Fine mapping of an epilepsy modifier gene on mouse Chromosome 19

Abstract

Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a(Q54) has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a(Q54) mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J x SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a(Q54) epilepsy phenotype: Moe1 (modifier of epilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 (Kcnv2), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 (Smarca2). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2. Modifier genes affecting the epilepsy phenotype of Scn2a(Q54) mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.

Figure 1

Fine mapping of Moe2 on Chromosome 19 with interval specific congenic strains. A. ISC lines with varying SJL-derived Chr 19 segments. The SJL-derived interval is shown in black, and grey denotes the interval containing the recombination. B. Percentage of animals with seizures in Q54 mice carrying the SJL-derived Chr 19 segments compared to B6.Q54 (*p<0.05, Fishers Exact Test).

Figure 2

Candidate gene analysis. A. Non-synonymous SNPs in the voltage-gated potassium channel gene Kcnv2 alter 2 amino acids in the cytoplasmic N-terminus within or near the T1 tetramerization domain. B. Evolutionary conservation of Arginine 208 and Glutamine 252.