Alternative titles; symbols
HGNC Approved Gene Symbol: GABRA1
Cytogenetic location: 5q34 Genomic coordinates (GRCh38): 5:161,847,191-161,899,971 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q34 | {Epilepsy, childhood absence, susceptibility to, 4} | 611136 | 3 | |
| {Epilepsy, juvenile myoclonic, susceptibility to, 5} | 611136 | 3 | ||
| Developmental and epileptic encephalopathy 19 | 615744 | Autosomal dominant | 3 |
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. Functional GABA-A receptors appear to be composed of 5 homologous, variable subunits arranged to form a central channel that conducts chloride ions through the cell membrane. Each subunit consists of a long, variable extracellular region, 4 transmembrane domains, and a variable cytoplasmic region between the third and fourth transmembrane domains. The subunits have been divided into different classes based on amino acid sequence homology, with 70 to 80% identity within a class, and 30 to 50% identity between classes (summary by Glatt et al., 1997).
GABA also acts through metabotropic GABA-B receptors (see 603540).
Garrett et al. (1988) isolated a cDNA clone of an alpha subunit of the human GABA-A receptor. The 1,055-bp GABRA1 clone contained an open reading frame and 260 nucleotides in the 5-prime noncoding region. The 351-amino acid sequence shows 97% homology with its bovine counterpart. Hybridization of the clone to Northern blots showed an RNA doublet in human cortex and in rat whole brain, cortex, hippocampus, midbrain, olfactory bulb, and cerebellum.
By in situ hybridization, Buckle et al. (1989) mapped 2 of the isoforms of the alpha subunit, GABRA1 and GABRA2 (137140), to 5q34-q35 and 4p13-p12, respectively. The gene for a beta subunit (GABRB1; 137190) also was mapped to 4p13-p12, where it may be located in tandem to the GABRA2 gene.
By linkage analysis using a highly polymorphic (CA)n repeat within the GABRA1 gene, Johnson et al. (1992) refined the assignment of the gene on distal 5q.
Russek (1999) determined that GABRA1 is a member of a gene cluster spanning approximately 480 kb of chromosome 5q34. The order of the genes is GABRB2 (600232)--GABRA6 (137143)--GABRA1--GABRG2 (137164).
By study of segregation in intersubspecies backcrosses, Keir et al. (1991) demonstrated that the mouse Gabra1 gene is on chromosome 11 between Il3 (147740) and Rel (164910).
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 glu137 and his141 and beta-3 glu182. The characteristically low zinc sensitivity of GABA-A receptors containing the gamma-2 (137164) subunit results from disruption of 2 of the 3 sites after subunit assembly.
Kash et al. (2003) showed that the optimal gating in the GABA-A receptor is dependent on electrostatic interactions between the negatively charged asp57 and asp149 residues in extracellular loops 2 and 7, and the positively charged lys279 residue in the transmembrane 2-3 linker region of the alpha-1 subunit. During gating, asp149 and lys279 seem to move closer to one another, providing a potential mechanism for the coupling of ligand binding to opening of the ion channel.
In an investigation of how neurosteroids interact with the GABA(A) receptor, Hosie et al. (2006) identified 2 discrete binding sites in the receptor's transmembrane domains that mediate the potentiating and direct activation effects of neurosteroids. They potentiate GABA responses from a cavity formed by the alpha subunit transmembrane domains, whereas direct receptor activation is initiated by interfacial residues between alpha and beta subunits and is enhanced by steroid binding to the potentiation site. Thus, significant receptor activation by neurosteroids relies on occupancy of both the activation and potentiation sites.
GABRA1 is phosphorylated and functionally maintained by the glycolytic enzyme GAPDH (138400), suggesting a functional link between regional cerebral glucose metabolism and GABAergic currents since the mechanism depends on locally produced glycolytic ATP and GAPDH activity. Laschet et al. (2007) found that cortical tissue isolated from epileptic patients, mostly with temporal lobe epilepsy (see ETL2; 608096), had decreased phosphorylation of the GABRA1 subunit compared to tissue from nonepileptic controls. There was no apparent difference in subunit composition between the 2 groups, suggesting a deficiency in endogenous phosphorylation. Patch-clamp studies on isolated neurons showed increased functional lability of GABAergic currents in epileptic tissue compared to normal controls.
