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.
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-TARDBPFALS, 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: G G Hicks; N Singh; A Nashabi; S Mai; G Bozek; L Klewes; D Arapovic; E K White; M J Koury; E M Oltz; L Van Kaer; H E Ruley Journal: Nat Genet Date: 2000-02 Impact factor: 38.330
Authors: Manuela Neumann; Sigrun Roeber; Hans A Kretzschmar; Rosa Rademakers; Matt Baker; Ian R A Mackenzie Journal: Acta Neuropathol Date: 2009-08-09 Impact factor: 17.088
Authors: B A Hosler; T Siddique; P C Sapp; W Sailor; M C Huang; A Hossain; J R Daube; M Nance; C Fan; J Kaplan; W Y Hung; D McKenna-Yasek; J L Haines; M A Pericak-Vance; H R Horvitz; R H Brown Journal: JAMA Date: 2000-10-04 Impact factor: 56.272
Authors: Y Yang; A Hentati; H X Deng; O Dabbagh; T Sasaki; M Hirano; W Y Hung; K Ouahchi; J Yan; A C Azim; N Cole; G Gascon; A Yagmour; M Ben-Hamida; M Pericak-Vance; F Hentati; T Siddique Journal: Nat Genet Date: 2001-10 Impact factor: 38.330
Authors: Ying-Zhang Chen; Craig L Bennett; Huy M Huynh; Ian P Blair; Imke Puls; Joy Irobi; Ines Dierick; Annette Abel; Marina L Kennerson; Bruce A Rabin; Garth A Nicholson; Michaela Auer-Grumbach; Klaus Wagner; Peter De Jonghe; John W Griffin; Kenneth H Fischbeck; Vincent Timmerman; David R Cornblath; Phillip F Chance Journal: Am J Hum Genet Date: 2004-04-21 Impact factor: 11.025
Authors: H X Deng; A Hentati; J A Tainer; Z Iqbal; A Cayabyab; W Y Hung; E D Getzoff; P Hu; B Herzfeldt; R P Roos Journal: Science Date: 1993-08-20 Impact factor: 47.728
Authors: Erika N Guerrero; Haibo Wang; Joy Mitra; Pavana M Hegde; Sara E Stowell; Nicole F Liachko; Brian C Kraemer; Ralph M Garruto; K S Rao; Muralidhar L Hegde Journal: Prog Neurobiol Date: 2016-09-28 Impact factor: 11.685