Aberrant Expression of a Non-muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy

  • Dev Cell. 2020 Mar 23;52(6):748-763.e6. doi: 10.1016/j.devcel.2020.01.037.
Chaitali Misra  1 ,  Sushant Bangru  2 ,  Feikai Lin  1 ,  Kin Lam  3 ,  Sara N Koenig  4 ,  Ellen R Lubbers  4 ,  Jamila Hedhli  5 ,  Nathaniel P Murphy  4 ,  Darren J Parker  1 ,  Lawrence W Dobrucki  6 ,  Thomas A Cooper  7 ,  Emad Tajkhorshid  8 ,  Peter J Mohler  4 ,  Auinash Kalsotra  9
Affiliations
  • 1. Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
  • 2. Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
  • 3. Department of Physics, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Centers for Macromolecular Modeling, Bioinformatics and Experimental Molecular Imaging at Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
  • 4. Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, College of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
  • 5. Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Centers for Macromolecular Modeling, Bioinformatics and Experimental Molecular Imaging at Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
  • 6. Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Centers for Macromolecular Modeling, Bioinformatics and Experimental Molecular Imaging at Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
  • 7. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
  • 8. Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Department of Physics, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Centers for Macromolecular Modeling, Bioinformatics and Experimental Molecular Imaging at Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
  • 9. Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA. Electronic address: [email protected].
PMID: 32109384 DOI: 10.1016/j.devcel.2020.01.037
Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the CTG repeat expansion in the 3'-untranslated region of DMPK gene. Heart dysfunctions occur in ∼80% of DM1 patients and are the second leading cause of DM1-related deaths. Herein, we report that upregulation of a non-muscle splice isoform of RNA-binding protein RBFOX2 in DM1 heart tissue-due to altered splicing factor and MicroRNA activities-induces cardiac conduction defects in DM1 individuals. Mice engineered to express the non-muscle RBFOX240 isoform in heart via tetracycline-inducible transgenesis, or CRISPR/Cas9-mediated genome editing, reproduced DM1-related cardiac conduction delay and spontaneous episodes of arrhythmia. Further, by integrating RNA binding with cardiac transcriptome datasets from DM1 patients and mice expressing the non-muscle RBFOX2 isoform, we identified RBFOX240-driven splicing defects in voltage-gated sodium and potassium channels, which alter their electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX240 isoform in DM1 cardiac pathogenesis.

Keywords
alternative splicing; cardiac arrhythmias; genome editing; genomics; ion channels; microRNA; molecular dynamics; myotonic dystrophy; protein-RNA interactions.