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

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...

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Authors: Van der Zee, Julie|||0000-0003-4381-8040, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica, Dillen, Lubina, Heeman, Bavo, Bäumer, Veerle, Engelborghs, Sebastiaan|||0000-0003-0304-9785, De Bleecker, Jan, Baets, Jonathan|||0000-0001-8295-5385, Gelpi, Ellen|||0000-0003-2948-4187, Rojas-Garcia, Ricard|||0000-0003-1411-5573, Clarimón, Jordi|||0000-0002-6824-6942, Lleó, Alberto|||0000-0002-2568-5478, Diehl-Schmid, Janine|||0000-0002-7745-1382, Alexopoulos, Panagiotis|||0000-0002-9047-6365, Perneczky, Robert|||0000-0003-1981-7435, Synofzik, Matthis|||0000-0002-2280-7273, Just, Jennifer, Schöls, Ludger|||0000-0001-7774-5025, Graff, Caroline|||0000-0002-9949-2951, Thonberg, Håkan|||0000-0003-4503-4717, Borroni, Barbara|||0000-0001-9340-9814, Padovani, Alessandro|||0000-0002-0119-3639, Jordanova, Albena, Sarafov, Stayko, Tournev, Ivailo, de Mendonça, Alexandre|||0000-0002-0488-1453, Miltenberger-Miltényi, Gabriel|||0000-0003-0224-1281, Simões do Couto, Frederico|||0000-0002-3916-2598, Ramirez, Alfredo|||0000-0003-4991-763X, Jessen, Frank, Heneka, Michael|||0000-0003-4996-1630, Gómez-Tortosa, Estrella, Danek, Adrian|||0000-0001-8857-5383, Cras, Patrick|||0000-0002-7265-7429, Vandenberghe, Rik|||0000-0001-6237-2502, De Jonghe, Peter, De Deyn, Peter Paul|||0000-0002-2228-2964, Sleegers, Kristel|||0000-0002-0283-2332, Cruts, Marc|||0000-0002-1338-992X, Van Broeckhoven, Christine|||0000-0003-0183-7665, Goeman, Johan, Nuytten, Dirk, Smets, Katrien, Robberecht, Wim, Damme, Philip Van, Bleecker, Jan De, Santens, Patrick|||0000-0002-8886-9776, Dermaut, Bart, Versijpt, Jan|||0000-0002-8710-5715, Michotte, Alex|||0000-0002-5652-6859, Ivanoiu, Adrian, Deryck, Olivier|||0000-0001-6720-5404, Bergmans, Bruno|||0000-0002-1463-8262, Delbeck, Jean, Bruyland, Marc, Willems, Christiana, Salmon, Eric|||0000-0003-2520-9241, Pastor, Pau|||0000-0002-7493-8777, Ortega-Cubero, Sara|||0000-0003-0520-9439, Benussi, Luisa|||0000-0003-2836-8141, Ghidoni, Roberta|||0000-0002-7691-1957, Binetti, Giuliano|||0000-0003-2759-5844, Hernández, Isabel|||0000-0001-8119-393X, Boada, Mercè|||0000-0003-2617-3009, Ruiz Laza, Agustín|||0000-0003-2633-2495, Sorbi, Sandro|||0000-0002-0380-6670, Nacmias, Benedetta|||0000-0001-9338-9040, Bagnoli, Silvia, Sánchez Valle, Raquel, Llado Plarrumani, Albert|||0000-0002-5066-4150, Santana, Isabel|||0000-0002-8114-9434, Rosário Almeida, Maria, Frisoni, Giovanni B.|||0000-0002-6419-1753, Maetzler, Walter|||0000-0002-5945-4694, Matej, Radoslav|||0000-0002-6152-6343, Fraidakis, Matthew Joseph|||0000-0003-3797-4741, Kovacs, Gabor G.|||0000-0003-3841-5511, Fabrizi, Gian Maria|||0000-0001-6804-0226, Testi, Silvia|||0000-0003-0267-0000
Format: article
Publication Date:2017
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:186059
Online Access:https://ddd.uab.cat/record/186059
https://dx.doi.org/urn:doi:10.1002/humu.23161
Access Level:Open access
Keyword:TANK-Binding Kinase 1
TBK1
Frontotemporal dementia
FTD
Amyotrophic lateral sclerosis
ALS
Mutations
NFκB luciferase reporter assay
Description
Summary: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.

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