title: TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
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.
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Van Mossevelde
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Lubina
authors.initials: L
authors.lastname: Dillen
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Bavo
authors.initials: B
authors.lastname: Heeman
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bäumer
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Bleecker
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Neurological Tissue Bank of the Biobanc - Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.affiliation: Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rojas-García
authors.affiliation: 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Diehl-Schmid
authors.affiliation: Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Alexopoulos
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Perneczky
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Just
authors.affiliation: Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany.|German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: 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.
authors.forename: Håkan
authors.initials: H
authors.lastname: Thonberg
authors.affiliation: Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.affiliation: Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: 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.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.affiliation: Department of Neurology, Medical University-Sofia, Sofia, Bulgaria.
authors.forename: Stayko
authors.initials: S
authors.lastname: Sarafov
authors.affiliation: Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.affiliation: Hospital Santa Maria, Lisbon, Portugal.|Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Mendonça
authors.affiliation: Hospital Santa Maria, Lisbon, Portugal.|Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Miltenberger-Miltényi
authors.affiliation: Hospital Santa Maria, Lisbon, Portugal.|Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Frederico
authors.initials: F
authors.lastname: Simões do Couto
authors.affiliation: 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.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: 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.
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Estrella
authors.initials: E
authors.lastname: Gómez-Tortosa
authors.affiliation: Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Danek
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.affiliation: Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium.|Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Christine
authors.initials: C
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Hospital Network Antwerp, Antwerp.
authors.forename: Johan
authors.initials: J
authors.lastname: Goeman
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Hospital Network Antwerp, Antwerp.
authors.forename: Dirk
authors.initials: D
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Antwerp University Hospital, Edegem.
authors.forename: Katrien
authors.initials: K
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospitals Leuven Gasthuisberg, Leuven.
authors.forename: Wim
authors.initials: W
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospitals Leuven Gasthuisberg, Leuven.
authors.forename: Philip Van
authors.initials: PV
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospital Ghent, Ghent.
authors.forename: Jan De
authors.initials: J
authors.lastname: Bleecker
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospital Ghent, Ghent.
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospital Ghent, Ghent.
authors.forename: Bart
authors.initials: B
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authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospital Brussels, Brussels.
authors.forename: Jan
authors.initials: J
authors.lastname: Versijpt
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University Hospital Brussels, Brussels.
authors.forename: Alex
authors.initials: A
authors.lastname: Michotte
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Saint-Luc University Hospital, Brussels.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivanoiu
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|General Hospital Sint-Jan Brugge, Bruges.
authors.forename: Olivier
authors.initials: O
authors.lastname: Deryck
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|General Hospital Sint-Jan Brugge, Bruges.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bergmans
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|General Hospital Sint-Maria, Halle.
authors.forename: Jean
authors.initials: J
authors.lastname: Delbeck
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|General Hospital Glorieux Ronse.
authors.forename: Marc
authors.initials: M
authors.lastname: Bruyland
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Jessa Hospital, Hasselt.
authors.forename: Christiana
authors.initials: C
authors.lastname: Willems
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University of Liège and Memory Clinic, CHU Liège, Liège.
authors.forename: Eric
authors.initials: E
authors.lastname: Salmon
authors.affiliation: 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.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|MAC Memory Center and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Hernández
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bagnoli
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|IRCCS Don Carlo Gnocchi Scandicci, Florence, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sanchez-Valle
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Llado
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University of Coimbra, Coimbra, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University of Coimbra, Coimbra, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: Rosário Almeida
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Hôpitaux Universitaires de Genève et Université de Genève, Genève, Switzerland and IRCCS Fatebenefratelli, Brescia, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Thomayer Hospital, Prague and Charles University, Prague, Czech Republic.
authors.forename: Radoslav
authors.initials: R
authors.lastname: Matej
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|NeuroRARE Centre for Rare and Genetic Neurological & Neuromuscular Diseases & Neurogenetics Athens, Greece.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fraidakis
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|Medical University of Vienna, Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University of Verona, Verona, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fabrizi
authors.affiliation: Center for Molecular Neurology, VIB, Antwerp, Belgium.|University of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Testi
mesh_terms: D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004789:Enzyme Activation; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D044465:White People / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
keywords: ALS; FTD; NFκB luciferase reporter assay; TANK-Binding Kinase 1; TBK1; amyotrophic lateral sclerosis; frontotemporal dementia; mutations