title: Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.
abstract: OBJECTIVE
  Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE).
  
  
  METHODS
  All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations.
  
  
  RESULTS
  We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations.
  
  
  CONCLUSIONS
  FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and approximately 4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.
authors.affiliation: Division of Neuromuscular Medicine, Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.forename: H-X
authors.initials: HX
authors.lastname: Deng
authors.forename: N
authors.initials: N
authors.lastname: Siddique
authors.forename: F
authors.initials: F
authors.lastname: Fecto
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: E
authors.initials: E
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Donkervoort
authors.forename: J G
authors.initials: JG
authors.lastname: Zheng
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: K B
authors.initials: KB
authors.lastname: Ahmeti
authors.forename: B
authors.initials: B
authors.lastname: Brooks
authors.forename: W K
authors.initials: WK
authors.lastname: Engel
authors.forename: T
authors.initials: T
authors.lastname: Siddique
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D018389:Codon, Nonsense / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders / Q000235:genetics*; D010375:Pedigree; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D034702:RNA-Binding Protein FUS