Fu Xu, Wang Ya-Juan, Kang Jing-Qiong, Mu Ting-Wei
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Epilepsy is one of the most common episodic neurological disorders, affecting 1% population worldwide. The genetic variations of γ-aminobutyric acid type A (GABA) receptor, including missense, nonsense, splice site and frameshift variants in , and , have been identified as some of the primary genetic causes of epilepsy. However, the lack of a complete understanding of the association between epilepsy syndromes and GABA receptor variants makes it challenging to develop effective therapeutics. Here, we summarize a comprehensive list of over 150 epilepsy-associated variants in the major α1, β2, β3, and γ2 subunits of GABA receptors and their functional defects. In addition, their spatial distribution is visualized in the cryo-EM structures of GABA receptors. Many of the variants lead to reduced receptor surface expression and thus loss of function due to protein conformational defects and impaired trafficking. This knowledge aids the development of precision medicine-based therapeutic strategies to treat epilepsy.
癫痫是最常见的发作性神经系统疾病之一，全球约1%的人口受其影响。γ-氨基丁酸A型（GABA）受体的基因变异，包括位于[具体位置]的错义、无义、剪接位点和移码变异，已被确定为癫痫的一些主要遗传病因。然而，由于对癫痫综合征与GABA受体变异之间的关联缺乏全面了解，开发有效的治疗方法具有挑战性。在此，我们总结了GABA受体主要α1、β2、β3和γ2亚基中150多个与癫痫相关的变异及其功能缺陷的综合列表。此外，它们的空间分布在GABA受体的冷冻电镜结构中得以可视化。许多变异导致受体表面表达减少，进而由于蛋白质构象缺陷和转运受损而丧失功能。这些知识有助于开发基于精准医学的癫痫治疗策略。
