Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis

Nicola J. Rutherford, Yong Jie Zhang, Matt Baker, Jennifer M. Gass, Ni Cole A. Finch, Ya Fei Xu, Heather Stewart, Brendan J. Kelley, Karen Kuntz, Richard J.P. Crook, Jemeen Sreedharan, Caroline Vance, Eric Sorenson, Carol Lippa, Eileen H. Bigio, Daniel H. Geschwind, David S. Knopman, Hiroshi Mitsumoto, Ronald C. Petersen, Neil R. Cashman & 11 others Mike Hutton, Christopher E. Shaw, Kevin B. Boylan, Bradley Boeve, Neill R. Graff-Radford, Zbigniew K. Wszolek, Richard J. Caselli, Dennis W. Dickson, Ian R. Mackenzie, Leonard Petrucelli, Rosa Rademakers

Research output: Contribution to journalArticle

287 Citations (Scopus)

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 ∼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.

Original languageEnglish (US)
Article numbere1000193
JournalPLoS Genetics
Volume4
Issue number9
DOIs
StatePublished - Sep 1 2008

Fingerprint

DNA-binding proteins
DNA-Binding Proteins
mutation
DNA
Mutation
protein
Amyotrophic Lateral Sclerosis
neurodegenerative diseases
Neurodegenerative Diseases
Proteins
cell lines
Frontotemporal Lobar Degeneration
Amyotrophic lateral sclerosis 1
amyotrophic lateral sclerosis
Cell Line
missense mutation
Poisons
caspases
protein-protein interactions
Missense Mutation

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Rutherford, N. J., Zhang, Y. J., Baker, M., Gass, J. M., Finch, N. C. A., Xu, Y. F., ... Rademakers, R. (2008). Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genetics, 4(9), [e1000193]. https://doi.org/10.1371/journal.pgen.1000193

Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis. / Rutherford, Nicola J.; Zhang, Yong Jie; Baker, Matt; Gass, Jennifer M.; Finch, Ni Cole A.; Xu, Ya Fei; Stewart, Heather; Kelley, Brendan J.; Kuntz, Karen; Crook, Richard J.P.; Sreedharan, Jemeen; Vance, Caroline; Sorenson, Eric; Lippa, Carol; Bigio, Eileen H.; Geschwind, Daniel H.; Knopman, David S.; Mitsumoto, Hiroshi; Petersen, Ronald C.; Cashman, Neil R.; Hutton, Mike; Shaw, Christopher E.; Boylan, Kevin B.; Boeve, Bradley; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Caselli, Richard J.; Dickson, Dennis W.; Mackenzie, Ian R.; Petrucelli, Leonard; Rademakers, Rosa.

In: PLoS Genetics, Vol. 4, No. 9, e1000193, 01.09.2008.

Research output: Contribution to journalArticle

Rutherford, NJ, Zhang, YJ, Baker, M, Gass, JM, Finch, NCA, Xu, YF, Stewart, H, Kelley, BJ, Kuntz, K, Crook, RJP, Sreedharan, J, Vance, C, Sorenson, E, Lippa, C, Bigio, EH, Geschwind, DH, Knopman, DS, Mitsumoto, H, Petersen, RC, Cashman, NR, Hutton, M, Shaw, CE, Boylan, KB, Boeve, B, Graff-Radford, NR, Wszolek, ZK, Caselli, RJ, Dickson, DW, Mackenzie, IR, Petrucelli, L & Rademakers, R 2008, 'Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis', PLoS Genetics, vol. 4, no. 9, e1000193. https://doi.org/10.1371/journal.pgen.1000193
Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NCA, Xu YF et al. Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genetics. 2008 Sep 1;4(9). e1000193. https://doi.org/10.1371/journal.pgen.1000193
Rutherford, Nicola J. ; Zhang, Yong Jie ; Baker, Matt ; Gass, Jennifer M. ; Finch, Ni Cole A. ; Xu, Ya Fei ; Stewart, Heather ; Kelley, Brendan J. ; Kuntz, Karen ; Crook, Richard J.P. ; Sreedharan, Jemeen ; Vance, Caroline ; Sorenson, Eric ; Lippa, Carol ; Bigio, Eileen H. ; Geschwind, Daniel H. ; Knopman, David S. ; Mitsumoto, Hiroshi ; Petersen, Ronald C. ; Cashman, Neil R. ; Hutton, Mike ; Shaw, Christopher E. ; Boylan, Kevin B. ; Boeve, Bradley ; Graff-Radford, Neill R. ; Wszolek, Zbigniew K. ; Caselli, Richard J. ; Dickson, Dennis W. ; Mackenzie, Ian R. ; Petrucelli, Leonard ; Rademakers, Rosa. / Novel mutations in TARDBP(TDP-43) in patients with familial amyotrophic lateral sclerosis. In: PLoS Genetics. 2008 ; Vol. 4, No. 9.
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AU - Finch, Ni Cole A.

AU - Xu, Ya Fei

AU - Stewart, Heather

AU - Kelley, Brendan J.

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AU - Crook, Richard J.P.

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AU - Sorenson, Eric

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AU - Graff-Radford, Neill R.

AU - Wszolek, Zbigniew K.

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