Chan Chung-Kin, Lim Kheng-Seang, Low Siew-Kee, Tan Chong-Tin, Ng Ching-Ching
Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia; Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
Epilepsy Res. 2023 Jan;189:107070. doi: 10.1016/j.eplepsyres.2022.107070. Epub 2022 Dec 21.
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 GABA receptors, and constitutively active ERBB4 receptors caused by the ERBB4 variant promote internalization of GABA 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.
癫痫是一种复杂的神经系统疾病，可由遗传和环境因素引起。已经进行了许多研究来调查癫痫的遗传风险变异和分子机制。兴奋-抑制平衡（E/I平衡）的破坏是癫痫广泛认可的疾病机制之一。E/I平衡的维持是一个由多种蛋白质调控的复杂过程。通过全外显子组测序（WES），我们在一个患有遗传性全身性癫痫（GGE）的马来西亚华裔家庭中鉴定出一种新的GABRA1基因c.448G>A（p.E150K）变异和ERBB4基因c.1972A>T（p.I658F，rs190654033）变异。GGE可能由E/I平衡机制失调引发。通过Sanger测序验证了该家庭中变异的分离情况。所有患有GGE的家庭成员都遗传了这两种变异。然而，仅携带其中一种变异的家庭成员未表现出任何GGE症状。MutationTaster和CADD预测GABRA1和ERBB4变异均具有破坏性，蛋白质结构分析表明这些变异导致突变蛋白中形成了额外的氢键。GABRA1变异可降低GABA受体的效率，而由ERBB4变异导致的组成型活性ERBB4受体促进GABA受体的内化。这两种变异之间的相互作用可能导致E/I平衡受到更大破坏，更有可能诱发癫痫发作。然而，该疾病模型来自一个单一的小家庭，仍需要进一步研究来证实所提出疾病模型的可验证性。
