1. TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis
- Author
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Isabel Santana, Estrella Gómez-Tortosa, Federica Perrone, Patrick Cras, Alexandre de Mendonça, Jonathan Baets, Panagiotis Alexopoulos, Peter De Jonghe, Alessandro Padovani, Giovanni B. Frisoni, Frederico Simões do Couto, Håkan Thonberg, Philip Van Damme, Silvia Testi, Peter Paul De Deyn, Roberta Ghidoni, Matthew J. Fraidakis, Marc Bruyland, Maria Rosário Almeida, Alex Michotte, Jordi Clarimón, Agustín Ruiz, Jean Delbeck, Ilse Gijselinck, Jennifer Just, Olivier Deryck, Raquel Sánchez-Valle, Wim Robberecht, Matthis Synofzik, Giuliano Binetti, Adrian Ivanoiu, Sara Ortega-Cubero, Rik Vandenberghe, Isabel Hernández, Walter Maetzler, Ludger Schöls, Robert Perneczky, Kristel Sleegers, Ellen Gelpi, Alberto Lleó, Christine Van Broeckhoven, Julie van der Zee, Mercè Boada, Lubina Dillen, Eric Salmon, Marc Cruts, Patrick Santens, Sebastiaan Engelborghs, Janine Diehl-Schmid, Albert Lladó, Gian Maria Fabrizi, Radoslav Matej, Silvia Bagnoli, Pau Pastor, Frank Jessen, Barbara Borroni, Dirk Nuytten, Adrian Danek, Jan Versijpt, Bavo Heeman, Stayko Sarafov, Caroline Graff, Benedetta Nacmias, Luisa Benussi, Bart Dermaut, Johan Goeman, Michael T. Heneka, Katrien Smets, Gabor G. Kovacs, Christiana Willems, Sara Van Mossevelde, Albena Jordanova, Jan De Bleecker, Ricardo Rojas-García, Alfredo Ramirez, Bruno Bergmans, Ivailo Tournev, Veerle Bäumer, Gabriel Miltenberger-Miltenyi, Sandro Sorbi, Frisoni, Giovanni, Repositório da Universidade de Lisboa, Belgian Neurology Consortium, and European Early-Onset Dementia Consortium
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0301 basic medicine ,Male ,ARGYROPHILIC GRAINS ,amyotrophic lateral sclerosis ,TBK1 ,TDP-43 ,diagnosis [Amyotrophic Lateral Sclerosis] ,FAMILIAL ALS ,medicine.disease_cause ,frontotemporal dementia ,DISEASE ,Cohort Studies ,ddc:616.89 ,diagnosis [Frontotemporal Dementia] ,0302 clinical medicine ,NFkB luciferase reporter assay ,metabolism [Protein Serine-Threonine Kinases] ,C9orf72 ,Medicine and Health Sciences ,Missense mutation ,Amyotrophic lateral sclerosis ,Mutation frequency ,genetics [Frontotemporal Dementia] ,Genetics (clinical) ,Research Articles ,Sequence Deletion ,Genetics ,Genetics & Heredity ,Mutation ,metabolism [Protein-Serine-Threonine Kinases] ,NF-kappa B ,FTD ,TBK1 protein, human ,Middle Aged ,Protein-Serine-Threonine Kinases ,genetics [Amyotrophic Lateral Sclerosis] ,genetics [European Continental Ancestry Group] ,Phenotype ,ALS ,NFκB luciferase reporter assay ,TANK-Binding Kinase 1 ,mutations ,metabolism [NF-kappa B] ,Female ,Life Sciences & Biomedicine ,Frontotemporal dementia ,Mutations ,Research Article ,TANK‐Binding Kinase 1 ,Heterozygote ,DIAGNOSTIC-CRITERIA ,epidemiology [Frontotemporal Dementia] ,genetics [White People] ,C9ORF72 ,genetics [Protein Serine-Threonine Kinases] ,epidemiology [Amyotrophic Lateral Sclerosis] ,Biology ,Protein Serine-Threonine Kinases ,genetics [Protein-Serine-Threonine Kinases] ,White People ,03 medical and health sciences ,mental disorders ,medicine ,Humans ,BELGIAN COHORT ,ddc:610 ,LOBAR DEGENERATION ,Gene ,Alleles ,Genetic Association Studies ,Aged ,0604 Genetics ,Science & Technology ,HEXANUCLEOTIDE REPEAT ,1103 Clinical Sciences ,medicine.disease ,REPEAT EXPANSION ,Enzyme Activation ,030104 developmental biology ,Amino Acid Substitution ,Case-Control Studies ,Human medicine ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery - Abstract
© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., 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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- 2016
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