title: Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis.
abstract: The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction.
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Medical School, Sheffield, UK. j.kirby@sheffield.ac.uk
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.forename: Emily F
authors.initials: EF
authors.lastname: Goodall
authors.forename: William
authors.initials: W
authors.lastname: Smith
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.forename: Rudo
authors.initials: R
authors.lastname: Masanzu
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Rachel
authors.initials: R
authors.lastname: Hibberd
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Hollinger
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
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; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype
chemical_list: D004268:DNA-Binding Proteins