Alternative titles; symbols
HGNC Approved Gene Symbol: GABRD
Cytogenetic location: 1p36.33 Genomic coordinates (GRCh38): 1:2,019,345-2,030,758 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.33 | {Epilepsy, idiopathic generalized, 10} | 613060 | Autosomal dominant | 3 |
| {Epilepsy, juvenile myoclonic, susceptibility to} | 613060 | Autosomal dominant | 3 | |
| {Generalized epilepsy with febrile seizures plus, type 5, susceptibility to} | 613060 | Autosomal dominant | 3 |
The GABRD gene encodes a subunit of the ligand-gated chloride channel for gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain (Windpassinger et al., 2002).
Windpassinger et al. (2002) isolated cDNAs corresponding to the human GABRD gene from a human fetal brain cDNA library. They identified 3 cDNA variants, which they called 1A, 1B, and 1C, that differed in the 5-prime region and that each spliced onto exon 2. The deduced 452-amino acid protein (variant 1A) contains a neurotransmitter-gated ion-channel ligand binding domain as well as a neurotransmitter-gated ion-channel transmembrane region. The GABRD variant 1A exhibited 93.8% identity to rat and 93.6% identity to mouse proteins. The 1B and 1C variants encode proteins of 428 and 466 amino acids, respectively. Northern blot analysis detected a 2.0-kb transcript in cerebellum, cerebral cortex, medulla, occipital lobe, frontal lobe, temporal lobe, and putamen with lower expression in kidney.
Sommer et al. (1990) isolated the murine gene for the GABAA receptor delta subunit and characterized it by high resolution mapping and DNA sequencing.
Windpassinger et al. (2002) determined that the 1A and 1B variants of human GABRD contain 9 exons and the 1C variant contains 8 exons.
Sommer et al. (1990) determined that the GABRD gene contains 9 exons and spans approximately 13 kb. The gene structure was similar to that seen in members of the nicotinic acetylcholine receptor family.
Many neurons receive a continuous, or 'tonic,' synaptic input, which increases their membrane conductance and so modifies the spatial and temporal integration of excitatory signals. In cerebellar granule cells, although the frequency of inhibitory synaptic currents is relatively low, the spillover of synaptically released GABA gives rise to a persistent conductance mediated by the GABA-A receptor that also modifies the excitability of granule cells. Brickley et al. (2001) showed that this tonic conductance was absent in granule cells from mice lacking the alpha-6 (137143) and delta subunits of the GABA-A receptor. The response of these granule cells to excitatory synaptic input remained unaltered, owing to an increase in a 'leak' conductance, which was present at rest, with properties characteristic of the 2-pore-domain potassium channel TASK1 (603220). Brickley et al. (2001) concluded that their results highlight the importance of tonic inhibition mediated by GABA-A receptors, loss of which triggers a form of homeostatic plasticity leading to a change in the magnitude of a voltage-independent potassium conductance that maintains normal neuronal behavior.
Stell et al. (2003) found that both dentate gyrus and cerebellar granule cells in mice displayed concentration-dependent enhancement of the tonic conductance in response to the naturally occurring neurosteroid 3-alpha-21, hydroxy-5-alpha-pregnan-20-one (THDOC). The neurosteroid-induced augmentation of this tonic conductance decreased neuronal excitability. In contrast, similar cells from Gabrd-null mice showed either much reduced or absent tonic GABA conductance. The results suggested that delta subunit-containing GABA-A receptors are a preferential target for neuroactive steroids, and that GABA tonic inhibitory conductance can be modulated by physiologic concentrations of neurosteroids.
Maguire et al. (2005) found enhanced expression of the Gabrd receptor in the late diestrus, high-progesterone phase of the ovarian cycle in mice. The enhanced expression increased tonic inhibition and reduced neuronal excitability during late diestrus as compared to estrus, as reflected by decreased seizure susceptibility and decreased anxiety. The findings were consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of GABRD subunits in individuals with catamenial epilepsy or premenstrual dysphoric disorder.
