2. Academic Validation
  3. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

  • Nat Genet. 2014 Dec;46(12):1327-32. doi: 10.1038/ng.3130.
Julian Schubert 1,  Aleksandra Siekierska 2,  Mélanie Langlois 3,  Patrick May 4,  Clément Huneau 5,  Felicitas Becker 1,  Hiltrud Muhle 6,  Arvid Suls 7,  Johannes R Lemke 8,  Carolien G F de Kovel 9,  Holger Thiele 10,  Kathryn Konrad 10,  Amit Kawalia 10,  Mohammad R Toliat 10,  Thomas Sander 10,  Franz Rüschendorf 11,  Almuth Caliebe 12,  Inga Nagel 12,  Bernard Kohl 13,  Angela Kecskés 2,  Maxime Jacmin 3,  Katia Hardies 7,  Sarah Weckhuysen 7,  Erik Riesch 14,  Thomas Dorn 15,  Eva H Brilstra 9,  Stephanie Baulac 16,  Rikke S Møller 17,  Helle Hjalgrim 17,  Bobby P C Koeleman 9,  EuroEPINOMICS RES Consortium,  Karin Jurkat-Rott 18,  Frank Lehman-Horn 18,  Jared C Roach 19,  Gustavo Glusman 19,  Leroy Hood 19,  David J Galas 20,  Benoit Martin 5,  Peter A M de Witte 2,  Saskia Biskup 21,  Peter De Jonghe 7,  Ingo Helbig 6,  Rudi Balling 3,  Peter Nürnberg 22,  Alexander D Crawford 23,  Camila V Esguerra 24,  Yvonne G Weber 1,  Holger Lerche 1
Affiliations

Affiliations

  • 1 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 2 Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
  • 3 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 4 1] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. [2] Institute for Systems Biology, Seattle, Washington, USA.
  • 5 1] INSERM, U1099, Rennes, France. [2] Université de Rennes 1, Laboratoire Traitement du Signal et de l'Image (LTSI), Rennes, France.
  • 6 Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
  • 7 1] Neurogenetics Group, VIB Department of Molecular Genetics, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  • 8 1] Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland. [2] Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
  • 9 Section of Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 10 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
  • 11 Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
  • 12 Institute of Human Genetics, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany.
  • 13 Kinderkrankenhaus Wilhelmstift, Rahlstedt, Germany.
  • 14 1] Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland. [2] CeGaT, Tübingen, Germany. [3] Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 15 Swiss Epilepsy Centre, Zurich, Switzerland.
  • 16 1] INSERM U1127, Centre National de la Recherche Scientifique (CNRS) UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie (UMPC) Université Paris 06 UMRS 1127, Paris, France. [2] Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France.
  • 17 1] Danish Epilepsy Centre, Dianalund, Denmark. [2] Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
  • 18 Division of Neurophysiology, University of Ulm, Ulm, Germany.
  • 19 Institute for Systems Biology, Seattle, Washington, USA.
  • 20 1] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. [2] Institute for Systems Biology, Seattle, Washington, USA. [3] Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA.
  • 21 1] CeGaT, Tübingen, Germany. [2] Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  • 22 1] Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • 23 1] Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium. [2] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 24 1] Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium. [2] Present address: Chemical Neuroscience Group, Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.
PMID: 25362483 DOI: 10.1038/ng.3130
Abstract

Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

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