Loss of Cardiac Splicing Regulator RBM20 Is Associated With Early-Onset Atrial Fibrillation

• Published in: JACC. Basic to translational science 2024-02, Vol.9 (2), p.163-180
• Main Authors: Vad, Oliver B., Angeli, Elisavet, Liss, Martin, Ahlberg, Gustav, Andreasen, Laura, Christophersen, Ingrid E., Hansen, Camilla C., Møller, Sophie, Hellsten, Ylva, Haunsoe, Stig, Tveit, Arnljot, Svendsen, Jesper H., Gotthardt, Michael, Lundegaard, Pia R., Olesen, Morten S.
• Format: Article
• Language: English
• Subjects: alternative splicing; atrial cardiomyopathy; atrial fibrillation; genetics; Original Research - Clinical; RBM20
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2023.08.008

[Display omitted] •Loss of function variants in the key cardiac splicing regulator RBM20 were associated with atrial fibrillation in 2 independent cohorts.•Loss of RBM20 facilitated structural and transcriptional changes in the atria and affected mitochondrial function.•Alternative splicing may act as a novel proarrhythmic mechanism in the atria through atrial remodeling and altered mitochondrial energetics. We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.