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Hum Mutat. 2017 Mar;38(3):297-309. doi: 10.1002/humu.23161. Epub 2017 Jan 19.

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

Author information

1
Center for Molecular Neurology, VIB, Antwerp, Belgium.
2
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
3
Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
4
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium.
5
Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
6
Neurological Tissue Bank of the Biobanc - Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
7
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
8
Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
9
Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
10
Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK.
11
West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, TW8 8DS, UK.
12
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tübingen, Germany.
13
German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
14
Department of Neurobiology, Care Sciences and Society (NVS), KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden.
15
Department of Geriatric Medicine, Genetics unit, Karolinska University Hospital, Stockholm, Sweden.
16
Neurology Unit, University of Brescia, Brescia, Italy.
17
Department of Biochemistry, Molecular Medicine Center, Medical University-Sofia, Sofia, Bulgaria.
18
Department of Neurology, Medical University-Sofia, Sofia, Bulgaria.
19
Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
20
Hospital Santa Maria, Lisbon, Portugal.
21
Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
22
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
23
Institute of Human Genetics, University of Bonn, Bonn, Germany.
24
Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
25
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
26
Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany.
27
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain.
28
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
29
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
30
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium.
31
Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
32
Hospital Network Antwerp, Antwerp.
33
Antwerp University Hospital, Edegem.
34
University Hospitals Leuven Gasthuisberg, Leuven.
35
University Hospital Ghent, Ghent.
36
University Hospital Brussels, Brussels.
37
Saint-Luc University Hospital, Brussels.
38
General Hospital Sint-Jan Brugge, Bruges.
39
General Hospital Sint-Maria, Halle.
40
General Hospital Glorieux Ronse.
41
Jessa Hospital, Hasselt.
42
University of Liège and Memory Clinic, CHU Liège, Liège.
43
University Hospital Mútua de Terrassa and Fundació Docència i Recerca Mútua Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain.
44
CIBERNED Instituto de Salud Carlos III, Madrid, Spain.
45
Deparment of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain.
46
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
47
MAC Memory Center and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
48
Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
49
Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
50
IRCCS Don Carlo Gnocchi Scandicci, Florence, Italy.
51
Hospital Clínic, IDIBAPS, Barcelona, Spain.
52
University of Coimbra, Coimbra, Portugal.
53
Hôpitaux Universitaires de Genève et Université de Genève, Genève, Switzerland and IRCCS Fatebenefratelli, Brescia, Italy.
54
Hertie Institute for Clinical Brain Research, Tübingen, Germany.
55
Thomayer Hospital, Prague and Charles University, Prague, Czech Republic.
56
NeuroRARE Centre for Rare and Genetic Neurological & Neuromuscular Diseases & Neurogenetics Athens, Greece.
57
Medical University of Vienna, Vienna, Austria.
58
University of Verona, Verona, Italy.

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.

KEYWORDS:

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

PMID:
28008748
PMCID:
PMC5324646
DOI:
10.1002/humu.23161
[Indexed for MEDLINE]
Free PMC Article

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