title: Novel TARDBP mutations in Nordic ALS patients.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.
authors.affiliation: Department of NVS, KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Huei-Hsin
authors.initials: HH
authors.lastname: Chiang
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Ole-Bjørn
authors.initials: OB
authors.lastname: Tysnes
authors.forename: Ole
authors.initials: O
authors.lastname: Gredal
authors.forename: Peter B
authors.initials: PB
authors.lastname: Christensen
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D003718:Denmark; D005387:Finland; D057180:Frontotemporal Dementia / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D059645:Mutation Rate; D020125:Mutation, Missense / Q000235:genetics*; D009664:Norway; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013548:Sweden
chemical_list: D004268:DNA-Binding Proteins