Andang et al. (2008) demonstrated that autocrine/paracrine gamma-aminobutyric acid signaling by means of GABA-A receptors negatively controls embryonic stem (ES) cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth, and proliferation in the boundary-cap stem cell niche, resulting in an attenuation of neuronal progeny from this stem cell niche. Activation of GABA-A receptors leads to hyperpolarization, increased cell volume, and accumulation of stem cells in S phase, thereby causing a rapid decrease in cell proliferation. GABA-A receptors signal through S-phase checkpoint kinases of the phosphatidylinositol-3-OH kinase-related kinase family and the histone variant H2AX (601772). This signaling pathway critically regulates proliferation independently of differentiation, apoptosis, and overt damage to DNA. Andang et al. (2008) concluded that their results indicated the presence of a fundamentally different mechanism of proliferation control in these stem cells, in comparison with most somatic cells, involving proteins in the DNA damage checkpoint pathway.
Tan et al. (2010) showed that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) receptors in nearby interneurons. Such disinhibition, which relies on alpha-1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Tan et al. (2010) concluded that, taken together, their data provide evidence that benzodiazepines share defining pharmacologic features of addictive drugs through cell type-specific expression of alpha-1-containing GABA(A) receptors in the ventral tegmental area. The data also suggested that subunit-selective benzodiazepines sparing alpha-1 may be devoid of addiction liability.
Idiopathic Generalized Epilepsy
Cossette et al. (2002) studied a French Canadian family in which all affected family members with epilepsy, in an autosomal dominant pedigree pattern, had a similar phenotype that fulfilled the criteria for juvenile myoclonic epilepsy (EJM5; see 611136). The only exception was an individual in the most recent of 4 affected generations who had an earlier onset of disease but clinical features that were otherwise indistinguishable from those of other members in the family. A genome scan provided evidence of linkage to 5q34, with a maximum lod score of 3.1 at theta = 0 for marker D5S414. The fine mapping showed that the candidate region included a cluster of GABA-A receptor subunits. Screening for mutations in these GABA receptor genes revealed an ala322-to-asp amino acid substitution (137160.0001) in all 8 of the affected members available for study and in none of the unaffected members of the family.
In a German boy with childhood absence epilepsy (ECA4; see 611136), Maljevic et al. (2006) identified a de novo heterozygous 1-bp deletion in the GABRA1 gene (137160.0002). The finding, together with that of Cossette et al. (2002), supported the hypothesis that these classic idiopathic generalized epilepsy phenotypes share a common genetic background.
In affected members of 2 unrelated French Canadian families with idiopathic generalized epilepsy-13 (EIG13; 611136), Lachance-Touchette et al. (2011) identified 2 different heterozygous mutations in the GABRA1 gene (137160.0006 and 137160.0007, respectively). In vitro studies showed that the mutations reduced surface expression of the proteins and altered neurotransmitter effectiveness, resulting in a detrimental effect on inhibitory control of neuronal circuits.
Developmental and Epileptic Encephalopathy 19
In a 2-year-old girl with developmental and epileptic encephalopathy-19 (DEE19; 615744), Carvill et al. (2014) identified a de novo heterozygous missense mutation in the GABRA1 gene (G251S; 137160.0003). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar phenotype identified 3 additional probands with de novo heterozygous missense GABRA1 mutations (R112Q, 137160.0004 and K306T, 137160.0005). Carvill et al. (2014) suggested that the seizures resulted from impaired functioning of GABA inhibition in the brain. The phenotype in all patients was reminiscent of Dravet syndrome (DRVT; 607208).
In a 13-year-old boy with DEE19, Steudle et al. (2020) identified a de novo heterozygous missense mutation (A332V; 137160.0007) in the GABRA1 gene. The mutation was found by whole-exome sequencing. In vitro studies in HEK293 cells showed that the mutation led to normal protein expression, receptor assembly, and cellular localization. Functional studies showed that the mutation resulted in increased receptor affinity for diazepam, an abnormal GABA dose response, and abnormal receptor desensitization, which was faster compared to the wildtype receptor. Steudle et al. (2020) concluded that these combined effects on GABA-A-containing receptors may underlie a broad range of adaptive cellular responses. The patient had his first seizure at age 2.5 months and was diagnosed with epilepsy with complex focal seizures, severe developmental retardation, and optic atrophy at age 18 months.
