title: Mutations in the 3' untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis.
abstract: Mutations in the gene encoding fused-in-sarcoma (FUS) have been identified in a subset of patients with sporadic and familial amyotrophic lateral sclerosis (ALS). Variants in the 3' untranslated region (3'UTR) of FUS have also been reported in ALS patients, but their pathogenic role has not been assessed. We sequenced the whole 3'UTR of FUS in 420 ALS patients who were negative for mutations in the currently known ALS genes and in 480 ethnically matched controls. We detected four 3'UTR variants (c.*48 G>A, c.*59 G>A, c.*108 C>T and c.*110 G>A) in four sporadic and in one familial ALS patients compared with none in controls (P = 0.02).We investigated whether these variants impaired FUS expression in primary fibroblast cultures from three patients harbouring the c.*59 G>A, c.*108 C>T and c.*110 G>A variants, respectively. The pattern of FUS expression was also investigated in fibroblasts from one ALS patient with FUS R521C mutation, in two ALS patients without mutations in the known ALS genes and in four control individuals. By immunostaining and immunoblotting, large amounts of FUS were observed in both the cytoplasm and nuclei of mutant 3'UTR FUS fibroblasts. In FUS R521C mutant fibroblasts, we observed a slight increase of FUS in the cytoplasm associated with a remarkable loss of detection in nuclei. Our findings show that mutations in 3'UTR of FUS are overrepresented in ALS patients and result into translation de-regulation of FUS. Overexpression and mislocalization of wild-type FUS likely contribute to ALS pathogenesis in these cases.
authors.affiliation: Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Sabatelli
authors.forename: Alice
authors.initials: A
authors.lastname: Moncada
authors.forename: Amelia
authors.initials: A
authors.lastname: Conte
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marangi
authors.forename: Marco
authors.initials: M
authors.lastname: Luigetti
authors.forename: Matteo
authors.initials: M
authors.lastname: Lucchini
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirabella
authors.forename: Angela
authors.initials: A
authors.lastname: Romano
authors.forename: Alessandra
authors.initials: A
authors.lastname: Del Grande
authors.forename: Giulia
authors.initials: G
authors.lastname: Bisogni
authors.forename: Paolo Niccolo'
authors.initials: PN
authors.lastname: Doronzio
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Rossini
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D034702:RNA-Binding Protein FUS