Mutations of FUS gene in sporadic amyotrophic lateral sclerosis

Lucia Corrado, Roberto Del Bo, Barbara Castellotti, Antonia Ratti, Cristina Cereda, Silvana Penco, Gianni Sorarù, Yari Carlomagno, Serena Ghezzi, Viviana Pensato, Claudia Colombrita, Stella Gagliardi, Lorena Cozzi, Valeria Orsetti, Michelangelo Mancuso, Gabriele Siciliano, Letizia Mazzini, Giacomo Pietro Comi, Cinzia Gellera, Mauro CeroniSandra D'Alfonso, Vincenzo Silani

Research output: Contribution to journalArticle

Abstract

Background Mutations in the FUS gene have recently been discovered to be a major cause of familial amyotrophic lateral sclerosis (FALS). Objective To determine the identity and frequency of FUS gene mutations in a large cohort of Italian patients enriched in sporadic cases (SALS). Methods Exons 5, 6, 14 and 15 of the FUS gene were screened for mutations in 1009 patients (45 FALS and 964 SALS). The genetic analysis was extended to the entire coding sequence of FUS in all the FALS and 293 of the SALS patients. Results Seven missense mutations (p.G191S, p.R216C, p.G225V, p.G230C, p.R234C, p.G507D and p.R521C) were identified in nine patients (seven SALS and two FALS), and none in 500 healthy Italian controls. All mutations are novel except for the p.R521C mutation identified in one SALS and one FALS case. Both patients showed a similar unusual presentation, with proximal, mostly symmetrical, upper limb weakness, with neck and axial involvement. With the exception of p.G507D and p.R521C, the mutations identified in SALS patients are all localised in the glycine-rich region encoded by exon 6. In addition, eight different in-frame deletions in two polyglycine motifs were detected, the frequency of which was not significantly different in patients and controls. Conclusions The results show that FUS missense mutations are present in 0.7% of Italian SALS cases, and confirm the previous mutational frequency reported in FALS (4.4%). An unusual proximal and axial clinical presentation seems to be associated with the presence of the p.R521C mutation.

Original languageEnglish
Pages (from-to)190-194
Number of pages5
JournalJournal of Medical Genetics
Volume47
Issue number3
DOIs
Publication statusPublished - Mar 2010

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Mutation
Genes
Missense Mutation
Exons
Amyotrophic lateral sclerosis 1
Gene Frequency
Upper Extremity
Glycine
Neck

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mutations of FUS gene in sporadic amyotrophic lateral sclerosis. / Corrado, Lucia; Del Bo, Roberto; Castellotti, Barbara; Ratti, Antonia; Cereda, Cristina; Penco, Silvana; Sorarù, Gianni; Carlomagno, Yari; Ghezzi, Serena; Pensato, Viviana; Colombrita, Claudia; Gagliardi, Stella; Cozzi, Lorena; Orsetti, Valeria; Mancuso, Michelangelo; Siciliano, Gabriele; Mazzini, Letizia; Comi, Giacomo Pietro; Gellera, Cinzia; Ceroni, Mauro; D'Alfonso, Sandra; Silani, Vincenzo.

In: Journal of Medical Genetics, Vol. 47, No. 3, 03.2010, p. 190-194.

Research output: Contribution to journalArticle

Corrado, L, Del Bo, R, Castellotti, B, Ratti, A, Cereda, C, Penco, S, Sorarù, G, Carlomagno, Y, Ghezzi, S, Pensato, V, Colombrita, C, Gagliardi, S, Cozzi, L, Orsetti, V, Mancuso, M, Siciliano, G, Mazzini, L, Comi, GP, Gellera, C, Ceroni, M, D'Alfonso, S & Silani, V 2010, 'Mutations of FUS gene in sporadic amyotrophic lateral sclerosis', Journal of Medical Genetics, vol. 47, no. 3, pp. 190-194. https://doi.org/10.1136/jmg.2009.071027
Corrado, Lucia ; Del Bo, Roberto ; Castellotti, Barbara ; Ratti, Antonia ; Cereda, Cristina ; Penco, Silvana ; Sorarù, Gianni ; Carlomagno, Yari ; Ghezzi, Serena ; Pensato, Viviana ; Colombrita, Claudia ; Gagliardi, Stella ; Cozzi, Lorena ; Orsetti, Valeria ; Mancuso, Michelangelo ; Siciliano, Gabriele ; Mazzini, Letizia ; Comi, Giacomo Pietro ; Gellera, Cinzia ; Ceroni, Mauro ; D'Alfonso, Sandra ; Silani, Vincenzo. / Mutations of FUS gene in sporadic amyotrophic lateral sclerosis. In: Journal of Medical Genetics. 2010 ; Vol. 47, No. 3. pp. 190-194.
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abstract = "Background Mutations in the FUS gene have recently been discovered to be a major cause of familial amyotrophic lateral sclerosis (FALS). Objective To determine the identity and frequency of FUS gene mutations in a large cohort of Italian patients enriched in sporadic cases (SALS). Methods Exons 5, 6, 14 and 15 of the FUS gene were screened for mutations in 1009 patients (45 FALS and 964 SALS). The genetic analysis was extended to the entire coding sequence of FUS in all the FALS and 293 of the SALS patients. Results Seven missense mutations (p.G191S, p.R216C, p.G225V, p.G230C, p.R234C, p.G507D and p.R521C) were identified in nine patients (seven SALS and two FALS), and none in 500 healthy Italian controls. All mutations are novel except for the p.R521C mutation identified in one SALS and one FALS case. Both patients showed a similar unusual presentation, with proximal, mostly symmetrical, upper limb weakness, with neck and axial involvement. With the exception of p.G507D and p.R521C, the mutations identified in SALS patients are all localised in the glycine-rich region encoded by exon 6. In addition, eight different in-frame deletions in two polyglycine motifs were detected, the frequency of which was not significantly different in patients and controls. Conclusions The results show that FUS missense mutations are present in 0.7{\%} of Italian SALS cases, and confirm the previous mutational frequency reported in FALS (4.4{\%}). An unusual proximal and axial clinical presentation seems to be associated with the presence of the p.R521C mutation.",
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T1 - Mutations of FUS gene in sporadic amyotrophic lateral sclerosis

