Publication
SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility
Publisher:
Springer Science and Business Media LLC
Date:
12-05-2022
DOI:
10.1007/S00401-022-02429-0
Abstract: Mesial temporal lobe epilepsy with hippoc al sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippoc al biopsy specimens of in iduals with mesial temporal lobe epilepsy with hippoc al sclerosis who underwent surgical treatment, and hippoc al neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy in iduals, hippoc al volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a , and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippoc al SCN1A expression differed by rs7587026 genotype (Kruskal–Wallis test P = 0.004). In iduals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn’s test P = 0.003), and to heterozygotes (Dunn’s test P = 0.035). No statistically significant differences in hippoc al neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, in iduals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippoc al volume compared to major allele homozygotes (Cohen’s D = − 0.28, P = 0.02), and to heterozygotes (Cohen’s D = − 0.36, P = 0.009). Compared to wild type, scn1lab -overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F (4,54) = 6.95 ( P 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F (4,15) = 10.75 ( P 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippoc al sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome.