FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands.
OBJECTIVE
To assess the frequency of FUS mutations in 52 probands with familial amyotrophic lateral sclerosis (FALS) and to provide careful documentation of clinical characteristics.


METHODS
FUS mutation analysis was performed using capillary sequencing on all coding regions of the gene in a cohort of patients with FALS. The clinical characteristics of patients carrying FUS mutations were described in detail.


METHODS
Three university hospitals in the Netherlands (referral centers for neuromuscular diseases).


METHODS
Fifty-two probands from unrelated pedigrees with FALS.


METHODS
FUS mutations.


RESULTS
We identified 3 mutations in 4 of 52 probands. We observed 2 previously identified mutations (p.Arg521Cys and p.Arg521His) and 1 novel mutation (p.Ser462Phe). In addition, a p.Gln210His polymorphism was identified in 1 proband and 3 healthy control subjects. Phenotypic analysis demonstrated that patients may lack upper motor neuron signs, which was confirmed at autopsy, and disease survival was short (<36 months for 8 of 10 patients).


CONCLUSIONS
We discovered FUS mutations in Dutch patients with FALS and the occurrence of benign variations in the gene. Therefore, caution is warranted when interpreting results in a clinical setting. Although the phenotype associated with FUS mutations is variable, most patients predominantly demonstrate loss of lower motor neurons and have short disease survival.
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan, Utrecht, the Netherlands.
Ewout J N
EJ
Groen
Michael A
MA
van Es
Paul W J
PW
van Vught
Wim G M
WG
Spliet
Jooyeon
J
van Engelen-Lee
Marianne
M
de Visser
John H J
JH
Wokke
Helenius J
HJ
Schelhaas
Roel A
RA
Ophoff
Katsumi
K
Fumoto
R Jeroen
RJ
Pasterkamp
Dennis
D
Dooijes
Edwin
E
Cuppen
Jan H
JH
Veldink
Leonard H
LH
van den Berg
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009426:Netherlands / Q000453:epidemiology; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism
D034702:RNA-Binding Protein FUS