@article{9b8c018c7d4b414a88fef98a1293797a,
title = "Aberrant Expression of a Non-muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy",
abstract = "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{\textemdash}due to altered splicing factor and microRNA activities{\textemdash}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.",
keywords = "myotonic dystrophy, alternative splicing, cardiac arrhythmias, genome editing, protein-RNA interactions, microRNA, ion channels, genomics, molecular dynamics",
author = "Chaitali Misra and Sushant Bangru and Feikai Lin and Kin Lam and Koenig, \{Sara N.\} and Lubbers, \{Ellen R.\} and Jamila Hedhli and Murphy, \{Nathaniel P.\} and Parker, \{Darren J.\} and Dobrucki, \{Lawrence W.\} and Cooper, \{Thomas A.\} and Emad Tajkhorshid and Mohler, \{Peter J.\} and Auinash Kalsotra",
note = "Funding Information: This research was supported through NIH ( R01HL126845 ) and Muscular Dystrophy Association ( MDA514335 ) grants to A.K., NIH ( R01HL134824 ; R35HL135754 ) to P.J.M., NIH ( P41-GM104601 , R01-GM122420 , and R01-GM123455 ) to E.T., and NIH ( R01AR045653 and R01HL045565 ) to T.A.C. C.M. was supported by American Heart Association post-doctoral fellowship ( 16POST29950018 ). S.B. was supported by the NIH Tissue microenvironment training program ( T32-EB019944 ). J.H. was supported by Beckman-Brown postdoctoral fellowship. All simulations were performed using the Blue Waters PRAC allocation (grant ACI1713784 to E.T.) of the National Center for Supercomputing Applications at UIUC . Three cores at UIUC supported this project: transgenic mouse facility core, high-throughput sequencing and genotyping core, and histology-microscopy core. Cardiovascular phenotyping was carried out in part in the Biomedical Imaging Center at the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign and in the Mouse Cardiovascular Phenotyping Core at the Washington University School of Medicine , St. Louis, MO. Funding Information: This research was supported through NIH (R01HL126845) and Muscular Dystrophy Association (MDA514335) grants to A.K. NIH (R01HL134824; R35HL135754) to P.J.M. NIH (P41-GM104601, R01-GM122420, and R01-GM123455) to E.T. and NIH (R01AR045653 and R01HL045565) to T.A.C. C.M. was supported by American Heart Association post-doctoral fellowship (16POST29950018). S.B. was supported by the NIH Tissue microenvironment training program (T32-EB019944). J.H. was supported by Beckman-Brown postdoctoral fellowship. All simulations were performed using the Blue Waters PRAC allocation (grant ACI1713784 to E.T.) of the National Center for Supercomputing Applications at UIUC. Three cores at UIUC supported this project: transgenic mouse facility core, high-throughput sequencing and genotyping core, and histology-microscopy core. Cardiovascular phenotyping was carried out in part in the Biomedical Imaging Center at the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign and in the Mouse Cardiovascular Phenotyping Core at the Washington University School of Medicine, St. Louis, MO. C.M. S.B. and A.K. conceived the project and designed the experiments. C.M. S.B. F.L. K.L. D.J.P. S.N.K. E.R.L. N.P.M. J.H. and L.W.D. performed experiments. T.A.C. and P.J.M. provided reagents. C.M. S.B. K.L. S.N.K. E.R.L. N.P.M. E.T. P.J.M. and A.K. interpreted results and wrote the manuscript. All authors discussed the results and edited the manuscript. The authors declare no competing interests.",
year = "2020",
month = mar,
day = "23",
doi = "10.1016/j.devcel.2020.01.037",
language = "English (US)",
volume = "52",
pages = "748--763.e6",
journal = "Developmental cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",
}