Mutations in the 3' untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis

Mario Sabatelli, Giuseppe Marangi, Matteo Lucchini, Massimiliano Mirabella, Marcella Zollino, Alice Moncada, Amelia Conte, Serena Lattante, Marco Luigetti, Angela Romano, Alessandra Del Grande, Giulia Bisogni, Paolo Maria Rossini

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

63 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)4748-4755
Numero di pagine8
RivistaHUMAN MOLECULAR GENETICS
Volume22
DOI
Stato di pubblicazionePubblicato - 2013

Keywords

  • 3'-UTR
  • Amyotrophic lateral sclerosis
  • FUS

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