Alternative titles; symbols
HGNC Approved Gene Symbol: GABRG2
Cytogenetic location: 5q34 Genomic coordinates (GRCh38): 5:162,067,465-162,155,539 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q34 | Developmental and epileptic encephalopathy 74 | 618396 | Autosomal dominant | 3 |
| Febrile seizures, familial, 8 | 607681 | Autosomal dominant | 3 | |
| Generalized epilepsy with febrile seizures plus, type 3 | 607681 | Autosomal dominant | 3 |
Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRG2 is a member of the GABA-A receptor gene family of heteromeric pentameric ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the mammalian brain, acts. GABA-A receptors are the site of action of a number of important pharmacologic agents including barbiturates, benzodiazepines, and ethanol (summary by Whiting et al., 1999).
For additional general information about the GABA-A receptor gene family, see GABRA1 (137160).
Pritchett et al. (1989) cloned a cDNA encoding a novel GABA-A receptor subunit, which they termed gamma-2 (GABRG2), that shares approximately 40% sequence identity with the alpha and beta subunits. The deduced 468-amino acid protein has a signal sequence, a disulfide-bonded beta-structural loop, and 3 potential N-glycosylation sites in its extracellular N-terminal half, and 4 transmembrane segments in its C-terminal half. A putative site site for tyrosine phosphorylation is located between transmembrane domains 3 and 4. Pritchett et al. (1989) found that GABRG2 mRNA was prominently localized in neuronal subpopulations throughout the central nervous system.
Whiting et al. (1990) cloned 2 splice variants of the bovine gamma-2 subunit, which they called gamma-2L and gamma-2S, that differed in the presence or absence of a 24-bp insertion, respectively. PCR analysis detected 2 gamma-2 isoforms in human and rat brain. The deduced gamma-2L protein contains an 8-amino acid insertion in a large cytoplasmic loop between transmembrane domains 3 and 4 compared with gamma-2S. The insertion introduced a functional site for PKC (see 176960)-dependent phosphorylation.
Jin et al. (2004) identified a third splice variant of human gamma-2, which they called gamma-2XL, that resulted in insertion of 40 additional amino acids in the long N-terminal extracellular domain. Quantitative PCR analysis detected expression of gamma-2XL and gamma-2S in adult and fetal total brain and in all adult brain regions examined. In all tissues, expression of gamma-2S predominated.
Harkin et al. (2002) noted that the GABRG2 gene contains 9 exons.
By examining a GABRG2 splice variant, Jin et al. (2004) identified an additional exon, between exons 5 and 6, that originated from an Alu element.
Warrington et al. (1992) mapped the GABRG2 gene to the immediate vicinity of the GABRA1 gene (137160) on the long arm of chromosome 5 by analysis of radiation hybrids. The 2 genes were found to be 6 cR apart on the radiation hybrid map; they were found to be present in a 450-kb YAC, giving a distance correlation of 75 kb per cR (Wilcox et al., 1992). (The cR(6500) value is the measure of distance in radiation hybrids and is equivalent to the cM value used as the measure of genetic distance in linkage mapping. It is necessary to note the dosage used, which in this case was 6,500 rads (Cox et al., 1990).) Using panels of chromosome-specific natural deletion hybrids, Wilcox et al. (1992) further localized the gamma-1 gene (GABRG1; 137166) to 4p14-q21.1 and the gamma-2 gene to 5q31.1-q33.2.
Gross (2017) mapped the GABRG2 gene to chromosome 5q34 based on an alignment of the GABRG2 sequence (GenBank BC059389) with the genomic sequence (GRCh38).
Buckwalter et al. (1992) demonstrated that the Gabrg2 gene is located on mouse chromosome 11.
Using a whole cell patch-clamp technique, Pritchett et al. (1989) found that coexpression of all 3 human GABA subunits (i.e., alpha, beta, and gamma-2), but not any 2 subunits alone, promoted large inward GABA-induced currents. All 3 subunits were also required to form a high-affinity benzodiazepine-binding site.
Kucken et al. (2000) identified benzodiazepine-binding site residues in the GABRG2 protein.
Liu et al. (2000) demonstrated that GABA-A ligand-gated channels complex selectively with dopamine D5 receptors (126453) through the direct binding of the D5 carboxy-terminal domain with the second intracellular loop of the GABA-A gamma-2 (short) receptor subunit. This physical association enables mutual inhibitory functional interactions between these receptor systems. Liu et al. (2000) concluded that the data highlight a previously unknown signal transduction mechanism whereby subtype-selective G protein-coupled receptors dynamically regulate synaptic strength independently of classically defined second-messenger systems, and suggest a possible framework in which to view these receptor systems in the maintenance of psychomotor disease states, particularly schizophrenia (181500).
Zinc ions regulate GABA-A receptors by inhibiting receptor function via an allosteric mechanism that is critically dependent on the receptor subunit composition. Hosie et al. (2003) used molecular modeling to identify 3 discrete sites that mediate zinc inhibition: one is located within the ion channel and comprises subunit beta-3 (137192) his267 and glu270, and the other 2 are on the external amino-terminal face of the receptor and require the coordination of subunit alpha-1 (137160) glu137 and his141 and beta-3 glu182. The characteristically low zinc sensitivity of GABA-A receptors containing the gamma-2 subunit results from disruption of 2 of the 3 sites after subunit assembly.
Using cotransfected HEK293 cells, Jin et al. (2004) found that a combination of alpha and beta subunits was sufficient to create GABA-binding sites, but that inclusion of gamma-2S was required to form benzodiazepine-binding sites. Inclusion of gamma-2XL did not reconstitute benzodiazepine-binding sites due to failure of gamma-2XL to target the alpha and beta subunits to the cell surface. Jin et al. (2004) found that the 40-amino acid insertion in gamma-2XL separated a conserved ser171-tyr172 motif that was required for cell surface expression of the GABA-A receptor.
Familial Febrile Seizures 8
It had been suggested for many decades that disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid is involved in epilepsy (Olsen et al., 1999). In 13 members of a 3-generation French family with a variable seizure phenotype most consistent with familial febrile seizures-8 (FEB8; 607681), Baulac et al. (2001) identified a heterozygous missense mutation in the GABRG2 gene (K289M; 137164.0001). Eight members had only febrile seizures, 3 had febrile and afebrile seizures, and 2 had afebrile seizures.
In affected members of a large 4-generation Australian family with FEB8, Wallace et al. (2001) identified a heterozygous missense mutation in the GABRG2 gene (R43Q; 137164.0002). Some of the mutation carriers also had childhood absence seizures (ECA2; see 607681), and the authors pointed out that the 2 syndromes, febrile seizures (FS) and childhood absence epilepsy (CAE), have different ages of onset, and that the physiology of absences and seizures is distinct. This suggested that the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes. Wallace et al. (2001) also stated that febrile seizures occur in about 3% of children and that 10 to 15% of persons with childhood absence epilepsy have febrile seizures before the onset of epilepsy. Febrile seizures are a common seizure type in relatives of childhood absence epilepsy probands (Italian League Against Epilepsy Genetic Collaborative Group, 1993).
