title: Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany.
abstract: OBJECTIVE
  Mutations in the FUS/TLS have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients.
  
  
  METHODS
  We screened 184 familial (FALS) and 200 sporadic German patients with ALS for FUS/TLS mutations by sequence analysis of exons 5, 6 and 13-15. We compared the phenotypes of patients with different FUS/TLS mutations.
  
  
  RESULTS
  We identified three missense mutations p.K510R, p.R514G, p.R521H, and the two truncating mutations p.R495X and p.G478LfsX23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses, whereas the p.R521H, p.R514G and in particular the p.K510R mutation showed a milder phenotype with disease durations ranging from 3 years to more than 26 years, the longest reported for a patient with a FUS/TLS mutation. Also, in a pair of monozygous twins with the p.K510R mutation, a remarkable similar disease course was observed.
  
  
  CONCLUSIONS
  Mutations in FUS/TLS account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling.
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Waibel
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Neumann
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rosenbohm
authors.affiliation: Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Birve
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: A E
authors.initials: AE
authors.lastname: Volk
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: J H
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: Department of Neurology, Humboldt University Berlin, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Department of Human Genetics, University of Giessen, Giessen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.|Department of Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: P M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: Ludolph
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D034702:RNA-Binding Protein FUS