Howard Hughes Medical Institute Research Laboratories, Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA.
Science. 2018 Aug 17;361(6403):709-712. doi: 10.1126/science.aas9963.
Mutations in the fragile X mental retardation 1 gene () cause the most common inherited human autism spectrum disorder. FMR1 influences messenger RNA (mRNA) translation, but identifying functional targets has been difficult. We analyzed quiescent oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that FMR1 enhances rather than represses the translation of mRNAs that overlap previously identified FMR1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets are associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Stored oocytes lacking FMR1 usually generate embryos with severe neural defects, unlike stored wild-type oocytes, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders.
脆性 X 智力低下 1 基因 () 的突变导致最常见的遗传性人类自闭症谱系障碍。FMR1 影响信使 RNA (mRNA) 的翻译，但确定功能靶标一直很困难。我们分析了静止的卵母细胞，它们与神经突触一样，严重依赖于翻译储存的 mRNA。核糖体分析显示，FMR1 增强而不是抑制与先前鉴定的 FMR1 靶标重叠的 mRNA 的翻译，并且优先作用于大蛋白。至少 20 个靶标的人类同源物与显性智力残疾有关，另外 30 个与隐性神经发育功能障碍有关。缺乏 FMR1 的储存卵母细胞通常产生严重神经缺陷的胚胎，与储存的野生型卵母细胞不同，这表明储存的 mRNA 翻译多个大蛋白在脆性 X 综合征和其他可能的自闭症谱系障碍中存在缺陷。