Developmental and Epileptic Encephalopathy 74
In 8 unrelated children with developmental and epileptic encephalopathy-74 (DEE74; 618396), Shen et al. (2017) identified 6 different de novo heterozygous missense mutations in the GABRG2 gene (see, e.g., 137164.0006; 137164.0008-137164.0009). The mutations, which were found by exome or genome sequencing or by sequencing of an epilepsy candidate gene panel, were confirmed by Sanger sequencing. The mutations occurred throughout the gene in different structural domains. Accordingly, in vitro functional expression studies showed variable effects: the variants decreased GABA-evoked currents to different extents and some altered zinc sensitivity. Some mutations caused reduced potency to GABA stimulation, whereas others caused kinetic abnormalities of the channel. Mutant proteins were stable in transfected HEK293 cells, but showed variably decreased surface and intracellular expression, suggesting impaired trafficking and abnormal retention of some of the mutants in the endoplasmic reticulum. For example, the R323Q mutation (137164.0006), which occurred at an invariant residue in the pore-forming M2 domain, decreased channel current by about 50%, increased zinc inhibition by about 25%, had reduced surface expression (about 50%), and had decreased response to GABA compared to wildtype. The A106T variant (137164.0008), which occurred in the N-terminal region, decreased channel currents by about 30%, had mildly decreased surface expression (about 75%), slowed deactivation of the channel, and had decreased response to GABA compared to wildtype. The findings expanded the epileptic phenotype associated with mutations in the GABRG2 gene.
Tan et al. (2007) found that mice homozygous for the Gabrg2 R43Q mutation (137164.0002) were rarely viable. Those that survived the perinatal period showed altered gait, severe tremor, and death by postnatal day 19. Heterozygous mice showed behavioral arrest associated with 6 to 7 Hz spike-and-wave discharges, which could be blocked by ethosuximide, a first-line treatment for absence epilepsy in humans. Seizures in mice showed an abrupt onset at around age 20 days, which corresponds to the childhood nature of this disease in humans. Brain tissue from R43Q-mutant mice showed impaired inhibitory activity specifically in the somatosensory cortex, as well as decreased expression of the mutant protein. There was no change in alpha-1 subunit expression, ruling out a dominant-negative effect. Tan et al. (2007) hypothesized that a subtle reduction in cortical inhibition, resulting from haploinsufficiency, underlies childhood absence epilepsy seen in humans with the R43Q mutation.
Chiu et al. (2008) generated a conditional mouse model allowing forebrain-specific switch of the R43Q mutation at specific times during development. Mice with activation of the hypomorphic gln43 allele during development showed increased seizure susceptibility compared to mice that expressed the mutation only after postnatal day 21. These results indicated that mutation-mediated dysfunction in channel activity during development is a critical determinant of seizure susceptibility in later life, and suggested that the mutation impacts neural network stability and perhaps structure.
Phillips et al. (2014) found that 50-day-old mice carrying the Gabrg2 R43Q mutation (i.e., after the onset of spontaneous spike-and-wave discharges and seizures) had reduced expression of Hcn1 (602780) in hippocampal CA1 neurons and reduced Hcn1-dependent hyperpolarization-activated currents compared with controls. In contrast, no change in Hcn1 expression was observed in R43Q mice at an age prior to onset of seizures or in a spike-and-wave discharge-free model where the R43Q mutation was crossed into a seizure-resistant genetic background.
In 13 members of a 3-generation French family with a variable seizure phenotype most consistent with familial febrile seizures-8 (FEB8; 607681), Baulac et al. (2001) identified a heterozygous A-to-T transversion in exon 8 of the GABRG2 gene, resulting in a lys289-to-met (K289M) substitution at a conserved residue in the extracellular loop between transmembrane segments M2 and M3. Eight members had only febrile seizures, 3 had febrile and afebrile seizures, and 2 had afebrile seizures. In addition, there were 3 unaffected mutation carriers and 1 patient with afebrile seizures who did not carry the mutation. Analysis of the mutated and wildtype alleles in Xenopus oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents.
By in vitro functional expression assays in HEK293T cells, Kang et al. (2006) demonstrated that brief increases in temperature resulted in impaired trafficking, accelerated endocytosis, and decreased surface expression of heterozygous K289M mutant GABA-alpha receptors. The findings provided an explanation for the triggering of seizures by fever in patients with the mutation.
In affected members of a large 4-generation Australian family with febrile seizures-8 (FEB8; 607681), Wallace et al. (2001) identified a heterozygous c.245G-A transition in the GABRG2 cDNA leading to an arg43-to-gln (R43Q) substitution in the mature GABRG2 protein. The mutation abolished in vitro sensitivity to diazepam, raising the possibility that endozepines, in fact, exist and have a physiologic role in preventing seizures. Wallace et al. (2001) noted that some of the mutation carriers also had childhood absence seizures (CAE; ECA2, see 607681), and pointed out that the 2 syndromes, FS and CAE, have different ages of onset, and that the physiology of absences and seizures is distinct. This suggested that the mutation has age-dependent effects on different neuronal networks that influence the expression of these clinically distinct, but genetically related, epilepsy phenotypes.
Sancar and Czajkowski (2004) found that the R43Q substitution in the gamma-2 subunit impaired cell surface expression of the subunit in transfected HEK293 cells. The substitution had no effect on GABA binding or GABA agonist-induced currents by alpha-1/beta-2 GABA-A receptors. However, lack of functional gamma-2 subunits in the complex abolished benzodiazepine binding and the ability of benzodiazepine to potentiate GABA agonist-induced currents.
By in vitro functional expression assays in HEK293T cells, Kang et al. (2006) demonstrated that brief increases in temperature resulted in impaired trafficking, accelerated endocytosis, and decreased surface expression of heterozygous R43Q mutant GABA-alpha receptors. The findings provided an explanation for the triggering of seizures by fever in patients with the mutation.
Using coimmunoprecipitation analysis, Frugier et al. (2007) found that the R43Q substitution did not alter interaction of the gamma-2 subunit with alpha-3 or beta-3 subunits. However, the stoichiometry of the interactions was different than wildtype, and mutant gamma-2 did not colocalize at the cell surface with alpha-3 or beta-3 in transfected rat hippocampal neurons or transfected COS-7 cells. Mutation analysis revealed that R43 is a major determinant to drive cell surface targeting of the gamma-2 subunit.
Chaumont et al. (2013) found that R43Q gamma-2 subunits were retained within the endoplasmic reticulum of transfected COS-7 cells and rat hippocampal neurons. They also found mutant gamma-2 subunits in GABA-A receptors expressed at the cell surface. However, receptors with R43Q gamma-2 had a shorter residency time at the plasma membrane than their wildtype counterparts and were highly subject to internalization via a clathrin (see 118955)- and dynamin (see 602377)-dependent mechanism. Blockade of endocytosis led to a major increase in surface targeting of R43Q gamma-2. Using molecular modeling, Chaumont et al. (2013) found that R43 in gamma-2 resides at the gamma-2/beta-2 interface in the extracellular domain.
In a mother and son with febrile seizures-8 (FEB8; 607681), Harkin et al. (2002) identified a heterozygous c.1168C-T transition in exon 9 of the GABRG2 gene, resulting in a gln351-to-ter (Q351X) substitution. The truncation mutation occurred in the intracellular loop between the third and fourth transmembrane domains. The mother also had a daughter with the mutation who had a phenotype consistent with severe myoclonic epilepsy of infancy, as well as a son without the mutation who had myoclonic-astatic epilepsy. There was also another family member with febrile seizures who did not carry the mutation. The paternal branch of the family had several individuals with febrile seizures, but genetic studies were not performed. GABA sensitivity in Xenopus oocytes expressing the mutant subunit was completely abolished, and fluorescent microscopy studies showed that receptors containing GFP-labeled mutant protein were retained in the lumen of the endoplasmic reticulum. The family, which had previously been described as 'family G' by Singh et al. (1999), had a complex seizure phenotype from both the maternal and paternal side, but not all affected individuals were studied genetically.
By in vitro functional expression assays in HEK293T cells, Kang et al. (2006) demonstrated that brief increases in temperature resulted in impaired trafficking, accelerated endocytosis, and decreased surface expression of heterozygous Q351X mutant GABA-alpha receptors. The findings provided an explanation for the triggering of seizures by fever in patients with the mutation.
In a father and his 2 children with familial febrile seizures-8 (FEB8; 607681), Kananura et al. (2002) identified a heterozygous T-to-G substitution at the splice donor site of intron 6, predicted to result in exon skipping, premature termination, and a nonfunctional protein. The father had isolated febrile seizures, whereas his 2 children had both febrile seizures and childhood absence epilepsy. The family was part of a cohort of 135 unrelated German patients with idiopathic absence epilepsy who underwent genetic studies.
In 3 affected members of a family with febrile seizures-8 (FEB8; 607681), Audenaert et al. (2006) identified a heterozygous c.529C-G transversion in exon 4 of the GABRG2 gene, resulting in an arg139-to-gly (R139G) substitution in the second benzodiazepine-binding site of the protein. Two affected sibs and their father carried the mutation. The paternal grandfather, who was reportedly unaffected, also carried the mutation, suggesting incomplete penetrance. All patients had normal mental development, and none developed epilepsy later in life. In vitro functional analysis showed that the mutant receptor currents desensitized more rapidly than wildtype and had significantly decreased sensitivity to diazepam. The mutation was not identified in 368 control chromosomes.
Generalized Epilepsy with Febrile Seizures Plus, Type 3
In a 2.5-year-old boy with generalized epilepsy with febrile seizures plus (see 607681), Carvill et al. (2013) identified a de novo heterozygous mutation in the GABRG2 gene, resulting in an arg323-to-gln (R323Q) substitution. The patient had onset of febrile seizures at age 8 months, followed by absence seizures, atonic seizures, myoclonic jerks, and tonic-clonic seizures. EEG was normal and he had normal development. The patient was ascertained from a large cohort of 500 patients with epileptic encephalopathy who underwent candidate gene sequencing; this was the only patient found to carry a GABRG2 mutation.
Developmental and Epileptic Encephalopathy 74
In 2 unrelated girls (patients 5 and 6) with developmental and epileptic encephalopathy-74 (DEE74; 618396), Shen et al. (2017) identified a de novo heterozygous c.968G-A transition in the GABRG2 gene, resulting in an R323Q substitution at a highly conserved residue in the pore-forming M2 domain. In vitro functional expression studies in transfected HEK293 cells showed that the R323Q mutation decreased channel current by about 50%, increased zinc inhibition by about 25%, had reduced surface expression (about 50%), and had decreased response to GABA compared to wildtype. The patients had onset of intractable focal and myoclonic seizures between 10 and 12 months of age.
This variant is classified as a variant of unknown significance because its contribution to idiopathic generalized epilepsy has not been confirmed.
In 9 members of a French Canadian family with idiopathic generalized epilepsy, Lachance-Touchette et al. (2011) identified a heterozygous mutation in the GABRG2 gene, resulting in a pro83-to-ser (P83S) substitution. One unaffected family member also carried the mutation, which was not found in 190 controls. Electrophysiologic studies showed that the currents elicited by GABA at receptors containing the mutant subunit were indistinguishable from wildtype, indicating that the mutant subunit was expressed normally at the plasma membrane. There was also no difference in sensitivity of the mutant receptors to the allosteric regulators zinc and benzodiazepine diazepam compared to wildtype. The patients had a combination of febrile and absence seizures.
In 2 unrelated patients (patients 1 and 2) with developmental and epileptic encephalopathy-74 (DEE74; 618396), Shen et al. (2017) identified a de novo heterozygous c.316G-A transition in the GABRG2 gene, resulting in an ala106-to-thr (A106T) substitution at a nonconserved residue in the N-terminal domain. In vitro functional expression studies in transfected HEK293 cells showed that the mutant protein decreased currents by about 30%, had mildly decreased surface expression (about 75%), slowed deactivation of the channel, and had decreased response to GABA compared to wildtype. The patients had onset of seizures at 1 day and 3 months of life, respectively. Both had severe global developmental delay and were nonverbal.
