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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