title: Pentamidine reverses the splicing defects associated with myotonic dystrophy.
abstract: Myotonic dystrophy (DM) is a genetic disorder caused by the expression (as RNA) of expanded CTG or CCTG repeats. The alternative splicing factor MBNL1 is sequestered to the expanded RNA repeats, resulting in missplicing of a subset of pre-mRNAs linked to symptoms found in DM patients. Current data suggest that if MBNL1 is released from sequestration, disease symptoms may be alleviated. We identified the small molecules pentamidine and neomycin B as compounds that disrupt MBNL1 binding to CUG repeats in vitro. We show in cell culture that pentamidine was able to reverse the missplicing of 2 pre-mRNAs affected in DM, whereas neomycin B had no effect. Pentamidine also significantly reduced the formation of ribonuclear foci in tissue culture cells, releasing MBNL1 from the foci in the treated cells. Furthermore, pentamidine partially rescued splicing defects of 2 pre-mRNAs in mice expressing expanded CUG repeats.
authors.affiliation: Department of Chemistry and Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
authors.forename: M Bryan
authors.initials: MB
authors.lastname: Warf
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Matthys
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Berglund
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D004195:Disease Models, Animal; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics*; D010419:Pentamidine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D012322:RNA Precursors / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects / Q000235:genetics
chemical_list: C493663:MBNL1 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D010419:Pentamidine