title: 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.
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford.
authors.forename: Louisa
authors.initials: L
authors.lastname: Kent
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Vizard
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Smith
authors.forename: Simon D
authors.initials: SD
authors.lastname: Topp
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Athina
authors.initials: A
authors.lastname: Gkazi
authors.forename: Jack
authors.initials: J
authors.lastname: Miller
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
mesh_terms: D000293:Adolescent; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D014162:Transfection; D055815:Young Adult
chemical_list: C489427:MYC protein, human; D039102:Poly(A)-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D034702:RNA-Binding Protein FUS
keywords: Amyotrophic lateral sclerosis; fused in sarcoma; truncation