Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons
Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons
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DOI：
10.1093/hmg/ddh327
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发表时间：
2004-12-15
影响因子：
3.5
通讯作者：
Thornton, CA
中科院分区：
文献类型：
--
作者：
Jiang, H;Mankodi, A;Thornton, CA
强直性肌营养不良1型（DM 1）是由DMPK基因中CTG重复序列扩增引起的。在骨骼肌中，DM 1可能涉及一种新的RNA显性疾病机制，其中来自突变DMPK等位基因的转录物在细胞核中积累并损害选择性剪接的调节。在这里，我们展示了大脑中类似疾病机制的证据。通过荧光原位杂交对死后DM 1组织的检查表明，在3 '-非翻译区具有扩展的CUG重复序列的突变DMPK mRNA在皮质和皮质下神经元中广泛表达。突变体转录物在神经元核内的离散病灶中积累。肌盲家族中的蛋白质被募集到RNA灶中，并在核质的其他地方耗尽。与此同时，神经元前mRNA的一个子集显示出异常调节的选择性剪接。这些观察结果表明，DM 1的CNS损伤可能是由于突变DMPK mRNA的有害功能获得所致。
Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene. In skeletal muscles, DM1 may involve a novel, RNA-dominant disease mechanism in which transcripts from the mutant DMPK allele accumulate in the nucleus and compromise the regulation of alternative splicing. Here we show evidence for a similar disease mechanism in brain. Examination of post-mortem DM1 tissue by fluorescence in situ hybridization indicates that the mutant DMPK mRNA, with its expanded CUG repeat in the 3'-untranslated region, is widely expressed in cortical and subcortical neurons. The mutant transcripts accumulate in discrete foci within neuronal nuclei. Proteins in the muscleblind family are recruited into the RNA foci and depleted elsewhere in the nucleoplasm. In parallel, a subset of neuronal pre-mRNAs show abnormal regulation of alternative splicing. These observations suggest that CNS impairment in DM1 may result from a deleterious gain-of-function by mutant DMPK mRNA.