A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice

Sci Rep. 2020 Oct 27;10(1):17894. doi: 10.1038/s41598-020-74800-8.


Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / physiopathology
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / physiopathology
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Male
  • Mice
  • Mutation
  • Mutation, Missense / genetics
  • Myocytes, Cardiac / metabolism
  • Nuclear Localization Signals / genetics
  • RNA Splicing
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism


  • Nuclear Localization Signals
  • RBM20 protein, mouse
  • RNA-Binding Proteins