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

• DOI: 10.1038/ng.3130
• Publication Date: 2014-11-02T19:45:15Z
• Authors: Julian Schubert; Aleksandra Siekie...; Mélanie Langlois; Patrick May; Clément Huneau; Felicitas Becker; Hiltrud Muhle; Arvid Suls; Johannes R Lemke; Carolien G F de K...; Holger Thiele; Kathryn Konrad; Amit Kawalia; Mohammad R Toliat; Thomas Sander; Franz Rüschendorf; Almuth Caliebe; Inga Nagel; Bernard Kohl; Angela Kecskés; Maxime Jacmin; Katia Hardies; Sarah Weckhuysen; Erik Riesch; Thomas Dorn; Eva H Brilstra; Stephanie Baulac; Rikke S Møller; Helle Hjalgrim; Bobby P C Koeleman; Karin Jurkat-Rott; Frank Lehmann-Horn; Jared C Roach; Gustavo Glusman; Leroy Hood; David J Galas; Benoit Martin; Peter A M de Witte; Saskia Biskup; Peter De Jonghe; Ingo Helbig; Rudi Balling; Peter Nürnberg; Alexander D Crawford; Camila V Esguerra; Yvonne G Weber; Holger Lerche
• Keywords: Male; 0301 basic medicine; Genetic Linkage; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Syntaxin 1; [SDV.GEN] Life Sciences [q-bio]/Genetics; Epilepsy/genetics; Febrile; Cohort Studies; Syntaxin 1/genetics; Exome; In Situ Hybridization; Zebrafish; In Situ Hybridization, Fluorescence; Comparative Genomic Hybridization; [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology; Temperature; Single Nucleotide; PAROXYSMAL KINESIGENIC DYSKINESIA SYNAPTIC VESICLE FUSION DE-NOVO MUTATIONS FEBRILE SEIZURES INFANTILE CONVULSIONS GENERALIZED EPILEPSY PRRT2 MUTATIONS GENERATION DISORDERS ZEBRAFISH; Pedigree; 3. Good health; Phenotype; Codon, Nonsense; Female; Sequence Analysis; Molecular Sequence Data; 610; Polymorphism, Single Nucleotide; Fluorescence; Seizures, Febrile; 03 medical and health sciences; Seizures; 616; Animals; Humans; Amino Acid Sequence; Polymorphism; Seizures, Febrile/genetics; Codon; [SDV.GEN]Life Sciences [q-bio]/Genetics; Epilepsy; [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; DNA; Febrile/genetics; Sequence Analysis, DNA; Nonsense; Mutation; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Gene Deletion

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.