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

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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; Soragia-Gkazi, Athina; Miller, Jack; Wong, Chun Hao; Vance, Caroline; Baas, Frank; ten Asbroek, Anneloor LMA.; 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 Jr., Robert H.; Silani, Vincenzo; Landers, John E.; Shaw, Christopher E.

In: Neurobiology of Aging, 25.06.2018.

Research output: Contribution to journalArticlepeer-review

Harvard

de Majo, M, Topp, SD, Smith, BN, Nishimura, AL, Chen, H-J, Soragia-Gkazi, A, 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 Jr., 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. https://doi.org/10.1016/j.neurobiolaging.2018.06.015

APA

de Majo, M., Topp, S. D., Smith, B. N., Nishimura, A. L., Chen, H-J., Soragia-Gkazi, A., Miller, J., Wong, C. H., Vance, C., Baas, F., ten Asbroek, A. LMA., Kenna, K. P., Ticozzi, N., Redondo, A. G., Esteban-Pérez, J., Tiloca, C., Verde, F., Duga, S., Morrison, K. E., ... Shaw, C. E. (2018). ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2018.06.015

Vancouver

de Majo M, Topp SD, Smith BN, Nishimura AL, Chen H-J, Soragia-Gkazi A et al. ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiology of Aging. 2018 Jun 25. https://doi.org/10.1016/j.neurobiolaging.2018.06.015

Author

de Majo, Martina ; Topp, Simon D. ; Smith, Bradley N. ; Nishimura, Agnes L. ; Chen, Han-Jou ; Soragia-Gkazi, Athina ; Miller, Jack ; Wong, Chun Hao ; Vance, Caroline ; Baas, Frank ; ten Asbroek, Anneloor LMA. ; 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 Jr., 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.

Bibtex - Download

@article{6c80002b24474eca86a92056bb5ea1c4,
title = "ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function",
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.",
keywords = "ALS, TBK1, FTD, WES, familial ALS",
author = "{de Majo}, Martina and Topp, {Simon D.} and Smith, {Bradley N.} and Nishimura, {Agnes L.} and Han-Jou Chen and Athina Soragia-Gkazi and Jack Miller and Wong, {Chun Hao} and Caroline Vance and Frank Baas and {ten Asbroek}, {Anneloor LMA.} and Kenna, {Kevin P.} and Nicola Ticozzi and Redondo, {Alberto Garcia} and Jes{\'u}s Esteban-P{\'e}rez and Cinzia Tiloca and Federico Verde and Stefano Duga and Morrison, {Karen E.} and Shaw, {Pamela J.} and Janine Kirby and Turner, {Martin R.} and Kevin Talbot and Orla Hardiman and Glass, {Jonathan D.} and {de Belleroche}, Jacqueline and Cinzia Gellera and Antonia Ratti and Ammar Al-Chalabi and {Brown Jr.}, {Robert H.} and Vincenzo Silani and Landers, {John E.} and Shaw, {Christopher E.}",
note = "{\textcopyright}2018 The Authors. ",
year = "2018",
month = jun,
day = "25",
doi = "10.1016/j.neurobiolaging.2018.06.015",
language = "English",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function

AU - de Majo, Martina

AU - Topp, Simon D.

AU - Smith, Bradley N.

AU - Nishimura, Agnes L.

AU - Chen, Han-Jou

AU - Soragia-Gkazi, Athina

AU - Miller, Jack

AU - Wong, Chun Hao

AU - Vance, Caroline

AU - Baas, Frank

AU - ten Asbroek, Anneloor LMA.

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 Jr., Robert H.

AU - Silani, Vincenzo

AU - Landers, John E.

AU - Shaw, Christopher E.

N1 - ©2018 The Authors.

PY - 2018/6/25

Y1 - 2018/6/25

N2 - 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.

AB - 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.

KW - ALS

KW - TBK1

KW - FTD

KW - WES

KW - familial ALS

U2 - 10.1016/j.neurobiolaging.2018.06.015

DO - 10.1016/j.neurobiolaging.2018.06.015

M3 - Article

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -