Affinage

GABRG2

Gamma-aminobutyric acid receptor subunit gamma-2 · UniProt P18507

Length
475 aa
Mass
55.2 kDa
Annotated
2026-04-28
91 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GABRG2 encodes the γ2 subunit of GABAA receptors, which is essential for receptor pentamer assembly in the endoplasmic reticulum, forward trafficking to the cell surface, synaptic clustering, and chloride channel gating that mediates fast inhibitory neurotransmission (PMID:27367160, PMID:19261880). Epilepsy-associated GABRG2 mutations reduce receptor function through diverse mechanisms—including nonsense-mediated mRNA decay, ER retention and ERAD of misfolded subunits via HRD1-dependent ubiquitination, dominant-negative trapping of wild-type partnering subunits (α1, β2), intracellular aggregation causing ER stress and caspase-3-mediated neurodegeneration, and channel gating defects—with phenotypic severity correlating with the specific functional consequence of each variant (PMID:23720301, PMID:26005849, PMID:38731820, PMID:40570274). Gain-of-function variants such as A106T, which enhance receptor gating, are associated with the most severe developmental and epileptic encephalopathies, while null loss-of-function alleles produce comparatively milder phenotypes than dominant-negative missense variants (PMID:40570274, PMID:41351427). Mutant γ2 subunit accumulation drives chronic neuroinflammation and neurodegeneration independent of seizure activity, and supplementation of wild-type γ2 or pharmacological chaperones that promote proper folding rescue receptor biogenesis and seizure phenotypes in vivo (PMID:32944937, PMID:28586508, PMID:37746768).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 Medium

    Early electrophysiology established that GABRG2 mutations associated with febrile seizures alter channel gating properties—specifically desensitization kinetics and benzodiazepine responsiveness—providing the first evidence that γ2 subunit variants cause epilepsy by changing receptor biophysics.

    Evidence Electrophysiology of recombinant mutant receptors in heterologous cells

    PMID:16924025

    Open questions at the time
    • Single study with limited mechanistic detail
    • No trafficking or assembly analysis performed
    • In vivo relevance not tested
  2. 2009 High

    The Q351X nonsense mutation revealed that truncated γ2 subunits are not simply lost but actively oligomerize with wild-type α1 and β2 subunits, trap them in the ER via glycosylation arrest and ERAD, and suppress surface receptor expression beyond haploinsufficiency—establishing the dominant-negative paradigm for GABRG2 mutations.

    Evidence Pulse-chase radiolabeling, co-immunoprecipitation, glycosylation assays, whole-cell patch clamp in HEK293T cells

    PMID:19261880

    Open questions at the time
    • Mechanism of selective ER retention not fully defined
    • In vivo validation pending at this point
  3. 2011 High

    Single-particle tracking of the K289M mutation demonstrated that γ2 subunit variants can alter lateral membrane dynamics of synaptic GABAA receptors in a temperature-dependent manner, providing a biophysical mechanism linking febrile seizure mutations to activity-dependent loss of synaptic inhibition.

    Evidence Single-particle tracking, mIPSC electrophysiology, pharmacological dissection in cultured neurons

    PMID:21908847

    Open questions at the time
    • Whether enhanced diffusion is a general mechanism for other GABRG2 mutations unknown
    • No in vivo validation of membrane diffusion phenotype
  4. 2012 High

    Studies of multiple mutation types (intronic splice-site IVS6+2T→G, early nonsense Q40X, frameshift c.1329delC) established that GABRG2 mutations engage NMD, aberrant splicing, and ER retention in mutation-specific combinations, and that aminoglycoside read-through can partially rescue premature stop codon variants—demonstrating therapeutic tractability.

    Evidence BAC constructs in HEK cells and transgenic mice, NMD analysis, surface biotinylation, electrophysiology, flow cytometry

    PMID:22539854 PMID:22750526 PMID:23069679

    Open questions at the time
    • Read-through efficiency in vivo not established
    • Relative contribution of NMD versus dominant-negative toxicity to disease severity unclear
  5. 2013 High

    Systematic comparison of multiple nonsense mutations revealed that truncated γ2 subunits in the last exon escape NMD and accumulate to cause graded dominant-negative suppression and differential ER stress, mechanistically linking mutant protein stability and abundance to epilepsy phenotypic severity.

    Evidence Pulse-chase, flow cytometry, immunohistochemistry, patch clamp, NMD minigene assay across multiple mutations

    PMID:23720301

    Open questions at the time
    • Quantitative relationship between ER stress level and seizure severity not fully calibrated
    • Cell-type specificity of degradation pathways not addressed
  6. 2014 High

    Missense mutations at the γ+/β− subunit interface (R82Q, P83S) and in the extracellular domain (R177G) were shown to impair pentamer assembly and destabilize unassembled subunits, with temperature rescue at 30°C partially restoring surface expression—establishing that conformational instability during assembly is a major disease mechanism for GABRG2 missense variants.

