title: Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
abstract: The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Gass
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Finch
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Heather
authors.initials: H
authors.lastname: Stewart
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Kelley
authors.forename: Karen
authors.initials: K
authors.lastname: Kuntz
authors.forename: Richard J P
authors.initials: RJ
authors.lastname: Crook
authors.forename: Jemeen
authors.initials: J
authors.lastname: Sreedharan
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Eric
authors.initials: E
authors.lastname: Sorenson
authors.forename: Carol
authors.initials: C
authors.lastname: Lippa
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.forename: Bradley
authors.initials: B
authors.lastname: Boeve
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010375:Pedigree
chemical_list: D004268:DNA-Binding Proteins