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 s...

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Bibliographic Details
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0903234106