Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene

作者：Kent Louisa; Vizard Thomas N; Smith Bradley N; Topp Simon D; Vance Caroline; Gkazi Athina; Miller Jack; Shaw Christopher E; Talbot Kevin^*

来源：Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014, 15(7-8): 557-562.

DOI：10.3109/21678421.2014.920033

• Amyotrophic lateral sclerosis
• fused in sarcoma
• truncation

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.

• 出版日期2014-12