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

Martina de Majo, Simon D. Topp, Bradley N. Smith, Agnes L. Nishimura, Han-Jou Chen, Athina Soragia-Gkazi, Jack Miller, Chun Hao Wong, Caroline Vance, Frank Baas, Anneloor LMA. ten Asbroek, Kevin P. Kenna, Nicola Ticozzi, Alberto Garcia Redondo, Jesús Esteban-Pérez, Cinzia Tiloca, Federico Verde, Stefano Duga, Karen E. Morrison, Pamela J. ShawJanine Kirby, Martin R. Turner, Kevin Talbot, Orla Hardiman, Jonathan D. Glass, Jacqueline de Belleroche, Cinzia Gellera, Antonia Ratti, Ammar Al-Chalabi, Robert H. Brown Jr., Vincenzo Silani, John E. Landers, Christopher E. Shaw

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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.
Original languageEnglish
Pages (from-to)266.e1-266.e10
JournalNeurobiology of Aging
Volume71
Issue number0
Early online date25 Jun 2018
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

  • ALS
  • TBK1
  • FTD
  • WES
  • familial ALS

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