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

Kimberly J. Van Zee, Ilse Gijselinck, Sara Van Mossevelde, F. Perrone, Lubina Dillen, Bavo Heeman, Veerle Bäumer, Sebastiaan Engelborghs, J. L. De Bleecker, Jonathan Baets, Ellen Gelpi, Ricard Rojas-García, J. Clarimón, Alberto Lleó, Janine Diehl-Schmid, Panos Alexopoulos, Robert Perneczky, Matthis Synofzik, J. Just, L. Schöls & 61 others Caroline Graff, Håkan Thonberg, B. Borroni, A. Padovani, Albena Jordanova, Stayko Sarafov, I. Tournev, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, F. Simões do Couto, A. Ramirez, Frank Jessen, Michael T. Heneka, Estrella Gómez-Tortosa, Adrian Danek, P. Cras, Rik Vandenberghe, P. de Jonghe, P. P. De Deyn, Kristel Sleegers, Marc Cruts, C. Van Broeckhoven, Johan Goeman, Dirk Nuytten, Katrin Smets, Wim Robberecht, Philip van Damme, Jan De Bleecker, Patrick Santens, Bart Dermaut, Jan Versijpt, Alex Michotte, Adrian Ivanoiu, Olivier Deryck, Bruno Bergmans, Jean Delbeck, M. Bruyland, C. Willems, E. Salmon, Pau Pastor, Sara Ortega-Cubero, L. Benussi, R. Ghidoni, G. Binetti, Isabel Hernández, M. Boada, A. Ruiz, S. Sorbi, B. Nacmias, Siro Bagnoli, Raquel Sanchez-Valle, A. Llado, Isabel Santana, Maria Do Rosário Almeida, G.B. Frisoni, Walter Maetzler, Radoslav Matej, Matthew J. Fraidakis, G. G. Kovacs, G. M. Fabrizi, Sergio Testi

Research output: Contribution to journalArticle

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 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. © 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.
Original languageEnglish
JournalHuman Mutation
DOIs
Publication statusPublished - 2016

Fingerprint

Phosphotransferases
Mutation
Missense Mutation
Nonsense Mediated mRNA Decay
Amino Acids
Frontotemporal Dementia
Proteins
Sequence Deletion
Amyotrophic Lateral Sclerosis
Mutation Rate
Frontotemporal Dementia With Motor Neuron Disease
Luciferases
Protein Kinases
Virulence
Dementia
Alleles
RNA
Genes

Keywords

  • ALS
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • FTD
  • mutations
  • NFκB luciferase reporter assay
  • TANK-Binding Kinase 1
  • TBK1

Cite this

Van Zee, K. J., Gijselinck, I., Van Mossevelde, S., Perrone, F., Dillen, L., Heeman, B., ... Testi, S. (2016). TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. Human Mutation. https://doi.org/10.1002/humu.23161

TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. / Van Zee, Kimberly J.; Gijselinck, Ilse; Van Mossevelde, Sara; Perrone, F.; Dillen, Lubina; Heeman, Bavo; Bäumer, Veerle; Engelborghs, Sebastiaan; De Bleecker, J. L.; Baets, Jonathan; Gelpi, Ellen; Rojas-García, Ricard; Clarimón, J.; Lleó, Alberto; Diehl-Schmid, Janine; Alexopoulos, Panos; Perneczky, Robert; Synofzik, Matthis; Just, J.; Schöls, L.; Graff, Caroline; Thonberg, Håkan; Borroni, B.; Padovani, A.; Jordanova, Albena; Sarafov, Stayko; Tournev, I.; de Mendonça, Alexandre; Miltenberger-Miltényi, Gabriel; Simões do Couto, F.; Ramirez, A.; Jessen, Frank; Heneka, Michael T.; Gómez-Tortosa, Estrella; Danek, Adrian; Cras, P.; Vandenberghe, Rik; Jonghe, P. de; De Deyn, P. P.; Sleegers, Kristel; Cruts, Marc; Van Broeckhoven, C.; Goeman, Johan; Nuytten, Dirk; Smets, Katrin; Robberecht, Wim; van Damme, Philip; De Bleecker, Jan; Santens, Patrick; Dermaut, Bart; Versijpt, Jan; Michotte, Alex; Ivanoiu, Adrian; Deryck, Olivier; Bergmans, Bruno; Delbeck, Jean; Bruyland, M.; Willems, C.; Salmon, E.; Pastor, Pau; Ortega-Cubero, Sara; Benussi, L.; Ghidoni, R.; Binetti, G.; Hernández, Isabel; Boada, M.; Ruiz, A.; Sorbi, S.; Nacmias, B.; Bagnoli, Siro; Sanchez-Valle, Raquel; Llado, A.; Santana, Isabel; Do Rosário Almeida, Maria; Frisoni, G.B.; Maetzler, Walter; Matej, Radoslav; Fraidakis, Matthew J.; Kovacs, G. G.; Fabrizi, G. M.; Testi, Sergio.

