEM43 has been identified as an ARVC-associated gene, molecular links between TMEM43 mutations and electrophysiological abnormalities in ARVC remain largely elusive. Here, using induced-pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and knock-in mice as models, it is demonstrated that a novel TMEM43 mutation (TMEM43-P386S) causes Ca²⁺ dysregulation that leads to arrhythmic phenotypes in ARVC, which can be prevented by flecainide. Mechanistically, TMEM43 interacts with lamin B2, and the TMEM43-P386S mutation induces lamin B2 mislocalization and abnormal nuclear envelope structure in ARVC iPSC-CMs, resulting in decreased chromatin opening of promoters associated with downregulated genes, including ryanodine receptor 2 (RYR2). RYR2s are downregulated and grouped into smaller clusters in ARVC iPSC-CMs, as revealed by Tau-STED super-resolution imaging, contributing to enhanced RYR2-mediated sarcoplasmic reticulum Ca²⁺ leak. These findings represent a novel mechanism underlying arrhythmogenesis in TMEM43-related ARVC and point to RYR2 stabilization as a potential therapeutic strategy.2025-01-01T00:00:00Z2025 Dec2026-06-05T23:12:32.849Z2026-05-23T03:13:50.164ZS-EPMC126776354094838810.1002/advs.202512058