ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function
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Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2018-11
Date Acceptance
2018-06-12
Citation
Neurobiology of Aging, 2018, 71, pp.266.e1-266.e10
ISSN
0197-4580
Publisher
Elsevier
Start Page
266.e1
End Page
266.e10
Journal / Book Title
Neurobiology of Aging
Volume
71
Copyright Statement
© 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/)
Sponsor
Medical Research Council (MRC)
Identifier
https://www.sciencedirect.com/science/article/pii/S0197458018302197?via%3Dihub
Grant Number
G0900688
Subjects
Science & Technology
Life Sciences & Biomedicine
Geriatrics & Gerontology
Neurosciences
Neurosciences & Neurology
ALS
TBK1
FTD
WES
Familial ALS
AMYOTROPHIC-LATERAL-SCLEROSIS
FRONTOTEMPORAL DEMENTIA
AUTOPHAGY
BINDING
PHOSPHORYLATION
OPTINEURIN
ACTIVATION
GENES
OPTN
ALS
FTD
Familial ALS
TBK1
WES
1103 Clinical Sciences
1109 Neurosciences
Neurology & Neurosurgery
Publication Status
Published
Date Publish Online
2018-06-25