Disease Mechanisms of C9ORF72 Repeat Expansions
Disease Mechanisms of C9ORF72 Repeat Expansions
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DOI：
10.1101/cshperspect.a024224
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发表时间：
2018-04-01
影响因子：
5.4
通讯作者：
Petrucelli, Leonard
中科院分区：
文献类型：
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作者：
Gendron, Tania F.;Petrucelli, Leonard
C9 ORF 72基因内的G（4）C（2）重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。这些双向转录的扩增导致（1）含有正义G（4）C（2）和反义G（2）C（4）重复序列的RNA的积累，（2）通过这些转录物的非常规翻译产生重复二肽的蛋白质，和（3）降低C9 ORF 72 mRNA和蛋白质表达。因此，C9 ORF 72突变有足够的机会引起一系列临床表现，从肌无力和萎缩到行为和认知的变化。因此，这三个看似完全不同的事件的调查往往集中在类似的假定病理机制，这是有点令人惊讶。本文旨在总结该领域的研究结果和问题，以破译C9 ORF 72重复扩增如何导致统称为“c9 ALS/FTD”的毁灭性疾病。
G(4)C(2) repeat expansions within the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectional ly transcribed expansions lead to (1) the accumulation of sense G(4)C(2) and antisense G(2)C(4) repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreased C9ORF72 mRNA and protein expression. Consequently, there is ample opportunity for the C9ORF72 mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in behavior and cognition. It is thus somewhat surprising that investigations of these three seemingly disparate events often converge on similar putative pathological mechanisms. This review aims to summarize the findings and questions emerging from the field's quest to decipher how C9ORF72 repeat expansions cause the devastating diseases collectively referred to as "c9ALS/FTD".