FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands

Arch Neurol. 2010 Feb;67(2):224-30. doi: 10.1001/archneurol.2009.329.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amino Acid Substitution / genetics
  • Amyotrophic Lateral Sclerosis / epidemiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • DNA Mutational Analysis / methods
  • Family Health*
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Netherlands / epidemiology
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism


  • RNA-Binding Protein FUS