Abstract：
Epilepsy is a complex neurological disease that can be caused by both genetic and environmental factors. Many studies have been conducted to investigate the genetic risk variants and molecular mechanisms of epilepsy. Disruption of excitation-inhibition balance (E/I balance) is one of the widely accepted disease mechanisms of epilepsy. The maintenance of E/I balance is an intricate process that is governed by multiple proteins. Using whole exome sequencing (WES), we identified a novel GABRA1 c.448G>A (p.E150K) variant and ERBB4 c.1972A>T (p.I658F, rs190654033) variant in a Malaysian Chinese family with genetic generalized epilepsy (GGE). The GGE may be triggered by dysregulation of E/I balance mechanism. Segregation of the variants in the family was verified by Sanger sequencing. All family members with GGE inherited both variants. However, family members who carried only one of the variants did not show any symptoms of GGE. Both the GABRA1 and ERBB4 variants were predicted damaging by MutationTaster and CADD, and protein structure analysis showed that the variants had resulted in the formation of additional hydrogen bonds in the mutant proteins. GABRA1 variant could reduce the efficiency of GABAA receptors, and constitutively active ERBB4 receptors caused by the ERBB4 variant promote internalization of GABAA receptors. The interaction between the two variants may cause a greater disruption in E/I balance, which is more likely to induce a seizure. Nevertheless, this disease model was derived from a single small family, further studies are still needed to confirm the verifiability of the purported disease model.
摘要：
癫痫是一种复杂的神经系统疾病，可能由遗传和环境因素引起。已经进行了许多研究以调查癫痫的遗传风险变异和分子机制。激发-抑制平衡(E/I平衡)的破坏是癫痫广泛接受的疾病机制之一。E/I平衡的维持是由多种蛋白质控制的复杂过程。使用全外显子组测序（WES），我们确定了一个新的GABRA1c.448G>A（p。E150K）变体和ERBB4c.1972A>T（p。I658F,rs190654033）在一个患有遗传性广泛性癫痫（GGE）的马来西亚华人家庭中的变异。GGE可由E/I平衡机制的失调触发。通过Sanger测序验证家族中变体的分离。具有GGE的所有家族成员都继承了这两种变体。然而,仅携带一种变种的家庭成员没有表现出任何GGE症状.GABRA1和ERBB4变体都被MutationTaster和CADD预测为破坏性的，和蛋白质结构分析表明，这些变体导致在突变蛋白中形成额外的氢键。GABRA1变体可以降低GABAA受体的效率，和由ERBB4变体引起的组成型活性ERBB4受体促进GABAA受体的内化。两种变体之间的相互作用可能会导致E/I平衡的更大破坏，更有可能诱发癫痫发作。然而，这个疾病模型来自一个小家庭，仍需要进一步的研究来证实所谓疾病模型的可验证性.