Rudolph et al. (1999) introduced a histidine-to-arginine point mutation at codon 101 (H101R) of the murine alpha-1 GABA-A receptor. Alpha-1 H101R mice showed no overt distinctive phenotype and bred normally. Immunoblotting confirmed that the mutant alpha-1 subunit and other major GABA-A receptor subunits were expressed in the alpha-1 H101R mice at normal levels. The immunohistochemical distribution of these subunits in mutant mice was indistinguishable from that of wildtype. The alpha-1 subunit gene is expressed mainly in cortical areas and thalamus and is rendered insensitive to allosteric modulation by benzodiazepine-site ligands in mutant mice, while regulation by GABA is preserved. Alpha-1 H101R mice failed to show the sedative, amnesic, and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing, and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA-A receptors found in the limbic system (alpha-2; alpha-5, 137142), in monoaminergic neurons (alpha-3, 305660), and in motoneurons (alpha-2, alpha-5). Thus, benzodiazepine-induced behavioral responses are regulated by specific GABA-A receptor subtypes that contribute to distinct neuronal circuits.
Fagiolini et al. (2004) used a mouse knockin mutation to GABA-A receptor alpha subunits that rendered individual GABA-A receptors insensitive to diazepam to show that a particular inhibitory network controls expression of the critical period. Only alpha-1-containing circuits drove cortical plasticity, whereas alpha-2-enriched connections separately regulated neuronal firing. Fagiolini et al. (2004) suggested that this dissociation carries implications for models of brain development and the safe design of benzodiazepines for use in infants.
Kralic et al. (2005) generated Gabra1 -/- mice and observed postural and kinetic tremor and motor incoordination characteristic of essential tremor disease (see 190300). Drugs used to treat essential tremor patients were efficacious in reducing tremor in Gabra1-null mice, as were several candidate drugs. Electrophysiologic studies revealed that cerebellar Purkinje cells in Gabra1-null mice had a profound loss of all responses to synaptic or exogenous GABA, but there were no differences in abundance, gross morphology, or spontaneous synaptic activity.
Arain et al. (2012) obtained Gabra1 -/- and Gabra1 +/- mice at the expected mendelian ratios, but mutant mice showed strain- and sex-dependent reductions in postnatal viability and in severity of abnormal neurologic activity. Gabra1 +/- mice exhibited increased spontaneous spike-wave discharges that were sometimes associated with behavior arrest. Treatment with ethosuximide significantly reduced the incidence of spike-wave discharges, suggesting that Gabra1 mutant mice suffered absence-like seizures.
In a French Canadian family with juvenile myoclonic epilepsy (see 611136) in 4 generations in an autosomal dominant pedigree pattern, Cossette et al. (2002) demonstrated that the phenotype mapped to 5q in a region where genes encoding GABA-A receptor subunits are located. A mutation screen showed an ala322-to-asp (A322D) mutation resulting from a C-to-A substitution changing GCC to GAC in the GABRA1 gene. In vitro functional expression studies in HEK293 cells showed that the mutation caused a substantial reduction in GABA-activated currents, suggesting a loss of function.
Bradley et al. (2008) found that transfection of the A322D mutation into HEK293 cells resulted in decreased or absent surface expression of GABRA1 and GABRB2 (600232), as well as significant decrease in total expression of the mutant receptor compared to control. The reduction in total mutant GABA-receptor expression was due to enhanced degradation by both the ubiquitin-proteasome system and lysosomal degradation. In addition, there was evidence of increased endocytosis of those mutant receptors that escaped the intracellular degradation process and were inserted into the plasma membrane.
Ding et al. (2010) previously showed that the A322D mutation, which occurs in M3 transmembrane domain, caused the GABRA1 protein to misfold and be degraded. The A322D-mutant subunit was expressed at substantially lower levels than wildtype, and GABA-A receptors that incorporate that mutant subunit have altered electrophysiologic properties. The A322D mutation resulted in a heterozygous loss of function. In their present study, the authors showed that residual nondegraded mutant A322D reduced the surface expression of GABA-A receptors by associating with wildtype subunits within the endoplasmic reticulum and preventing them from trafficking to the cell surface. In vitro cellular studies indicated that the mutant A322D subunit reduced surface expression of alpha-3 (GABRA3; 305660)-containing receptors by a greater amount than alpha-1-containing receptors, thus altering cell surface GABA-A receptor composition and likely contributing to cortical excitability. When transfected into cultured cortical neurons, the mutant A322D subunit altered the time course of miniature inhibitory postsynaptic current kinetics and reduced miniature inhibitory postsynaptic current amplitudes. Ding et al. (2010) concluded that, in addition to causing a heterozygous loss of function, the A322D mutation also elicited a modest dominant-negative effect that likely contributed to the epilepsy phenotype.
