Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene. Issue 7 (December 2014)

• Record Type: Journal Article
• Authors: Kent, Louisa; Vizard, Thomas N.; Smith, Bradley N.; Topp, Simon D.; Vance, Caroline; Gkazi, Athina; Miller, Jack; Shaw, Christopher E.; Talbot, Kevin
• Is Part Of: Amyotrophic lateral sclerosis and frontotemporal degeneration. Volume 15:Issue 7/8(2014)
• Page Start: 557
• Page End: 562
• Publication Date: 2014-12
• Subjects: 616.839
• DOI: 10.3109/21678421.2014.920033
• Languages: English
• ISSNs: 2167-8421

Abstract

<abstract> <title>Abstract</title> <p>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.</p> </abstract>