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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. 1 Dept. Medical Sciences, IRCAD, A. Avogadro University, Novara, Italy;
  2. 2 Dino Ferrari Center, Dept. of Neurological Sciences, Università degli Studi di Milano, IRCCS, Italy;
  3. 3 Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico, Italy;
  4. 4 Dept Neurology and Laboratory of Neuroscience, Dino Ferrari Center, Università degli Studi di, Italy;
  5. 5 Laboratory of Experimental Neurobiology IRCCS Neurological Institute C. Mondino, Pavia, Italy;
  6. 6 SS Medical Genetics and Neurology Unit Hospital Niguarda Ca'Granda, Milan, Italy;
  7. 7 Dept. of Neurosciences, University of Padua, Italy;
  8. 8 Dept. of Neuroscience, Neurological Institute, University of Pisa, Pisa, Italy;
  9. 9 Dept. of Neurology, A. Avogadro University and Maggiore della Carita' Hospital, Novara, Italy
  1. Correspondence to: Lucia Corrado, Dept. Medical Sciences, A. Avogadro University, via solaroli 17, Novara, 28100, Italy; lucia.corrado{at}med.unipmn.it

Abstract

Background: Mutations in the FUS gene have been recently discovered as a major cause of familial Amyotrophic Lateral Sclerosis (FALS).

Objective: This study aims to determine the identity and frequency of FUS gene mutations in a large cohort of Italian patients enriched in sporadic cases (SALS).

Methods: We screened exons 5, 6, 14, and 15 of FUS gene for mutations in 1009 Italian ALS patients (45 FALS and 964 SALS). The genetic analysis was extended to the entire coding sequence of FUS in all the FALS and in 293 of the SALS patients.

Results: We identified 7 missense mutations (p.G191S, p.R216C, p.G225V, p.G230C, p.R234C, p.G507D, and p.R521C) in 9 patients (7 SALS and 2 FALS) and none in 500 healthy Italian controls. All mutations are novel with the exception of the p.R521C that we 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 individuals are all localized in the glycine-rich region encoded by exon 6. In addition, we detected 8 different in-frame deletions in two poly-glycine motifs whose frequency was not significantly different in patients and controls.

Conclusions Our 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 associated to the presence of the p.R521C mutation.

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