title: Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor.
abstract: Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain, Universitat Pompeu Fabra (UPF), Barcelona, Spain, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain, CRG CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia 08003, Spain, hyunhor@yahoo.com xavier.estivill@crg.cat pastorpau@gmail.com.
authors.forename: Hyun
authors.initials: H
authors.lastname: Hor
authors.affiliation: Center for Human Disease Modeling, Duke University, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Francescatto
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland, Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Luca
authors.initials: L
authors.lastname: Bartesaghi
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), and Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Pamplona, Navarra 31008, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ortega-Cubero
authors.affiliation: Center for Human Disease Modeling, Duke University, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kousi
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), and Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Pamplona, Navarra 31008, Spain.
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Lorenzo-Betancor
authors.affiliation: Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid 28030, Spain.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Jiménez-Jiménez
authors.affiliation: Movement Disorders Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain, Sant Pau Biomedical Research Institute, Barcelona, Spain.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gironell
authors.affiliation: Sant Pau Biomedical Research Institute, Barcelona, Spain, Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Catalonia 08026, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Oliver
authors.initials: O
authors.lastname: Drechsel
authors.affiliation: Department of Pharmacology.
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
authors.affiliation: Faculty of Sciences and Department of Biomedicine, Friedrich Miescher Institute of Biomedical Research, Novartis Research Foundation and University of Basel, Basel 4058, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kenzelmann Broz
authors.affiliation: Faculty of Sciences and Department of Biomedicine, Friedrich Miescher Institute of Biomedical Research, Novartis Research Foundation and University of Basel, Basel 4058, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Chiquet-Ehrismann
authors.affiliation: Sant Pau Biomedical Research Institute, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Clinic for Nervous Disorders, Service of Neurology, Son Espases University Hospital, Palma de Mallorca 07120, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Coria
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Extremadura, Cáceres 10071, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martin
authors.affiliation: Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid 28030, Spain.
authors.forename: Hortensia
authors.initials: H
authors.lastname: Alonso-Navarro
authors.affiliation: Movement Disorders Unit, Neurology Service, Hospital Clinic, CIBERNED and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia 08036, Spain and.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Martí
authors.affiliation: Movement Disorders Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain, Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Catalonia 08026, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Kulisevsky
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain, Universitat Pompeu Fabra (UPF), Barcelona, Spain, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain, CRG CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia 08003, Spain.
authors.forename: Charlotte N
authors.initials: CN
authors.lastname: Hor
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ossowski
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland, Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
authors.affiliation: Center for Human Disease Modeling, Duke University, Duke University Medical Center, Durham NC 27710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), and Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine and Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Pamplona, Navarra 31008, Spain, hyunhor@yahoo.com xavier.estivill@crg.cat pastorpau@gmail.com.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain, Universitat Pompeu Fabra (UPF), Barcelona, Spain, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain, CRG CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Catalonia 08003, Spain, Dexeus Women's Health, University Hospital Quiron-Dexeus, Barcelona, Catalonia 08028, Spain hyunhor@yahoo.com xavier.estivill@crg.cat pastorpau@gmail.com.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D000328:Adult; D000818:Animals; D001369:Axons / Q000473:pathology*; D004252:DNA Mutational Analysis; D020329:Essential Tremor / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D009836:Oligodendroglia / Q000473:pathology*; D010375:Pedigree; D021381:Protein Transport; D055815:Young Adult; D015027:Zebrafish / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; C576539:TENM4 protein, human