Department of Neurology; G.H. Sergievsky Center, Columbia University, New York, NY, USA.
Genes Brain Behav. 2014 Mar;13(3):341-9. doi: 10.1111/gbb.12116. Epub 2014 Jan 27.
Identification of genes contributing to mouse seizure susceptibility can reveal novel genes or pathways that provide insight into human epilepsy. Using mouse chromosome substitution strains and interval-specific congenic strains (ISCS), we previously identified an interval conferring pilocarpine-induced limbic seizure susceptibility on distal mouse chromosome 10 (Ch10). We narrowed the region by generating subcongenics with smaller A/J Ch10 segments on a C57BL/6J (B6) background and tested them with pilocarpine. We also tested pilocarpine-susceptible congenics for 6-Hz ECT (electroconvulsive threshold), another model of limbic seizure susceptibility, to determine whether the susceptibility locus might have a broad effect on neuronal hyperexcitability across more than one mode of limbic seizure induction. The ISCS Line 1, which contained the distal 2.7 Mb segment from A/J (starting at rs29382217), was more susceptible to both pilocarpine and ECT. Line 2, which was a subcongenic of Line 1 (starting at rs13480828), was not susceptible, thus defining a 1.0 Mb critical region that was unique to Line 1. Bioinformatic approaches identified 45 human orthologs within the unique Line 1 susceptibility region, the majority syntenic to human Ch12. Applying an epilepsy network analysis of known and suspected excitability genes and examination of interstrain genomic and brain expression differences revealed novel candidates within the region. These include Stat2, which plays a role in hippocampal GABA receptor expression after status epilepticus, and novel candidates Pan2, Cdk2, Gls2 and Cs, which are involved in neural cell differentiation, cellular remodeling and embryonic development. Our strategy may facilitate discovery of novel human epilepsy genes.
鉴定导致小鼠癫痫易感性的基因可以揭示新的基因或途径，从而深入了解人类癫痫。我们之前使用小鼠染色体替代品系和区间特异性同系品系（ISCS），鉴定出一个在远端小鼠 10 号染色体（Ch10）上赋予匹鲁卡品诱导的边缘性癫痫易感性的区间。我们通过在 C57BL/6J（B6）背景上生成具有较小 A/J Ch10 片段的亚同系品系，并使用匹鲁卡品对其进行测试，从而缩小了该区域。我们还测试了匹鲁卡品易感同系品系的 6-Hz ECT（电惊厥阈），这是另一种边缘性癫痫易感性模型，以确定易感基因座是否可能对神经元过度兴奋具有广泛影响，跨越不止一种边缘性癫痫诱导模式。包含来自 A/J 的远端 2.7 Mb 片段（起始于 rs29382217）的 ISCS 品系 1 对匹鲁卡品和 ECT 均更为敏感。而作为品系 1 的亚同系品系 2（起始于 rs13480828）则不敏感，因此定义了一个独特的 1.0 Mb 关键区域，该区域仅存在于品系 1 中。生物信息学方法在独特的品系 1 易感区域内鉴定出 45 个人类直系同源物，其中大多数与人类 Ch12 基因座同基因。应用已知和可疑兴奋性基因的癫痫网络分析以及对种间基因组和大脑表达差异的研究，揭示了该区域内的新候选基因。这些候选基因包括在癫痫持续状态后影响海马 GABA 受体表达的 Stat2，以及参与神经细胞分化、细胞重塑和胚胎发育的新候选基因 Pan2、Cdk2、Gls2 和 Cs。我们的策略可能有助于发现新的人类癫痫基因。