In a German boy with childhood absence epilepsy (ECA4; see 611136), Maljevic et al. (2006) identified a de novo heterozygous 1-bp deletion (975delC) in the GABRA1 gene, resulting in a frameshift and premature termination of the protein at codon 328 within the third transmembrane domain. Both unaffected parents and an unaffected brother carried 2 wildtype alleles. The mutation was absent in 292 ethnically matched controls. Functional expression studies in HEK293 cells showed that the mutant protein had no channel current and that the mutant subunit was retained in the cytoplasm and was not integrated into the plasma membrane. When mutant and wildtype subunits were cotransfected, no dominant-negative effect was observed.
In a 2-year-old girl with developmental and epileptic encephalopathy-19 (DEE19; 615744), Carvill et al. (2014) identified a de novo heterozygous c.751G-A transition in the GABRA1 gene, resulting in a gly251-to-ser (G251S) substitution. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project database. In vitro functional expression studies in Xenopus oocytes showed that the G251S mutant protein caused a 2.6-fold reduction in the amplitude of GABA-induced currents, as well as a 5-fold decrease in GABA sensitivity. Carvill et al. (2014) suggested that the seizures resulted from impaired functioning of GABA inhibition in the brain. The patient had onset of hemiclonic seizures at age 8 months and later developed focal dyscognitive seizures, status epilepticus, and tonic-clonic seizures. She had mild intellectual delay, but normal EEG and MRI. The phenotype was consistent with a clinical diagnosis of Dravet syndrome.
In 2 unrelated patients (T16706 and T23532) with developmental and epileptic encephalopathy-19 (DEE19; 615744), Carvill et al. (2014) identified a heterozygous c.335G-A transition in the GABRA1 gene, resulting in an arg112-to-gln (R112Q) substitution at a highly conserved residue. The mutation was confirmed to occur de novo in 1 patient; parental DNA was not available from the second patient. Functional studies of the variant were not performed. The patients had onset of febrile seizures at 11 months of age. The phenotype was consistent with a clinical diagnosis of Dravet syndrome.
In an 18-month-old boy (patient Co05) with developmental and epileptic encephalopathy-19 (DEE19; 615744), Carvill et al. (2014) identified a de novo heterozygous c.917A-C transversion in the GABRA1 gene, resulting in a lys306-to-thr (K306T) substitution at a highly conserved residue. Functional studies of the variant were not performed. The patient had onset of seizures with status epilepticus at 8 months of age. The phenotype was consistent with a clinical diagnosis of Dravet syndrome.
In 3 affected members of a French Canadian family with idiopathic generalized epilepsy-13 (EIG13; 611136), Lachance-Touchette et al. (2011) identified a heterozygous 25-bp insertion close to intron 10 of the GABRA1 gene, resulting in a complex rearrangement of the transcript. RT-PCR analysis of patient cells showed that this insertion resulted in a splicing defect with retention of intron 10, a deletion of the fourth transmembrane domain, and the insertion of 18 amino acids and a premature stop codon (Lys353delins18Ter). An unaffected obligate carrier in the family also carried this mutation, which was not present in 109 healthy controls. In vitro expression studies showed that the mutant protein was retained in the endoplasmic reticulum and did not localize to the plasma membrane. Functional studies showed that the mutant subunit had no current in response to GABA, suggesting a detrimental effect on inhibitory control of neuronal circuits. The patients had late-onset afebrile, generalized tonic-clonic seizures, as well as photosensitivity.
In 4 affected members of a French Canadian family with idiopathic generalized epilepsy-13 (EIG13; 611136), Lachance-Touchette et al. (2011) identified a heterozygous G-to-A transition in the GABRA1 gene, resulting in an asp219-to-asn (D219N) substitution. The mutation was not found in 109 healthy controls. In vitro expression studies showed that the mutant protein was partially retained in the endoplasmic reticulum and had about 50% decreased expression at the plasma membrane. Electrophysiologic studies showed that the mutation caused decreased current amplitude in response to GABA compared to wildtype and that it altered receptor gating kinetics, including faster desensitization. The patients had febrile seizures with or without generalized tonic-clonic and absence seizures.
