Kent Louisa, Vizard Thomas N, Smith Bradley N, Topp Simon D, Vance Caroline, Gkazi Athina, Miller Jack, Shaw Christopher E, Talbot Kevin
Nuffield Department of Clinical Neurosciences, University of Oxford.
Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7-8):557-62. doi: 10.3109/21678421.2014.920033. Epub 2014 Jun 5.
Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) account for 4 - 5% of familial cases of amyotrophic lateral sclerosis (ALS). We describe the identification and in vitro cellular characterization of a genetic mutation in a family in which the index case, and subsequently her two children, each developed rapidly progressive ALS at a young age and died within a year of onset. Exome capture and sequencing revealed a mutation in the FUS gene consisting of a 2-bp deletion, c.1509_1510delAG, resulting in a predicted truncated protein, p.G504Wfs * 12, lacking the nuclear localization signal. Expression of this mutation in HEK293 and NSC-34 cells demonstrated severe cytoplasmic mislocalization of mutant FUS, and colocalization with stress granules when compared to wild-type, R521C and P525L mutant FUS. This study provides further evidence of a broad correlation between clinical severity of FUS-related ALS and mislocalization of the protein to the cytoplasm.
编码与肉瘤融合的RNA结合蛋白（FUS）的基因发生突变，在家族性肌萎缩侧索硬化症（ALS）病例中占4%-5%。我们描述了一个家族中基因突变的鉴定及体外细胞特征，该家族的先证者及其两个孩子均在年轻时患快速进展性ALS，并在发病后一年内死亡。外显子捕获和测序显示FUS基因存在一个由2个碱基对缺失组成的突变，即c.1509_1510delAG，导致预测的截短蛋白p.G504Wfs*12，缺乏核定位信号。该突变在HEK293和NSC-34细胞中的表达表明，与野生型、R521C和P525L突变型FUS相比，突变型FUS严重错定位于细胞质中，并与应激颗粒共定位。本研究进一步证明了FUS相关ALS的临床严重程度与蛋白错定位于细胞质之间存在广泛关联。
