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 - 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.
PY - 2018
Y1 - 2018
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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85050160974&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30033073
U2 - https://doi.org/10.1016/j.neurobiolaging.2018.06.015
DO - https://doi.org/10.1016/j.neurobiolaging.2018.06.015
M3 - Article
C2 - 30033073
SN - 0197-4580
VL - 71
SP - 266.e1-266.e10
JO - Neurobiology of aging
JF - Neurobiology of aging
ER -