In a 10-year-old girl (patient 4) with developmental and epileptic encephalopathy-74 (DEE74; 618396), Shen et al. (2017) identified a de novo heterozygous c.844C-T transition in the GABRG2 gene, resulting in a pro282-to-ser (P282S) substitution at a highly conserved residue in transmembrane domain 1 (M1), which delineates the pore region of the channel. In vitro functional expression studies in transfected HEK293 cells showed that the mutant protein decreased currents by about 30%, increased zinc inhibition by about 25%, had mildly decreased surface expression (about 65%) and was retained abnormally in the endoplasmic reticulum, and slowed deactivation of the channel compared to wildtype. The patient had onset of intractable seizures at 1 year of age. She had severe global developmental delay and was nonverbal.
Audenaert, D., Schwartz, E., Claeys, K. G., Claes, L., Deprez, L., Suls, A., Van Dyck, T., Lagae, L., Van Broeckhoven, C., Macdonald, R. L., De Jonghe, P. A novel GABRG2 mutation associated with febrile seizures. Neurology 67: 687-690, 2006. [PubMed: 16924025] [Full Text: https://doi.org/10.1212/01.wnl.0000230145.73496.a2]
Baulac, S., Huberfeld, G., Gourfinkel-An, I., Mitropoulou, G., Beranger, A., Prud'homme, J.-F., Baulac, M., Brice, A., Bruzzone, R., LeGuern, E. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma-2-subunit gene. Nature Genet. 28: 46-48, 2001. [PubMed: 11326274] [Full Text: https://doi.org/10.1038/ng0501-46]
Buckwalter, M. S., Lossie, A. C., Scarlett, L. M., Camper, S. A. Localization of the human chromosome 5q genes Gabra-1, Gabrg-2, I1-4, I1-5, and Irf-1 on mouse chromosome 11. Mammalian Genome 3: 604-607, 1992. [PubMed: 1358285] [Full Text: https://doi.org/10.1007/BF00350629]
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
Chaumont, S., Andre, C., Perrais, D., Boue-Grabot, E., Taly, A., Garret, M. Agonist-dependent endocytosis of gamma-aminobutyric acid type A (GABA-A) receptors revealed by a gamma-2(R43Q) epilepsy mutation. J. Biol. Chem. 288: 28254-28265, 2013. [PubMed: 23935098] [Full Text: https://doi.org/10.1074/jbc.M113.470807]
Chiu, C., Reid, C. A., Tan, H. O., Davies, P. J., Single, F. N., Koukoulas, I., Berkovic, S. F., Tan, S.-S., Sprengel, R., Jones, M. V., Petrou, S. Developmental impact of a familial GABA-A receptor epilepsy mutation. Ann. Neurol. 64: 284-293, 2008. [PubMed: 18825662] [Full Text: https://doi.org/10.1002/ana.21440]
Cox, D. R., Burmeister, M., Price, E. R., Kim, S., Myers, R. M. Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes. Science 250: 245-250, 1990. [PubMed: 2218528] [Full Text: https://doi.org/10.1126/science.2218528]
Frugier, G., Coussen, F., Giraud, M.-F., Odessa, M.-F., Emerit, M. B., Boue-Grabot, E., Garret, M. A gamma-2(R43Q) mutation, linked to epilepsy in humans, alters GABA-A receptor assembly and modifies subunit composition on the cell surface. J. Biol. Chem. 282: 3819-3828, 2007. [PubMed: 17148443] [Full Text: https://doi.org/10.1074/jbc.M608910200]
Gross, M. B. Personal Communication. Baltimore, Md. 8/8/2017.
Harkin, L. A., Bowser, D. N., Dibbens, L. M., Singh, R., Phillips, F., Wallace, R. H., Richards, M. C., Williams, D. A., Mulley, J. C., Berkovic, S. F., Scheffer, I. E., Petrou, S. Truncation of the GABA-A-receptor gamma-2 subunit in a family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 70: 530-536, 2002. [PubMed: 11748509] [Full Text: https://doi.org/10.1086/338710]
Hosie, A. M., Dunne, E. L., Harvey, R. J., Smart, T. G. Zinc-mediated inhibition of GABA-A receptors: discrete binding sites underlie subtype specificity. Nature Neurosci. 6: 362-369, 2003. [PubMed: 12640458] [Full Text: https://doi.org/10.1038/nn1030]
Italian League Against Epilepsy Genetic Collaborative Group. Concordance of clinical forms of epilepsy in families with several affected members. Epilepsia 34: 819-826, 1993. [PubMed: 8404731] [Full Text: https://doi.org/10.1111/j.1528-1157.1993.tb02096.x]
Jin, P., Zhang, J., Rowe-Teeter, C., Yang, J., Stuve, L. L., Fu, G. K. Cloning and characterization of a GABA-A receptor gamma-2 subunit variant. J. Biol. Chem. 279: 1408-1414, 2004. [PubMed: 14593118] [Full Text: https://doi.org/10.1074/jbc.M308656200]
Kananura, C., Haug, K., Sander, T., Runge, U., Gu, W., Hallmann, K., Rebstock, J., Heils, A., Steinlein, O. K. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch. Neurol. 59: 1137-1141, 2002. [PubMed: 12117362] [Full Text: https://doi.org/10.1001/archneur.59.7.1137]
Kang, J.-Q., Shen, W., Macdonald, R. L. Why does fever trigger febrile seizures? GABAA receptor gamma-2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. J. Neurosci. 26: 2590-2597, 2006. [PubMed: 16510738] [Full Text: https://doi.org/10.1523/JNEUROSCI.4243-05.2006]
Kucken, A. M., Wagner, D. A., Ward, P. R., Teissere, J. A., Boileau, A. J., Czajkowski, C. Identification of benzodiazepine binding site residues in the gamma-2 subunit of the gamma-aminobutyric acid(A) receptor. Molec. Pharm. 57: 932-939, 2000. [PubMed: 10779376]
Lachance-Touchette, P., Brown, P., Meloche, C., Kinirons, P., Lapointe, L., Lacasse, H., Lortie, A., Carmant, L., Bedford, F., Bowie, D., Cossette, P. Novel alpha-1 and gamma-2 GABA-A receptor subunit mutations in families with idiopathic generalized epilepsy. Europ. J. Neurosci. 34: 237-249, 2011. [PubMed: 21714819] [Full Text: https://doi.org/10.1111/j.1460-9568.2011.07767.x]
Liu, F., Wan, Q., Pristupa, Z. B., Yu, X.-M., Wang, Y. T., Niznik, H. B. Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors. Nature 403: 274-280, 2000. [PubMed: 10659839] [Full Text: https://doi.org/10.1038/35002014]
Olsen, R. W., DeLorey, T. M., Gordey, M., Kang, M.-H. GABA receptor function and epilepsy. Adv. Neurol. 79: 499-510, 1999. [PubMed: 10514838]
Phillips, A. M., Kim, T., Vargas, E., Petrou, S., Reid, C. A. Spike-and-wave discharge mediated reduction in hippocampal HCN1 channel function associates with learning deficits in a genetic mouse model of epilepsy. Neurobiol. Dis. 64: 30-35, 2014. [PubMed: 24368169] [Full Text: https://doi.org/10.1016/j.nbd.2013.12.007]
Pritchett, D. B., Sontheimer, H., Shivers, B. D., Ymer, S., Kettermann, H., Schofield, P. R., Seeburg, P. H. Importance of a novel GABA(A) receptor subunit for benzodiazepine pharmacology. Nature 338: 582-585, 1989. [PubMed: 2538761] [Full Text: https://doi.org/10.1038/338582a0]
Sancar, F., Czajkowski, C. A GABA-A receptor mutation linked to human epilepsy (gamma-2-R43Q) impairs cell surface expression of alpha-beta-gamma receptors. J. Biol. Chem. 279: 47034-47039, 2004. [PubMed: 15342642] [Full Text: https://doi.org/10.1074/jbc.M403388200]
Shen, D., Hernandez, C. C., Shen, W., Hu, N., Poduri, A., Shiedley, B., Rotenberg, A., Datta, A. N., Leiz, S., Patzer, S., Boor, R., Ramsey, K., Goldberg, E., Helbig, I., Ortiz-Gonzalez, X. R., Lemke, J. R., Marsh, E. D., Macdonald, R. L. De novo GABRG2 mutations associated with epileptic encephalopathies. Brain 140: 49-67, 2017. [PubMed: 27864268] [Full Text: https://doi.org/10.1093/brain/aww272]
Singh, R., Scheffer, I. E., Crossland, K., Berkovic, S. F. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann. Neurol. 45: 75-81, 1999. [PubMed: 9894880] [Full Text: https://doi.org/10.1002/1531-8249(199901)45:1<75::aid-art13>3.0.co;2-w]
Tan, H. O., Reid, C. A., Single, F. N., Davies, P. J., Chiu, C., Murphy, S., Clarke, A. L., Dibbens, L., Krestel, H., Mulley, J. C., Jones, M. V., Seeburg, P. H., Sakmann, B., Berkovic, S. F., Sprengel, R., Petrou, S. Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy. Proc. Nat. Acad. Sci. 104: 17536-17541, 2007. [PubMed: 17947380] [Full Text: https://doi.org/10.1073/pnas.0708440104]
Wallace, R. H., Marini, C., Petrou, S., Harkin, L. A., Bowser, D. N., Panchal, R. G., Williams, D. A., Sutherland, G. R., Mulley, J. C., Scheffer, I. E., Berkovic, S. F. Mutant GABA(A) receptor gamma-2-subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 28: 49-52, 2001. [PubMed: 11326275] [Full Text: https://doi.org/10.1038/ng0501-49]
Warrington, J. A., Bailey, S. K., Armstrong, E., Aprelikova, O., Alitalo, K., Dolganov, G. M., Wilcox, A. S., Sikela, J. M., Wolfe, S. F., Lovett, M., Wasmuth, J. J. A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5. Genomics 13: 803-808, 1992. [PubMed: 1322355] [Full Text: https://doi.org/10.1016/0888-7543(92)90156-m]
Whiting, P. J., Bonnert, T. P., McKernan, R. M., Farrar, S., le Bourdelles, B., Heavens, R. P., Smith, D. W., Hewson, L., Rigby, M. R., Sirinathsinghji, D. J. S., Thompson, S. A., Wafford, K. A. Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann. N.Y. Acad. Sci. 868: 645-653, 1999. [PubMed: 10414349] [Full Text: https://doi.org/10.1111/j.1749-6632.1999.tb11341.x]
Whiting, P., McKernan, R. M., Iversen, L. L. Another mechanism for creating diversity in gamma-aminobutyrate type A receptors: RNA splicing directs expression of two forms of gamma-2 subunit, one of which contains a protein kinase C phosphorylation site. Proc. Nat. Acad. Sci. 87: 9966-9970, 1990. [PubMed: 1702226] [Full Text: https://doi.org/10.1073/pnas.87.24.9966]
Wilcox, A. S., Warrington, J. A., Gardiner, K., Berger, R., Whiting, P., Altherr, M. R., Wasmuth, J. J., Patterson, D., Sikela, J. M. Human chromosomal localization of genes encoding the gamma-1 and gamma-2 subunits of the gamma-aminobutyric acid receptor indicates members of this gene family are often clustered in the genome. Proc. Nat. Acad. Sci. 89: 5857-5861, 1992. [PubMed: 1321425] [Full Text: https://doi.org/10.1073/pnas.89.13.5857]