title: Identification of Srp9 as a febrile seizure susceptibility gene.
abstract: OBJECTIVE
  Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans.
  
  
  METHODS
  We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients.
  
  
  RESULTS
  Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE.
  
  
  CONCLUSIONS
  Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Ellen V S
authors.initials: EV
authors.lastname: Hessel
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: de Wit
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Inge G
authors.initials: IG
authors.lastname: Wolterink-Donselaar
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Karst
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University Utrecht, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: de Graaff
authors.affiliation: Program Emotion and Cognition, Division of Animal Welfare and Laboratory Animal Science, Department of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University and Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Hein A
authors.initials: HA
authors.lastname: van Lith
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Ewart
authors.initials: E
authors.lastname: de Bruijn
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Sophietje
authors.initials: S
authors.lastname: de Sonnaville
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Nienke E
authors.initials: NE
authors.lastname: Verbeek
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands ; SEIN Epilepsy Institute in the Netherlands Heemstede, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: van Kempen
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Brilstra
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht Utrecht, The Netherlands ; Department of Medical Genetics, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Loos
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands.
authors.forename: Sabine S
authors.initials: SS
authors.lastname: Spijker
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Kan
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands ; Master program Neuroscience and Cognition, Utrecht University Utrecht, The Netherlands.
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Baars
authors.affiliation: Department of Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Peter C
authors.initials: PC
authors.lastname: van Rijen
authors.affiliation: Department of Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Gosselaar
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Marian J A
authors.initials: MJ
authors.lastname: Groot Koerkamp
authors.affiliation: Department of Molecular Cancer Research, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, The Netherlands.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Vergeer
authors.affiliation: Department of Pediatrics, Erasmus Medical Center Rotterdam, The Netherlands.
authors.forename: Henriette A
authors.initials: HA
authors.lastname: Moll
authors.affiliation: Department of Neurology, Oslo University Hospital Oslo, Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Taubøll
authors.affiliation: Department of Neurology, Oslo University Hospital Oslo, Norway.
authors.forename: Kjell
authors.initials: K
authors.lastname: Heuser
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Geert M J
authors.initials: GM
authors.lastname: Ramakers
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Onno
authors.initials: O
authors.lastname: van Nieuwenhuizen
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University Utrecht, The Netherlands.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Martien J H
authors.initials: MJ
authors.lastname: Kas
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.
authors.forename: Pierre N E
authors.initials: PN
authors.lastname: de Graan