【译文】脆性X染色体综合症(FXS)是一种多器官疾病,它会导致智力发育迟缓、男性巨睾丸症以及女性带菌者早熟卵巢功能不全。FXS也是一种与自闭症谱系障碍(ASD)相关的显著单基因病。FXS主要是由脆性X智力低下1号基因(FMR1)表达的缺失引起的,FMR1编码RNA结合蛋白FMRP。本研究发现了与FMRP两种独立RNA结合结构域相对应的不同RNA识别元件,除了野生型和I304N突变的FMRP亚型以及FMRP类似物FXR1P 和FXR2P信使RNA靶点内的结合位点。RNA识别元件频率、比例以及分布决定了靶mRNA与FMRP之间的关系。在高度丰富的靶点中,我们鉴定出了许多与ASD相关的基因,并标明在人细胞、小鼠卵巢和人脑中FMRP会影响它们的蛋白水平。 值得注意的是,我们发现这些靶点也在表现出早熟卵泡发育过度的Fmr1−/−小鼠卵巢中失调。这些结果表明不同细胞背景,FMRP靶点共享信号通路。由于FXS和ASD中信号通路的重要性日益突出,我们的结果为这些神经疾病新的治疗靶点的选择提供了基因清单作为基础。


[Title]: FMRP targets distinct mRNA sequence elements to regulate protein expression

[Authors]:Manuel Ascano,1 Neelanjan Mukherjee,2, 5 Pradeep Bandaru,1 Jason B. Miller,1 Jeffrey D. Nusbaum,1 David L. Corcoran,2 Christine Langlois,3 Mathias Munschauer,1 Scott Dewell,4 Markus Hafner,1 Zev Williams,1, 3 Uwe Ohler2, 5 & Thomas Tuschl1

[Abstract]Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP. Among highly enriched targets, we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1−/− mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders.


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