HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy
Moyi Li, Yan Zhuang, Ranjan Batra, James D. Thomas, Li Mao, Curtis A. Nutter, Marina M. Scotti, Helmut A. Carter, Zhan Jun Wang, Xusheng Huang, Chuan Qiang Pu, Maurice S. Swanson, Wei Xie
Abstract
Significance Myotonic dystrophy type 1 (DM1) is a model for RNA-mediated disease in microsatellite expansion disorders. DM1 is caused by CTG expansions (CTG exp ) and expression of CUG exp RNAs that sequester muscleblind-like (MBNL) proteins, while also triggering hyperphosphorylation of CUGBP1/ETR3-like factor 1 (CELF1). These proteins regulate developmental transitions in RNA processing, so DM1 is characterized by retention of fetal RNA processing patterns in adults. Although current evidence indicates that CELF1 is a specific antagonist of MBNL activity, this study reveals that another protein, HNRNPA1, is also downregulated during normal development but upregulated in DM1, where it also induces fetal splicing shifts. Thus, DM1 disease results from an imbalance in the expression of multiple RNA processing factors important for both proliferation and differentiation.