INSERM U781, Université Paris Descartes, Hôpital Necker Enfants Malades, 156 rue de Vaugirard, Paris Cedex 15, France.
Hum Mol Genet. 2011 Oct 15;20(R2):R116-23. doi: 10.1093/hmg/ddr343. Epub 2011 Aug 5.
Expanded, non-coding RNAs can exhibit a deleterious gain-of-function causing human disease through abnormal interactions with RNA-binding proteins. Myotonic dystrophy (DM), the prototypical example of an RNA-dominant disorder, is mediated by trinucleotide repeat-containing transcripts that deregulate alternative splicing. Spliceopathy has therefore been a major focus of DM research. However, changes in gene expression, protein translation and micro-RNA metabolism may also contribute to disease pathology. The exciting finding of bidirectional transcription and non-conventional RNA translation of trinucleotide repeat sequences points to a new scenario, in which DM is not mediated by one single expanded RNA transcript, but involves multiple pathogenic elements and pathways. The study of the growing number of human diseases associated with toxic repeat-containing transcripts provides important insight into the understanding of the complex pathways of RNA toxicity. This review describes some of the recent advances in the understanding of the molecular mechanisms behind DM and other RNA-dominant disorders.
扩展的非编码 RNA 可以通过与 RNA 结合蛋白的异常相互作用表现出有害的获得性功能，从而导致人类疾病。肌强直性营养不良 (DM) 是 RNA 主导疾病的典型范例，由三核苷酸重复序列转录本介导，这些转录本会使选择性剪接失调。因此，剪接病已成为 DM 研究的主要焦点。然而，基因表达、蛋白质翻译和 micro-RNA 代谢的变化也可能导致疾病病理。三核苷酸重复序列的双向转录和非传统 RNA 翻译的令人兴奋的发现表明了一种新的情况，即 DM 不是由单个扩展的 RNA 转录本介导，而是涉及多个致病元件和途径。对与毒性重复序列相关的越来越多的人类疾病的研究为理解 RNA 毒性的复杂途径提供了重要的见解。本文综述了对 DM 和其他 RNA 主导疾病背后的分子机制的一些最新认识。
