Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy
Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy
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DOI：
10.1093/emboj/19.17.4439
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发表时间：
2000-09-01
期刊：
影响因子：
11.4
通讯作者：
Swanson, MS
中科院分区：
文献类型：
--
作者：
Miller, JW;Urbinati, CR;Swanson, MS
强直性肌营养不良（DM1）是一种常染色体显性遗传神经肌肉疾病，与DM1蛋白激酶（DMPK）基因3 '非翻译区的a（CTG）扩增相关。为了解释疾病的发病机制，RNA显性模型提出，DM1突变在RNA水平上产生功能获得，其中CUG重复序列形成RNA发夹，其隔离适当肌肉发育和维持所需的核因子。在这里，我们确定了三重重复扩增（EXP）RNA结合蛋白作为候选人的隔离因子。如RNA优势模型所预测的，EXP蛋白的结合对dsCUG RNA具有特异性，并且与三联体重复扩增的大小成比例。值得注意的是，EXP蛋白与果蝇肌肉和感光细胞终末分化所需的肌盲蛋白同源。EXP表达在哺乳动物成肌细胞分化过程中也被激活，但EXP蛋白在成肌细胞的核灶中积累。我们认为DM1疾病是由EXP蛋白异常募集到DMPK转录本（CUG）（n）扩增引起的。
Myotonic dystrophy (DM1) is an autosomal dominant neuromuscular disorder associated with a (CTG), expansion in the 3'-untranslated region of the DM1 protein kinase (DMPK) gene. To explain disease pathogenesis, the RNA dominance model proposes that the DM1 mutation produces a gain-of-function at the RNA level in which CUG repeats form RNA hairpins that sequester nuclear factors required for proper muscle development and maintenance. Here, we identify the triplet repeat expansion (EXP) RNA-binding proteins as candidate sequestered factors. As predicted by the RNA dominance model, binding of the EXP proteins is specific for dsCUG RNAs and proportional to the size of the triplet repeat expansion. Remarkably, the EXP proteins are homologous to the Drosophila muscleblind proteins required for terminal differentiation of muscle and photoreceptor cells. EXP expression is also activated during mammalian myoblast differentiation, but the EXP proteins accumulate in nuclear foci in DMI cells. We propose that DM1 disease is caused by aberrant recruitment of the EXP proteins to the DMPK transcript (CUG)(n) expansion.