ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function
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UMass Chan Affiliations
Department of NeurologyDocument Type
Journal ArticlePublication Date
2018-06-25
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Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized 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 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring 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.Source
Neurobiol Aging. 2018 Jun 25. pii: S0197-4580(18)30219-7. doi: 10.1016/j.neurobiolaging.2018.06.015. [Epub ahead of print] Link to article on publisher's site
DOI
10.1016/j.neurobiolaging.2018.06.015Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40721PubMed ID
30033073Notes
Full author list omitted for brevity. For the full list of authors, see article.
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Copyright 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.neurobiolaging.2018.06.015
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Except where otherwise noted, this item's license is described as Copyright 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).