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author Hessel, Ellen V S
de Wit, Marina
Wolterink-Donselaar, Inge G
Karst, Henk
de Graaff, Esther
van Lith, Hein A
de Bruijn, Ewart
de Sonnaville, Sophietje
Verbeek, Nienke E
Lindhout, Dick
de Kovel, Carolien G F
Koeleman, Bobby P C
van Kempen, Marjan
Brilstra, Eva
Cuppen, Edwin
Loos, Maarten
Spijker, Sabine S
Kan, Anne A
Baars, Susanne E
van Rijen, Peter C
Gosselaar, Peter H
Groot Koerkamp, Marian J A
Holstege, Frank C P
van Duijn, Cornelia
Vergeer, Jeanette
Moll, Henriette A
Taubøll, Erik
Heuser, Kjell
Ramakers, Geert M J
Pasterkamp, R Jeroen
van Nieuwenhuizen, Onno
Hoogenraad, Casper C
Kas, Martien J H
de Graan, Pierre N E
author_facet Hessel, Ellen V S
de Wit, Marina
Wolterink-Donselaar, Inge G
Karst, Henk
de Graaff, Esther
van Lith, Hein A
de Bruijn, Ewart
de Sonnaville, Sophietje
Verbeek, Nienke E
Lindhout, Dick
de Kovel, Carolien G F
Koeleman, Bobby P C
van Kempen, Marjan
Brilstra, Eva
Cuppen, Edwin
Loos, Maarten
Spijker, Sabine S
Kan, Anne A
Baars, Susanne E
van Rijen, Peter C
Gosselaar, Peter H
Groot Koerkamp, Marian J A
Holstege, Frank C P
van Duijn, Cornelia
Vergeer, Jeanette
Moll, Henriette A
Taubøll, Erik
Heuser, Kjell
Ramakers, Geert M J
Pasterkamp, R Jeroen
van Nieuwenhuizen, Onno
Hoogenraad, Casper C
Kas, Martien J H
de Graan, Pierre N E
author_sort Hessel, Ellen V S
collection PubMed
description 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.
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spelling pubmed-42927412015-01-14 Identification of Srp9 as a febrile seizure susceptibility gene Hessel, Ellen V S de Wit, Marina Wolterink-Donselaar, Inge G Karst, Henk de Graaff, Esther van Lith, Hein A de Bruijn, Ewart de Sonnaville, Sophietje Verbeek, Nienke E Lindhout, Dick de Kovel, Carolien G F Koeleman, Bobby P C van Kempen, Marjan Brilstra, Eva Cuppen, Edwin Loos, Maarten Spijker, Sabine S Kan, Anne A Baars, Susanne E van Rijen, Peter C Gosselaar, Peter H Groot Koerkamp, Marian J A Holstege, Frank C P van Duijn, Cornelia Vergeer, Jeanette Moll, Henriette A Taubøll, Erik Heuser, Kjell Ramakers, Geert M J Pasterkamp, R Jeroen van Nieuwenhuizen, Onno Hoogenraad, Casper C Kas, Martien J H de Graan, Pierre N E Ann Clin Transl Neurol Research Papers 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. Blackwell Publishing Ltd 2014-04 2014-03-12 /pmc/articles/PMC4292741/ /pubmed/25590037 http://dx.doi.org/10.1002/acn3.48 Text en © 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Research Papers
Hessel, Ellen V S
de Wit, Marina
Wolterink-Donselaar, Inge G
Karst, Henk
de Graaff, Esther
van Lith, Hein A
de Bruijn, Ewart
de Sonnaville, Sophietje
Verbeek, Nienke E
Lindhout, Dick
de Kovel, Carolien G F
Koeleman, Bobby P C
van Kempen, Marjan
Brilstra, Eva
Cuppen, Edwin
Loos, Maarten
Spijker, Sabine S
Kan, Anne A
Baars, Susanne E
van Rijen, Peter C
Gosselaar, Peter H
Groot Koerkamp, Marian J A
Holstege, Frank C P
van Duijn, Cornelia
Vergeer, Jeanette
Moll, Henriette A
Taubøll, Erik
Heuser, Kjell
Ramakers, Geert M J
Pasterkamp, R Jeroen
van Nieuwenhuizen, Onno
Hoogenraad, Casper C
Kas, Martien J H
de Graan, Pierre N E
Identification of Srp9 as a febrile seizure susceptibility gene
title Identification of Srp9 as a febrile seizure susceptibility gene
title_full Identification of Srp9 as a febrile seizure susceptibility gene
title_fullStr Identification of Srp9 as a febrile seizure susceptibility gene
title_full_unstemmed Identification of Srp9 as a febrile seizure susceptibility gene
title_short Identification of Srp9 as a febrile seizure susceptibility gene
title_sort identification of srp9 as a febrile seizure susceptibility gene
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292741/
https://www.ncbi.nlm.nih.gov/pubmed/25590037
http://dx.doi.org/10.1002/acn3.48
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