In: Human Mutation, 2016.

Research output: Contribution to journalArticle

Van Zee, KJ, Gijselinck, I, Van Mossevelde, S, Perrone, F, Dillen, L, Heeman, B, Bäumer, V, Engelborghs, S, De Bleecker, JL, Baets, J, Gelpi, E, Rojas-García, R, Clarimón, J, Lleó, A, Diehl-Schmid, J, Alexopoulos, P, Perneczky, R, Synofzik, M, Just, J, Schöls, L, Graff, C, Thonberg, H, Borroni, B, Padovani, A, Jordanova, A, Sarafov, S, Tournev, I, de Mendonça, A, Miltenberger-Miltényi, G, Simões do Couto, F, Ramirez, A, Jessen, F, Heneka, MT, Gómez-Tortosa, E, Danek, A, Cras, P, Vandenberghe, R, Jonghe, PD, De Deyn, PP, Sleegers, K, Cruts, M, Van Broeckhoven, C, Goeman, J, Nuytten, D, Smets, K, Robberecht, W, van Damme, P, De Bleecker, J, Santens, P, Dermaut, B, Versijpt, J, Michotte, A, Ivanoiu, A, Deryck, O, Bergmans, B, Delbeck, J, Bruyland, M, Willems, C, Salmon, E, Pastor, P, Ortega-Cubero, S, Benussi, L, Ghidoni, R, Binetti, G, Hernández, I, Boada, M, Ruiz, A, Sorbi, S, Nacmias, B, Bagnoli, S, Sanchez-Valle, R, Llado, A, Santana, I, Do Rosário Almeida, M, Frisoni, GB, Maetzler, W, Matej, R, Fraidakis, MJ, Kovacs, GG, Fabrizi, GM & Testi, S 2016, 'TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis', Human Mutation. https://doi.org/10.1002/humu.23161
Van Zee, Kimberly J. ; Gijselinck, Ilse ; Van Mossevelde, Sara ; Perrone, F. ; Dillen, Lubina ; Heeman, Bavo ; Bäumer, Veerle ; Engelborghs, Sebastiaan ; De Bleecker, J. L. ; Baets, Jonathan ; Gelpi, Ellen ; Rojas-García, Ricard ; Clarimón, J. ; Lleó, Alberto ; Diehl-Schmid, Janine ; Alexopoulos, Panos ; Perneczky, Robert ; Synofzik, Matthis ; Just, J. ; Schöls, L. ; Graff, Caroline ; Thonberg, Håkan ; Borroni, B. ; Padovani, A. ; Jordanova, Albena ; Sarafov, Stayko ; Tournev, I. ; de Mendonça, Alexandre ; Miltenberger-Miltényi, Gabriel ; Simões do Couto, F. ; Ramirez, A. ; Jessen, Frank ; Heneka, Michael T. ; Gómez-Tortosa, Estrella ; Danek, Adrian ; Cras, P. ; Vandenberghe, Rik ; Jonghe, P. de ; De Deyn, P. P. ; Sleegers, Kristel ; Cruts, Marc ; Van Broeckhoven, C. ; Goeman, Johan ; Nuytten, Dirk ; Smets, Katrin ; Robberecht, Wim ; van Damme, Philip ; De Bleecker, Jan ; Santens, Patrick ; Dermaut, Bart ; Versijpt, Jan ; Michotte, Alex ; Ivanoiu, Adrian ; Deryck, Olivier ; Bergmans, Bruno ; Delbeck, Jean ; Bruyland, M. ; Willems, C. ; Salmon, E. ; Pastor, Pau ; Ortega-Cubero, Sara ; Benussi, L. ; Ghidoni, R. ; Binetti, G. ; Hernández, Isabel ; Boada, M. ; Ruiz, A. ; Sorbi, S. ; Nacmias, B. ; Bagnoli, Siro ; Sanchez-Valle, Raquel ; Llado, A. ; Santana, Isabel ; Do Rosário Almeida, Maria ; Frisoni, G.B. ; Maetzler, Walter ; Matej, Radoslav ; Fraidakis, Matthew J. ; Kovacs, G. G. ; Fabrizi, G. M. ; Testi, Sergio. / TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. In: Human Mutation. 2016.
@article{5027dce373a443599808bf6788f2a572,
title = "TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis",
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 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. {\circledC} 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.",
keywords = "ALS, amyotrophic lateral sclerosis, frontotemporal dementia, FTD, mutations, NFκB luciferase reporter assay, TANK-Binding Kinase 1, TBK1",
