Pentamidine reverses the splicing defects associated with myotonic dystrophy
Pentamidine reverses the splicing defects associated with myotonic dystrophy
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DOI：
10.1073/pnas.0903234106
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发表时间：
2009-11-03
影响因子：
11.1
通讯作者：
Berglund, J. Andrew
中科院分区：
文献类型：
--
作者：
Warf, M. Bryan;Nakamori, Masayuki;Berglund, J. Andrew
肌强直性营养不良（DM）是一种由扩增的CTG或CCTG重复序列（如RNA）表达引起的遗传性疾病。替代剪接因子MBNL1被隔离到扩展的RNA重复序列上，导致与糖尿病患者症状相关的前mrna亚群剪接错误。目前的数据表明，如果MBNL1从隔离中释放出来，疾病症状可能会减轻。我们在体外鉴定出小分子戊脒和新霉素B是破坏MBNL1与CUG重复序列结合的化合物。我们在细胞培养中发现，pentamidine能够逆转DM中受影响的2个前mrna的错误剪接，而新霉素B没有作用。喷他脒还显著减少了组织培养细胞中核糖核灶的形成，并从处理细胞中的灶中释放出MBNL1。此外，喷他脒在表达扩增CUG重复序列的小鼠中部分修复了2个前mrna的剪接缺陷。
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.