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Overexpression of a Non-Muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy

73 Pages Posted: 15 Jul 2019 Publication Status: Published

See all articles by Chaitali Misra

Chaitali Misra

University of Illinois at Urbana-Champaign - Department of Biochemistry

Sushant Bangru

University of Illinois at Urbana-Champaign - Department of Biochemistry

Feikai Lin

University of Illinois at Urbana-Champaign - Department of Biochemistry

Kin Lam

University of Illinois at Urbana-Champaign

Sara N. Koenig

Ohio State University (OSU)

Ellen R. Lubbers

Ohio State University (OSU)

Jamila Hedhli

University of Illinois at Urbana-Champaign

Nathaniel P. Murphy

Ohio State University (OSU)

Darren J. Parker

University of Illinois at Urbana-Champaign - Department of Biochemistry

Lawrence W. Dobrucki

University of Illinois at Urbana-Champaign

Thomas A. Cooper

Baylor College of Medicine

Emad Tajkhorshid

University of Illinois at Urbana-Champaign - Center for Biophysics and Computational Biology; University of Illinois at Urbana-Champaign - Beckman Institute for Advanced Science and Technology

Peter J. Mohler

Ohio State University (OSU)

Auinash Kalsotra

University of Illinois at Urbana-Champaign - Department of Biochemistry

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Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG trinucleotide repeat expansion in the 3′ untranslated region of DMPK gene. Heart dysfunctions occur in nearly 80% of DM1 patients and are the second leading cause of DM1-related deaths. Despite these figures, the mechanisms underlying cardiac-based DM1 phenotypes are unknown. 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 RBFOX2 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 both DM1 patients and mice expressing the non-muscle RBFOX2 isoform, we identified RBFOX2-driven splicing defects in the voltage-gated sodium and potassium channels, which can alter their electrophysiological properties. Thus, our results uncover a trans-dominant role for an aberrantly expressed RBFOX2 isoform in DM1 cardiac pathogenesis.

Keywords: Myotonic dystrophy, alternative splicing, cardiac arrhythmias, genome editing, Protein-RNA interactions, microRNA, genomics, molecular dynamics

Suggested Citation

Misra, Chaitali and Bangru, Sushant and Lin, Feikai and Lam, Kin and Koenig, Sara N. and Lubbers, Ellen R. and Hedhli, Jamila and Murphy, Nathaniel P. and Parker, Darren J. and Dobrucki, Lawrence W. and Cooper, Thomas A. and Tajkhorshid, Emad and Mohler, Peter J. and Kalsotra, Auinash, Overexpression of a Non-Muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy (July 13, 2019). Available at SSRN: https://ssrn.com/abstract=3419213 or http://dx.doi.org/10.2139/ssrn.3419213
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Chaitali Misra

University of Illinois at Urbana-Champaign - Department of Biochemistry ( email )

United States

Sushant Bangru

University of Illinois at Urbana-Champaign - Department of Biochemistry ( email )

United States

Feikai Lin

University of Illinois at Urbana-Champaign - Department of Biochemistry ( email )

United States

Kin Lam

University of Illinois at Urbana-Champaign

601 E John St
Champaign, IL 61820
United States

Sara N. Koenig

Ohio State University (OSU) ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH OH 43210
United States

Ellen R. Lubbers

Ohio State University (OSU) ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH OH 43210
United States

Jamila Hedhli

University of Illinois at Urbana-Champaign ( email )

601 E John St
Champaign, IL 61820
United States

Nathaniel P. Murphy

Ohio State University (OSU) ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH OH 43210
United States

Darren J. Parker

University of Illinois at Urbana-Champaign - Department of Biochemistry ( email )

United States

Lawrence W. Dobrucki

University of Illinois at Urbana-Champaign ( email )

601 E John St
Champaign, IL 61820
United States

Thomas A. Cooper

Baylor College of Medicine

Waco, TX 76798
United States

Emad Tajkhorshid

University of Illinois at Urbana-Champaign - Center for Biophysics and Computational Biology

601 E John St
Champaign, IL 61820
United States

University of Illinois at Urbana-Champaign - Beckman Institute for Advanced Science and Technology

601 E John St
Champaign, IL 61820
United States

Peter J. Mohler

Ohio State University (OSU)

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH OH 43210
United States

Auinash Kalsotra (Contact Author)

University of Illinois at Urbana-Champaign - Department of Biochemistry ( email )

United States

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