Mouse with Na(v)1.1 haploinsufficiency, a model for Dravet syndrome, exhibits lowered sociability and learning impairment.
Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Department of Pediatrics, Graduate School of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan.
Dravet syndrome is an intractable epileptic encephalopathy characterized by early onset epileptic seizures followed by cognitive decline, hyperactivity, autistic behaviors and ataxia.
Most Dravet syndrome patients possess heterozygous mutations of SCN1A gene encoding voltage-gated sodium channel α(I) subunit (Na(v)1.1). We have previously reported that mice heterozygous for a nonsense mutation in Scn1a developed early onset epileptic seizures. However, the learning ability and sociability of the mice remained to be investigated.
In the present study, we subjected heterozygous Scn1a mice to a comprehensive behavioral test battery. We found that while heterozygous Scn1a mice had lowered spontaneous motor activity in home cage, they were hyperactive in novel environments.
Moreover, the mice had low sociability and poor spatial learning ability that correspond to the autistic behaviors and cognitive decline seen in Dravet syndrome patients. These results suggest that Na(v)1.1 haploinsufficiency intrinsically contributes to not only epileptic seizures but also lowered sociability and learning impairment in heterozygous Scn1a mutant mice, as it should also be the case in patients with Dravet syndrome.
Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.
Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies.
Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive.
To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study including 3,020 patients with GGEs and 3,954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1,434 patients with genetic absence epilepsies (GAEs) and 1,134 patients with juvenile myoclonic epilepsy (JME).
Joint Stage-1&2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations.
The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.