author = "{Van Zee}, {Kimberly J.} and Ilse Gijselinck and {Van Mossevelde}, Sara and F. Perrone and Lubina Dillen and Bavo Heeman and Veerle B{\"a}umer and Sebastiaan Engelborghs and {De Bleecker}, {J. L.} and Jonathan Baets and Ellen Gelpi and Ricard Rojas-Garc{\'i}a and J. Clarim{\'o}n and Alberto Lle{\'o} and Janine Diehl-Schmid and Panos Alexopoulos and Robert Perneczky and Matthis Synofzik and J. Just and L. Sch{\"o}ls and Caroline Graff and H{\aa}kan Thonberg and B. Borroni and A. Padovani and Albena Jordanova and Stayko Sarafov and I. Tournev and {de Mendon{\cc}a}, Alexandre and Gabriel Miltenberger-Milt{\'e}nyi and {Sim{\~o}es do Couto}, F. and A. Ramirez and Frank Jessen and Heneka, {Michael T.} and Estrella G{\'o}mez-Tortosa and Adrian Danek and P. Cras and Rik Vandenberghe and Jonghe, {P. de} and {De Deyn}, {P. P.} and Kristel Sleegers and Marc Cruts and {Van Broeckhoven}, C. and Johan Goeman and Dirk Nuytten and Katrin Smets and Wim Robberecht and {van Damme}, Philip and {De Bleecker}, Jan and Patrick Santens and Bart Dermaut and Jan Versijpt and Alex Michotte and Adrian Ivanoiu and Olivier Deryck and Bruno Bergmans and Jean Delbeck and M. Bruyland and C. Willems and E. Salmon and Pau Pastor and Sara Ortega-Cubero and L. Benussi and R. Ghidoni and G. Binetti and Isabel Hern{\'a}ndez and M. Boada and A. Ruiz and S. Sorbi and B. Nacmias and Siro Bagnoli and Raquel Sanchez-Valle and A. Llado and Isabel Santana and {Do Ros{\'a}rio Almeida}, Maria and G.B. Frisoni and Walter Maetzler and Radoslav Matej and Fraidakis, {Matthew J.} and Kovacs, {G. G.} and Fabrizi, {G. M.} and Sergio Testi",
note = "Export Date: 16 March 2017 CODEN: HUMUE Correspondence Address: Van Broeckhoven, C.; Center for Molecular Neurology, VIBBelgium; email: christine.vanbroeckhoven@molgen.vib-ua.be Funding details: BELSPO, Federaal Wetenschapsbeleid Funding details: 2011.0264, Fondazione Cassa di Risparmio di Pistoia e Pescia Funding details: 2013.0347, Fondazione Cassa di Risparmio di Pistoia e Pescia Funding details: 2014.0310, Ente Cassa di Risparmio di Firenze Funding details: 2014.0365, Fondazione Cassa di Risparmio di Pistoia e Pescia Funding details: EKMS 018, EKFS, Else Kr{\"o}ner-Fresenius-Stiftung Funding details: FWO, Fonds Wetenschappelijk Onderzoek Funding details: Gun och Bertil Stohnes Stiftelse Funding details: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse Funding details: SBP, Swedish Brain Power Funding details: 2015-02926, VR, Vetenskapsr{\aa}det Funding details: 521-2010-3134, VR, Vetenskapsr{\aa}det Funding text: The authors thank the personnel of the Neuromics Support Facility of the VIB Center for Molecular Neurology (http://www.vibgeneticservicefacility.be) and the Antwerp Biobank of the Institute Born-Bunge for their expert support. The Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS thanks all brain donors and families for generous brain donation for research and the Neurological Tissue Bank of the IDIBAPS Biobank for data and sample procurement. Caroline Graff wishes to express her acknowledgements to Inger Nennesmo (for the neuropathological assessments), Huei-Hsin Chiang, Jenny Bj{\"o}rkstr{\"o}m, Lena Lilius, Charlotte Forsell, Marie Fallstr{\"o}m (Department of Neurobiology, Care Sciences and Society [NVS], Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet and Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden), and The Brain Bank at Karolinska Institutet. The LMU Munich site acknowledges the essential support of the team at Zentrum f{\"u}r Neuropathologie und Prionforschung, Ludwig-Maximilians-Universit{\"a}t Munich (Thomas Arzberger, Sigrun Roeber, Manuela Neumann, Armin Giese, and Hans Kretzschmar) for their neuropathological work and the safekeeping of DNA samples. Disclosure statement: The authors declare no conflict of interest. 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year = "2016",
doi = "10.1002/humu.23161",
language = "English",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

AU - Van Zee, Kimberly J.

AU - Gijselinck, Ilse

AU - Van Mossevelde, Sara

AU - Perrone, F.

AU - Dillen, Lubina

AU - Heeman, Bavo

AU - Bäumer, Veerle

AU - Engelborghs, Sebastiaan

AU - De Bleecker, J. L.

