Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy
Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy
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DOI：
10.1126/science.280.5364.737
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发表时间：
1998-05-01
期刊：
影响因子：
56.9
通讯作者：
Cooper, TA
中科院分区：
文献类型：
--
作者：
Philips, AV;Timchenko, LT;Cooper, TA
强直性肌营养不良（DM）是由DM基因3'非翻译区的CTG扩增引起的。DM发病机制的一个模型表明，来自扩展等位基因的RNA通过蛋白质与CUG重复的不适当结合而产生功能获得性突变。这里提出的数据表明，保守的异质核核糖核蛋白，CUG结合蛋白（CUG-BP），可能介导的RNA的反式显性效应。CUG-BP被发现与人心肌肌钙蛋白T（cTNT）前信使RNA结合并调节其选择性剪接。在DM横纹肌和表达含有CUG重复序列的转录本的正常细胞中，cTNT的剪接被破坏。因此，CUG-BP转录后调节基因表达的改变可能有助于DM的发病机制。
Myotonic dystrophy (DM) is caused by a CTG expansion in the 3' untranslated region of the DM gene. One model of DM pathogenesis suggests that RNAs from the expanded allele create a gain-of-function mutation by the inappropriate binding of proteins to the CUG repeats. Data presented here indicate that the conserved heterogeneous nuclear ribonucleoprotein, CUG-binding protein (CUG-BP), may mediate the trans-dominant effect of the RNA. CUG-BP was found to bind to the human cardiac troponin T (cTNT) pre-messenger RNA and regulate its alternative splicing. Splicing of cTNT was disrupted in DM striated muscle and in normal cells expressing transcripts that contain CUG repeats. Altered expression of genes regulated posttranscriptionally by CUG-BP therefore may contribute to DM pathogenesis.