Pentamidine reverses the splicing defects associated with myotonic dystrophy.
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.
Warf
M Bryan
MB
Department of Chemistry and Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Nakamori
Masayuki
M
Matthys
Catherine M
CM
Thornton
Charles A
CA
Berglund
J Andrew
JA
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
C493663:MBNL1 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D010419:Pentamidine