    Evidence Flow cytometry, patch clamp, cycloheximide chase, structural modeling, temperature rescue in HEK293T cells

    PMID:24798517 PMID:24874541

    Open questions at the time
    • No crystal or cryo-EM structure of mutant subunits
    • Temperature rescue not translatable to in vivo therapy
  7. 2015 High

    The Gabrg2+/Q390X knock-in mouse demonstrated that mutant γ2 subunit accumulation and aggregation in neurons activates caspase-3 and causes age-dependent neurodegeneration in vivo—establishing that dominant-negative GABRG2 mutations produce proteotoxicity beyond simple loss of inhibition.

    Evidence Knock-in mouse, immunohistochemistry, caspase-3 activation assay, behavioral analysis, EEG

    PMID:26005849

    Open questions at the time
    • Specific aggregation-prone domains not mapped
    • Whether neurodegeneration is reversible upon aggregate clearance unknown
  8. 2016 High

    Direct comparison of knock-in (dominant-negative) versus knockout (haploinsufficiency) mice established that intracellular mutant protein accumulation, not merely reduced γ2 expression, drives more severe seizures, and comprehensive characterization of six de novo mutations confirmed that each variant reduces surface expression and/or channel function to different degrees correlating with clinical severity.

    Evidence KI vs. KO mouse comparison with Western blot, IHC, EEG, behavioral tests; patch clamp and confocal imaging of six mutations in HEK293T cells

    PMID:27340224 PMID:27762395 PMID:27864268

    Open questions at the time
    • Cell-type-specific vulnerability to dominant-negative effects not mapped
    • Contribution of brainstem-specific receptor loss to SUDEP risk correlational
  9. 2017 High

    Genetic rescue via BAC-mediated wild-type γ2 overexpression in Gabrg2+/Q390X mice restored partnering subunit levels, increased mIPSC amplitudes, and raised seizure threshold—proving that supplementing wild-type γ2 can overcome dominant-negative suppression in vivo.

    Evidence Transgenic cross, Western blot, IHC, mIPSC recordings, EEG, PTZ seizure threshold in mice

    PMID:28586508

    Open questions at the time
    • Optimal expression level for therapeutic benefit not defined
    • Whether gene therapy approaches can achieve sufficient γ2 expression in humans unknown
  10. 2019 High

    Circuit-level dissection revealed that impaired GABAergic inhibition specifically in central amygdala neurons underlies anxiety comorbidity in both KI and KO mice, with chemogenetic manipulation of these neurons bidirectionally modulating anxiety—linking GABRG2 loss to specific neural circuit dysfunction.

    Evidence Slice electrophysiology, subcellular fractionation, chemogenetics (DREADDs), behavioral tests in KI and KO mice

    PMID:31087664

    Open questions at the time
    • Whether other comorbidities (cognitive, social) map to distinct circuits unknown
    • Human amygdala circuit involvement not confirmed
  11. 2020 High

    Chronic mutant γ2 protein accumulation was shown to drive neuroinflammation (elevated TNF-α, IL-1β, IL-6) throughout development independent of seizures, via sustained ER stress—adding neuroinflammation as a seizure-independent pathogenic mechanism and distinguishing KI from KO pathology.

    Evidence ELISA, immunoprecipitation, immunoblot in KI vs. KO mice and cultured neurons

    PMID:32944937

    Open questions at the time
    • Whether anti-inflammatory therapy alone reduces seizure burden unknown
    • Specific ER stress sensors mediating cytokine induction not identified
  12. 2023 High

    4-Phenylbutyrate (PBA) was shown to reduce mutant γ2 aggregates, enhance wild-type receptor trafficking to the membrane, and mitigate seizures in KI mice—establishing pharmacological chaperoning as a viable therapeutic strategy that acts on wild-type receptor biogenesis rather than mutant channel correction.

    Evidence Differential allele tagging, live brain slice surface biotinylation, microsome isolation, patch-clamp, video-EEG in KI mice

    PMID:37746768

    Open questions at the time
    • Long-term efficacy and safety of PBA in chronic treatment not assessed
    • Whether PBA acts on all GABRG2 mutation types unclear
  13. 2024 Medium

    Identification of HRD1 as the E3 ubiquitin ligase mediating ERAD of both wild-type and mutant γ2 subunits provided the first specific molecular component of the quality-control pathway, and pharmacological upregulation of HRD1 by zonisamide reduced seizures and partially rescued surface trafficking.

    Evidence IP, Western blot, HRD1 overexpression/knockdown, ERAD pathway analysis, seizure monitoring in mice

    PMID:38731820

    Open questions at the time
    • Other E3 ligases or co-chaperones in the pathway not identified
    • Specificity of HRD1 for γ2 versus other GABAA subunits not determined
    • Single study requiring independent confirmation
  14. 2025 High

    Systematic functional classification of 17 missense variants revealed that gain-of-function variants (e.g., A106T) cause the most severe epileptic encephalopathies while null loss-of-function variants produce milder phenotypes, overturning the assumption that all pathogenic GABRG2 variants act through loss of function and establishing bidirectional functional change as a determinant of severity.

    Evidence Patch-clamp electrophysiology of recombinant receptors, clinical cohort of 44 individuals; knock-in mouse modeling of A106T with transcriptomics

    PMID:40570274 PMID:41053028 PMID:41351427

    Open questions at the time
    • Structural basis of gain-of-function for A106T based on homology modeling only—cryo-EM structure needed
    • Whether GoF variants require different therapeutic strategies than LoF variants untested
    • Neuroinflammation preceding seizures in A106T KI mice requires mechanistic dissection

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of gain-of-function mutations at atomic resolution, whether targeting neuroinflammation or ER stress independently of receptor function can prevent epileptogenesis, and which specific neuronal populations are most vulnerable to dominant-negative proteotoxicity versus simple haploinsufficiency.
  • No cryo-EM or crystal structure of mutant γ2 subunit-containing receptors
  • Cell-type-specific vulnerability to proteotoxicity not mapped
  • Whether gene therapy or antisense strategies can selectively suppress mutant allele expression in vivo untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0005198 structural molecule activity 3
Localization
GO:0005783 endoplasmic reticulum 6 GO:0005886 plasma membrane 6 GO:0005829 cytosol 2
Pathway
R-HSA-9609507 Protein localization 6 R-HSA-112316 Neuronal System 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3
Partners
GABRA1GABRB2GABRB3HRD1
Complex memberships
GABAA receptor (α1β2γ2 pentamer)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 GABRG2 mutations reduce GABAA receptor channel function by diverse mechanisms including nonsense-mediated mRNA decay (NMD), endoplasmic reticulum-associated protein degradation (ERAD), dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death, and gating defects. The γ2 subunit is critical for GABAA receptor trafficking and clustering at synapses; it oligomerizes with α and β subunits in the ER and only correctly assembled pentameric receptors traffic to the cell surface. Review synthesizing in vitro expression assays, patch clamp, immunoblotting, confocal imaging, mouse models JAMA neurology High 27367160
2009 The GABRG2 nonsense mutation Q351X produces a trafficking-deficient, ER-retained truncated γ2 subunit that exerts dominant-negative suppression of wild-type receptors: the mutant subunit oligomerizes with wild-type α1 and β2 subunits, traps them in the ER, subjects them to glycosylation arrest and ERAD via the ubiquitin-proteasome system, and reduces GABAA receptor surface expression and function beyond what simple haploinsufficiency would produce. Pulse-chase radiolabeling, co-immunoprecipitation, glycosylation assays, whole-cell patch clamp, immunoblotting in HEK293T cells The Journal of neuroscience High 19261880
2015 In Gabrg2+/Q390X knock-in mice, the mutant γ2(Q390X) subunit accumulates and aggregates intracellularly in neurons, activates caspase-3, and causes widespread age-dependent neurodegeneration, demonstrating that the mutant subunit exerts toxicity beyond simple loss of GABAergic inhibition. Knock-in mouse model, immunohistochemistry, caspase-3 activation assay, behavioral analysis, EEG Nature neuroscience High 26005849
2012 The intronic GABRG2 mutation IVS6+2T→G abolishes normal intron 6 splicing, activates a cryptic splice site causing partial intron retention and a frameshift that creates a premature stop codon. The resulting mutant mRNA is partially degraded by NMD; undegraded mRNA is translated to a stable truncated γ2-PTC subunit that is retained in the ER, oligomerizes with α1 and β2 subunits, and exerts a dominant-negative effect on αβγ2 receptor surface expression. BAC constructs expressed in HEK293T cells and transgenic mice, mRNA splicing analysis, immunoblotting, surface expression assays, electrophysiology The Journal of neuroscience High 22539854
2013 Different GABRG2 nonsense mutations produce truncated γ2 subunits with different degradation rates, stabilities, and levels of polyubiquitin conjugation; those in the last exon escape NMD and accumulate intracellularly, causing graded dominant-negative suppression of wild-type GABAA receptor biogenesis and function, and differential ER stress—mechanistically linking mutant subunit amount to epilepsy phenotypic severity. 35S radiolabeling pulse-chase, flow cytometry, immunoblotting, immunohistochemistry, whole-cell patch clamp in non-neuronal cells and neurons, NMD minigene assay Annals of neurology High 23720301
2012 The GABRG2 nonsense mutation Q40X activates NMD to degrade mutant γ2 mRNA; residual mRNA is translated to a truncated peptide (likely signal peptide) that is cleaved. The mutant subunit fails to assemble into functional GABAA receptors. Aminoglycoside-induced stop-codon read-through with gentamicin partially restored full-length γ2 subunit synthesis and rescued surface GABAA receptor expression and function. BAC constructs, NMD analysis, surface biotinylation, whole-cell patch clamp in HEK cells Neurobiology of disease High 22750526
2014 Three GABRG2 missense mutations (R82Q, P83S, N79S) at the γ+/β− subunit interface disrupt GABAA receptor assembly to different extents: R82Q and P83S cause ER retention and degradation of unassembled subunits by impairing pentamer assembly, while N79S has minimal effect. Structural modeling predicted increased conformational variability at assembly motifs for R82Q and P83S. Lowering incubation temperature to 30°C partially rescued surface expression of mutant subunits by stabilizing receptor folding. Flow cytometry, immunoblotting, whole-cell patch clamp, structural modeling, temperature rescue experiment in HEK293T cells Neurobiology of disease High 24798517
2014 The GABRG2 R177G febrile seizure mutation decreases GABAA receptor cell surface expression by causing ER retention and ERAD of mutant γ2L subunits. Wild-type γ2L subunits have a competitive advantage over R177G mutant subunits for receptor assembly/trafficking. Cycloheximide experiments showed the mutation primarily destabilizes unassembled γ2L subunits. Molecular modeling indicated disruption of intrasubunit salt bridges, destabilizing secondary and tertiary structure. Electrophysiology, flow cytometry, immunoblotting, cycloheximide chase, molecular modeling in HEK293T cells Neurobiology of disease High 24874541
2014 The GABRG2 R136* nonsense mutation produces γ2 subunits with reduced total and cell-surface expression that accumulate in intracellular aggregates surrounding the nucleus and ER, impairing receptor trafficking; co-expression with α1 and β2 subunits leads to reduced GABA-evoked currents. In vitro expression in HEK293T cells, flow cytometry, immunoblotting, whole-cell patch clamp, immunofluorescence Neurobiology of disease Medium 24407264
2016 Different nonsense mutations in GABRG2 (R136*, Q390*, W429*) produce truncated γ2 subunits with different structural stabilities, surface hydrophobicities, and tendencies to dimerize, leading to differential suppression of wild-type partnering subunit surface expression and differentially reduced GABA-evoked current amplitudes—correlating with clinical epilepsy severity. Structural modeling, flow cytometry, immunoblotting, whole-cell patch clamp in HEK293T cells Scientific reports Medium 27762395
2016 In de novo GABRG2 mutations associated with epileptic encephalopathy (A106T, I107T, P282S, R323W, F343L, R323Q), GABAA receptors containing mutant γ2 subunits show reduced cell surface expression with altered subunit stoichiometry or decreased GABA-evoked current amplitudes in HEK293T cells, with different levels of reduction for each mutation. Patch clamp recording, immunoblotting, confocal imaging, structural modelling in HEK293T cells Brain High 27864268
2016 Comparing Gabrg2+/Q390X knock-in (KI) and Gabrg2+/- knockout (KO) mice showed that dominant-negative KI mice accumulate mutant γ2 subunits intracellularly in neurons, have reduced wild-type γ2 subunit expression in dendrites and synapses, and exhibit more severe seizures and behavioral comorbidities than KO haploinsufficient mice, which show no intracellular accumulation and unaffected wild-type subunit biogenesis. Western blot, immunohistochemistry, EEG, behavioral tests in knock-in vs. knockout mice Human molecular genetics High 27340224
2012 The GABRG2 frameshift mutation c.1329delC produces a stable mutant γ2S subunit with a modified elongated C-terminus that is retained in the ER and not expressed on the cell surface, resulting in haploinsufficiency; co-expression with α1 and β2 subunits produces currents comparable to α1β2 receptors lacking γ2 subunit, indicating loss of γ2 function. Immunoblotting, flow cytometry, whole-cell patch clamp in HEK293T cells Neurobiology of disease Medium 23069679
2014 The GABRG2 Q40X mutation in dizygotic twins with Dravet syndrome causes reduced GABA-induced currents in reconstituted HEK cell receptors; microinjection of mutant γ2(Q40X) cDNA into HEK cells severely inhibited intracellular trafficking of GABAA receptor subunits α1 and β2, retaining them in the ER. In neurons, the mutant γ2 subunit also impairs axonal transport of α1 and β2 subunits. Electrophysiology in HEK cells, immunohistochemistry, microinjection, axonal transport analysis in neurons Epilepsy research Medium 24480790
2011 The GABRG2 K289M mutation accelerates receptor deactivation. Upon raising temperature, neurons expressing K289M mutant γ2 show increased lateral membrane diffusion of synaptic GABAA receptors (tracked by single-particle tracking), loss of receptor clusters, and reduced miniature inhibitory postsynaptic current frequency. This enhanced activity-dependent mobility during hyperthermia is blocked by glutamate receptor antagonists and mimicked by 4-aminopyridine, identifying altered membrane diffusion as a mechanism for temperature-sensitive epilepsy. Single-particle tracking, mIPSC electrophysiology, live imaging in neurons Cerebral cortex High 21908847
2017 Overexpression of wild-type γ2 subunits via BAC transgene in Gabrg2+/Q390X knock-in mice increased wild-type γ2, α1, and β2/3 subunit expression, increased mIPSC amplitudes in cortical neurons, reduced thalamocortical network oscillations, and raised PTZ seizure threshold—demonstrating that seizures caused by dominant-negative γ2(Q390X) can be rescued by supplementing wild-type γ2 subunit. Transgenic cross, Western blot, immunohistochemistry, whole-cell patch clamp (mIPSC), EEG, PTZ seizure threshold testing in mice Epilepsia High 28586508
2019 In Gabrg2+/Q390X knock-in and Gabrg2+/- knockout mice, impaired GABAergic neurotransmission in the central nucleus of the amygdala (CeA)—but not basolateral amygdala—underlies comorbid anxiety, caused by reduced GABAA receptor subunit expression from the mutations. Chemogenetic activation or inactivation of inhibitory CeA neurons alone modulates anxiety-like behavior, and pharmacological enhancement of γ2-containing receptor signaling relieves anxiety. Brain slice electrophysiology, subcellular fractionation, Western blot, immunohistochemistry, confocal microscopy, behavioral tests, chemogenetics (DREADDs) in knock-in and knockout mice Epilepsia High 31087664
2020 In Gabrg2+/Q390X knock-in mice, proinflammatory cytokines (TNF-α, IL-1β, IL-6) are increased in multiple brain regions throughout development independent of seizure occurrence, driven by chronic mutant protein accumulation and ER stress. Pharmacological induction of ER stress upregulates cytokines in wild-type and KO but not in KI mice, and the mutant protein dampens cytokine induction upon further cellular stress. ELISA, immunoprecipitation, nuclei purification, immunoblot, immunohistochemistry, confocal microscopy in KI and KO mice and cultured neurons Epilepsia High 32944937
2016 In Gabrg2+/Q390X knock-in mice associated with Dravet syndrome, synaptic GABAA receptors are reduced while intracellular non-functional γ2(Q390X) subunits are accumulated in brainstem nuclei (solitary tract, pre-Bötzinger complex, Kölliker-Fuse nuclei) controlling respiratory function, suggesting that impaired GABAergic transmission in these nuclei contributes to cardiorespiratory failure in SUDEP. Western blot, immunohistochemistry comparing KI and KO mice in specific brainstem nuclei Epilepsy research Medium 27131289
2021 Neocortex- and hippocampus-specific conditional knockout of Gabrg2 in mice produces temperature-dependent myoclonic jerks, generalized tonic-clonic seizures, increased seizure susceptibility (to PTZ and hyperthermia), cortical hyperexcitability on EEG, and neuronal loss in cortical layers V–VI and hippocampus—establishing that loss of γ2 specifically in excitatory cortical and hippocampal neurons is sufficient to cause febrile seizure-like phenotypes. Cre/loxP conditional knockout, EEG, PTZ seizure threshold, behavioral tests, histology in mice Cell death & disease Medium 34050134
2023 4-Phenylbutyrate (PBA) reduces mutant γ2(Q390X) subunit protein aggregates, enhances trafficking of wild-type GABAA receptor subunits to the membrane in HEK293T cells and neurons, increases GABA-evoked current amplitudes, reduces ER stress, and mitigates seizures and EEG abnormalities in Gabrg2+/Q390X mice—acting not by directly modulating the mutant channel but by facilitating folding and transport of wild-type receptors. Biochemistry, differential allele tagging, live brain slice surface biotinylation, microsome isolation, patch-clamp, video-EEG in KI mice Epilepsia High 37746768
2024 HRD1, an ER-associated E3 ubiquitin ligase, is identified as a strong modulator of wild-type and mutant γ2(Q390X) subunit expression; overexpressing or knocking down HRD1 dose-dependently reduces γ2(Q390X) subunit levels. Zonisamide, which upregulates HRD1, reduces seizures in Gabrg2 mice and partially rescues surface trafficking of GABAA receptors sequestered in the ER by the dominant-negative γ2(Q390X) subunit. Immunoprecipitation, Western blot, overexpression/knockdown of HRD1, ERAD pathway analysis, seizure monitoring in mice International journal of molecular sciences Medium 38731820
2021 Dravet syndrome-associated GABRG2 variants (T90R, P342L) primarily cause trafficking defects in GABAA receptor biogenesis (reduced surface expression), in contrast to GABRA1 and GABRB2 Dravet variants which express well at the surface but are functionally deficient (gating defects), suggesting subunit-specific mechanisms for the same disease phenotype. Patch clamp, immunoblotting, surface biotinylation, confocal microscopy in HEK293T cells Brain communications Medium 34095830
2022 GABRG2 variants associated with sleep-related hypermotor epilepsy (T90M and T317N) decrease GABA-evoked current amplitudes by diverse mechanisms: T90M causes impaired surface expression and ER retention; T317N causes channel gating defects. The Q217X variant reduces synaptic clustering and distribution of GABAA receptors. Electrophysiology, Western blot, flow cytometry, confocal microscopy in neuronal and non-neuronal cells Journal of neurology Medium 35486215
2020 Transgenic zebrafish overexpressing mutant human GABRG2(F343L) display spontaneous seizure-like behaviors, hyperactivity, and light-stimulation-induced seizures; they show upregulation of c-fos (a marker of epileptogenesis), altered GABAA receptor subunit expression, and upregulation of 33 genes associated with protein processing. HDAC inhibition with SAHA alleviates seizure-like phenotypes. Transgenic zebrafish model, RT-qPCR, in situ hybridization, automated locomotion tracking, RNA sequencing, pharmacological treatment Annals of translational medicine Medium 33437759
2022 Transgenic zebrafish overexpressing mutant GABRG2(F343L) display not only postsynaptic defects (altered GABAA receptor subunit expression) but also presynaptic defects in synaptic protein expression and synapse ultrastructure, expanding the mechanistic paradigm from channelopathy to synaptopathy for GABRG2-related epileptic encephalopathy. RT-qPCR, in situ hybridization, Western blot, synaptic protein immunostaining, electron microscopy in transgenic zebrafish Human molecular genetics Medium 34957497
2025 Functional assessment of 17 GABRG2 missense variants revealed that 9 cause loss-of-function (LoF), 3 cause gain-of-function (GoF), and 5 do not alter receptor function. GoF variants (e.g., A106T) are associated with the most severe phenotypes (DEE, early onset at 2 months, severe developmental impairment), while null LoF variants are associated with milder phenotypes than missense LoF variants, establishing that phenotypic severity depends on the functional consequence of the variant type. Electrophysiological recordings (patch clamp) of missense variants in recombinant receptors, clinical cohort analysis Neurology High 40570274
2025 The recurrent GABRG2 p.A106T variant is a gain-of-function mutation confirmed by electrophysiological recordings. Structural homology modeling indicates the variant may enhance receptor gating by facilitating a hydrogen bond between the extracellular and transmembrane domains, a mechanism not observed with p.A106P (a functionally neutral variant at the same residue). Electrophysiological recordings, homology-based structural modeling Epilepsia Medium 41351427
2006 A novel GABRG2 mutation associated with febrile seizures alters GABAA receptor current desensitization kinetics and reduces benzodiazepine enhancement of receptor currents, as demonstrated by electrophysiological studies of mutant receptors. Electrophysiology of recombinant mutant receptors Neurology Medium 16924025
2025 In Gabrg2+/A105T knock-in mice (modeling human A106T), γ2 subunit protein expression is selectively reduced in the hippocampus; mIPSC amplitudes are significantly decreased, indicating impaired synaptic GABAergic inhibition. Neuroinflammation (microglia activation, neuronal loss) precedes seizure onset, suggesting neuroinflammatory processes exacerbate epileptogenesis. Western blot, mIPSC electrophysiology, hippocampal transcriptome profiling, histology in knock-in mice Cell death discovery Medium 41053028

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Archives of neurology 221 12117362
2006 A novel GABRG2 mutation associated with febrile seizures. Neurology 120 16924025
2016 Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome. JAMA neurology 105 27367160
2016 De novo GABRG2 mutations associated with epileptic encephalopathies. Brain : a journal of neurology 91 27864268
2015 The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration. Nature neuroscience 80 26005849
2009 The GABRG2 mutation, Q351X, associated with generalized epilepsy with febrile seizures plus, has both loss of function and dominant-negative suppression. The Journal of neuroscience : the official journal of the Society for Neuroscience 79 19261880
2022 Molecular and clinical descriptions of patients with GABAA receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation. Epilepsia 67 35718920
2008 SCN1A, SCN1B, and GABRG2 gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus. Journal of human genetics 56 18566737
2004 Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations. Epilepsia 49 14738422
2016 Differential molecular and behavioural alterations in mouse models of GABRG2 haploinsufficiency versus dominant negative mutations associated with human epilepsy. Human molecular genetics 44 27340224
2013 GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenetics and genomics 41 24061200
2014 Three epilepsy-associated GABRG2 missense mutations at the γ+/β- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents. Neurobiology of disease 38 24798517
2012 The GABRG2 nonsense mutation, Q40X, associated with Dravet syndrome activated NMD and generated a truncated subunit that was partially rescued by aminoglycoside-induced stop codon read-through. Neurobiology of disease 36 22750526
2021 Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors. Brain communications 35 34095830
2005 Haplotype association between GABAA receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder. The pharmacogenomics journal 35 15772696
2014 A novel GABRG2 mutation, p.R136*, in a family with GEFS+ and extended phenotypes. Neurobiology of disease 34 24407264
2014 Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy. Epilepsy research 34 24480790
2013 Trafficking-deficient mutant GABRG2 subunit amount may modify epilepsy phenotype. Annals of neurology 34 23720301
2014 GABAA receptor biogenesis is impaired by the γ2 subunit febrile seizure-associated mutation, GABRG2(R177G). Neurobiology of disease 33 24874541
2012 The intronic GABRG2 mutation, IVS6+2T->G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated γ2 subunit. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 22539854
2007 Association of GABRG2 polymorphisms with idiopathic generalized epilepsy. Pediatric neurology 31 17162195
2011 A human mutation in Gabrg2 associated with generalized epilepsy alters the membrane dynamics of GABAA receptors. Cerebral cortex (New York, N.Y. : 1991) 30 21908847
2015 Novel GABRG2 mutations cause familial febrile seizures. Neurology. Genetics 28 27066572
2012 Role of MDR1 C3435T and GABRG2 C588T gene polymorphisms in seizure occurrence and MDR1 effect on anti-epileptic drug (phenytoin) absorption. Genetic testing and molecular biomarkers 28 22239287
2012 Impaired surface αβγ GABA(A) receptor expression in familial epilepsy due to a GABRG2 frameshift mutation. Neurobiology of disease 27 23069679
2010 Mutational analysis of GABRG2 in a Japanese cohort with childhood epilepsies. Journal of human genetics 24 20485450
2015 Contribution of GABRG2 Polymorphisms to Risk of Epilepsy and Febrile Seizure: a Multicenter Cohort Study and Meta-analysis. Molecular neurobiology 22 26452361
2003 Failure to find causal mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients. Neuroscience letters 22 12759178
2019 Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders. Seizure 20 31004928
2017 Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice. Epilepsy research 20 28505490
2017 Overexpressing wild-type γ2 subunits rescued the seizure phenotype in Gabrg2+/Q390X Dravet syndrome mice. Epilepsia 20 28586508
2011 GABRG2 gene polymorphisms in Egyptian children with simple febrile seizures. Indian journal of pediatrics 20 21983990
2023 GABRG2 Variants Associated with Febrile Seizures. Biomolecules 17 36979350
2005 Mutation screen of GABRA1, GABRB2 and GABRG2 genes in Japanese patients with absence seizures. Neuroscience letters 17 15955415
2016 GABRG2 C588T gene polymorphisms might be a predictive genetic marker of febrile seizures and generalized recurrent seizures: a case-control study in a Romanian pediatric population. Archives of medical science : AMS 16 29379546
2012 GABRG2 rs211037 polymorphism and epilepsy: a systematic review and meta-analysis. Seizure 16 23140995
2017 Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype. Journal of neurogenetics 15 28460589
2016 Altered GABAA receptor expression in brainstem nuclei and SUDEP in Gabrg2(+/Q390X) mice associated with epileptic encephalopathy. Epilepsy research 15 27131289
2016 Differential protein structural disturbances and suppression of assembly partners produced by nonsense GABRG2 epilepsy mutations: implications for disease phenotypic heterogeneity. Scientific reports 15 27762395
2020 The GABRG2 F343L allele causes spontaneous seizures in a novel transgenic zebrafish model that can be treated with suberanilohydroxamic acid (SAHA). Annals of translational medicine 14 33437759
2012 Lack of association between rs211037 of the GABRG2 gene and juvenile myoclonic epilepsy in Brazilian population. Neurology India 14 23287319
2003 No evidence of GABRG2 mutations in severe myoclonic epilepsy of infancy. Epilepsy research 14 12694927
2021 Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice. Cell death & disease 12 34050134
2020 Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2+/Q390X knockin: A link between genetic and acquired epilepsy? Epilepsia 12 32944937
2019 The therapeutic effect of stiripentol in Gabrg2+/Q390X mice associated with epileptic encephalopathy. Epilepsy research 12 31022638
2019 Molecular basis for and chemogenetic modulation of comorbidities in GABRG2-deficient epilepsies. Epilepsia 12 31087664
2014 Association study of GABRG2 polymorphisms with suicidal behaviour in schizophrenia patients with alcohol use disorder. Neuropsychobiology 12 24776921
2005 Mutations in GABRA1, GABRA5, GABRG2 and GABRD receptor genes are not a major factor in the pathogenesis of familial focal epilepsy preceded by febrile seizures. Neuroscience letters 12 16256272
2020 Interactions of the GABRG2 polymorphisms and childhood trauma on suicide attempt and related traits in depressed patients. Journal of affective disorders 11 32056912
2020 GABRG2 Deletion Linked to Genetic Epilepsy with Febrile Seizures Plus Affects the Expression of GABAA Receptor Subunits and Other Genes at Different Temperatures. Neuroscience 11 32418750
2015 Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population. The Journal of dermatology 10 25573302
2022 Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy. Journal of neurology 9 35486215
2021 Analysis of GABRG2 C588T polymorphism in genetic epilepsy and evaluation of GABRG2 in drug treatment. Clinical and translational science 9 33650258
2022 An epileptic encephalopathy associated GABRG2 missense mutation leads to pre- and postsynaptic defects in zebrafish. Human molecular genetics 8 34957497
2021 Genetic Polymorphism of GABRG2 rs211037 is Associated with Drug Response and Adverse Drug Reactions to Valproic Acid in Chinese Southern Children with Epilepsy. Pharmacogenomics and personalized medicine 8 34552348
2012 Investigation of the role of the GABRG2 gene variant in migraine. Journal of the neurological sciences 8 22572707
2023 4-Phenylbutyrate promoted wild-type γ-aminobutyric acid type A receptor trafficking, reduced endoplasmic reticulum stress, and mitigated seizures in Gabrg2+/Q390X mice associated with Dravet syndrome. Epilepsia 7 37746768
2016 Association of a novel GABRG2 splicing variation and a PTGS2/COX-2 single nucleotide polymorphism with Taiwanese febrile seizures. Epilepsy research 7 27871023
2025 Phenotypic Spectrum in Individuals With Pathogenic GABRG2 Loss- and Gain-of-Function Variants. Neurology 6 40570274
2024 Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome. International journal of molecular sciences 6 38731820
2024 GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics. Journal of translational medicine 6 39143639
2022 GABRG2 C588T Polymorphism Is Associated with Idiopathic Generalized Epilepsy but Not with Antiepileptic Drug Resistance in Pakistani Cohort. BioMed research international 6 36425336
2019 Human GABRG2 generalized epilepsy: Increased somatosensory and striatothalamic connectivity. Neurology. Genetics 6 31321301
2016 Mutations in GABRG2 receptor gene are not a major factor in the pathogenesis of mesial temporal lobe epilepsy in Indian population. Annals of Indian Academy of Neurology 6 27293336
2024 Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations. CNS neuroscience & therapeutics 5 38357846
