TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Por:
van der Zee, J, Gijselinck, I, Van Mossevelde, S, Perrone, F, Dillen, L, Heeman, B, Baumer, V, Engelborghs, S, De Bleecker, J, Baets, J, Gelpi, E, Rojas-Garcia, R, Clarimon, J, Lleo, A, Diehl-Schmid, J, Alexopoulos, P, Perneczky, R, Synofzik, M, Just, J, Schols, L, Graff, C, Thonberg, H, Borroni, B, Padovani, A, Jordanova, A, Sarafov, S, Tournev, I, de Mendonca, A, Miltenberger-Miltenyi, G, Simoes do Couto, F, Ramirez, A, Jessen, F, Heneka, MT, Gomez-Tortosa, E, Danek, A, Cras, P, Vandenberghe, R, De Jonghe, P, De Deyn, PP, Sleegers, K, Cruts, M, Van Broeckhoven, C
Publicada:
1 mar 2017
Resumen:
We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
Filiaciones:
van der Zee, J:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Gijselinck, I:
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Van Mossevelde, S:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Univ Antwerp Hosp, Dept Neurol, Edegem, Belgium
Perrone, F:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Dillen, L:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Heeman, B:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Baumer, V:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Engelborghs, S:
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Dept Neurol, Antwerp, Belgium
Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Memory Clin, Antwerp, Belgium
De Bleecker, J:
Univ Hosp Ghent, Dept Neurol, Ghent, Belgium
Univ Ghent, Ghent, Belgium
Baets, J:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Univ Antwerp Hosp, Dept Neurol, Edegem, Belgium
Gelpi, E:
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Neurol Tissue Bank Biobanc, Barcelona, Spain
Rojas-Garcia, R:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Neurol, IIB Sant Pau, Barcelona, Spain
Clarimon, J:
Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Neurol, IIB Sant Pau, Barcelona, Spain
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Lleo, A:
Ctr Networker Biomed Res Neurodegenerat Dis CIBER, Madrid, Spain
Diehl-Schmid, J:
Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany
Alexopoulos, P:
Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany
Perneczky, R:
Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany
Imperial Coll Sci Technol & Med, Sch Publ Hlth, Neuroepidemiol & Ageing Res Unit, London, England
West London Cognit Disorders Treatment & Res Unit, West London Mental Hlth Trust, London TW8 8DS, England
Synofzik, M:
Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany
Ctr Neurol, Tubingen, Germany
German Res Ctr Neurodegenerat Dis DZNE, Tubingen, Germany
Just, J:
Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany
Ctr Neurol, Tubingen, Germany
German Res Ctr Neurodegenerat Dis DZNE, Tubingen, Germany
Schols, L:
Hertie Inst Clin Brain Res, Dept Neurodegenerat, Tubingen, Germany
Ctr Neurol, Tubingen, Germany
German Res Ctr Neurodegenerat Dis DZNE, Tubingen, Germany
Graff, C:
Karolinska Inst, KI Alzheimer Dis Res Ctr, Dept Neurobiol, Care Sci & Soc NVS, Stockholm, Sweden
Karolinska Univ Hosp, Dept Geriatr Med, Genet Unit, Stockholm, Sweden
Thonberg, H:
Karolinska Inst, KI Alzheimer Dis Res Ctr, Dept Neurobiol, Care Sci & Soc NVS, Stockholm, Sweden
Karolinska Univ Hosp, Dept Geriatr Med, Genet Unit, Stockholm, Sweden
Borroni, B:
Univ Brescia, Neurol Unit, Brescia, Italy
Padovani, A:
Univ Brescia, Neurol Unit, Brescia, Italy
Jordanova, A:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Med Univ Sofia, Mol Med Ctr, Dept Biochem, Sofia, Bulgaria
Sarafov, S:
Med Univ Sofia, Dept Neurol, Sofia, Bulgaria
Tournev, I:
New Bulgarian Univ, Dept Cognit Sci & Psychol, Sofia, Bulgaria
de Mendonca, A:
Hosp Santa Maria, Lisbon, Portugal
Univ Lisbon, Fac Med, Lisbon, Portugal
Univ Lisbon, Inst Mol Med, Lisbon, Portugal
Miltenberger-Miltenyi, G:
Hosp Santa Maria, Lisbon, Portugal
Univ Lisbon, Fac Med, Lisbon, Portugal
Univ Lisbon, Inst Mol Med, Lisbon, Portugal
Simoes do Couto, F:
Hosp Santa Maria, Lisbon, Portugal
Univ Lisbon, Fac Med, Lisbon, Portugal
Univ Lisbon, Inst Mol Med, Lisbon, Portugal
Ramirez, A:
Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany
Univ Bonn, Inst Human Genet, Bonn, Germany
Univ Cologne, Dept Psychiat & Psychotherapy, Cologne, Germany
Jessen, F:
Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany
Univ Cologne, Dept Psychiat & Psychotherapy, Cologne, Germany
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Heneka, MT:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Bonn, Dept Neurol, Clin Neurosci Unit, Bonn, Germany
Gomez-Tortosa, E:
Dept Neurol, Fundac Jimenez Diaz, Madrid, Spain
Danek, A:
Ludwig Maximilians Univ Munchen, Dept Neurol, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Cras, P:
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Univ Antwerp Hosp, Dept Neurol, Edegem, Belgium
Vandenberghe, R:
Katholieke Univ Leuven, Fac Med, Dept Neurosci, Leuven, Belgium
Univ Hosp Leuven, Dept Neurol, Leuven, Belgium
De Jonghe, P:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Univ Antwerp Hosp, Dept Neurol, Edegem, Belgium
De Deyn, PP:
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Dept Neurol, Antwerp, Belgium
Hosp Network Antwerp ZNA Middelheim & Hoge Beuken, Memory Clin, Antwerp, Belgium
Sleegers, K:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Cruts, M:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Van Broeckhoven, C:
VIB, Ctr Mol Neurol, Antwerp, Belgium
Univ Antwerp, Inst Born Bunge, Antwerp, Belgium
Green Published, Hybrid Gold
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