Department of Pathology, University of Virginia, Charlottesville, VA, USA.
Hum Mol Genet. 2019 Jul 15;28(14):2330-2338. doi: 10.1093/hmg/ddz065.
Myotonic dystrophy type 1 (DM1) is caused by an expanded (CTG)n tract in the 3'UTR of the DM protein kinase (DMPK) gene. The RNA transcripts produced from the expanded allele sequester or alter the function of RNA-binding proteins (MBNL1, CUGBP1, etc.). The sequestration of MBNL1 results in RNA-splicing defects that contribute to disease. Overexpression of MBNL1 in skeletal muscle has been shown to rescue some of the DM1 features in a mouse model and has been proposed as a therapeutic strategy for DM1. Here, we sought to confirm if overexpression of MBNL1 rescues the phenotypes in a different mouse model of RNA toxicity. Using an inducible mouse model of RNA toxicity in which expression of the mutant DMPK 3'UTR results in RNA foci formation, MBNL1 sequestration, splicing defects, myotonia and cardiac conduction defects, we find that MBNL1 overexpression did not rescue skeletal muscle function nor beneficially affect cardiac conduction. Surprisingly, MBNL1 overexpression also did not rescue myotonia, though variable rescue of Clcn1 splicing and other splicing defects was seen. Additionally, contrary to the previous study, we found evidence for increased muscle histopathology with MBNL1 overexpression. Overall, we did not find evidence for beneficial effects from overexpression of MBNL1 as a means to correct RNA toxicity mediated by mRNAs containing an expanded DMPK 3'UTR.
1 型肌强直性营养不良（DM1）是由 DM 蛋白激酶（DMPK）基因 3'UTR 中扩展的（CTG）n 重复序列引起的。从扩展等位基因产生的 RNA 转录本隔离或改变 RNA 结合蛋白（MBNL1、CUGBP1 等）的功能。MBNL1 的隔离导致 RNA 剪接缺陷，这有助于疾病的发生。在骨骼肌中过表达 MBNL1 已被证明可以挽救小鼠模型中的一些 DM1 特征，并被提议作为 DM1 的治疗策略。在这里，我们试图确认在另一种 RNA 毒性的小鼠模型中过表达 MBNL1 是否可以挽救表型。使用一种可诱导的 RNA 毒性小鼠模型，其中突变 DMPK 3'UTR 的表达导致 RNA 焦点形成、MBNL1 隔离、剪接缺陷、肌强直和心脏传导缺陷，我们发现 MBNL1 过表达不能挽救骨骼肌功能，也不能对心脏传导产生有益影响。令人惊讶的是，MBNL1 过表达也不能挽救肌强直，尽管观察到 Clcn1 剪接和其他剪接缺陷的可变挽救。此外，与之前的研究相反，我们发现证据表明 MBNL1 过表达会增加肌肉组织病理学。总的来说，我们没有发现过表达 MBNL1 作为纠正含有扩展 DMPK 3'UTR 的 mRNAs 介导的 RNA 毒性的方法的有益效果的证据。
