Mapping of a FEB3 homologous febrile seizure locus on mouse chromosome 2 containing candidate genes Scn1a and Scn3a.
Febrile seizures (FS) are the most common seizure type in children. Recurrent FS are a risk factor for developing temporal lobe epilepsy later in life and are known to have a strong genetic component. Experimental FS (eFS) can be elicited in mice by warm-air induced hyperthermia. We used this model to screen the chromosome substitution strain (CSS) panel derived from C57BL/6J and A/J for FS susceptibility and identified C57BL/6J-Chr2A/NaJ (CSS2), as the strain with the strongest FS susceptibility phenotype. The aim of this study was to map FS susceptibility loci and select candidate genes on mouse chromosome 2. We generated an F2population by intercrossing the hybrids (F1) that were derived from CSS2 and C57BL/6J mice. All CSS2-F2individuals were genotyped and phenotyped for eFS susceptibility, and QTL analysis was performed. Candidate gene selection was based on bioinformatics analyses and differential brain expression between CSS2 and C57BL/6J strains determined by microarray analysis. Genetic mapping of the eFS susceptibility trait identified two significant loci: FS-QTL2a (LOD-score 3.6) and FS-QTL2b (LOD-score 6.2). FS-QTL2a contained 44 genes expressed in the brain at post natal day 14. Four of these (Arl6ip6, Cytip, Fmnl2 Ifih1) contained a non-synonymous SNP comparing CSS2 and C57BL/6J, six genes (March7, Nr4a2, Gpd2, Grb14, Scn1a, Scn3a) were differentially expressed between these strains. A region within FS-QTL2a is homologous to the human FEB3 locus. The fact that we identify mouse FS-QTL2a with high FEB3 homology is strong support for the validity of the eFS mouse model to study genetics of human FS.
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Ellen V S
EV
Hessel
Division of Animal Welfare & Laboratory Animal Science, Department of Animals in Science & Society, Faculty of Veterinary Medicine and Brain Center Rudolf Magnus, Utrecht University, Utrecht, The Netherlands.
Hein A
HA
van Lith
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Inge G
IG
Wolterink-Donselaar
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Marina
M
de Wit
Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
Marian J A
MJ
Groot Koerkamp
Department of Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.
Frank C P
FC
Holstege
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.|Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
Martien J H
MJ
Kas
Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Cathy
C
Fernandes
Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Pierre N E
PN
de Graan
D000818:Animals; D002875:Chromosomes / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics*; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D003294:Seizures, Febrile / Q000235:genetics*; D017385:Sequence Homology
D062550:NAV1.1 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human; C568249:Scn1a protein, mouse; C515216:Scn3a protein, mouse
chromosome substitution strain; hyperthermia; quantitatve trait loci; temporal lobe epilepsy