AU - Baets, Jonathan

AU - Gelpi, Ellen

AU - Rojas-García, Ricard

AU - Clarimón, J.

AU - Lleó, Alberto

AU - Diehl-Schmid, Janine

AU - Alexopoulos, Panos

AU - Perneczky, Robert

AU - Synofzik, Matthis

AU - Just, J.

AU - Schöls, L.

AU - Graff, Caroline

AU - Thonberg, Håkan

AU - Borroni, B.

AU - Padovani, A.

AU - Jordanova, Albena

AU - Sarafov, Stayko

AU - Tournev, I.

AU - de Mendonça, Alexandre

AU - Miltenberger-Miltényi, Gabriel

AU - Simões do Couto, F.

AU - Ramirez, A.

AU - Jessen, Frank

AU - Heneka, Michael T.

AU - Gómez-Tortosa, Estrella

AU - Danek, Adrian

AU - Cras, P.

AU - Vandenberghe, Rik

AU - Jonghe, P. de

AU - De Deyn, P. P.

AU - Sleegers, Kristel

AU - Cruts, Marc

AU - Van Broeckhoven, C.

AU - Goeman, Johan

AU - Nuytten, Dirk

AU - Smets, Katrin

AU - Robberecht, Wim

AU - van Damme, Philip

AU - De Bleecker, Jan

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, M.

AU - Willems, C.

AU - Salmon, E.

AU - Pastor, Pau

AU - Ortega-Cubero, Sara

AU - Benussi, L.

AU - Ghidoni, R.

AU - Binetti, G.

AU - Hernández, Isabel

AU - Boada, M.

AU - Ruiz, A.

AU - Sorbi, S.

AU - Nacmias, B.

AU - Bagnoli, Siro

AU - Sanchez-Valle, Raquel

AU - Llado, A.

AU - Santana, Isabel

AU - Do Rosário Almeida, Maria

AU - Frisoni, G.B.

AU - Maetzler, Walter

AU - Matej, Radoslav

AU - Fraidakis, Matthew J.

AU - Kovacs, G. G.

AU - Fabrizi, G. M.

AU - Testi, Sergio

N1 - Export Date: 16 March 2017 CODEN: HUMUE Correspondence Address: Van Broeckhoven, C.; Center for Molecular Neurology, VIBBelgium; email: christine.vanbroeckhoven@molgen.vib-ua.be Funding details: BELSPO, Federaal Wetenschapsbeleid Funding details: 2011.0264, Fondazione Cassa di Risparmio di Pistoia e Pescia Funding details: 2013.0347, Fondazione Cassa di Risparmio di Pistoia e Pescia Funding details: 2014.0310, Ente Cassa di Risparmio di Firenze Funding details: 2014.0365, Fondazione Cassa di Risparmio di Pistoia e Pescia Funding details: EKMS 018, EKFS, Else Kröner-Fresenius-Stiftung Funding details: FWO, Fonds Wetenschappelijk Onderzoek Funding details: Gun och Bertil Stohnes Stiftelse Funding details: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse Funding details: SBP, Swedish Brain Power Funding details: 2015-02926, VR, Vetenskapsrådet Funding details: 521-2010-3134, VR, Vetenskapsrådet Funding text: The authors thank the personnel of the Neuromics Support Facility of the VIB Center for Molecular Neurology (http://www.vibgeneticservicefacility.be) and the Antwerp Biobank of the Institute Born-Bunge for their expert support. The Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS thanks all brain donors and families for generous brain donation for research and the Neurological Tissue Bank of the IDIBAPS Biobank for data and sample procurement. Caroline Graff wishes to express her acknowledgements to Inger Nennesmo (for the neuropathological assessments), Huei-Hsin Chiang, Jenny Björkström, Lena Lilius, Charlotte Forsell, Marie Fallström (Department of Neurobiology, Care Sciences and Society [NVS], Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet and Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital, Stockholm, Sweden), and The Brain Bank at Karolinska Institutet. The LMU Munich site acknowledges the essential support of the team at Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität Munich (Thomas Arzberger, Sigrun Roeber, Manuela Neumann, Armin Giese, and Hans Kretzschmar) for their neuropathological work and the safekeeping of DNA samples. Disclosure statement: The authors declare no conflict of interest. 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PY - 2016

Y1 - 2016

N2 - 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. © 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

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%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS. © 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

KW - ALS

KW - amyotrophic lateral sclerosis

KW - frontotemporal dementia

KW - FTD

KW - mutations

KW - NFκB luciferase reporter assay

KW - TANK-Binding Kinase 1

KW - TBK1

U2 - 10.1002/humu.23161

DO - 10.1002/humu.23161

M3 - Article

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

ER -