Pentamidine reverses the splicing defects associated with myotonic dystrophy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-11, Vol.106 (44), p.18551-18556
• Main Authors: Warf, M. Bryan, Nakamori, Masayuki, Matthys, Catherine M, Thornton, Charles A, Berglund, J. Andrew
• Format: Article
• Language: English
• Subjects: Alternative splicing; Alternative Splicing - drug effects; Animals; Biological Sciences; Cell culture; Disease Models, Animal; Dosage; Exons; Gels; Gene expression; Genetic disorders; HeLa Cells; Humans; Mice; Molecules; Myotonic dystrophy; Myotonic Dystrophy - drug therapy; Myotonic Dystrophy - genetics; P values; Pentamidine - chemistry; Pentamidine - pharmacology; Pentamidine - therapeutic use; Ribonucleic acid; RNA; RNA Precursors - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Rodents; Splicing; Trinucleotide Repeat Expansion - drug effects; Trinucleotide Repeat Expansion - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0903234106

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.