Epilepsy is one of the most common episodic neurological disorders, affecting 1% population worldwide. The genetic variations of γ-aminobutyric acid type A (GABAA) receptor, including missense, nonsense, splice site and frameshift variants in GABRA1-6, GABRB1-3, GABRG1-3, and GABRD, 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 GABAA 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 GABAA receptors and their functional defects. In addition, their spatial distribution is visualized in the cryo-EM structures of GABAA 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.
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