Pentamidine reverses the splicing defects associated with myotonic dystrophy
- M. Bryan Warfa,1,
- Masayuki Nakamorib,1,
- Catherine M. Matthysa,
- Charles A. Thorntonb and
- J. Andrew Berglunda,2
- aDepartment of Chemistry and Institute of Molecular Biology, University of Oregon, Eugene, OR 97403; and
- bDepartment of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642
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Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved September 9, 2009
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↵1M.B.W. and M.N. contributed equally to this work. (received for review March 25, 2009)
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.
Footnotes
- 2To whom correspondence should be addressed. E-mail: aberglund{at}molbio.uoregon.edu
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Author contributions: M.B.W., M.N., C.M.M., C.A.T., and J.A.B. designed research; M.B.W., M.N., and C.M.M. performed research; M.B.W. contributed new reagents/analytic tools; M.B.W., M.N., C.M.M., C.A.T., and J.A.B. analyzed data; and M.B.W. and J.A.B. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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See Commentary on page 18433.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0903234106/DCSupplemental.
