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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 publication




Journal article


Amyotroph Lateral Scler Frontotemporal Degener

Publication Date





557 - 562


Amyotrophic lateral sclerosis, fused in sarcoma, truncation, Adolescent, Aged, Amyotrophic Lateral Sclerosis, DNA Mutational Analysis, Disease Progression, Family Health, Female, Genetic Predisposition to Disease, HEK293 Cells, Humans, Male, Mutation, Poly(A)-Binding Proteins, Proto-Oncogene Proteins c-myc, RNA-Binding Protein FUS, Transfection, Young Adult