Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila
Myotonic dystrophy associated expanded CUG repeat muscleblind positive ribonuclear foci are not toxic to Drosophila
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DOI：
10.1093/hmg/ddi080
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发表时间：
2005-03-15
影响因子：
3.5
通讯作者：
Monckton, DG
中科院分区：
文献类型：
--
作者：
Houseley, JM;Wang, Z;Monckton, DG
1型肌强直性营养不良是一种常染色体显性遗传病，与DMPK基因30非翻译区（UTR） CTG重复扩增有关。最近的数据表明，发病机制主要是由突变转录物的功能获得介导的。在患者中，这些扩增的含有CUG重复序列的转录本被隔离到含有肌盲样蛋白的核糖核灶中。为了进一步了解肌盲功能和肌强直性营养不良的发病机制，我们在一个报告基因的3'-UTR中产生了含有CTG重复序列的果蝇。在患者中，扩大的CUG重复序列在果蝇肌肉细胞中形成离散的核灶，与肌盲共定位。然而，出乎意料的是，并不是在所有的细胞类型中都观察到病灶，肌盲对于它们的形成既不是必要的，也不是充分的。病灶是动态的瞬态结构，半衰期短，不与蛋白酶体共定位，这表明它们不太可能含有折叠错误的蛋白质。然而，它们确实与非a共定位，其人类同源物涉及RNA剪接和dsRNA附着到核基质上。肌肉盲也被发现在稳定CUG转录本中具有以前未被认识到的作用。最有趣的是，表达（CUG）（162）重复序列的果蝇没有可检测到的病理表型，这表明与扩增的含聚谷氨酰胺蛋白相比，扩增的CUG重复序列RNA和核糖核病灶都没有直接毒性。
Myotonic dystrophy type 1 is an autosomal dominant disorder associated with the expansion of a CTG repeat in the 30 untranslated region (UTR) of the DMPK gene. Recent data suggest that pathogenesis is predominantly mediated by a gain of function of the mutant transcript. In patients, these expanded CUG repeat-containing transcripts are sequestered into ribonuclear foci that also contain the muscleblind-like proteins. To provide further insights into muscleblind function and the pathogenesis of myotonic dystrophy, we generated Drosophila incorporating CTG repeats in the 3'-UTR of a reporter gene. As in patients, expanded CUG repeats form discrete ribonuclear foci in Drosophila muscle cells that co-localize with muscleblind. Unexpectedly, however, foci are not observed in all cell types and muscleblind is neither necessary nor sufficient for their formation. The foci are dynamic transient structures with short half- lifes that do not co- localize with the proteasome, suggesting they are unlikely to contain mis- folded proteins. However, they do co- localize with non-A, the human orthologs of which are implicated in both RNA splicing and attachment of dsRNA to the nuclear matrix. Muscleblind is also revealed as having a previously unrecognized role in stabilizing CUG transcripts. Most interestingly, Drosophila expressing (CUG)(162) repeats has no detectable pathological phenotype suggesting that in contrast to expanded polyglutamine- containing proteins, neither the expanded CUG repeat RNA nor the ribonuclear foci are directly toxic.