[en] 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.
Disciplines :
Neurology
Author, co-author :
van der Zee, Julie; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Gijselinck, Ilse; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van Mossevelde, Sara; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Perrone, Federica; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Dillen, Lubina; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Heeman, Bavo; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Bäumer, Veerle; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Engelborghs, Sebastiaan; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
De Bleecker, Jan; Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium
Baets, Jonathan; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Gelpi, Ellen; Neurological Tissue Bank of the Biobanc - Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Rojas-García, Ricardo; Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Clarimón, Jordi; Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain ; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Lleó, Alberto; Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain ; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Diehl-Schmid, Janine; Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany
Alexopoulos, Panagiotis; Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany
Perneczky, Robert; Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany ; Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK ; West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, TW8 8DS, UK
Synofzik, Matthis; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Just, Jennifer; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Schöls, Ludger; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Graff, Caroline; Department of Neurobiology, Care Sciences and Society (NVS), KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden ; Department of Geriatric Medicine, Genetics unit, Karolinska University Hospital, Stockholm, Sweden
Thonberg, Håkan; Department of Neurobiology, Care Sciences and Society (NVS), KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden ; Department of Geriatric Medicine, Genetics unit, Karolinska University Hospital, Stockholm, Sweden
Borroni, Barbara; Neurology Unit, University of Brescia, Brescia, Italy
Padovani, Alessandro; Neurology Unit, University of Brescia, Brescia, Italy
Jordanova, Albena; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria
Sarafov, Stayko; Department of Neurology, Medical University-Sofia, Sofia, Bulgaria
Tournev, Ivailo; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
de Mendonça, Alexandre; Hospital Santa Maria, Lisbon, Portugal ; Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Miltenberger-Miltényi, Gabriel; Hospital Santa Maria, Lisbon, Portugal ; Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Simões do Couto, Frederico; Hospital Santa Maria, Lisbon, Portugal ; Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Ramirez, Alfredo; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany ; Institute of Human Genetics, University of Bonn, Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
Jessen, Frank; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
HENEKA, Michael ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
Gómez-Tortosa, Estrella; Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain
Danek, Adrian; Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany ; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Cras, Patrick; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Vandenberghe, Rik; Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium ; Department of Neurology, University Hospitals Leuven, Leuven, Belgium
De Jonghe, Peter; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
De Deyn, Peter P; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
Sleegers, Kristel; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Cruts, Marc; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van Broeckhoven, Christine; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Goeman, Johan; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Hospital Network Antwerp, Antwerp
Nuytten, Dirk; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Hospital Network Antwerp, Antwerp
Smets, Katrien; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Antwerp University Hospital, Edegem
Robberecht, Wim; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospitals Leuven Gasthuisberg, Leuven
Damme, Philip Van; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospitals Leuven Gasthuisberg, Leuven
Bleecker, Jan De; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospital Ghent, Ghent
Santens, Patrick; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospital Ghent, Ghent
Dermaut, Bart; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospital Ghent, Ghent
Versijpt, Jan; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospital Brussels, Brussels
Michotte, Alex; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospital Brussels, Brussels
Ivanoiu, Adrian; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Saint-Luc University Hospital, Brussels