In a 13-year-old boy with developmental and epileptic encephalopathy-19 (DEE19; 615744), Steudle et al. (2020) identified a de novo heterozygous c.995C-T transition (c.995C-T, NM_000806.5) in exon 10 of the GABRA1 gene, resulting in an ala332-to-val (A332V) substitution at a conserved residue in the TM3 domain near the subunit interface of the protein. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. In vitro studies in HEK293 cells showed that the mutation led to a normal level of protein expression, receptor assembly, and cellular localization, but resulted in increased receptor affinity for diazepam and an abnormal GABA dose response. The patient had his first seizure at age 2.5 months and was diagnosed with epilepsy with complex focal seizures, severe developmental retardation, and optic atrophy at age 18 months.
Andang, M., Hjerling-Leffler, J., Moliner, A., Lundgren, T. K., Castelo-Branco, G., Nanou, E., Pozas, E., Bryja, V., Halliez, S., Nishimaru, H., Wilbertz, J., Arenas, E., Koltzenburg, M., Charnay, P., El Manira, A., Ibanez, C. F., Ernfors, P. Histone H2AX-dependent GABA(A) receptor regulation of stem cell proliferation. Nature 451: 460-464, 2008. [PubMed: 18185516] [Full Text: https://doi.org/10.1038/nature06488]
Arain, F. M., Boyd, K. L., Gallagher, M. J. Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABA(A) receptor alpha-I subunit. Epilepsia 53: e161-e165, 2012. Note: Electronic Article. [PubMed: 22812724] [Full Text: https://doi.org/10.1111/j.1528-1167.2012.03596.x]
Bradley, C. A., Taghibiglou, C., Collingridge, G. L., Wang, Y. T. Mechanisms involved in the reduction of GABA-A receptor alpha-1-subunit expression caused by the epilepsy mutation A322D in the trafficking-competent receptor. J. Biol. Chem. 283: 22043-220050, 2008. [PubMed: 18534981] [Full Text: https://doi.org/10.1074/jbc.M801708200]
Buckle, V. J., Fujita, N., Bateson, A. N., Darlison, M. G., Barnard, E. A. Localization of human GABA-A receptor subunit genes to chromosomes 4 and 5. (Abstract) Cytogenet. Cell Genet. 51: 972 only, 1989.
Carvill, G. L., Weckhuysen, S., McMahon, J. M., Hartmann, C., Moller, R. S., Hjalgrim, H., Cook, J., Geraghty, E., O'Roak, B. J., Petrou, S., Clarke, A., Gill, D., and 14 others. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 82: 1245-1253, 2014. [PubMed: 24623842] [Full Text: https://doi.org/10.1212/WNL.0000000000000291]
Cossette, P., Liu, L., Brisebois, K., Dong, H., Lortie, A., Vanasse, M., Saint-Hilaire, J.-M., Carmant, L., Verner, A., Lu, W.-Y., Wang, Y. T., Rouleau, G. A. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genet. 31: 184-189, 2002. [PubMed: 11992121] [Full Text: https://doi.org/10.1038/ng885]
Ding, L., Feng, H.-J., Macdonald, R. L., Botzolakis, E. J., Hu, N., Gallagher, M. J. GABA(A) receptor alpha-1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J. Biol. Chem. 285: 26390-26405, 2010. [PubMed: 20551311] [Full Text: https://doi.org/10.1074/jbc.M110.142299]
Fagiolini, M., Fritschy, J.-M., Low, K., Mohler, H., Rudolph, U., Hensch, T. K. Specific GABA(A) circuits for visual cortical plasticity. Science 303: 1681-1683, 2004. [PubMed: 15017002] [Full Text: https://doi.org/10.1126/science.1091032]
Garrett, K. M., Duman, R. S., Saito, N., Blume, A. J., Vitek, M. P., Tallman, J. F. Isolation of a cDNA clone for the alpha subunit of the human GABA-A receptor. Biochem. Biophys. Res. Commun. 156: 1039-1045, 1988. [PubMed: 2847710] [Full Text: https://doi.org/10.1016/s0006-291x(88)80949-5]
