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Title: TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Authors: van der Zee, Julie ×
Gijselinck, Ilse
Van Mossevelde, Sara
Perrone, Federica
Dillen, Lubina
Heeman, Bavo
Bäumer, Veerle
Engelborghs, Sebastiaan
de Bleecker, Jan
Baets, Jonathan
Gelpi, Ellen
Rojas-García, Ricardo
Clarimón, Jordi
Lleó, Alberto
Diehl-Schmid, Janine
Alexopoulos, Panagiotis
Perneczky, Robert
Synofzik, Matthis
Just, Jennifer
Schöls, Ludger
Graff, Caroline
Thonberg, Håkan
Borroni, Barbara
Padovani, Alessandro
Jordanova, Albena
Sarafov, Stayko
Tournev, Ivailo
de Mendonça, Alexandre
Miltenberger-Miltényi, Gabriel
Simões do Couto, Frederico
Ramirez, Alfredo
Jessen, Frank
Heneka, Michael T
Gómez-Tortosa, Estrella
Danek, Adrian
Cras, Patrick
Vandenberghe, Rik
De Jonghe, Peter
De Deyn, Peter P
Sleegers, Kristel
Cruts, Marc
Van Broeckhoven, Christine
Goeman, Johan
Nuytten, Dirk
Smets, Katrien
Robberecht, Wim
Van Damme, Philip
Bleecker, Jan De
Santens, Patrick
Dermaut, Bart
Versijpt, Jan
Michotte, Alex
Ivanoiu, Adrian
Deryck, Olivier
Bergmans, Bruno
Delbeck, Jean
Bruyland, Marc
Willems, Christiana
Salmon, Eric
Pastor, Pau
Ortega-Cubero, Sara
Benussi, Luisa
Ghidoni, Roberta
Binetti, Giuliano
Hernández, Isabel
Boada, Mercè
Ruiz, Agustín
Sorbi, Sandro
Nacmias, Benedetta
Bagnoli, Silvia
Sorbi, Sandro
Sanchez-Valle, Raquel
Llado, Albert
Santana, Isabel
Rosário Almeida, Maria
Frisoni, Giovanni B
Maetzler, Walter
Matej, Radoslav
Fraidakis, Matthew J
Kovacs, Gabor G
Fabrizi, Gian Maria
Testi, Silvia #
Issue Date: Mar-2017
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:38 issue:3 pages:297-309
Article number: 10.1002/humu.23161
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.
URI: 
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicine Teaching Programs
Studiegebied Gezondheidszorg - VIVES Noord
Thomas More Mechelen-Antwerpen (TMMA)
Laboratory for Cognitive Neurology
Faculty of Movement and Rehabilitation Sciences - miscellaneous
Laboratory for Neurobiology
× corresponding author
# (joint) last author

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