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

Louisa Kent, Thomas N. Vizard, Bradley N. Smith, Simon D. Topp, Caroline Vance, Athina Gkazi, Jack Miller, Christopher E. Shaw, Kevin Talbot*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)557-562
Number of pages6
JournalAmyotrophic lateral sclerosis & frontotemporal degeneration
Volume15
Issue number7-8
DOIs
Publication statusPublished - 1 Dec 2014

Keywords

  • Amyotrophic lateral sclerosis
  • Fused in sarcoma
  • Truncation

Fingerprint

Dive into the research topics of 'Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene'. Together they form a unique fingerprint.

Cite this