Kwiatkowski T J, Bosco D A, Leclerc A L, Tamrazian E, Vanderburg C R, Russ C, Davis A, Gilchrist J, Kasarskis E J, Munsat T, Valdmanis P, Rouleau G A, Hosler B A, Cortelli P, de Jong P J, Yoshinaga Y, Haines J L, Pericak-Vance M A, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp P C, Horvitz H R, Landers J E, Brown R H
Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
Science. 2009 Feb 27;323(5918):1205-8. doi: 10.1126/science.1166066.
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
肌萎缩侧索硬化症（ALS）是一种致命的退行性运动神经元疾病。10%的病例是遗传性的；大多数涉及未确定的基因。我们在此报告了16号染色体上融合于肉瘤/脂肪肉瘤中翻译的（FUS/TLS）基因的13种突变，这些突变是家族性ALS所特有的。FUS/TLS蛋白与RNA结合，在多种过程中发挥作用，通常主要位于细胞核中。相比之下，FUS/TLS的突变形式在神经元细胞质中积累，这种病理现象与TAR DNA结合蛋白43（TDP43）基因的病理现象相似，TDP43的突变也会导致ALS。因此，神经元细胞质蛋白聚集和有缺陷的RNA代谢似乎是ALS以及可能其他神经退行性疾病共同的致病机制。
