title: Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.
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.
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Axel
authors: A
authors: Freischmidt
authors: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Thomas
authors: T
authors: Wieland
authors: Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
authors: Benjamin
authors: B
authors: Richter
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Wolfgang
authors: W
authors: Ruf
authors: Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
authors: Veronique
authors: V
authors: Schaeffer
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Kathrin
authors: K
authors: Müller
authors: 1] Department of Neurology, Ulm University, Ulm, Germany. [2] Institute of Human Genetics, Ulm University, Ulm, Germany.
authors: Nicolai
authors: N
authors: Marroquin
authors: Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.
authors: Frida
authors: F
authors: Nordin
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Annemarie
authors: A
authors: Hübers
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Patrick
authors: P
authors: Weydt
authors: Institute of Physiology and Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors: Susana
authors: S
authors: Pinto
authors: Department of Neurology, Karolinska Hospital Huddinge, Stockholm, Sweden.
authors: Rayomond
authors: R
authors: Press
authors: Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR7225, Inserm U1127, Sorbonne Universités, Université Pierre et Marie (UPMC) P6 UMRS1127, Paris, France.
authors: Stéphanie
authors: S
authors: Millecamps
authors: Centre Hospitalier Territorial Gaston Bourret, Noumea, New Caledonia.
authors: Nicolas
authors: N
authors: Molko
authors: Centre de référence SLA, Hôpital Neurologique Pierre Wertheimer, CHU de Lyon, Bron, France.
authors: Emilien
authors: E
authors: Bernard
authors: Centre de Référence Maladies Neuromusculaires et SLA, Hôpital Archet, CHU de Nice, France.
authors: Claude
authors: C
authors: Desnuelle
authors: Centre de Référence Maladies Neuromusculaires et SLA, Hôpital Archet, CHU de Nice, France.
authors: Marie-Hélène
authors: MH
authors: Soriani
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Johannes
authors: J
authors: Dorst
authors: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Elisabeth
authors: E
authors: Graf
authors: Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.
authors: Ulrika
authors: U
authors: Nordström
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Marisa S
authors: MS
authors: Feiler
authors: Institute of Anatomy and Cell Biology, Ulm University, Faculty of Medicine, Ulm, Germany.
authors: Stefan
authors: S
authors: Putz
authors: Institute of Anatomy and Cell Biology, Ulm University, Faculty of Medicine, Ulm, Germany.
authors: Tobias M
authors: TM
authors: Boeckers
authors: Charité University Hospital, Humboldt-University, Berlin, Germany.
authors: Thomas
authors: T
authors: Meyer
authors: Department of Neurology, Technical University of Munich, Munich, Germany.
authors: Andrea S
authors: AS
authors: Winkler
authors: Department of Neurology, Technical University of Munich, Munich, Germany.
authors: Juliane
authors: J
authors: Winkelman
authors: 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.
authors: Mamede
authors: M
authors: de Carvalho
authors: Institute of Pathology-Laboratory of Neuropathology, Ulm University, Ulm, Germany.
authors: Dietmar R
authors: DR
authors: Thal
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Markus
authors: M
authors: Otto
authors: Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors: Thomas
authors: T
authors: Brännström
authors: 1] Institute of Human Genetics, Ulm University, Ulm, Germany. [2] Institute of Human Genetics, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
authors: Alexander E
authors: AE
authors: Volk
authors: 1] University of Oulu Biocenter, Faculty of Biochemistry and Molecular Medicine, Oulu, Finland. [2] Department of Biomedicine, University of Bergen, Bergen, Norway.
authors: Petri
authors: P
authors: Kursula
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Karin M
authors: KM
authors: Danzer
authors: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors: Peter
authors: P
authors: Lichtner
authors: Institute of Biochemistry II, Goethe University Medical School, Frankfurt, Germany.
authors: Ivan
authors: I
authors: Dikic
authors: 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.
authors: Thomas
authors: T
authors: Meitinger
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Albert C
authors: AC
authors: Ludolph
authors: 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors: Tim M
authors: TM
authors: Strom
authors: 1] Department of Neurology, Ulm University, Ulm, Germany. [2] Department of Pharmacology and Clinical Neurosience, Umeå University, Umeå, Sweden.
authors: Peter M
authors: PM
authors: Andersen
authors: Department of Neurology, Ulm University, Ulm, Germany.
authors: Jochen H
authors: JH
authors: Weishaupt
mesh_terms: D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D059472:Exome; D005260:Female; D057180:Frontotemporal Dementia / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D020125:Mutation, Missense; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D035582:Transcription Factor TFIIIA / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human