Mutations in GABAA receptor subunits associated with genetic epilepsies

Abstract

Mutations in inhibitory GABAA receptor subunit genes (GABRA1, GABRB3, GABRG2 and GABRD) have been associated with genetic epilepsy syndromes including childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), pure febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS)/severe myoclonic epilepsy in infancy (SMEI). These mutations are found in both translated and untranslated gene regions and have been shown to affect the GABAA receptors by altering receptor function and/or by impairing receptor biogenesis by multiple mechanisms including reducing subunit mRNA transcription or stability, impairing subunit folding, stability, or oligomerization and by inhibiting receptor trafficking.

Figure 1. GABA_A receptor subunit mutations associated with genetic epilepsy syndromes

GABA_A receptor subunits are translated as a precursor protein whose signal sequence (green) is removed leaving a mature protein consisting of a large extracellular domain at the N-terminus, four transmembrane domains (M1–M4) and a large cytoplasmic domain. In this figure, we depicted GABA_A receptor α1 (blue), β3 (pink), γ2 (red) and δ (yellow) subunit mutations associated with genetic epilepsy syndromes at their appropriate protein domain within the subunit.