Mutations of FUS gene in sporadic amyotrophic lateral sclerosis.
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.
Corrado
Lucia
L
Department of Medical Sciences, Via Solaroli, 17, 28100 Novara, Italy. lucia.corrado@med.unipmn.it
Del Bo
Roberto
R
Castellotti
Barbara
B
Ratti
Antonia
A
Cereda
Cristina
C
Penco
Silvana
S
Sorarù
Gianni
G
Carlomagno
Yari
Y
Ghezzi
Serena
S
Pensato
Viviana
V
Colombrita
Claudia
C
Gagliardi
Stella
S
Cozzi
Lorena
L
Orsetti
Valeria
V
Mancuso
Michelangelo
M
Siciliano
Gabriele
G
Mazzini
Letizia
L
Comi
Giacomo Pietro
GP
Gellera
Cinzia
C
Ceroni
Mauro
M
D'Alfonso
Sandra
S
Silani
Vincenzo
V
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D034702:RNA-Binding Protein FUS / Q000235:genetics*
D034702:RNA-Binding Protein FUS