TY  - JOUR
AU  - van der Zee, Julie
AU  - Gijselinck, Ilse
AU  - Van Mossevelde, Sara
AU  - Perrone, Federica
AU  - Dillen, Lubina
AU  - Heeman, Bavo
AU  - Bäumer, Veerle
AU  - Engelborghs, Sebastiaan
AU  - De Bleecker, Jan
AU  - Baets, Jonathan
AU  - Gelpi, Ellen
AU  - Rojas-García, Ricardo
AU  - Clarimón, Jordi
AU  - Lleó, Alberto
AU  - Diehl-Schmid, Janine
AU  - Alexopoulos, Panagiotis
AU  - Perneczky, Robert
AU  - Synofzik, Matthis
AU  - Just, Jennifer
AU  - Schöls, Ludger
AU  - Graff, Caroline
AU  - Thonberg, Håkan
AU  - Borroni, Barbara
AU  - Padovani, Alessandro
AU  - Jordanova, Albena
AU  - Sarafov, Stayko
AU  - Tournev, Ivailo
AU  - de Mendonça, Alexandre
AU  - Miltenberger-Miltényi, Gabriel
AU  - Simões do Couto, Frederico
AU  - Ramirez, Alfredo
AU  - Jessen, Frank
AU  - Heneka, Michael T
AU  - Gómez-Tortosa, Estrella
AU  - Danek, Adrian
AU  - Cras, Patrick
AU  - Vandenberghe, Rik
AU  - De Jonghe, Peter
AU  - De Deyn, Peter P
AU  - Sleegers, Kristel
AU  - Cruts, Marc
AU  - Van Broeckhoven, Christine
AU  - Goeman, Johan
AU  - Nuytten, Dirk
AU  - Smets, Katrien
AU  - Robberecht, Wim
AU  - Damme, Philip Van
AU  - Bleecker, Jan De
AU  - Santens, Patrick
AU  - Dermaut, Bart
AU  - Versijpt, Jan
AU  - Michotte, Alex
AU  - Ivanoiu, Adrian
AU  - Deryck, Olivier
AU  - Bergmans, Bruno
AU  - Delbeck, Jean
AU  - Bruyland, Marc
AU  - Willems, Christiana
AU  - Salmon, Eric
AU  - Pastor, Pau
AU  - Ortega-Cubero, Sara
AU  - Benussi, Luisa
AU  - Ghidoni, Roberta
AU  - Binetti, Giuliano
AU  - Hernández, Isabel
AU  - Boada, Mercè
AU  - Ruiz, Agustín
AU  - Sorbi, Sandro
AU  - Nacmias, Benedetta
AU  - Bagnoli, Silvia
AU  - Sorbi, Sandro
AU  - Sanchez-Valle, Raquel
AU  - Llado, Albert
AU  - Santana, Isabel
AU  - Rosário Almeida, Maria
AU  - Frisoni, Giovanni B
AU  - Maetzler, Walter
AU  - Matej, Radoslav
AU  - Fraidakis, Matthew J
AU  - Kovacs, Gabor G
AU  - Fabrizi, Gian Maria
AU  - Testi, Silvia
TI  - TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
JO  - Human mutation
VL  - 38
IS  - 3
SN  - 1059-7794
CY  - New York, NY [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2020-05389
SP  - 297-309
PY  - 2017
AB  - 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
KW  - Protein Serine-Threonine Kinases: genetics
KW  - Aged
KW  - Alleles
KW  - Amino Acid Substitution
KW  - Amyotrophic Lateral Sclerosis: diagnosis
KW  - Amyotrophic Lateral Sclerosis: epidemiology
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Case-Control Studies
KW  - Cohort Studies
KW  - Enzyme Activation
KW  - European Continental Ancestry Group: genetics
KW  - Female
KW  - Frontotemporal Dementia: diagnosis
KW  - Frontotemporal Dementia: epidemiology
KW  - Frontotemporal Dementia: genetics
KW  - Genetic Association Studies
KW  - Heterozygote
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Mutation
KW  - NF-kappa B: metabolism
KW  - Phenotype
KW  - Protein-Serine-Threonine Kinases: genetics
KW  - Protein-Serine-Threonine Kinases: metabolism
KW  - Sequence Deletion
KW  - Protein Serine-Threonine Kinases: metabolism
KW  - White People: genetics
KW  - NF-kappa B (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
KW  - TBK1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28008748
C2  - pmc:PMC5324646
DO  - DOI:10.1002/humu.23161
UR  - https://pub.dzne.de/record/139067
ER  -