Pathogenic mechanisms of myotonic dystrophy.
Pathogenic mechanisms of myotonic dystrophy.
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DOI：
10.1042/bst0371281
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发表时间：
2009-12
影响因子：
3.9
通讯作者：
Cooper TA
中科院分区：
文献类型：
--
作者：
Lee JE;Cooper TA
DM（强直性肌营养不良）是一种显性遗传性遗传疾病，是成人肌营养不良症的最常见原因，影响全球1/8500的个体。两个位点的不同微卫星扩增导致具有相似特征的不同形式的疾病：DM 1（DM 1型）由DMPK（肌强直性营养不良蛋白激酶）3′-非翻译区内的三（CTG）核苷酸扩增引起，DM 2（DM 2型）由ZNF 9（锌指9）基因内含子1内的四（CCTG）核苷酸扩增引起。该疾病的致病机制涉及从含有（CUG）n或（CCUG）n的长片段的扩增等位基因转录的RNA。RNA通过两种RNA结合蛋白产生毒性作用：MBNL 1（muscleblind-like 1）和CUGBP 1（CUG结合蛋白1）。在DM 1中，MBNL 1被隔离在含有CUG重复序列的RNA上，导致其功能丧失，而CUGBP 1通过信号传导途径上调。下游效应包括对选择性剪接、mRNA翻译和mRNA稳定性的破坏调节，这有助于DM 1的多种特征。本文就RNA功能获得性疾病的发病机制、MBNL 1和CUGBP 1在DM 1中的重要作用以及与其他RNA显性疾病的相关性进行综述。
DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)n or (CCUG)n. The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.