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

Chaitali Misra, Sushant Bangru, Feikai Lin, Kin Lam, Sara N. Koenig, Ellen R. Lubbers, Jamila Hedhli, Nathaniel P. Murphy, Darren J. Parker, Lawrence W. Dobrucki, Thomas A. Cooper, Emad Tajkhorshid, Peter J. Mohler, Auinash Kalsotra

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)748-763.e6
JournalDevelopmental cell
Issue number6
StatePublished - Mar 23 2020


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

ASJC Scopus subject areas

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology


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