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

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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.

TidsskriftJACC: Basic to Translational Science
Udgave nummer2
Sider (fra-til)163-180
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This research has been conducted using the UK Biobank resource under application number 43247. The authors thank all individuals for their participation in this study. The Visual Abstract and Figure 6E were created using BioRender.

Publisher Copyright:
© 2024 The Authors

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