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Nat Neurosci. 2015 May;18(5):631-6. doi: 10.1038/nn.4000. Epub 2015 Mar 24.

Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.

Author information

1
Department of Neurology, Ulm University, Ulm, Germany.
2
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
3
Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
4
1] Department of Neurology, Ulm University, Ulm, Germany. [2] Institute of Human Genetics, Ulm University, Ulm, Germany.
5
Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.
6
Institute of Physiology and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
7
Department of Neurology, Karolinska Hospital Huddinge, Stockholm, Sweden.
8
Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR7225, Inserm U1127, Sorbonne Universités, Université Pierre et Marie (UPMC) P6 UMRS1127, Paris, France.
9
Centre Hospitalier Territorial Gaston Bourret, Noumea, New Caledonia.
10
Centre de référence SLA, Hôpital Neurologique Pierre Wertheimer, CHU de Lyon, Bron, France.
11
Centre de Référence Maladies Neuromusculaires et SLA, Hôpital Archet, CHU de Nice, France.
12
Institute of Anatomy and Cell Biology, Ulm University, Faculty of Medicine, Ulm, Germany.
13
Charité University Hospital, Humboldt-University, Berlin, Germany.
14
Department of Neurology, Technical University of Munich, Munich, Germany.
15
1] Institute of Physiology and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal. [2] Department of Neurosciences, Hospital de Santa Maria-CHLN, Lisbon, Portugal.
16
Institute of Pathology-Laboratory of Neuropathology, Ulm University, Ulm, Germany.
17
Department of Medical Biosciences, Umeå University, Umeå, Sweden.
18
1] Institute of Human Genetics, Ulm University, Ulm, Germany. [2] Institute of Human Genetics, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
19
1] University of Oulu Biocenter, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland. [2] Department of Biomedicine, University of Bergen, Bergen, Norway.
20
1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany. [3] SyNergy, Munich Cluster for Systems Neurology, Ludwig Maximilians Universität München, Munich, Germany.
21
1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
22
1] Department of Neurology, Ulm University, Ulm, Germany. [2] Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.

Abstract

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

PMID:
25803835
DOI:
10.1038/nn.4000
[Indexed for MEDLINE]

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