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

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.

Key words::

• Amyotrophic lateral sclerosis
• fused in sarcoma
• truncation

Acknowledgements

The authors gratefully acknowledge the Patrick Berthoud Charitable Trust and the MND Association for funding, Peter Oliver for supplying the original constructs and Dirk Bäumer for providing exon 14 primers.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.