Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome

Abstract

Objective: In this review article, we focus on the molecular pathogenic basis for genetic generalized epilepsies associated with mutations in the inhibitory γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2 (OMIM 137164), an established epilepsy gene.

Observations: The γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2, is abundantly expressed in the mammalian brain, and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABAA receptor isoforms in the brain. The γ2 subunits have a critical role in GABAA receptor trafficking and clustering at synapses. They reside inside the endoplasmic reticulum after synthesis, where they oligomerize with other binding partners, such as α and β subunits, and further assemble into pentameric receptors. Only correctly assembled receptors can traffic beyond the endoplasmic reticulum and reach the cell surface and synapses, where they conduct chloride ion current when activated by GABA. Mutations in GABRG2 have been associated with simple febrile seizures and with genetic epilepsy syndromes, including childhood absence epilepsy, generalized epilepsy with febrile seizures plus, and Dravet syndrome or severe myoclonic epilepsy in infancy. The mutations include missense, nonsense, and frameshift mutations, as well as splice-site and deletion mutations. The mutations have been identified in both coding and noncoding sequences like splice sites. In the coding sequence, these mutations are found in multiple locations, including the extracellular N-terminus, transmembrane domains, and transmembrane 3-transmembrane 4 intracellular loop. All of these mutations reduced channel function but to different extents and by diverse mechanisms, including nonsense-mediated messenger RNA decay, endoplasmic reticulum-associated protein degradation, dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death, and gating defects.

Conclusions and relevance: We conclude that the epilepsy phenotypic heterogeneity associated with GABRG2 mutations may be related to the extent of the reduction of GABAA receptor channel function and the differential dominant negative suppression, as well to toxicity related to the metabolism of mutant subunit proteins resulting from each mutant γ2 subunit, in addition to different genetic backgrounds.

Figure 1. Schematic representation showing the GABA_A receptor subunit biogenesis, assembly and trafficking

The mutant subunits (mutant) resulting from missense or nonsense GABRG2 mutations are subject to NMD and/or ERAD. Therefore, the mutant subunits are unlikely to be present on the cell surface and in synapses as are wild-type receptors. The arrows designate the targeted subcellular locations of wild-type or mutant subunits. The normal trafficking route of GABA_A receptors. Only those receptors that reach the cell surface and synapses and conduct chloride ions and have function while those subunits residing in intracellular compartments have no function.

Figure 2. Schematic representation of a GABA_A receptor subunit topology, showing the location of epilepsy mutations in GABRG2 identified by different groups up to date

The schematic presentation of γ2 subunit protein and the mutations identified in GABRG2 to date. Abbreviations: CAE, childhood absence epilepsy; FS, febrile seizures; GEFS+, generalized epilepsy with febrile seizures plus; JME, juvenile myoclonic epilepsy GABRG2 mutations associated with seizures and epilepsy syndromes

Figure 3. Schematic representation showing the GABRG2 mutations and the severity of epilepsy syndromes

(A). The mutations in GABRG2 are associated with a spectrum of epilepsy syndromes with different clinical severities. (B). Schematic illustration of the reduction of the γ2 subunit-containing receptors and increase of αβ receptors in mild epilepsy and further reduction of the γ2 subunit-containing receptors with or without the increase of αβ receptors in severe epilepsies. A spectrum of clinical phenotypes of seizures and epilepsy syndromes associated with GABRG2 mutations