2. Academic Validation
  3. Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

  • Hum Mol Genet. 2015 Oct 15;24(20):5677-86. doi: 10.1093/hmg/ddv281.
Hyun Hor 1,  Ludmila Francescatto 2,  Luca Bartesaghi 3,  Sara Ortega-Cubero 4,  Maria Kousi 2,  Oswaldo Lorenzo-Betancor 4,  Felix J Jiménez-Jiménez 5,  Alexandre Gironell 6,  Jordi Clarimón 7,  Oliver Drechsel 8,  José A G Agúndez 9,  Daniela Kenzelmann Broz 10,  Ruth Chiquet-Ehrismann 10,  Alberto Lleó 11,  Francisco Coria 12,  Elena García-Martin 13,  Hortensia Alonso-Navarro 5,  Maria J Martí 14,  Jaume Kulisevsky 15,  Charlotte N Hor 16,  Stephan Ossowski 8,  Roman Chrast 3,  Nicholas Katsanis 2,  Pau Pastor 17,  Xavier Estivill 18
Affiliations

Affiliations

  • 1 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, [email protected] [email protected] [email protected].
  • 2 Center for Human Disease Modeling, Duke University, Duke University Medical Center, Durham NC 27710, USA.
  • 3 Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland, Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden.
  • 4 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.
  • 5 Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid 28030, Spain.
  • 6 Movement Disorders Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain, Sant Pau Biomedical Research Institute, Barcelona, Spain.
  • 7 Sant Pau Biomedical Research Institute, Barcelona, Spain, Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Catalonia 08026, Spain.
  • 8 Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 9 Department of Pharmacology.
  • 10 Faculty of Sciences and Department of Biomedicine, Friedrich Miescher Institute of Biomedical Research, Novartis Research Foundation and University of Basel, Basel 4058, Switzerland.
  • 11 Sant Pau Biomedical Research Institute, Barcelona, Spain.
  • 12 Clinic for Nervous Disorders, Service of Neurology, Son Espases University Hospital, Palma de Mallorca 07120, Spain.
  • 13 Department of Biochemistry and Molecular Biology, University of Extremadura, Cáceres 10071, Spain.
  • 14 Movement Disorders Unit, Neurology Service, Hospital Clinic, CIBERNED and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia 08036, Spain and.
  • 15 Movement Disorders Unit, Neurology Department, Hospital de Sant Pau, Barcelona, Spain, Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Catalonia 08026, Spain.
  • 16 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.
  • 17 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, [email protected] [email protected] [email protected].
  • 18 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 [email protected] [email protected] [email protected].
PMID: 26188006 DOI: 10.1093/hmg/ddv281
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.

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