Identification of Srp9 as a febrile seizure susceptibility gene
Hessel EVS., de Wit M., Wolterink-Donselaar IG., Karst H., de Graaff E., van Lith HA., de Bruijn E., de Sonnaville S., Verbeek NE., Lindhout D., de Kovel CGF., Koeleman BPC., van Kempen M., Brilstra E., Cuppen E., Loos M., Spijker SS., Kan AA., Baars SE., van Rijen PC., Gosselaar PH., Groot Koerkamp MJA., Holstege FCP., van Duijn C., Vergeer J., Moll HA., Taubøll E., Heuser K., Ramakers GMJ., Pasterkamp RJ., van Nieuwenhuizen O., Hoogenraad CC., Kas MJH., de Graan PNE.
© 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 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. Interpretation: 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.