AU - Corrado, Lucia

AU - Del Bo, Roberto

AU - Castellotti, Barbara

AU - Ratti, Antonia

AU - Cereda, Cristina

AU - Penco, Silvana

AU - Sorarù, Gianni

AU - Carlomagno, Yari

AU - Ghezzi, Serena

AU - Pensato, Viviana

AU - Colombrita, Claudia

AU - Gagliardi, Stella

AU - Cozzi, Lorena

AU - Orsetti, Valeria

AU - Mancuso, Michelangelo

AU - Siciliano, Gabriele

AU - Mazzini, Letizia

AU - Comi, Giacomo Pietro

AU - Gellera, Cinzia

AU - Ceroni, Mauro

AU - D'Alfonso, Sandra

AU - Silani, Vincenzo

PY - 2010/3

Y1 - 2010/3

N2 - Background Mutations in the FUS gene have recently been discovered to be a major cause of familial amyotrophic lateral sclerosis (FALS). Objective To determine the identity and frequency of FUS gene mutations in a large cohort of Italian patients enriched in sporadic cases (SALS). Methods Exons 5, 6, 14 and 15 of the FUS gene were screened for mutations in 1009 patients (45 FALS and 964 SALS). The genetic analysis was extended to the entire coding sequence of FUS in all the FALS and 293 of the SALS patients. Results Seven missense mutations (p.G191S, p.R216C, p.G225V, p.G230C, p.R234C, p.G507D and p.R521C) were identified in nine patients (seven SALS and two FALS), and none in 500 healthy Italian controls. All mutations are novel except for the p.R521C mutation identified in one SALS and one FALS case. Both patients showed a similar unusual presentation, with proximal, mostly symmetrical, upper limb weakness, with neck and axial involvement. With the exception of p.G507D and p.R521C, the mutations identified in SALS patients are all localised in the glycine-rich region encoded by exon 6. In addition, eight different in-frame deletions in two polyglycine motifs were detected, the frequency of which was not significantly different in patients and controls. Conclusions The results show that FUS missense mutations are present in 0.7% of Italian SALS cases, and confirm the previous mutational frequency reported in FALS (4.4%). An unusual proximal and axial clinical presentation seems to be associated with the presence of the p.R521C mutation.

AB - Background Mutations in the FUS gene have recently been discovered to be a major cause of familial amyotrophic lateral sclerosis (FALS). Objective To determine the identity and frequency of FUS gene mutations in a large cohort of Italian patients enriched in sporadic cases (SALS). Methods Exons 5, 6, 14 and 15 of the FUS gene were screened for mutations in 1009 patients (45 FALS and 964 SALS). The genetic analysis was extended to the entire coding sequence of FUS in all the FALS and 293 of the SALS patients. Results Seven missense mutations (p.G191S, p.R216C, p.G225V, p.G230C, p.R234C, p.G507D and p.R521C) were identified in nine patients (seven SALS and two FALS), and none in 500 healthy Italian controls. All mutations are novel except for the p.R521C mutation identified in one SALS and one FALS case. Both patients showed a similar unusual presentation, with proximal, mostly symmetrical, upper limb weakness, with neck and axial involvement. With the exception of p.G507D and p.R521C, the mutations identified in SALS patients are all localised in the glycine-rich region encoded by exon 6. In addition, eight different in-frame deletions in two polyglycine motifs were detected, the frequency of which was not significantly different in patients and controls. Conclusions The results show that FUS missense mutations are present in 0.7% of Italian SALS cases, and confirm the previous mutational frequency reported in FALS (4.4%). An unusual proximal and axial clinical presentation seems to be associated with the presence of the p.R521C mutation.

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