期刊
DEVELOPMENTAL CELL
卷 52, 期 6, 页码 748-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2020.01.037
关键词
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资金
- NIH [R01AR045653, R01HL045565, R01HL126845, R01HL134824, R35HL135754, P41-GM104601, R01-GM122420, R01GM123455]
- Muscular Dystrophy Association [MDA514335]
- American Heart Association [16POST29950018]
- NIH Tissue microenvironment training program [T32-EB019944]
- Beckman-Brown postdoctoral fellowship
- National Center for Supercomputing Applications at UIUC [ACI1713784]
Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the CTG repeat expansion in the 30 -untranslated region of DMPK gene. Heart dysfunctions occur in similar to 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 RBFOX2(40) 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 RBFOX2(40)-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 RBFOX2(40) isoform in DM1 cardiac pathogenesis.
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