TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Kimberly J. Van Zee, Ilse Gijselinck, Sara Van Mossevelde, F. Perrone, Lubina Dillen, Bavo Heeman, Veerle Bäumer, Sebastiaan Engelborghs, J. L. De Bleecker, Jonathan Baets, Ellen Gelpi, Ricard Rojas-García, J. Clarimón, Alberto Lleó, Janine Diehl-Schmid, Panos Alexopoulos, Robert Perneczky, Matthis Synofzik, J. Just, L. SchölsCaroline Graff, Håkan Thonberg, B. Borroni, A. Padovani, Albena Jordanova, Stayko Sarafov, I. Tournev, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, F. Simões do Couto, A. Ramirez, Frank Jessen, Michael T. Heneka, Estrella Gómez-Tortosa, Adrian Danek, P. Cras, Rik Vandenberghe, P. de Jonghe, P. P. De Deyn, Kristel Sleegers, Marc Cruts, C. Van Broeckhoven, Johan Goeman, Dirk Nuytten, Katrin Smets, Wim Robberecht, Philip van Damme, Jan De Bleecker, Patrick Santens, Bart Dermaut, Jan Versijpt, Alex Michotte, Adrian Ivanoiu, Olivier Deryck, Bruno Bergmans, Jean Delbeck, M. Bruyland, C. Willems, E. Salmon, Pau Pastor, Sara Ortega-Cubero, L. Benussi, R. Ghidoni, G. Binetti, Isabel Hernández, M. Boada, A. Ruiz, S. Sorbi, B. Nacmias, Siro Bagnoli, Raquel Sanchez-Valle, A. Llado, Isabel Santana, Maria Do Rosário Almeida, G.B. Frisoni, Walter Maetzler, Radoslav Matej, Matthew J. Fraidakis, G. G. Kovacs, G. M. Fabrizi, Sergio Testi

Research output: Contribution to journalArticlepeer-review


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 NFκB-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 NFκB 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. © 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.
Original languageEnglish
JournalHuman Mutation
Publication statusPublished - 2016


  • ALS
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • FTD
  • mutations
  • NFκB luciferase reporter assay
  • TANK-Binding Kinase 1
  • TBK1

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