van der Zee, Julie, Gijselinck, Ilse, Van Mossevelde, Sara, Perrone, Federica ORCID: 0000-0002-4079-8972, Dillen, Lubina, Heeman, Bavo, Baumer, Veerle, Engelborghs, Sebastiaan, De Bleecker, Jan, Baets, Jonathan, Gelpi, Ellen, Rojas-Garcia, Ricardo, Clarimon, Jordi, Lleo, Alberto, Diehl-Schmid, Janine ORCID: 0000-0002-7745-1382, Alexopoulos, Panagiotis, Perneczky, Robert ORCID: 0000-0003-1981-7435, Synofzik, Matthis, Just, Jennifer, Schoels, Ludger, Graff, Caroline, Thonberg, Hakan, Borroni, Barbara, Padovani, Alessandro, Jordanova, Albena ORCID: 0000-0002-3833-3754, Sarafov, Stayko, Tournev, Ivailo, de Mendonca, Alexandre ORCID: 0000-0002-0488-1453, Miltenberger-Miltenyi, Gabriel ORCID: 0000-0003-0224-1281, Simoes do Couto, Frederico, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Jessen, Frank, Heneka, Michael T., Gomez-Tortosa, Estrella, Danek, Adrian ORCID: 0000-0001-8857-5383, Cras, Patrick, Vandenberghe, Rik ORCID: 0000-0001-6237-2502, De Jonghe, Peter, De Deyn, Peter P., Sleegers, Kristel, Cruts, Marc and Van Broeckhoven, Christine ORCID: 0000-0003-0183-7665 (2017). TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Hum. Mutat., 38 (3). S. 297 - 310. HOBOKEN: WILEY. ISSN 1098-1004

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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 NFB-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 NFB 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
van der Zee, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gijselinck, IlseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Mossevelde, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perrone, FedericaUNSPECIFIEDorcid.org/0000-0002-4079-8972UNSPECIFIED
Dillen, LubinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heeman, BavoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumer, VeerleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engelborghs, SebastiaanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Bleecker, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baets, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gelpi, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rojas-Garcia, RicardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clarimon, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lleo, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diehl-Schmid, JanineUNSPECIFIEDorcid.org/0000-0002-7745-1382UNSPECIFIED
Alexopoulos, PanagiotisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perneczky, RobertUNSPECIFIEDorcid.org/0000-0003-1981-7435UNSPECIFIED
Synofzik, MatthisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Just, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoels, LudgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graff, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thonberg, HakanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borroni, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Padovani, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jordanova, AlbenaUNSPECIFIEDorcid.org/0000-0002-3833-3754UNSPECIFIED
Sarafov, StaykoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tournev, IvailoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Mendonca, AlexandreUNSPECIFIEDorcid.org/0000-0002-0488-1453UNSPECIFIED
Miltenberger-Miltenyi, GabrielUNSPECIFIEDorcid.org/0000-0003-0224-1281UNSPECIFIED
Simoes do Couto, FredericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Jessen, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heneka, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gomez-Tortosa, EstrellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danek, AdrianUNSPECIFIEDorcid.org/0000-0001-8857-5383UNSPECIFIED
Cras, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandenberghe, RikUNSPECIFIEDorcid.org/0000-0001-6237-2502UNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Deyn, Peter P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sleegers, KristelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruts, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Broeckhoven, ChristineUNSPECIFIEDorcid.org/0000-0003-0183-7665UNSPECIFIED
URN: urn:nbn:de:hbz:38-239003
DOI: 10.1002/humu.23161
Journal or Publication Title: Hum. Mutat.
Volume: 38
Number: 3
Page Range: S. 297 - 310
Date: 2017
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LOBAR DEGENERATION; REPEAT EXPANSION; HEXANUCLEOTIDE REPEAT; ARGYROPHILIC GRAINS; C9ORF72; TDP-43; INDIVIDUALS; CRITERIA; GENE; ALSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23900

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