Investigation of the Dravet syndrome using a mouse model

Objective To identify genetic heterogeneity which influence the severity and mortality of the disease Method We first generated a point mutation allele of Scn1a in the R1 mouse ES cell using a recombineering approach. Germline chimeras were mated with 129/J females to generate mutant mice in a pure 129 stain. Some of the resulting heterozygous mutant males were outcrossed to C57BL/6 females to generate F1 hybrids that mutant progenies in the heterogeneous genetic backgrounds with various degrees of phenotypic presentations can be obtained by F1 intercrosses. Result In the pure 129 stain, heterozygous mutant mice were resistant to the disease. However, the homozygous mutant pups became malnourished and showed a significant reduction in their body weight and sizes within 2 weeks. They were also found to have an unstable gait and developed spontaneous seizures. All of them died within the third postnatal week. In contrast, when the mutant allele was brought to a heterogeneous 129 and C57BL/6 mixed stain, sporadic sudden death was observed in some heterozygous animals after the third postnatal week. The survival rate of the adult heterozygotes was reduced to 60% at 7 weeks. These results suggested that some modifier loci in the two different genetic backgrounds have different effects on the mutant phenotypes. Conclusion We successfully generated a mouse model for Dravet syndrome. The fact that Scn1a mutant seizure severity and gross lethality differ in 129 and C57BL/6 stains indicates an invaluable opportunity to identify modifier genes using these mutant strains.