Steun ons werk
Decorative header background

Identification of Srp9 as a febrile seizure susceptibility gene

Publicatiejaar 2014
Gepubliceerd in Annals of Clinical and Translational Neurology
Auteur(s) Ellen V S Hessel, Marina de Wit, Inge G Wolterink-Donselaar, Henk Karst, Esther de Graaff, Hein A van Lith, Ewart de Bruijn, Sophietje de Sonnaville, Nienke E Verbeek, Dick Lindhout, Carolien G F de Kovel, Bobby P C Koeleman, Marjan van Kempen, Eva H Brilstra, Edwin Cuppen, Maarten Loos, Sabine Spijker, Anne A Kan, Susanne E Baars, Peter C van Rijen, Peter H Gosselaar, Marian J A Groot Koerkamp, Frank C P Holstege, Cornelia M van Duijn, Jeanette Vergeer, Henriette A Moll, Erik Taubøll, Kjell Heuser, G.M.J. Ramakers, R Jeroen Pasterkamp, Onno van Nieuwenhuizen, Casper C Hoogenraad, Martien J H Kas, Pierre N E de Graan

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.

Steun ons werk

De Stichting Vrienden van het Herseninstituut ondersteunt baanbrekend hersenonderzoek. U kunt ons daarbij helpen.

Steun ons werk