title: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
authors.affiliation: Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
authors.forename: Jemeen
authors.initials: J
authors.lastname: Sreedharan
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.forename: Vineeta B
authors.initials: VB
authors.lastname: Tripathi
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Steven
authors.initials: S
authors.lastname: Ackerley
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Durnall
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Williams
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
authors.forename: Francisco
authors.initials: F
authors.lastname: Baralle
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Belleroche
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Mitchell
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Miller
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002642:Chick Embryo; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D047108:Embryonic Development; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000502:physiology; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins