Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis

Arch Neurol. 2010 Apr;67(4):455-61. doi: 10.1001/archneurol.2010.52.


Objective: To determine the frequency of and clinicopathologic phenotypes associated with FUS/TLS mutations in a large cohort of amyotrophic lateral sclerosis (ALS) cases from the north of England.

Design: Genetic screening project with neuropathologic examination of postmortem tissue in selected cases. The clinical details of selected cases are also presented.

Setting: Neurology departments of 2 university teaching hospitals in the north of England.

Participants: The 15 exons of FUS/TLS were sequenced in an initial cohort of 42 familial ALS (FALS) and 117 sporadic ALS (SALS) cases. Exons 14 and 15 were subsequently screened in a larger cohort of 431 SALS cases. Regions mutated in ALS cases were also screened in 293 controls.

Main outcome measure: Evaluation of gene-sequencing chromatographs and detailed histopathologic analysis of the central nervous system.

Results: Four heterozygous mutations, 1 of which is novel, were identified in 6 patients with ALS (4 with FALS and 2 with SALS). Two of the substitutions were not found to be present in controls, and neuropathology in these cases revealed neuronal and/or glial cytoplasmic inclusions positive for the FUS/TLS protein. One of these cases is also the first reported SALS case with an FUS/TLS mutation. The other 2 substitutions identified were also identified in control cases. Neuropathology in these cases revealed typical SALS pathology, suggesting that they are likely to represent benign polymorphisms.

Conclusions: FUS/TLS mutations represented approximately 5% of FALS cases screened. A FUS/TLS mutation was also identified in a single SALS case. Subsequent screening of this region in a larger cohort of SALS cases, however, did not reveal any additional mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Case-Control Studies
  • Central Nervous System / metabolism
  • Central Nervous System / pathology*
  • Central Nervous System / physiopathology
  • Cohort Studies
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Genotype
  • Humans
  • Inheritance Patterns
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • RNA-Binding Protein FUS / genetics*


  • Genetic Markers
  • RNA-Binding Protein FUS