研究業績

RNA binding motif protein 20 (RBM20) is a critical splicing regulator in cardiomyocytes, and mutations in its RSRSP domain are associated with severe dilated cardiomyopathy (DCM) and a high prevalence of atrial fibrillation (AF). RBM20 mutation has long been thought to cause DCM through the disturbed splicing of the target genes by its loss of function. However, recent studies have highlighted that the gain of function of mutant RBM20, independent of splicing defects, may also play a critical role in the pathogenesis of DCM. Despite these findings, the contribution of the gain of function of mutant RBM20 to the development of AF remains poorly understood. In this study, we aimed to elucidate the contribution of mutant RBM20 in atrial arrhythmogenicity by generating a novel atrial-specific mutant RBM20-expressing mouse model (SlnCre/+; LSL-Rbm20S637A mice). These mice specifically expressed mutant RBM20 in the atria while maintaining RBM20-dependent alternative splicing. Analyses revealed the spontaneous development of atrial tachycardia and increased inducibility of AF, despite the absence of atrial structural remodeling or heart failure in SlnCre/+; LSL-Rbm20S637A mice. Reduced atrial conduction velocity was observed, along with decreased and mislocalized expression of connexin 43, as well as abnormal Ca2+ handling and altered phosphorylation of Ca2+-handling proteins. These findings suggest that mutant RBM20 contributes to the arrhythmogenicity through mechanisms independent of splicing regulation, involving alterations in Ca2+ handling and electrical conduction property in murine atria.