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

Julie van der Zee, Ilse Gijselinck, Sara Van Mossevelde, Federica Perrone, Lubina Dillen, Bavo Heeman, Veerle Bäumer, Sebastiaan Engelborghs, Jan De Bleecker, Jonathan Baets, Ellen Gelpi, Ricardo Rojas-García, Jordi Clarimón, Alberto Lleó, Janine Diehl-Schmid, Panagiotis Alexopoulos, Robert Perneczky, Matthis Synofzik, Jennifer Just, Ludger SchölsCaroline Graff, Håkan Thonberg, Barbara Borroni, Alessandro Padovani, Albena Jordanova, Stayko Sarafov, Ivailo Tournev, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, Frederico Simões do Couto, Alfredo Ramirez, Frank Jessen, Michael T. Heneka, Estrella Gómez-Tortosa, Adrian Danek, Patrick Cras, Rik Vandenberghe, Peter De Jonghe, Peter P. De Deyn, Kristel Sleegers, Marc Cruts, Christine van Broeckhoven, Johan Goeman, Dirk Nuytten, Katrien 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, Marc Bruyland, Christiana Willems, Eric Salmon, Pau Pastor, Sara Ortega-Cubero, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Isabel Hernández, Mercè Boada, Agustín Ruiz, Sandro Sorbi, Benedetta Nacmias, Silvia Bagnoli, Sandro Sorbi, Raquel Sanchez-Valle, Albert Llado, Isabel Santana, Maria Do Rosário Almeida, Giovanni B. Frisoni, Walter Maetzler, Radoslav Matej, Matthew J. Fraidakis, Gabor Kovacs, Gian Maria Fabrizi, Silvia Testi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)297-309
Number of pages13
JournalHuman Mutation
Volume38
Issue number3
DOIs
Publication statusPublished - Mar 1 2017

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    van der Zee, J., Gijselinck, I., Van Mossevelde, S., Perrone, F., Dillen, L., Heeman, B., Bäumer, V., Engelborghs, S., De Bleecker, J., Baets, J., Gelpi, E., Rojas-García, R., Clarimón, J., Lleó, A., Diehl-Schmid, J., Alexopoulos, P., Perneczky, R., Synofzik, M., Just, J., ... Testi, S. (2017). TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Human Mutation, 38(3), 297-309. https://doi.org/10.1002/humu.23161