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, and Auinash
Kalsotra.
Aberrant expression of a non-muscle RBFOX2 isoform triggers cardiac
conduction defects in myotonic dystrophy.
Developmental Cell, 52:748-763, 2020.
(PMC: PMC7098852)
MISR2020-ET
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 80the 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.
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