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 journalArticle

7 Citations (Scopus)

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 1 2018

Fingerprint

Phosphotransferases
Mutation
Missense Mutation
Phosphorylation
Exome
Haploinsufficiency
Amyotrophic Lateral Sclerosis
Cell Line

Keywords

  • ALS
  • Familial ALS
  • FTD
  • TBK1
  • WES

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

de Majo, M., Topp, S. D., Smith, B. N., Nishimura, A. L., Chen, H. J., Gkazi, A. S., ... Shaw, C. E. (2018). ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiology of Aging, 71, 266.e1-266.e10. https://doi.org/10.1016/j.neurobiolaging.2018.06.015

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. / de Majo, Martina; Topp, Simon D.; Smith, Bradley N.; Nishimura, Agnes L.; Chen, Han Jou; Gkazi, Athina Soragia; Miller, Jack; Wong, Chun Hao; Vance, Caroline; Baas, Frank; ten Asbroek, Anneloor L.M.A.; Kenna, Kevin P.; Ticozzi, Nicola; Redondo, Alberto Garcia; Esteban-Pérez, Jesús; Tiloca, Cinzia; Verde, Federico; Duga, Stefano; Morrison, Karen E.; Shaw, Pamela J.; Kirby, Janine; Turner, Martin R.; Talbot, Kevin; Hardiman, Orla; Glass, Jonathan D.; de Belleroche, Jacqueline; Gellera, Cinzia; Ratti, Antonia; Al-Chalabi, Ammar; Brown, Robert H.; Silani, Vincenzo; Landers, John E.; Shaw, Christopher E.

In: Neurobiology of Aging, Vol. 71, 01.11.2018, p. 266.e1-266.e10.

Research output: Contribution to journalArticle

de Majo, M, Topp, SD, Smith, BN, Nishimura, AL, Chen, HJ, Gkazi, AS, Miller, J, Wong, CH, Vance, C, Baas, F, ten Asbroek, ALMA, Kenna, KP, Ticozzi, N, Redondo, AG, Esteban-Pérez, J, Tiloca, C, Verde, F, Duga, S, Morrison, KE, Shaw, PJ, Kirby, J, Turner, MR, Talbot, K, Hardiman, O, Glass, JD, de Belleroche, J, Gellera, C, Ratti, A, Al-Chalabi, A, Brown, RH, Silani, V, Landers, JE & Shaw, CE 2018, 'ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function', Neurobiology of Aging, vol. 71, pp. 266.e1-266.e10. https://doi.org/10.1016/j.neurobiolaging.2018.06.015
de Majo, Martina ; Topp, Simon D. ; Smith, Bradley N. ; Nishimura, Agnes L. ; Chen, Han Jou ; Gkazi, Athina Soragia ; Miller, Jack ; Wong, Chun Hao ; Vance, Caroline ; Baas, Frank ; ten Asbroek, Anneloor L.M.A. ; Kenna, Kevin P. ; Ticozzi, Nicola ; Redondo, Alberto Garcia ; Esteban-Pérez, Jesús ; Tiloca, Cinzia ; Verde, Federico ; Duga, Stefano ; Morrison, Karen E. ; Shaw, Pamela J. ; Kirby, Janine ; Turner, Martin R. ; Talbot, Kevin ; Hardiman, Orla ; Glass, Jonathan D. ; de Belleroche, Jacqueline ; Gellera, Cinzia ; Ratti, Antonia ; Al-Chalabi, Ammar ; Brown, Robert H. ; Silani, Vincenzo ; Landers, John E. ; Shaw, Christopher E. / ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. In: Neurobiology of Aging. 2018 ; Vol. 71. pp. 266.e1-266.e10.
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AU - de Majo, Martina

AU - Topp, Simon D.

AU - Smith, Bradley N.

AU - Nishimura, Agnes L.

AU - Chen, Han Jou

AU - Gkazi, Athina Soragia

AU - Miller, Jack

AU - Wong, Chun Hao

AU - Vance, Caroline

AU - Baas, Frank

AU - ten Asbroek, Anneloor L.M.A.

AU - Kenna, Kevin P.

AU - Ticozzi, Nicola

AU - Redondo, Alberto Garcia

AU - Esteban-Pérez, Jesús

AU - Tiloca, Cinzia

AU - Verde, Federico

AU - Duga, Stefano

AU - Morrison, Karen E.

AU - Shaw, Pamela J.

AU - Kirby, Janine

AU - Turner, Martin R.

AU - Talbot, Kevin

AU - Hardiman, Orla

AU - Glass, Jonathan D.

AU - de Belleroche, Jacqueline

AU - Gellera, Cinzia

AU - Ratti, Antonia

AU - Al-Chalabi, Ammar

AU - Brown, Robert H.

AU - Silani, Vincenzo

AU - Landers, John E.

AU - Shaw, Christopher E.

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N2 - 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.

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KW - FTD

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KW - WES

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