Overexpression of CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 but Not from Myotonic Dystrophy Type 2
Overexpression of CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 but Not from Myotonic Dystrophy Type 2
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DOI：
10.1371/journal.pone.0083777
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发表时间：
2013-12-20
期刊：
影响因子：
3.7
通讯作者：
Meola, Giovanni
中科院分区：
文献类型：
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作者：
Cardani, Rosanna;Bugiardini, Enrico;Meola, Giovanni
强直性肌营养不良1型（DM1）和2型（DM2）是由两个不同的遗传基因座的相似突变引起的进行性多系统疾病。DM发病机制的共同关键特征是突变RNA的核积累，其通过改变两种RNA结合蛋白MBNL1和CUGBP1的功能而引起特异性前mRNA的异常选择性剪接。然而，DM1和DM2显示出疾病特异性特征，使它们清楚地分离疾病，这表明可能涉及其他细胞和分子途径。在这项研究中，我们分析了组织病理学和生物分子特征的骨骼肌活检从DM 1和DM 2患者的表型，以更好地定义分子发病机制。特别是，CUGBP1蛋白的表达已被检查，以澄清该因子是否可作为DM中疾病特异性表现的修饰剂。结果表明，所观察到的剪接和肌肉病理学改变与DM 1和DM 2中的临床表型相关，并且CUGBP1似乎在经典DM 1中起作用，但在DM 2中不起作用。总之，我们的研究结果表明，DM病理的多系统疾病谱可能不能仅用剪接病变来解释，从而证实了DM的分子病理机制比实际所建议的更为复杂。
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations a two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested.