title: Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.
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.
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schubert
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Siekierska
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Langlois
authors.affiliation: 1] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. [2] Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Patrick
authors.identifier: 0000000186983770
authors.initials: P
authors.lastname: May
authors.affiliation: 1] INSERM, U1099, Rennes, France. [2] Université de Rennes 1, Laboratoire Traitement du Signal et de l'Image (LTSI), Rennes, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Huneau
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.affiliation: 1] Neurogenetics Group, VIB Department of Molecular Genetics, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.affiliation: 1] Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland. [2] Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Section of Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Carolien G F
authors.identifier: 0000000278181396
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Konrad
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Kawalia
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
authors.affiliation: Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.affiliation: Institute of Human Genetics, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Almuth
authors.initials: A
authors.lastname: Caliebe
authors.affiliation: Institute of Human Genetics, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Nagel
authors.affiliation: Kinderkrankenhaus Wilhelmstift, Rahlstedt, Germany.
authors.forename: Bernard
authors.initials: B
authors.lastname: Kohl
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Angela
authors.initials: A
authors.lastname: Kecskés
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Maxime
authors.initials: M
authors.lastname: Jacmin
authors.affiliation: 1] Neurogenetics Group, VIB Department of Molecular Genetics, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Katia
authors.initials: K
authors.lastname: Hardies
authors.affiliation: 1] Neurogenetics Group, VIB Department of Molecular Genetics, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: 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.
authors.forename: Erik
authors.initials: E
authors.lastname: Riesch
authors.affiliation: Swiss Epilepsy Centre, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dorn
authors.affiliation: Section of Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: 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.
authors.forename: Stephanie
authors.identifier: 0000000164304693
authors.initials: S
authors.lastname: Baulac
authors.affiliation: 1] Danish Epilepsy Centre, Dianalund, Denmark. [2] Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: 1] Danish Epilepsy Centre, Dianalund, Denmark. [2] Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: Section of Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.affiliation: Division of Neurophysiology, University of Ulm, Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.affiliation: Division of Neurophysiology, University of Ulm, Ulm, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lehman-Horn
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Jared C
authors.initials: JC
authors.lastname: Roach
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Glusman
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Galas
authors.affiliation: 1] INSERM, U1099, Rennes, France. [2] Université de Rennes 1, Laboratoire Traitement du Signal et de l'Image (LTSI), Rennes, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Martin
authors.affiliation: Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Peter A M
authors.initials: PA
authors.lastname: de Witte
authors.affiliation: 1] CeGaT, Tübingen, Germany. [2] Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: 1] Neurogenetics Group, VIB Department of Molecular Genetics, Antwerp, Belgium. [2] Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 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.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Crawford
authors.affiliation: 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.
authors.forename: Camila V
authors.initials: CV
authors.lastname: Esguerra
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
authors.affiliation: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018389:Codon, Nonsense; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004827:Epilepsy / Q000235:genetics*; D059472:Exome; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D003294:Seizures, Febrile / Q000235:genetics*; D017422:Sequence Analysis, DNA; D050827:Syntaxin 1 / Q000235:genetics*; D013696:Temperature; D015027:Zebrafish
chemical_list: D018389:Codon, Nonsense; D050827:Syntaxin 1