Olah et al. (2009) showed that individual neurogliaform cells release enough GABA for volume transmission within the axonal cloud and, thus, that neurogliaform cells do not require synapses to produce inhibitory responses in the overwhelming majority of nearby neurons. Neurogliaform cells suppress connections between other neurons acting on presynaptic terminals that do not receive synapses at all in the cerebral cortex. They also reach extrasynaptic, delta-subunit-containing GABA-A receptors responsible for tonic inhibition. Olah et al. (2009) showed that GABA-A-delta receptors are localized to neurogliaform cells preferentially among cortical interneurons. Neurosteroids, which are modulators of GABA-A-delta receptors, alter unitary GABA-mediated effects between neurogliaform cells. In contrast to the specifically placed synapses formed by other interneurons, the output of nonsteroid-sensitive neurogliaform cells represents the ultimate form of the lack of spatial specificity in GABA-mediated systems, leading to long-lasting network hyperpolarization combined with widespread suppression of communication in the local circuit.
In pubertal mice, Shen et al. (2010) found that expression of inhibitory alpha-4-beta-delta-GABA-A receptors, composed of the alpha-4 GABA-A receptor (GABRA4; 137141), the beta-2 GABA-A receptor (GABRB2; 600232), and GABRD, increases perisynaptic to excitatory synapses in the CA1 hippocampus. Shunting inhibition via these receptors reduced N-methyl-D-aspartate receptor (see 138249) activation, impairing induction of long-term potentiation (LTP). Pubertal mice also failed to learn a hippocampal, LTP-dependent spatial task that was easily acquired by delta-null mice. However, the stress steroid THP (3-alpha-OH-5-alpha(beta)-pregnan-20-one), which reduces tonic inhibition at puberty, facilitated learning. Shen et al. (2010) concluded that the emergence of alpha-4-beta-delta GABA-A receptors at puberty impairs learning, an effect that can be reversed by stress steroid.
Sommer et al. (1990) mapped the human GABRD gene to chromosome 1p by hybridization to a panel of human-rodent somatic cell hybrid DNAs. By radiation hybrid analysis, Emberger et al. (2000) localized the GABRD gene to 1p36.3.
By FISH, Windpassinger et al. (2002) mapped the GABRD gene to 1p36.33, flanked by PRKCZ (176982) and KIAA1751. As the GABRD gene lies within the critical region of gene loss for the 1p36 gene deletion syndrome (607872), Windpassinger et al. (2002) suggested that its absence may contribute to the neurologic phenotype in that disorder.
Dibbens et al. (2004) identified a heterozygous mutation in the GABRD gene (137163.0001) in 2 affected members of a family with GEFS+ (see 613060). The unaffected mother also carried the mutation, suggesting that it represents a susceptibility allele.
Dibbens et al. (2004) also identified a different heterozygous polymorphism (R220H; 137163.0002) in 8.3% of patients with idiopathic generalized epilepsy (EIG10; 613060), 3.1% with GEFS+, and 4.2% of control individuals. One individual with juvenile myoclonic epilepsy (EJM7; see 613060) was homozygous for the mutation. Both of these alterations resulted in decreased GABA-A receptor current amplitudes. Since GABA-A receptors mediate neuronal inhibition, the authors hypothesized that reduced receptor current associated with both variants may be associated with increased neuronal excitability and may contribute to the common generalized epilepsies.
In contrast to the findings of Dibbens et al. (2004), Lenzen et al. (2005) found no association between the R220H variant and idiopathic generalized epilepsy or juvenile myoclonic epilepsy among 562 German patients and 664 controls.
Jones et al. (1997) created mice deficient in the alpha-6 subunit (GABRA6; 137143) of the GABA-A receptor by targeted disruption. In alpha-6 -/- granule cells, the delta subunit was selectively degraded, as demonstrated by immunoprecipitation, immunocytochemistry, and immunoblot analysis for delta subunit-specific antibodies. The delta subunit mRNA was present at wildtype levels in the mutant granule cells, indicating a posttranslational loss of the delta subunit. Jones et al. (1997) concluded that their results provide genetic evidence for a specific association between the alpha-6 and delta subunits. Despite deficiency of alpha-6 and delta subunits, these mice showed no behavioral abnormalities.
