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

• DOI: 10.1016/j.devcel.2020.01.037
• Publication Date: 2020-02-27T15:35:36Z
• Authors: 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
• Keywords: Cardiac muscle

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