Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules

Jessica L. Childs-Disney, Ewa Stepniak-Konieczna, Tuan Tran, Ilyas Yildirim, Ha Jeung Park, Catherine Z. Chen, Jason Hoskins, Noel Southall, Juan J. Marugan, Samarjit Patnaik, Wei Zheng, Chris P. Austin, George C. Schatz, Krzysztof Sobczak, Charles A. Thornton, Matthew D. Disney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.

Original languageEnglish (US)
Article number2044
JournalNature communications
StatePublished - Jun 28 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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