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FUS Mutations in Familial Amyotrophic Lateral Sclerosis in the Netherlands
Ewout J. N. Groen, MSc;
Michael A. van Es, MD;
Paul W. J. van Vught, PhD;
Wim G. M. Spliet, MD;
Jooyeon van Engelen-Lee, MD;
Marianne de Visser, MD, PhD;
John H. J. Wokke, MD, PhD;
Helenius J. Schelhaas, MD, PhD;
Roel A. Ophoff, PhD;
Katsumi Fumoto, PhD;
R. Jeroen Pasterkamp, PhD;
Dennis Dooijes, MD, PhD;
Edwin Cuppen, PhD;
Jan H. Veldink, MD, PhD;
Leonard H. van den Berg, MD, PhD
Arch Neurol. 2010;67(2):224-230.
Objectives To assess the frequency of FUS mutations in 52 probands with familial amyotrophic lateral sclerosis (FALS) and to provide careful documentation of clinical characteristics.
Design 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.
Setting Three university hospitals in the Netherlands (referral centers for neuromuscular diseases).
Patients Fifty-two probands from unrelated pedigrees with FALS.
Main Outcome Measure 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.
Author Affiliations: Departments of Neurology (Drs Groen, van Es, van Vught, Wokke, Veldink, and van den Berg) and Neuroscience and Pharmacology (Drs Fumoto and Pasterkamp), Rudolf Magnus Institute of Neuroscience, and Departments of Pathology (Drs Spliet and van Engelen-Lee) and Medical Genetics (Drs Ophoff, Dooijes, and Cuppen), University Medical Centre Utrecht, and Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences (Dr Cuppen), Utrecht, the Netherlands; Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands (Dr de Visser); Department of Neurology/Clinical Neurophysiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (Dr Schelhaas); and UCLA Center for Neurobehavioral Genetics, Los Angeles, California (Dr Ophoff).
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