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

Oliver B Vad, Elisavet Angeli, Martin Liss, Gustav Ahlberg, Laura Andreasen, Ingrid E Christophersen, Camilla C Hansen, Sophie Møller, Ylva Hellsten, Stig Haunsoe, Arnljot Tveit, Jesper H Svendsen, Michael Gotthardt, Pia R Lundegaard, Morten S Olesen*

*Corresponding author for this work

Abstract

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.

Original languageEnglish
JournalJACC. Basic to translational science
Volume9
Issue number2
Pages (from-to)163-180
Number of pages18
ISSN2452-302X
DOIs
Publication statusPublished - Feb 2024

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