MWi001: Identification of Srp9 as a febrile seizure susceptibility gene

Febrile seizures (FS) are the most common type of seizures in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). Twin studies and mutations in families with complex epilepsy syndromes including FS, indicate a genetic contribution to FS susceptibility. By employing a phenotype driven genetic strategy using consomics we mapped a quantitative trait locus (QTL) for hyperthermia-induced FS susceptibility on mouse chromosome 1. Signal Recognition Particle 9 (Srp9) in the QTL was differentially expressed between parental strains, and its binding partner Srp14 was co-identified as a strong candidate gene in another FS susceptibility QTL. The SRP complex plays a key role in the synthesis of membrane proteins, such as glutamate receptors. In vivo knock-down of brain Srp9 or inhibition of protein synthesis reduced FS susceptibility. The mouse strain (CSS1) with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Down-regulation of Srp9 in hippocampal neurons reduced surface expression of AMPA receptor subunit GluA1. Consistent with a role of SRP9 in human FS, we detected increased hippocampal SRP9 expression in mTLE patients with antecedent FS. Comparing mTLE patients and healthy controls we found an association of a SRP9 promoter SNP (rs12403575 G/A) with FS and mTLE, which was replicated in FS patients. Our findings identify SRP9 as a novel FS susceptibility gene and implicate ER-dependent protein synthesis and glutamate receptor expression in the mechanism. Dual channel mouse microarrays were analyzed. RNA samples were isolated from 4 individual mouse P14 brains per strain, for strains Bl6, CSS1 and CSS2. Bl6 RNA was also used to make a reference pool used against all individual samples. Of each 4 samples analysed per group, 2 were labeled in dyeswap.