Identification of Srp9 as a febrile seizure susceptibility gene. (12th March 2014)

• Record Type: Journal Article
• Authors: Hessel, Ellen V. S.; de, Marina; Wolterink‐Donselaar, Inge G.; Karst, Henk; de, Esther; van, Hein A.; de, Ewart; de, Sophietje; Verbeek, Nienke E.; Lindhout, Dick; de, Carolien G. F.; Koeleman, Bobby P. C.; van, Marjan; Brilstra, Eva; Cuppen, Edwin; Loos, Maarten; Spijker, Sabine S.; Kan, Anne A.; Baars, Susanne E.; van, Peter C.; Gosselaar, Peter H.; Groot Koerkamp, Marian J. A.; Holstege, Frank C. P.; van, Cornelia; Vergeer, Jeanette; Moll, Henriette A.; Taubøll, Erik; Heuser, Kjell; Ramakers, Geert M. J.; Pasterkamp, R. Jeroen; van, Onno; Hoogenraad, Casper C.; Kas, Martien J. H.; de, Pierre N. E.;
• Is Part Of: Annals of clinical and translational neurology. Volume 1:Number 4(2014:Apr.)
• Page Start: 239
• Page End: 250
• Publication Date: 2014-03-12
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.48
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn348-abs-0001"> <title>Abstract</title> <sec id="acn348-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="acn348-sec-0002" sec-type="section"> <title>Methods</title> <p>We mapped a quantitative trait locus (QTL1) for hyperthermia‐induced FS on mouse chromosome 1, containing the signal recognition particle 9 (<italic>Srp9</italic>) gene. Effects of differential <italic>Srp9</italic> expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients.</p> </sec> <sec id="acn348-sec-0003" sec-type="section"> <title>Results</title> <p> <italic>Srp9</italic> was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and <italic>Srp9</italic> expression than C57BL/6J mice. In vivo knockdown of brain <italic>Srp9</italic> reduced FS susceptibility. Mice with reduced <italic>Srp9</italic> expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal <italic>Srp9</italic> reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher <italic>SRP9</italic> expression than patients without. <italic>SRP9</italic> promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE.</p> </sec> <sec id="acn348-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Our findings identify <italic>SRP9</italic> as a novel FS susceptibility gene and indicate that <italic>SRP9</italic> 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.</p> </sec> </abstract>