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 L M A 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, Vincenzo Silani, John E Landers, Christopher E Shaw

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)266.e1-266.e10
JournalNeurobiology of Aging
Volume71
DOIs
Publication statusPublished - Nov 2018
Externally publishedYes

Keywords

  • Amyotrophic Lateral Sclerosis/genetics
  • Cell Cycle Proteins
  • Codon, Nonsense
  • Exons
  • Female
  • Genetic Association Studies
  • Humans
  • Interferon Regulatory Factor-3/genetics
  • Male
  • Membrane Transport Proteins
  • Mutation, Missense
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases/chemistry
  • Transcription Factor TFIIIA/genetics

Fingerprint

Dive into the research topics of 'ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function'. Together they form a unique fingerprint.

Cite this