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Neurobiol Aging. 2018 Nov;71:266.e1-266.e10. doi: 10.1016/j.neurobiolaging.2018.06.015. Epub 2018 Jun 25.

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function.

Author information

1
United Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
2
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
3
Department of Genome analysis, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands.
4
Department of Neurology, University of Massachusetts Medical School, Worcester, MA.
5
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Centre, Università degli Studi di Milano, Milan, Italy.
6
Unidad de ELA, Instituto de Investigación Hospital 12 de Octubre de Madrid, SERMAS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid, Spain.
7
Department of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy; Humanitas Clinical and Research Center, Rozzano-Milan, Italy.
8
University of Southampton, Southampton General Hospital, UK.
9
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
10
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
11
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Republic of Ireland.
12
Department of Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
13
Neurogenetics Group, Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK.
14
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
15
United Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address: chris.shaw@kcl.ac.uk.

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.

KEYWORDS:

ALS; FTD; Familial ALS; TBK1; WES

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