Pentamidine Reverses the Splicing Defects Associated with Myotonic Dystrophy

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Oct 14

PMID 19822739

Citations 153

Authors

M Bryan Warf

Masayuki Nakamori

Catherine M Matthys

Charles A Thornton

J Andrew Berglund

Affiliations

Soon will be listed here.

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.

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