Tuffery-Giraud Sylvie, Miro Julie, Koenig Michel, Claustres Mireille
Laboratoire de Génétique de Maladies Rares (LGMR, EA7402), University of Montpellier, Institut Universitaire de Recherche Clinique (IURC), 641 av du Doyen G. Giraud, Montpellier, Cedex 5, 34093, France.
Laboratoire de Génétique Moléculaire, CHU Montpellier, Montpellier, France.
Hum Genet. 2017 Sep;136(9):1155-1172. doi: 10.1007/s00439-017-1820-9. Epub 2017 Jun 9.
Splicing of pre-mRNA is a crucial regulatory stage in the pathway of gene expression controlled by multiple post- and co-transcriptional mechanisms. The large Duchenne muscular dystrophy gene encoding the protein dystrophin provides a striking example of the complexity of human pre-mRNAs. In this review, we summarize the current state of knowledge about canonical and non-canonical splicing in the DMD pre-mRNA, with a focus on mechanisms that take place in the full-length transcript isoform expressed in human skeletal muscle. In particular, we highlight recent work demonstrating that multi-step events are required for long DMD intron removal. The role of temporary intron retention in the occurrence of alternative splicing events is also discussed. Even though the proportion of splicing mutations is lower than reported in other genes, a great diversity of splicing defects linked to point mutations, but also large genomic rearrangements are observed in the DMD gene. We provide an overview of the molecular mechanisms underlying aberrant splicing in patients with Duchenne or Becker muscular dystrophy, and we also detail how alternative splicing can serve as a disease modifier in patients by changing the outcome of the primary defect.
前体mRNA的剪接是由多种转录后和共转录机制控制的基因表达途径中的一个关键调控阶段。编码抗肌萎缩蛋白的大型杜兴氏肌营养不良基因是人类前体mRNA复杂性的一个显著例子。在这篇综述中，我们总结了关于杜兴肌营养不良症（DMD）前体mRNA中典型和非典型剪接的当前知识状态，重点关注在人类骨骼肌中表达的全长转录本异构体中发生的机制。特别是，我们强调了最近的研究工作，这些研究表明去除长DMD内含子需要多步骤事件。还讨论了临时内含子保留在可变剪接事件发生中的作用。尽管剪接突变的比例低于其他基因的报道，但在DMD基因中观察到与点突变相关的多种剪接缺陷，以及大型基因组重排。我们概述了杜兴或贝克型肌营养不良症患者异常剪接的分子机制，还详细阐述了可变剪接如何通过改变原发性缺陷的结果而成为患者的疾病修饰因子。
