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Clinical Implications of Basic Neuroscience Research |

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

Jing-Qiong Kang, MD, PhD1; Robert L. Macdonald, MD, PhD1,2,3
[+] Author Affiliations
1Department of Neurology, Vanderbilt University, Nashville, Tennessee
2Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
3Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
JAMA Neurol. 2016;73(8):1009-1016. doi:10.1001/jamaneurol.2016.0449.
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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.

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Figure 1.
Schematic Representation Showing the γ-Aminobutyric Acid (GABAA) Receptor Subunit Biogenesis, Assembly, and Trafficking

Shown is the normal trafficking route of GABAA receptors. Only those receptors that reach the cell surface and synapses can conduct chloride ions and have function, while those subunits residing in intracellular compartments have no function. The mutant subunits (mutant) resulting from missense or nonsense GABRG2 mutations are subject to nonsense-mediated messenger RNA decay or endoplasmic reticulum–associated degradation. Therefore, the mutant subunits are unlikely to be present on the cell surface and in synapses, as are wild-type receptors. The arrows show the targeted subcellular locations of wild-type or mutant subunits.

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Figure 2.
Schematic Representation of an γ-Aminobutyric Acid (GABAA) Receptor Subunit Topology Showing the Location of the Epilepsy Mutations in GABRG2 Identified by Different Groups to Date

GABRG2 mutations are associated with seizures and epilepsy syndromes. Shown are the γ2 subunit protein and the mutations identified in GABRG2 to date. CAE indicates childhood absence epilepsy; FS, febrile seizures; GEFS+, generalized epilepsy with febrile seizures plus; GTCS, generalized tonic-clonic seizures; TM, transmembrane; and SMEI, severe myoclonic epilepsy in infancy.

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Figure 3.
Schematic Representation Showing GABRG2 Mutations and the Severity of Epilepsy Syndromes

Various clinical phenotypes of seizures and epilepsy syndromes are associated with GABRG2 mutations. CAE indicates childhood absence epilepsy; FS, febrile seizures; and GEFS+, generalized epilepsy with febrile seizures plus.

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