Neurosteroids are neuroactive steroids produced in the brain that are believed to regulate anxiety, stress, and neuronal excitability by modulating GABA-A receptors (Olsen and Sapp, 1995). Mihalek et al. (1999) found that Gabrd-null mice showed selective attenuation of responses to neuroactive steroids, but not to other modulatory drugs, suggesting that the delta subunit has a role in modulating behavioral responses to endogenous neurosteroids.
The activation of peri- or extrasynaptic GABA receptors by ambient GABA causes a persistently active, or tonic, inhibitory current. Extrasynaptic GABA-A receptors in thalamocortical neurons contain the delta subunit. In an established rat model of absence epilepsy with spontaneous spike-wave discharges (see, e.g., ECA1; 600131) called GAERS (genetic absence epilepsy rat from Strasbourg), Cope et al. (2009) found increased tonic current amplitude at thalamocortical GABA-A receptors beginning at postnatal day 17 compared to controls. Similarly increased tonic GABA-A receptor activation was observed in other mouse strains of absence epilepsy, including stargazer and lethargic, but not in tottering mice. In addition, pharmacologic spike-wave discharge-inducing agents were found to enhance the tonic GABA-A receptor current in thalamocortical neurons. Increased tonic inhibition was due to compromised GABA uptake by the GABA transporter GAT1 (SLC6A1; 137165) in the thalamus. Blockade of GAT1 in normal animals induced absence-like seizures. Finally, mice without thalamic GABA-A receptors were resistant to pharmacologically induced seizures. Overall, these results showed that enhanced extrasynaptic GABA-A receptor activation in the thalamus may underlie absence seizures.
Clarkson et al. (2010) showed that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA-A receptors and is caused by an impairment in GABA transporter function. To counteract the heightened inhibition, Clarkson et al. (2010) administered in vivo a benzodiazepine inverse agonist specific for alpha-5-subunit (GABRA5; 137142)-containing extrasynaptic GABA-A receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of alpha-5- or delta-subunit-containing GABA-A receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA-A receptor function.
In a small family with generalized epilepsy with febrile seizures plus (GEFS+; see 604233), Dibbens et al. (2004) found a heterozygous 530A-C transversion in exon 5 of the GABRD gene resulting in a glu177-to-ala substitution (E177A) in the N-terminal extracellular domain of the protein. The unaffected mother also carried the mutation, suggesting that it represents a susceptibility allele. Receptors heterozygous and homozygous for E177A had a significantly reduced maximal current compared with wildtype receptors, although this variant did not significantly alter agonist binding.
Dibbens et al. (2004) identified a heterozygous 659G-A transition polymorphism in exon 6 of the GABRD gene, resulting in an arg220-to-his (R220H) substitution in the N-terminal extracellular domain of the protein, that was associated with different forms of epilepsy. The polymorphism was identified in 8.3% of patients with idiopathic generalized epilepsy (EIG10; 613060), 3.1% with GEFS+ (see 613060), and 4.2% of control individuals. One individual with juvenile myoclonic epilepsy (EJM7; see 613060) was homozygous for the mutation. Receptors heterozygous for the mutation had significantly decreased maximal current compared with wildtype receptors. Receptors homozygous for R220H showed a greater reduction in current amplitude than that recorded in heterozygotes.
In contrast to the findings of Dibbens et al. (2004), Lenzen et al. (2005) found no association between the R220H variant and idiopathic generalized epilepsy or juvenile myoclonic epilepsy among 562 German patients and 664 controls.
