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Mutations of FUS gene in sporadic amyotrophic lateral sclerosis
  1. Lucia Corrado1,
  2. Roberto Del Bo2,
  3. Barbara Castellotti3,
  4. Antonia Ratti4,
  5. Cristina Cereda5,
  6. Silvana Penco6,
  7. Gianni Sorarù7,
  8. Yari Carlomagno1,
  9. Serena Ghezzi2,
  10. Viviana Pensato3,
  11. Claudia Colombrita4,
  12. Stella Gagliardi5,
  13. Lorena Cozzi6,
  14. Valeria Orsetti7,
  15. Michelangelo Mancuso8,
  16. Gabriele Siciliano8,
  17. Letizia Mazzini9,
  18. Giacomo Pietro Comi2,
  19. Cinzia Gellera3,
  20. Mauro Ceroni5,
  21. Sandra D'Alfonso1,
  22. Vincenzo Silani4
  1. 1Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), ‘A Avogadro’ University, Novara, Italy
  2. 2Dino Ferrari Center, Department of Neurological Sciences, Università degli Studi di Milano, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy
  3. 3Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy
  4. 4Department Neurology and Laboratory of Neuroscience, ‘Dino Ferrari’ Center, Università degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Milan, Italy
  5. 5Laboratory of Experimental Neurobiology IRCCS Neurological Institute “C. Mondino”, Pavia, Italy
  6. 6SS Medical Genetics and Neurology Unit Hospital Niguarda Ca'Granda, Milan, Italy
  7. 7Department of Neurosciences, University of Padua, Padua, Italy
  8. 8Department of Neuroscience, Neurological Institute, University of Pisa, Pisa, Italy
  9. 9Department of Neurology, ‘A Avogadro’ University and Maggiore della Carita' Hospital, Novara, Italy
  1. Correspondence to Lucia Corrado, Department of Medical Sciences, Via Solaroli, 17, 28100 Novara, Italy; lucia.corrado{at}


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.

  • Amyotrophic lateral sclerosis
  • FUS mutation
  • motor neuron disease
  • sporadic
  • polyglycine length polymorphism
  • genetics
  • molecular genetics
  • screening

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  • Lucia Corrado and Roberto Del Bo contributed equally

  • Competing interests None.

  • Ethics approval The study was approved by the following local hospital ethics committees: Ospedale Maggiore della Carita' Novara, Italy, IRCCS Istituto Auxologico Italiano, Milan, Italy, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy, IRCCS Neurological Institute ‘C Mondino’, Pavia, Italy.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.