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

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

Research output: Contribution to journalArticlepeer-review


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 matchedcontrols.Wedetected four 3′UTRvariants (c.*48G>A, c.*59G>A, c.*108C>Tand c.*110G>A) in four sporadic and in one familial ALS patients compared with none in controls (P 5 0.02).We investigated whether these variants impaired FUS expression in primary fibroblast cultures from three patients harbouring the c.*59G>A, c.*108 C>T and c.*110G>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 theknownALSgenes and in four control individuals.Byimmunostaining 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,weobserved a slight increase ofFUSin the cytoplasmassociated 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.

Original languageEnglish
Article numberddt328
Pages (from-to)4748-4755
Number of pages8
JournalHuman Molecular Genetics
Issue number23
Publication statusPublished - Dec 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


Dive into the research topics of 'Mutations in the 3′ untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this