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Clarkson, A. N., Huang, B. S., MacIsaac, S. E., Mody, I., Carmichael, S. T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468: 305-309, 2010. [PubMed: 21048709] [Full Text: https://doi.org/10.1038/nature09511]
Cope, D. W., Di Giovanni, G., Fyson, S. J., Orban, G., Errington, A. C., Lorincz, M. L., Gould, T. M., Carter, D. A., Crunelli, V. Enhanced tonic GABA-A inhibition in typical absence epilepsy. Nature Med. 15: 1392-1398, 2009. [PubMed: 19966779] [Full Text: https://doi.org/10.1038/nm.2058]
Dibbens, L. M., Feng, H.-J., Richards, M. C., Harkin, L. A., Hodgson, B. L., Scott, D., Jenkins, M., Petrou, S., Sutherland, G. R., Scheffer, I. E., Berkovic, S. F., Macdonald, R. L., Mulley, J. C. GABRD encoding a protein for extra- or peri-synaptic GABA-A receptors is a susceptibility locus for generalized epilepsies. Hum. Molec. Genet. 13: 1315-1319, 2004. [PubMed: 15115768] [Full Text: https://doi.org/10.1093/hmg/ddh146]
Emberger, W., Windpassinger, C., Petek, E., Kroisel, P. M., Wagner, K. Assignment of the human GABAA receptor delta-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping. Cytogenet. Cell Genet. 89: 281-282, 2000. [PubMed: 10965146] [Full Text: https://doi.org/10.1159/000015636]
Jones, A., Korpi, E. R., McKernan, R. M., Pelz, R., Nusser, Z., Makela, R., Mellor, J. R., Pollard, S., Bahn, S., Stephenson, F. A., Randall, A. D., Sieghart, W., Somogyi, P., Smith, A. J., Wisden, W. Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J. Neurosci. 17: 1350-1362, 1997. [PubMed: 9006978] [Full Text: https://doi.org/10.1523/JNEUROSCI.17-04-01350.1997]
Lenzen, K. P., Heils, A., Lorenz, S., Hempelmann, A., Sander, T. Association analysis of the arg220-to-his variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Res. 65: 53-57, 2005. [PubMed: 16023832] [Full Text: https://doi.org/10.1016/j.eplepsyres.2005.04.005]
Maguire, J. L., Stell, B. M., Rafizadeh, M., Mody, I. Ovarian cycle-linked changes in GABA-A receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nature Neurosci. 8: 797-804, 2005. [PubMed: 15895085] [Full Text: https://doi.org/10.1038/nn1469]
Mihalek, R. M., Banerjee, P. K., Korpi, E. R., Quinlan, J. J., Firestone, L. L., Mi, Z.-P., Lagenaur, C., Tretter, V., Sieghart, W., Anagnostaras, S. G., Sage, J. R., Fanselow, M. S., Guidotti, A., Spigelman, I., Li, Z., DeLorey, T. M., Olsen, R. W., Homanics, G. E. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc. Nat. Acad. Sci. 96: 12905-12910, 1999. [PubMed: 10536021] [Full Text: https://doi.org/10.1073/pnas.96.22.12905]
Olah, S., Fule, M., Komlosi, G., Varga, C., Baldi, R., Barzo, P., Tamas, G. Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 461: 1278-1281, 2009. [PubMed: 19865171] [Full Text: https://doi.org/10.1038/nature08503]
Olsen, R. W., Sapp, D. W. Neuroactive steroid modulation of GABAA receptors. Adv. Biochem. Psychopharmacol. 48: 57-74, 1995. [PubMed: 7653326]
Shen, H., Sabaliauskas, N., Sherpa, A., Fenton, A. A., Stelzer, A., Aoki, C., Smith, S. S. A critical role for alpha-4-beta-delta GABA-A receptors in shaping learning deficits at puberty in mice. Science 327: 1515-1518, 2010. [PubMed: 20299596] [Full Text: https://doi.org/10.1126/science.1184245]
Sommer, B., Poustka, A., Spurr, N. K., Seeburg, P. H. The murine GABAA receptor delta-subunit gene: structure and assignment to human chromosome 1. DNA Cell Biol. 9: 561-568, 1990. [PubMed: 2176788] [Full Text: https://doi.org/10.1089/dna.1990.9.561]
Stell, B. M., Brickley, S. G., Tang, C. Y., Farrant, M., Mody, I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta-subunit-containing GABA-A receptors. Proc. Nat. Acad. Sci. 100: 14439-14444, 2003. [PubMed: 14623958] [Full Text: https://doi.org/10.1073/pnas.2435457100]
Windpassinger, C., Kroisel, P. M., Wagner, K., Petek, E. The human gamma-aminobutyric acid A receptor delta (GABRD) gene: molecular characterisation and tissue-specific expression. Gene 292: 25-31, 2002. [PubMed: 12119096] [Full Text: https://doi.org/10.1016/s0378-1119(02)00649-2]