Glatt, K., Glatt, H., Lalande, M. Structure and organization of GABRB3 and GABRA5. Genomics 41: 63-69, 1997. Note: Erratum: Genomics 44: 155 only, 1997. [PubMed: 9126483] [Full Text: https://doi.org/10.1006/geno.1997.4639]
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]
Hosie, A. M., Wilkins, M. E., da Silva, H. M. A., Smart, T. G. Endogenous neurosteroids regulate GABA(A) receptors through two discrete transmembrane sites. Nature 444: 486-489, 2006. [PubMed: 17108970] [Full Text: https://doi.org/10.1038/nature05324]
Johnson, K. J., Sander, T., Hicks, A. A., van Marle, A., Janz, D., Mullan, M. J., Riley, B. P., Darlison, M. G. Confirmation of the localization of the human GABA-A receptor alpha-1-subunit gene (GABRA1) to distal 5q by linkage analysis. Genomics 14: 745-748, 1992. [PubMed: 1330891] [Full Text: https://doi.org/10.1016/s0888-7543(05)80178-8]
Kash, T. L., Jenkins, A., Kelley, J. C., Trudell, J. R., Harrison, N. L. Coupling of agonist binding to channel gating in the GABA-A receptor. Nature 421: 272-275, 2003. [PubMed: 12529644] [Full Text: https://doi.org/10.1038/nature01280]
Keir, W. J., Kozak, C. A., Chakraborti, A., Deitrich, R. A., Sikela, J. M. The cDNA sequence and chromosomal location of the murine GABA(A) alpha-1 receptor gene. Genomics 9: 390-395, 1991. [PubMed: 1848528] [Full Text: https://doi.org/10.1016/0888-7543(91)90272-g]
Kralic, J. E., Criswell, H. E., Osterman, J. L., O'Buckley, T. K., Wilkie, M. E., Matthews, D. B., Hamre, K., Breese, G. R., Homanics, G. E., Morrow, A. L. Genetic essential tremor in gamma-aminobutyric acid-A receptor alpha-1 subunit knockout mice. J. Clin. Invest. 115: 774-779, 2005. [PubMed: 15765150] [Full Text: https://doi.org/10.1172/JCI23625]
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]
Laschet, J. J., Kurcewicz, I., Minier, F., Trottier, S., Khallou-Laschet, J., Louvel, J., Gigout, S., Turak, B., Biraben, A., Scarabin, J.-M., Devaux, B., Chauvel, P., Pumain, R. Dysfunction of GABA-A receptor glycolysis-dependent modulation in human partial epilepsy. Proc. Nat. Acad. Sci. 104: 3472-3477, 2007. [PubMed: 17360668] [Full Text: https://doi.org/10.1073/pnas.0606451104]
Maljevic, S., Krampfl, K., Cobilanschi, J., Tilgen, N., Beyer, S., Weber, Y. G., Schlesinger, F., Ursu, D., Melzer, W., Cossette, P., Bufler, J., Lerche, H., Heils, A. A mutation in the GABA-A receptor alpha-1-subunit is associated with absence epilepsy. Ann. Neurol. 59: 983-987, 2006. [PubMed: 16718694] [Full Text: https://doi.org/10.1002/ana.20874]
Rudolph, U., Crestani, F., Benke, D., Brunig, I., Benson, J. A., Fritschy, J.-M., Martin, J. R., Bluethmann, H., Mohler, H. Benzodiazepine actions mediated by specific gamma-aminobutyric acid-A receptor subtypes. Nature 401: 796-800, 1999. Note: Erratum: Nature 404: 629 only, 2000. [PubMed: 10548105] [Full Text: https://doi.org/10.1038/44579]
Russek, S. J. Evolution of GABA-A receptor diversity in the human genome. Gene 227: 213-222, 1999. [PubMed: 10023064] [Full Text: https://doi.org/10.1016/s0378-1119(98)00594-0]
Steudle, F., Rehman, S., Bampali, K., Simeone, X., Rona, Z., Hauser, E., Schmidt, W. M., Scholze, P., Ernst, M. A novel de novo variant of GABRA1 causes increased sensitivity for GABA in vitro. Sci. Rep. 10: 2379, 2020. Note: Electronic Article. [PubMed: 32047208] [Full Text: https://doi.org/10.1038/s41598-020-59323-6]
Tan, K. R., Brown, M., Labouebe, G., Yvon, C., Creton, C., Fritschy, J.-M., Rudolph, U., Luscher, C. Neural bases for addictive properties of benzodiazepines. Nature 463: 769-774, 2010. [PubMed: 20148031] [Full Text: https://doi.org/10.1038/nature08758]