Alternative titles; symbols
HGNC Approved Gene Symbol: GABRA3
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:152,166,234-152,451,315 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features | 301091 | X-linked | 3 |
Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRA3 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).
Using a bovine GABA-A alpha-3 subunit cDNA probe to screen a human fetal brain cDNA library, Hadingham et al. (1993) cloned cDNAs corresponding to the human alpha-3 subunit gene. The human GABRA3 predicted 492-amino acid protein is 97% identical to the bovine alpha-3 subunit.
Using GABA-A receptor point-mutated knockin mice in which specific GABA-A receptor subtypes had been selectively rendered insensitive to benzodiazepine-site ligands, Knabl et al. (2008) demonstrated that pronounced analgesia can be achieved by specifically targeting spinal GABA-A receptors containing the alpha-2 (GABRA2; 137140) and/or alpha-3 subunits. Knabl et al. (2008) showed that their selective activation by the nonsedative (alpha-1-sparing) benzodiazepine-site ligand L-838,417 is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment, and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional MRI in rats. Knabl et al. (2008) suggested that their results provided a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.
Barnard et al. (1989) mapped an isoform of the alpha subunit of the GABA-A receptor, Gabra3, to proximal mouse X chromosome by pedigree breakpoint analysis in a mouse interspecies backcross. They found the gene to lie distal to Hprt (308000) and proximal to Gdx (312070). They predicted that the corresponding gene in man would be found to lie close to the colorblindness loci (see, e.g., 303800). See also Derry and Barnard (1991).
Buckle et al. (1989) mapped the human GABRA3 gene to Xq28 by in situ hybridization. Bell et al. (1989) found physical linkage of GABRA3 and DXS374 by using pulsed field gel electrophoresis. They had previously demonstrated that DXS374 is genetically and physically located within the Xq28 region about 15 cM distal to the fragile X syndrome mutation, but tightly linked to the DXS52 and F8C (300841) loci. Bell et al. (1989) also cited Southern blot data from somatic cell hybrids indicating location in Xq28.
In a physical mapping of the terminal 12 Mb of the long arm of the X chromosome, Poustka et al. (1991) localized the GABRA3 gene to a site about 4 Mb proximal to the telomere; F8 and G6PD (305900) are distal to it. See also GABRE (300093).
In affected members of 2 unrelated families (families 1 and 2) with X-linked epilepsy-2 with or without impaired intellectual development and dysmorphic features (EPILX2; 301091), Niturad et al. (2017) identified hemizygous or heterozygous missense mutations in the GABRA3 gene (305660.0001-305660.0002). Another boy (family 3) carried a heterozygous intragenic microduplication (305660.0004) that was inherited from his unaffected mother. The mutations, which were found by exome sequencing, segregated with the disorder in the families, although there was variable expressivity and incomplete penetrance. Two additional girls with the disorder carried a de novo heterozygous missense variant (Y474C; 305660.0003). Most of the mutations were absent from the gnomAD database; 1 variant was present once in gnomAD. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutations resulted in a significant reduction in GABA-evoked current amplitudes compared to controls, consistent with a loss of function. X-inactivation studies, performed in several individuals, did not show significant skewing patterns. Niturad et al. (2017) identified 2 additional variants in the GABRA3 gene in 2 more families (families 6 and 7), but these variants did not segregate with the disorder in the families. The proband in family 6 was a boy with speech delay and autism spectrum disorder, but no seizures, associated with a hemizygous G47R variant. He had a similarly affected brother who did not carry the variant. The proband in family 7 was a girl with onset of seizures at 8 years of age associated with a heterozygous T336M variant that was inherited from her unaffected mother. Her sister and father both had seizures, but did not carry the GABRA3 variant.
Syed et al. (2020) used an HEK293 cell-neuron coculture expression system to analyze the effect of 4 GABRA3 variants on inhibitory postsynaptic currents (IPSCs) mediated by GABA-A receptors. T166M (305660.0002) and Y474C (305660.0003) decreased the IPSC decay rate, whereas T336M accelerated the IPSC decay rate compared to controls. Q242L (305660.0001) had no effect on the IPSC parameters. Midazolam partially restored the T336M abnormalities. In contrast, the variants did not affect average peak amplitudes or 10 to 90% rise time of synaptic currents. Immunostaining demonstrated that all mutations caused decreased GABRA3 cell surface expression (40 to 75% decrease) compared to wildtype.
In 2 affected males and 2 affected females in a 2-generation family of Israeli Jewish origin (family 1) with X-linked epilepsy-2 with impaired intellectual development and dysmorphic features (EPILX2; 301091), Niturad et al. (2017) identified a hemizygous or heterozygous c.725A-T transversion (c.725A-T, NM_000808) in the GABRA3 gene, resulting in a gln242-to-leu (Q242L) substitution at a highly conserved residue in the N terminus. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was absent from the ExAC and gnomAD databases. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation resulted in an 85% reduction in GABA-evoked current amplitudes compared to controls, consistent with a loss of function. The male mutation carriers had early-onset pharmacoresistant epileptic encephalopathy with developmental delay and severely impaired intellectual development. The female mutation carriers had a less severe phenotype with mild epilepsy and learning disabilities. All patients had dysmorphic features, including cleft palate, microretrognathia, and nystagmus.
