UMMS Affiliation

Department of Neurology

Publication Date


Document Type



Nervous System Diseases | Neuroscience and Neurobiology


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.


ALS, FTD, Familial ALS, TBK1, WES

Rights and Permissions

Copyright 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (

DOI of Published Version



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

Journal/Book/Conference Title

Neurobiology of aging


Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.