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SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2022-05-12 , DOI: 10.1007/s00401-022-02429-0
Katri Silvennoinen 1, 2 , Kinga Gawel 3, 4 , Despina Tsortouktzidis 5, 6 , Julika Pitsch 5, 6 , Saud Alhusaini 7, 8 , Karen M J van Loo 5, 9 , Richard Picardo 10 , Zuzanna Michalak 10 , Susanna Pagni 1, 2 , Helena Martins Custodio 1, 2 , James Mills 1, 2 , Christopher D Whelan 7, 11 , Greig I de Zubicaray 12 , Katie L McMahon 13 , Wietske van der Ent 3 , Karolina J Kirstein-Smardzewska 3 , Ettore Tiraboschi 3 , Jonathan M Mudge 14 , Adam Frankish 14 , Maria Thom 10 , Margaret J Wright 15 , Paul M Thompson 11 , Susanne Schoch 5, 6 , Albert J Becker 5 , Camila V Esguerra 3 , Sanjay M Sisodiya 1, 2
Affiliation  

Mesial temporal lobe epilepsy with hippocampal 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 hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal 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. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal–Wallis test P = 0.004). Individuals 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 hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal 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 hippocampal 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.



中文翻译:

SCN1A 过表达,与以常见癫痫风险变异为标志的基因组区域相关,会增加癫痫发作的易感性

伴有海马硬化和高热惊厥史的颞叶内侧癫痫与位于 SCN1A 启动子区域的 rs7587026 的常见变异有关我们试图探索可能的潜在机制。在接受手术治疗的颞叶内侧癫痫伴海马硬化患者的海马活检标本中分析SCN1A表达,并使用免疫组织化学定量评估海马神经元细胞丢失。在健康个体中,使用 MRI 测量海马体积。按 rs7587026 类型分层进行分析。研究增加的SCN1A的功能后果表达,我们产生,使用转座子介导的细菌人工染色体转基因,表达外源scn1a的斑马鱼系,并在受精后 4 天对幼虫视顶盖进行脑电图分析。最后,我们使用体外启动子分析来研究含有 rs7587026 的遗传基序是否影响启动子活性。海马SCN1A表达因 rs7587026 基因型而异(Kruskal-Wallis 检验P  = 0.004)。与主要等位基因纯合子(邓恩检验P  = 0.003)和杂合子(邓恩检验P = 0.035)。在三种基因型之间未观察到海马神经元细胞丢失的统计学显着差异。在 597 名健康参与者中,与主要等位基因纯合子 (Cohen's D  = - 0.28, P  = 0.02) 和杂合子 (Cohen's D  = - 0.36, P  = 0.009)相比,rs7587026 次要等位基因纯合子的平均海马体积显着减少. 与野生型相比,过表达 scn1lab的斑马鱼幼虫表现出更频繁的自发性癫痫发作 [单向方差分析F (4,54) = 6.95 ( P  < 0.001)]。脑电图放电次数与scn1lab水平相关过表达 [单向方差分析F (4,15) = 10.75 ( P  < 0.001]。最后,我们发现含有 rs7587026 的 50 bp 启动子基序对SCN1A表达具有很强的调节作用,尽管我们不能直接将其与 rs7587026 联系起来我们的研究结果发展了 rs7587026 与伴有海马硬化和高热惊厥病史的颞叶内侧癫痫之间的机制联系。此外,我们提出,在目前旨在治疗 SCN1A 条件下癫痫发作的策略中增加 SCN1A 表达定量精度可能很重要单倍体不足,例如 Dravet 综合征。

更新日期:2022-05-12
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