In 4 males and 4 females from a 2-generation Polish family (family 2) with X-linked epilepsy-2 with or without impaired intellectual development and dysmorphic features (EPILX2; 301091), Niturad et al. (2017) identified a heterozygous c.497C-T transition (c.497C-T, NM_000808) in the GABRA3 gene, resulting in a thr166-to-met (T166M) substitution at a highly conserved residue in the N terminus. The mutation, which was found by X-chromosome exome sequencing of 480 families with X-linked intellectual disability, segregated with the disorder in the family, although there was 1 unaffected male carrier, indicating incomplete penetrance. The variant was found once in the gnomAD database (frequency of 5.6 x 10(-6)). In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation resulted in a 75% reduction in GABA-evoked current amplitudes compared to controls, consistent with a loss of function. There was intrafamilial phenotypic variability: 4 mutation carriers (2 females and 2 males) had absence seizures and 7 mutation carriers (4 females and 3 males) had mildly impaired intellectual development with speech delay and learning disabilities. Common dysmorphic features included micrognathia, tall stature, sloping shoulders, high-arched palate, and nystagmus. One male mutation carrier was unaffected at age 25 years, indicating incomplete penetrance.
In 2 unrelated girls (families 4 and 5) with X-linked epilepsy-2 with impaired intellectual development and dysmorphic features (EPILX2; 301091), Niturad et al. (2017) identified a de novo heterozygous c.1421A-G transition (c.1421A-G, NM_000808) in the GABRA3 gene, resulting in a tyr474-to-cys (Y474C) substitution at a highly conserved residue in transmembrane segment 4. The mutation, which was found by exome sequencing, was not present in the ExAC or gnomAD databases. In vitro electrophysiologic studies in Xenopus oocytes showed that the mutation resulted in a 68% reduction in GABA-evoked current amplitudes compared to controls, consistent with a loss of function. The girls had onset of seizures in the first years of life and also demonstrated mildly impaired intellectual development and behavioral abnormalities. One had microtia and strabismus.
In a 9-year-old Italian boy (family 3) with X-linked epilepsy-2 without dysmorphic features (EPILX2; 301091), Niturad et al. (2017) identified a heterozygous intragenic microduplication encompassing exons 1 through 3 of the GABRA3 gene. The microduplication was inherited from his unaffected mother. Analysis of patient fibroblasts showed that the duplication disrupted expression of the GABRA3 gene, consistent with a loss of function. The patient had early-onset mostly refractory seizures and borderline intellectual functioning.
Barnard, P. J., Derry, J. M. J., Ryder-Cook, A. S., Barnard, E. A. Localization of the GABA(A) receptor alpha-3 subunit gene on the mouse X chromosome. (Abstract) Cytogenet. Cell Genet. 51: 958 only, 1989.
Bell, M. V., Bloomfield, J., McKinley, M., Patterson, M. N., Darlison, M. G., Barnard, E. A., Davies, K. E. Physical linkage of a GABA-A receptor subunit gene to the DXS374 locus in human Xq28. Am. J. Hum. Genet. 45: 883-888, 1989. [PubMed: 2574000]
Buckle, V. J., Fujita, N., Ryder-Cook, A. S., Derry, J. M. J., Barnard, P. J., Lebo, R. V., Schofield, P. R., Seeburg, P. H., Bateson, A. N., Darlison, M. G., Barnard, E. A. Chromosomal localization of GABA-A receptor subunit genes: relationship to human genetic disease. Neuron 3: 647-654, 1989. [PubMed: 2561974] [Full Text: https://doi.org/10.1016/0896-6273(89)90275-4]
Derry, J. M. J., Barnard, P. J. Mapping of the glycine receptor alpha-2-subunit gene and the GABA-A alpha-3-subunit gene on the mouse X chromosome. Genomics 10: 593-597, 1991. [PubMed: 1679744] [Full Text: https://doi.org/10.1016/0888-7543(91)90441-g]
Hadingham, K. L., Wingrove, P., Le Bourdelles, B., Palmer, K. J., Ragan, C. I., Whiting, P. J. Cloning of cDNA sequences encoding human alpha-2 and alpha-3 gamma-aminobutyric acid-A receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha-1-, alpha-2-, alpha-3-, and alpha-5-containing human gamma-aminobutyric acid-a receptors. Molec. Pharm. 43: 970-975, 1993. [PubMed: 8391122]
Knabl, J., Witschi, R., Hosl, K., Reinold, H., Zeilhofer, U. B., Ahmadi, S., Brockhaus, J., Sergejeva, M., Hess, A., Brune, K., Fritschy, J.-M., Rudolph, U., Mohler, H., Zeilhofer, H. U. Reversal of pathological pain through specific spinal GABA(A) receptor subtypes. Nature 451: 330-334, 2008. [PubMed: 18202657] [Full Text: https://doi.org/10.1038/nature06493]
Niturad, C. E., Lev, D., Kalscheuer, V. M., Charzewska, A., Schubert, J., Lerman-Sagie, T., Kroes, H. Y., Oegema, R., Traverso, M., Specchio, N., Lassota, M., Chelly, J., and 28 others. Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain 140: 2879-2894, 2017. [PubMed: 29053855] [Full Text: https://doi.org/10.1093/brain/awx236]
Poustka, A., Dietrich, A., Langenstein, G., Toniolo, D., Warren, S. T., Lehrach, H. Physical map of human Xq27-qter: localizing the region of the fragile X mutation. Proc. Nat. Acad. Sci. 88: 8302-8306, 1991. [PubMed: 1924290] [Full Text: https://doi.org/10.1073/pnas.88.19.8302]
Syed, P., Durisic, N., Harvey, R. J., Sah, P., Lynch, J. W. Effects of GABA(A) receptor alpha-3 subunit epilepsy mutations on inhibitory synaptic signaling. Front. Molec. Neurosci. 13: 602559, 2020. [PubMed: 33328885] [Full Text: https://doi.org/10.3389/fnmol.2020.602559]
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]