title: Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis.
abstract: 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.
  
  
  METHODS
  Genetic screening project with neuropathologic examination of postmortem tissue in selected cases. The clinical details of selected cases are also presented.
  
  
  METHODS
  Neurology departments of 2 university teaching hospitals in the north of England.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Academic Unit of Neurology, University of Sheffield, Medical School, Beech Hill Road, Sheffield S10 2RX, England.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hewitt
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Rachael
authors.initials: R
authors.lastname: Hibberd
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Hollinger
authors.forename: Tim L
authors.initials: TL
authors.lastname: Williams
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McDermott
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D016022:Case-Control Studies; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D034702:RNA-Binding Protein FUS