Complex seizure disorder caused by Brunol4 deficiency in mice.
Idiopathic epilepsy is a common human disorder with a strong genetic component, usually exhibiting complex inheritance. We describe a new mouse mutation in C57BL/6J mice, called frequent-flyer (Ff), in which disruption of the gene encoding RNA-binding protein Bruno-like 4 (Brunol4) leads to limbic and severe tonic-clonic seizures in heterozygous mutants beginning in their third month. Younger heterozygous adults have a reduced seizure threshold. Although homozygotes do not survive well on the C57BL/6J background, on mixed backgrounds homozygotes and some heterozygotes also display spike-wave discharges, the electroencephalographic manifestation of absence epilepsy. Brunol4 is widely expressed in the brain with enrichment in the hippocampus. Gene expression profiling and subsequent analysis revealed the down-regulation of at least four RNA molecules encoding proteins known to be involved in neuroexcitability, particularly in mutant hippocampus. Genetic and phenotypic assessment suggests that Brunol4 deficiency in mice results in a complex seizure phenotype, likely due to the coordinate dysregulation of several molecules, providing a unique new animal model of epilepsy that mimics the complex genetic architecture of common disease.
Yang
Yan
Y
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Mahaffey
Connie L
CL
Bérubé
Nathalie
N
Maddatu
Terry P
TP
Cox
Gregory A
GA
Frankel
Wayne N
WN
D000818:Animals; D000067878:CELF Proteins; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis* / Q000235:genetics*; D020869:Gene Expression Profiling; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000235:genetics*; D019076:Transgenes
D000067878:CELF Proteins; C470022:Celf4 protein, mouse; D016601:RNA-Binding Proteins