Deryck, Olivier; Center for Molecular Neurology, VIB, Antwerp, Belgium ; General Hospital Sint-Jan Brugge, Bruges
Bergmans, Bruno; Center for Molecular Neurology, VIB, Antwerp, Belgium ; General Hospital Sint-Jan Brugge, Bruges
Delbeck, Jean; Center for Molecular Neurology, VIB, Antwerp, Belgium ; General Hospital Sint-Maria, Halle
Bruyland, Marc; Center for Molecular Neurology, VIB, Antwerp, Belgium ; General Hospital Glorieux Ronse
Willems, Christiana; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Jessa Hospital, Hasselt
Salmon, Eric; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University of Liège and Memory Clinic, CHU Liège, Liège
Pastor, Pau; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University Hospital Mútua de Terrassa and Fundació Docència i Recerca Mútua Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain ; CIBERNED Instituto de Salud Carlos III, Madrid, Spain
Ortega-Cubero, Sara; Center for Molecular Neurology, VIB, Antwerp, Belgium ; CIBERNED Instituto de Salud Carlos III, Madrid, Spain ; Deparment of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain
Benussi, Luisa; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Ghidoni, Roberta; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Binetti, Giuliano; Center for Molecular Neurology, VIB, Antwerp, Belgium ; MAC Memory Center and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Hernández, Isabel; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Boada, Mercè; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Ruiz, Agustín; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Sorbi, Sandro; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
Nacmias, Benedetta; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
Bagnoli, Silvia; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
Sorbi, Sandro; Center for Molecular Neurology, VIB, Antwerp, Belgium ; IRCCS Don Carlo Gnocchi Scandicci, Florence, Italy
Sanchez-Valle, Raquel; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Hospital Clínic, IDIBAPS, Barcelona, Spain
Llado, Albert; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Hospital Clínic, IDIBAPS, Barcelona, Spain
Santana, Isabel; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University of Coimbra, Coimbra, Portugal
Rosário Almeida, Maria; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University of Coimbra, Coimbra, Portugal
Frisoni, Giovanni B; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Hôpitaux Universitaires de Genève et Université de Genève, Genève, Switzerland and IRCCS Fatebenefratelli, Brescia, Italy
Maetzler, Walter; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Hertie Institute for Clinical Brain Research, Tübingen, Germany
Matej, Radoslav; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Thomayer Hospital, Prague and Charles University, Prague, Czech Republic
Fraidakis, Matthew J; Center for Molecular Neurology, VIB, Antwerp, Belgium ; NeuroRARE Centre for Rare and Genetic Neurological & Neuromuscular Diseases & Neurogenetics Athens, Greece
Kovacs, Gabor G; Center for Molecular Neurology, VIB, Antwerp, Belgium ; Medical University of Vienna, Vienna, Austria
Fabrizi, Gian Maria; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University of Verona, Verona, Italy
Testi, Silvia; Center for Molecular Neurology, VIB, Antwerp, Belgium ; University of Verona, Verona, Italy
Federaal Wetenschapsbeleid Flemish Government (Flanders Impulse Program on Networks for Dementia Research Methusalem Excellence Program Fonds Wetenschappelijk Onderzoek University of Antwerp Research Fund Fondazione Cassa di Risparmio di Pistoia e Pescia Cassa di Risparmio di Firenze Fondo di Ateno 2014 Ricerca Corrente Italian Ministry of Health Else Kröner-Fresenius-Stiftung Swedish Brain Power Vetenskapsrådet Gun and Bertil Stohne Gamla tjänarinnor Demensfonden Sweden Alzheimer Foundation Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse StratNeuro at Karolinska Institute (KI)
Funding text :
The authors thank the personnel of the Neuromics Support Facility of the VIB Center for Molecular Neurology (http://www.vibgeneticservicefacility.be) and the Antwerp Biobank of the Institute Born-Bunge for their expert support. The Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS thanks all brain donors and families for generous brain donation for research and the Neurological Tissue Bank of the IDIBAPS Biobank for data and sample procurement. Caroline Graff wishes to express her acknowledgements to Inger Nennesmo (for the neuropathological assessments), Huei-Hsin Chiang, Jenny Björkström, Lena Lilius, Charlotte Forsell, Marie Fallström (Department of Neurobiology, Care Sciences and Society [NVS], Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet and Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden), and The Brain Bank at Karolinska Institutet. The LMU Munich site acknowledges the essential support of the team at Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität Munich (Thomas Arzberger, Sigrun Roeber, Manuela Neumann, Armin Giese, and Hans Kretzschmar) for their neuropathological work and the safekeeping of DNA samples. Disclosure statement: The authors declare no conflict of interest.
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