TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
van der Zee, Julie (University of Antwerp)
Gijselinck, Ilse (University of Antwerp)
Van Mossevelde, Sara (University Hospital Antwerp (Bèlgica))
Perrone, Federica (University of Antwerp)
Dillen, Lubina (University of Antwerp)
Heeman, Bavo (University of Antwerp)
Bäumer, Veerle (University of Antwerp)
Engelborghs, Sebastiaan (University Hospital Antwerp (Bèlgica))
De Bleecker, Jan (Universitair Ziekenhuis Gent)
Baets, Jonathan (University Hospital Antwerp (Bèlgica))
Gelpi, Ellen (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Rojas-Garcia, Ricard (Universitat Autònoma de Barcelona)
Clarimón, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Lleó Bisa, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Diehl-Schmid, Janine (Technische Universität München)
Alexopoulos, Panagiotis (Technische Universität München)
Perneczky, Robert (West London Mental Health Trust)
Synofzik, Matthis (German Research Center for Neurodegenerative Diseases (DZNE))
Just, Jennifer (German Research Center for Neurodegenerative Diseases (DZNE))
Schöls, Ludger (German Research Center for Neurodegenerative Diseases (DZNE))
Graff, Caroline (Karolinska University Hospital and Karolinska Institutet (Suècia))
Thonberg, Håkan (Karolinska University Hospital and Karolinska Institutet (Suècia))
Borroni, Barbara (University of Brescia)
Padovani, Alessandro (University of Brescia)
Jordanova, Albena (Medical University-Sofia)
Sarafov, Stayko (Medical University-Sofia)
Tournev, Ivailo (New Bulgarian University)
de Mendonça, Alexandre (University of Lisbon)
Miltenberger-Miltényi, Gabriel (University of Lisbon)
Simões do Couto, Frederico (University of Lisbon)
Ramirez, Alfredo (University of Cologne)
Jessen, Frank (German Center for Neurodegenerative Diseases (DZNE))
Heneka, Michael T. (University of Bonn)
Gómez-Tortosa, Estrella (Hospital Universitario Fundación Jiménez Díaz)
Danek, Adrian (German Center for Neurodegenerative Diseases (DZNE))
Cras, Patrick (University Hospital Antwerp (Bèlgica))
Vandenberghe, Rik (University Hospitals Leuven (Bèlgica))
De Jonghe, Peter (University Hospital Antwerp (Bèlgica))
De Deyn, Peter Paul (University Hospital Antwerp (Bèlgica))
Sleegers, Kristel (University of Antwerp)
Cruts, Marc (University of Antwerp)
Van Broeckhoven, Christine (University of Antwerp)
Goeman, Johan (University Hospital Antwerp (Bèlgica))
Nuytten, Dirk (University Hospital Antwerp (Bèlgica))
Smets, Katrien (University Hospital Antwerp (Bèlgica))
Robberecht, Wim (University Hospitals Gasthuisberg (Leuven, Bélgica))
Damme, Philip Van (University Hospitals Gasthuisberg (Leuven, Bélgica))
Bleecker, Jan De (Universitair Ziekenhuis Gent)
Santens, Patrick (Universitair Ziekenhuis Gent)
Dermaut, Bart (Universitair Ziekenhuis Gent)
Versijpt, Jan (University Hospital Brussels)
Michotte, Alex (University Hospital Brussels)
Ivanoiu, Adrian (Saint-Luc University Hospital)
Deryck, Olivier (General Hospital Sint-Jan Brugge)
Bergmans, Bruno (General Hospital Sint-Jan Brugge)
Delbeck, Jean (General Hospital Sint-Maria)
Bruyland, Marc (General Hospital Glorieux Ronse)
Willems, Christiana (Jessa Hospital)
Salmon, Eric (University of Liège and Memory Clinic)
Pastor, Pau (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Ortega-Cubero, Sara (Deparment of Neurology, Complejo Asistencial Universitario de Palencia)
Benussi, Luisa (Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Ghidoni, Roberta (Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Binetti, Giuliano (MAC Memory Center and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli)
Hernández, Isabel (Institut Català de Neurociènces Aplicades)
Boada, Mercè (Institut Català de Neurociènces Aplicades)
Ruiz Laza, Agustín (Institut Català de Neurociènces Aplicades)
Sorbi, Sandro (Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence)
Nacmias, Benedetta (Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence)
Bagnoli, Silvia (Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence)
Sorbi, Sandro (IRCCS Don Carlo Gnocchi Scandicci)
Sánchez Valle, Raquel (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Llado Plarrumani, Albert (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Santana, Isabel (University of Coimbra)
Rosário Almeida, Maria (University of Coimbra)
Frisoni, Giovanni B. (Hôpitaux Universitaires de Genève et Université de Genève, Genève, Switzerland and IRCCS Fatebenefratelli)
Maetzler, Walter (Hertie Institute for Clinical Brain Research)
Matej, Radoslav (Charles University. Faculty of Medicine in Hradec Králové)
Fraidakis, Matthew J. (NeuroRARE Centre for Rare and Genetic Neurological & Neuromuscular Diseases & Neurogenetics)
Kovacs, Gabor G. (Medical University of Vienna)
Fabrizi, Gian Maria (University of Verona)
Testi, Silvia (University of Verona)
Universitat Autònoma de Barcelona

Data:	2017
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	TANK-Binding Kinase 1 ; TBK1 ; Frontotemporal dementia ; FTD ; Amyotrophic lateral sclerosis ; ALS ; Mutations ; NFκB luciferase reporter assay
Publicat a:	Human mutation, Vol. 38, Issue 3 (March 2017) , p. 297-309, ISSN 1098-1004

DOI: 10.1002/humu.23161
PMID: 28008748

13 p, 955.5 KB

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