2024 Preliminary study on the mechanism of SAHA in the treatment of refractory epilepsy induced by GABRG2(F343L) mutation. Biochemical pharmacology 5 39053637
2023 Precision medicine: Vinpocetine as a potential treatment for GABRG2-related epilepsy. Epileptic disorders : international epilepsy journal with videotape 5 37536979
2023 Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human. Experimental neurology 5 37703949
2016 Contribution of Common Variants in GABRG2, RELN and NRG3 and Interaction Networks to the Risk of Hirschsprung Disease. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 27889765
2009 The GABA(A)-receptor γ2 (GABRG2) gene in obsessive-compulsive disorder. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) 5 20098824
2024 Repetitive Transcranial Magnetic Stimulation-Mediated Neuroprotection in the 5xFAD Mouse Model of Alzheimer's Disease Through GABRG2 and SNAP25 Modulation. Molecular neurobiology 4 39052185
2022 Electroacupuncture at PC6 (Neiguan) Attenuates Angina Pectoris in Rats with Myocardial Ischemia-Reperfusion Injury Through Regulating the Alternative Splicing of the Major Inhibitory Neurotransmitter Receptor GABRG2. Journal of cardiovascular translational research 4 35377129
2021 Association of rs211037 GABRG2 gene polymorphism with susceptibility to idiopathic generalized epilepsy. Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina 4 34080406
2021 The Effects of Gene Variations of GABRA2, GABRB1, GABRG2, GAD1 and SLC1A3 on Patients with Propofol During Anesthesia Induction. Pharmacogenomics and personalized medicine 4 34557020
2008 GEFS+ is not related to the most common mutations of SCN1B, SCN1A and GABRG2 in two Tunisian families. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 4 18175077
2025 Insight into molecular and mutational scrutiny of epilepsy associated gene Gabrg2 leading to novel computer-aided drug designing. Scientific reports 3 40000820
2023 A novel GABRG2 variant in Sunflower syndrome: A case report and video EEG monitoring. Epileptic disorders : international epilepsy journal with videotape 2 37632399
2018 Mutational screening of GABRG2 gene in Pakistani population of Punjab with generalized tonic clonic seizures and children with childhood absence epilepsy. Journal of the Chinese Medical Association : JCMA 2 29929832
2008 [Analysis of the GABRG2 gene mutation in a Chinese family with generalized epilepsy with febrile seizures plus]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 19065515
2025 The Functional Interplay among GAD2, GABRG2, and CACNA1G Genes in Cancers. Asian Pacific journal of cancer prevention : APJCP 1 40849687
2025 A knock-in mouse model for GABRG2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment. Cell death discovery 1 41053028
2025 Association of GABRG2 gene polymorphisms with idiopathic generalized epilepsy in Egyptian children: a case-control study. European journal of medical research 1 41146305
2000 Complete genomic sequence of 195 Kb of human DNA containing the gene GABRG2. DNA sequence : the journal of DNA sequencing and mapping 1 11328646
2025 Phenotypic variation in a family with GABRG2-related epilepsy caused by a novel missense variant. Seizure 0 40811894
2025 Mass Spectrometry Imaging Reveals the Distribution of a GABRG2 Targeting Antisense Oligonucleotide and Its Functional Effect in Rat Brain. ACS chemical neuroscience 0 41031595
2025 Beyond Impaired GABAergic Signaling: Inflammation and Metabolic Dysfunction in Genetic Epilepsy Induced by GABRG2 Mutation. Molecular neurobiology 0 41193790
2025 Early neurological symptoms and epilepsy outcomes in individuals with the recurrent GABRG2 p.(Ala106Thr) gain-of-function variant: Structural and phenotypic insights. Epilepsia 0 41351427
2025 Increased excitability of layer 5 neocortical pyramidal neurons and its contribution to seizure activity in Gabrg2 gene-deficient mice. iScience 0 41537003
2024 Genetic predisposition of suicidal behavior: variants in GRIN2B, GABRG2, and ODC1 genes in attempted and completed suicide in two Balkan populations. European archives of psychiatry and clinical neuroscience 0 39297975
2023 Association between GABRG2 Gene Single Nucleotide Polymorphisms and Susceptibility to Ischemic Stroke in a Chinese Population. Journal of integrative neuroscience 0 38176934
2022 The likelihood approach for potential role of "GABRG2 (C588T, C315T) gene polymorphisms" on the poor response to carbamazepine therapy in Pakhtun population of Pakistan. Medicine 0 36221407