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.
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References
Wijesekera, L. C., Leigh, P. N. Amyotrophic lateral sclerosis. Orphanet. J. Rare Dis. 4, 3 2009.
Andersen, P. M., Borasio, G. D., Dengler, R., Hardiman, O., Kollewe, K., Leigh, P. N. et al. Good practice in the management of amyotrophic lateral sclerosis: clinical guidelines. An evidence-based review with good practice points. EALSC Working Group. Amyotroph. Lateral Scler. 8, 195–213 2007.
Lomen-Hoerth, C., Anderson, T., Miller, B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 59, 1077–1079 2002.
Phukan, J., Pender, N. P., Hardiman, O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 6, 994–1003 2007.
Strong, M. J., Grace, G. M., Freedman, M., Lomen-Hoerth, C., Woolley, S., Goldstein, L. H. et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 10, 131–146 2009.
Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 2006.
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 314, 130–133 2006.
Gitcho, M. A., Baloh, R. H., Chakraverty, S., Mayo, K., Norton, J. B., Levitch, D. et al. TDP-43 A315T mutation in familial motor neuron disease. Ann. Neurol. 63, 535–538 2008.
Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Vande Velde, C. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 2008.
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 319, 1668–1672 2008.
Yokoseki, A., Shiga, A., Tan, C. F., Tagawa, A., Kaneko, H., Koyama, A. et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann. Neurol. 63, 538–542 2008.
Benajiba, L., Le Ber, I., Camuzat, A., Lacoste, M., Thomas-Anterion, C., Couratier, P. et al. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann. Neurol. 65, 470–473 2009.
Borroni, B., Bonvicini, C., Alberici, A., Buratti, E., Agosti, C., Archetti, S. et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum. Mutat. 30, E974–E983 2009.
Borroni, B., Archetti, S., Del Bo, R., Papetti, A., Buratti, E., Bonvicini, C. et al. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res. 13, 509–517 2010.
Brooks, B. R. El Escorial world federation of neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on motor neuron diseases/amyotrophic lateral sclerosis of the world federation of neurology research group on neuromuscular diseases and the El Escorial ‘Clinical limits of amyotrophic lateral sclerosis’ workshop contributors. J. Neurol. Sci. 124 (Suppl), 96–107 1994.
Guerreiro, R. J., Schymick, J. C., Crews, C., Singleton, A., Hardy, J., Traynor, B. J. TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS One 3, e2450 2008.
Winton, M. J., Van Deerlin, V. M., Kwong, L. K., Yuan, W., Wood, E. M., Yu, C. E. et al. A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett. 582, 2252–2256 2008.
Corrado, L., Ratti, A., Gellera, C., Buratti, E., Castellotti, B., Carlomagno, Y. et al. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum. Mutat. 30, 688–694 2009.
Gijselinck, I., Sleegers, K., Engelborghs, S., Robberecht, W., Martin, J. J., Vandenberghe, R. et al. Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS. Neurobiol. Aging. 30, 1329–1331 2009.
Acknowledgements
We are indebted to the patients and their families for their participation in this project. Furthermore, Sabine Björk for her help with compiling clinical data and Ann-Charloth Nilsson for mutation analysis in other ALS genes. We also thank Laura Fratiglioni for providing the control samples. This project has been supported by Swedish Brain Power, Gun and Bertil Stohne's foundation, Gamla tjänarinnors foundation, Swedish Alzheimer foundation, Marianne & Marcus Wallenberg foundation, Knut and Alice Wallenberg foundation, Swedish Research Council, Swedish Brain Research Foundation, Hållstens Research Foundation and Swedish association for the neurologically disabled.
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Chiang, HH., Andersen, P., Tysnes, OB. et al. Novel TARDBP mutations in Nordic ALS patients. J Hum Genet 57, 316–319 (2012). https://doi.org/10.1038/jhg.2012.24
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DOI: https://doi.org/10.1038/jhg.2012.24
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