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TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis

(2017) HUMAN MUTATION. 38(3). p.297-309
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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.
Keywords
TANK-Binding Kinase 1, TBK1, frontotemporal dementia, FTD, amyotrophic lateral sclerosis, ALS, mutations, NFkB luciferase reporter assay, LOBAR DEGENERATION, REPEAT EXPANSION, HEXANUCLEOTIDE REPEAT, ARGYROPHILIC GRAINS, DIAGNOSTIC-CRITERIA, BELGIAN COHORT, FAMILIAL ALS, C9ORF72, DISEASE, TDP-43

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Citation

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Chicago
van der Zee, Julie, Ilse Gijselinck, Sara Van Mossevelde, Federica Perrone, Lubina Dillen, Bavo Heeman, Veerle Bäumer, et al. 2017. “TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.” Human Mutation 38 (3): 297–309.
APA
van der Zee, J., Gijselinck, I., Van Mossevelde, S., Perrone, F., Dillen, L., Heeman, B., Bäumer, V., et al. (2017). TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis. HUMAN MUTATION, 38(3), 297–309.
Vancouver
1.
van der Zee J, Gijselinck I, Van Mossevelde S, Perrone F, Dillen L, Heeman B, et al. TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis. HUMAN MUTATION. 2017;38(3):297–309.
MLA
van der Zee, Julie, Ilse Gijselinck, Sara Van Mossevelde, et al. “TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.” HUMAN MUTATION 38.3 (2017): 297–309. Print.
@article{8507724,
  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.},
  author       = {van der Zee, Julie and Gijselinck, Ilse and Van Mossevelde, Sara and Perrone, Federica and Dillen, Lubina and Heeman, Bavo and B{\"a}umer, Veerle and Engelborghs, Sebastiaan and De Bleecker, Jan and Baets, Jonathan and Gelpi, Ellen and Rojas-Garc{\'i}a, Ricardo and Clarim{\'o}n, Jordi and Lle{\'o}, Alberto and Diehl-Schmid, Janine and Alexopoulos, Panagiotis and Perneczky, Robert and Synofzik, Matthis and Just, Jennifer and Sch{\"o}ls, Ludger and Graff, Caroline and Thonberg, H{\aa}kan and Borroni, Barbara and Padovani, Alessandro and Jordanova, Albena and Sarafov, Stayko and Tournev, Ivailo and de Mendon\c{c}a, Alexandre and Miltenberger-Milt{\'e}nyi, Gabriel and Sim{\~o}es do Couto, Frederico and Ramirez, Alfredo and Jessen, Frank and Heneka, Michael T and G{\'o}mez-Tortosa, Estrella and Danek, Adrian and Cras, Patrick and Vandenberghe, Rik and De Jonghe, Peter and De Deyn, Peter P and Sleegers, Kristel and Cruts, Marc and Van Broeckhoven, Christine and Belgian Neurology Consortium, the and Santens, Patrick and Dermaut, Bart},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  language     = {eng},
  number       = {3},
  pages        = {297--309},
  title        = {TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis},
  url          = {http://dx.doi.org/10.1002/humu.23161},
  volume       = {38},
  year         = {2017},
}

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