Decreased RYR2 Cluster Size and Abnormal SR Ca²⁺ Release Contribute to Arrhythmogenesis in TMEM43-Related ARVC.

ABSTRACT: 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 open

SUBMITTER: Shen J 

PROVIDER: S-EPMC12677635 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature