Decreased RYR2 Cluster Size and Abnormal SR Ca²⁺ 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.