de Majo, Martina, Topp, Simon D., Smith, Bradley N. et al. (30 more authors) (2018) ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiology of Aging. ISSN 0197-4580
Abstract
Mutations in TBK1 have been linked to amyotrophic lateral sclerosis (ALS). Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency, however many other mutations are missense with unknown functional effect. We exome sequenced 699 familial ALS patients and identified 16 TBK1 novel or extremely rare protein changing variants. We characterised a subset of these: p.G217R, p.R357X and p.C471Y. Here we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate two of its kinase targets, IRF3 and OPTN and to undergo phosphorylation. They both inhibit binding to OPTN and the p.G217R, within the TBK1 kinase domain, reduces homodimerisation, essential for TBK1 activation and function. Lastly, we show that the proportion TBK1 that is active (phosphorylated) is reduced in five lymphoblastoid cell lines derived from patients harbouring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | ©2018 The Authors. |
Keywords: | ALS,TBK1,FTD,WES,familial ALS |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 13 Aug 2018 16:40 |
Last Modified: | 04 Feb 2025 00:06 |
Published Version: | https://doi.org/10.1016/j.neurobiolaging.2018.06.0... |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1016/j.neurobiolaging.2018.06.015 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:134542 |
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