TY - JOUR
T1 - Mutations in the 3′ untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis
AU - Sabatelli, Mario
AU - Moncada, Alice
AU - Contel, Amelia
AU - Lattante, Serena
AU - Marangi, Giuseppe
AU - Luigetti, Marco
AU - Lucchini, Matteo
AU - Mirabella, Massimiliano
AU - Romano, Angela
AU - Del Grande, Alessandra
AU - Bisogni, Giulia
AU - Doronzio, Paolo Niccolo
AU - Rossini, Paolo Maria
AU - Zollino, Marcella
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddt328
DO - 10.1093/hmg/ddt328
M3 - Article
C2 - 23847048
AN - SCOPUS:84887510924
VL - 22
SP - 4748
EP - 4755
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
M1 - ddt328
ER -