Cytoplasmic mutant RBM20 causes arrhythmogenicity in murine atria.

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Mutations in RNA binding motif protein 20 (RBM20) are linked to dilated cardiomyopathy (DCM) and atrial fibrillation (AF).
• While RBM20's loss of function impacts splicing, its gain of function in DCM pathogenesis is increasingly recognized.
• The specific role of mutant RBM20 gain of function in atrial arrhythmogenicity remains unclear.

Purpose of the Study:

• To investigate the contribution of mutant RBM20 gain of function to atrial arrhythmogenicity.
• To elucidate the underlying mechanisms of atrial dysfunction caused by mutant RBM20.

Main Methods:

• Generation of a novel atrial-specific mutant RBM20-expressing mouse model (Sln^Cre/+; LSL-Rbm20^S637A).
• Assessment of cardiac electrophysiology, structure, and molecular changes in the generated mouse model.
• Analysis of connexin 43 expression and calcium handling proteins.

Main Results:

• Mice expressing mutant RBM20 specifically in the atria developed spontaneous atrial tachycardia and increased AF inducibility.
• These arrhythmogenic phenotypes occurred without significant atrial structural remodeling or heart failure.
• Reduced atrial conduction velocity, decreased/mislocalized connexin 43, abnormal Ca²⁺ handling, and altered Ca²⁺-handling protein phosphorylation were observed.

Conclusions:

• Mutant RBM20 contributes to atrial arrhythmogenicity through mechanisms independent of splicing defects.
• Alterations in Ca²⁺ handling and impaired electrical conduction are key mechanisms involved.
• These findings highlight a novel role for RBM20 gain of function in AF pathogenesis.