Alternative titles; symbols
HGNC Approved Gene Symbol: GABRA5
Cytogenetic location: 15q12 Genomic coordinates (GRCh38): 15:26,866,719-26,949,208 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q12 | Developmental and epileptic encephalopathy 79 | 618559 | Autosomal dominant | 3 |
Gamma-aminobutyric acid (GABA) receptors are a family of proteins involved in the GABAergic neurotransmission of the mammalian central nervous system. GABRA5 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).
Wingrove et al. (1991) reported the cloning and expression of a cDNA corresponding to GABRA5. Overall, the human protein has 94% amino acid sequence identity with the rat alpha-5 subunit, with most of the differences occurring in the signal peptide and the putative large cytoplasmic loop domain. Human alpha-5 has 57% sequence identity with human alpha-1, again most of the amino acid differences being in the signal peptide and the putative large cytoplasmic loop domain. The expression studies indicated that GABA-A receptor subtypes containing alpha-5, like their rat equivalent, have a unique benzodiazepine pharmacology.
By fluorescence in situ hybridization, Knoll et al. (1992) mapped the GABRA5 gene to chromosome 15q11-q13.
Russek and Farb (1994) stated that the gene encoding the gamma-3 form of the GABA-A receptor (GABRG3; 600233) is located on 15q11-q13 in a cluster with GABRA5 and GABRB3 (137192).
Glatt et al. (1997) reported that the GABRA5 gene contains 11 exons spanning 86 kb. There are 3 alternative first exons, a noncoding second exon, and a translation initiation site in exon 3.
Using coding SNPs within the GABA receptor gene cluster on chromosome 15q11-q13, Hogart et al. (2007) demonstrated that the GABRG3, GABRB3, and GABRA5 genes were biallelically expressed in the cerebral cortex of 21 postmortem human brain samples.
Glatt et al. (1992) demonstrated a dinucleotide repeat polymorphism at the GABRA5 locus. A single maternal allele was observed in classic Prader-Willi syndrome (176270) cases and a single paternal allele in classic Angelman syndrome (105830) cases in which deletions had previously been demonstrated.
Ritchie et al. (1998) reported a partial duplication of GABRA5 within the imprinted 15q11-q13 region. The duplicated locus mapped to the pericentromeric region of 15q, proximal to the large deletions associated Angelman and Prader-Willi syndromes. They also observed variation in the number of copies of this locus in different individuals, indicating that the duplication is part of the variable repeat. Investigation of the duplication in individuals with a normal karyotype revealed between 1 and 4 copies of the repeat on each chromosome 15, whereas from 8 to 20 copies were found in individuals possessing a cytogenetically detectable elongation of the 15q region. The variable region is roughly 1 Mb long and contains 2 other nonprocessed duplications, the immunoglobulin heavy chain (IgH) D segment gene (IGHD; 147170) on 14q and the NF1 gene (613113) on chromosome 17. One unit of the pericentromeric repeat is thus composed of duplications of genes from different chromosomal regions. Ritchie et al. (1998) also found replication asynchrony across the GABRA5 duplication, suggesting for the first time that the imprinted part of chromosome 15q extends proximal of the region commonly deleted in Angelman and Prader-Willi syndromes.
Papadimitriou et al. (1998) found an association between a 282-bp CA repeat in the gene encoding GABRA5 and bipolar affective disorder in 48 unrelated southern Greek patients but not in 50 healthy individuals drawn from the same population. No association was seen in another sample of 40 unipolar patients in the same specimen. Even though the authors applied the Bonferroni correction for the total numbers of genes tested, they cautioned that the level of significance in association studies is still a matter of debate. They believed that the 282-bp allele is unlikely to have functional significance but does not represent stratification in their sample. Rather, they considered that the allele may be in linkage disequilibrium with a functional mutation elsewhere in the GABRA5 gene or another gene in close proximity.
Developmental and Epileptic Encephalopathy 79
In a 2-year-old boy (patient 1), born of unrelated parents, with developmental and epileptic encephalopathy-79 (DEE79; 618559), Butler et al. (2018) identified a de novo heterozygous missense mutation in the GABRA5 gene (V294L; 137142.0001). The mutation, which was found by trio-based whole-genome sequencing and confirmed by Sanger sequencing, occurred in the pore-forming transmembrane domain and was not found in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the mutant subunit was expressed at the surface and incorporated into the channel, but the mutant channel was 10 times more sensitive to GABA compared to wildtype. This increased sensitization resulted in increased receptor desensitization to GABA, with a reduced maximal GABA-evoked current and impaired capacity to pass GABAergic chloride current.
In 2 unrelated children (patients 1 and 2) with DEE79, Hernandez et al. (2019) identified de novo heterozygous mutations in the GABRA5 gene (V294F, 137142.0002 and S413F, 137142.0003). The mutations, which were found by next-generation sequencing of a targeted gene panel of 480 candidate genes in a cohort of 1,969 patients with a similar phenotype, were confirmed by Sanger sequencing and not present in the gnomAD database. In vitro functional expression studies of the mutations in rat primary hippocampal neurons and HEK293 cells showed variable abnormalities, including decreased expression of the mutant V294F protein at dendritic GABAergic synapses compared to wildtype; both variants resulted in decreased GABA-evoked current amplitudes compared to wildtype.
In mice, Clarkson et al. (2010) showed that after a stroke, 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-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 (GABRD; 137163)-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 2-year-old boy (patient 1), born of unrelated parents, with developmental and epileptic encephalopathy-79 (DEE79; 618559), Butler et al. (2018) identified a de novo heterozygous c.880G-C transversion (c.880G-C, NM_000810) in the GABRA5 gene, resulting in a val294-to-leu (V294L) substitution at a highly conserved residue in the pore-forming M2 transmembrane domain. The mutation, which was found by trio-based whole-genome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro functional expression studies in HEK293 cells showed that the mutant subunit was expressed at the surface and incorporated into the channel, but the mutant channel was 10 times more sensitive to GABA compared to wildtype. This increased sensitization resulted in increased receptor desensitization to GABA, with a reduced maximal GABA-evoked current and impaired capacity to pass GABAergic chloride current. The patient had onset of various types of seizures at 4 months of age.
In a 4-year-old boy (patient 1) with developmental and epileptic encephalopathy-79 (DEE79; 618559), Hernandez et al. (2019) identified a de novo heterozygous c.880G-T transversion (c.880G-T, NM_000810.3) in the GABRA5 gene, resulting in a val294-to-phe (V294F) substitution at a conserved residue in the M2 pore domain. The mutation, which was found by next-generation sequencing of a targeted gene panel and confirmed by Sanger sequencing, was not found in the gnomAD database. Expression of the mutation in rat primary hippocampal neurons resulted in decreased expression of the mutant protein at dendritic GABAergic synapses compared to wildtype. The mutant protein showed aberrant accumulation within the soma of neurons and localization to the ER, suggesting a possible trafficking defect. Functional studies in neurons and HEK293 cells showed decreased cell surface expression of the mutant subunit and decreased GABA-evoked current amplitudes compared to wildtype. The patient presented with onset of multifocal seizures at 4 months of age.
In a 7-year-old boy (patient 2) with developmental and epileptic encephalopathy-79 (DEE79; 618559), Hernandez et al. (2019) identified a de novo heterozygous c.1238C-T transition (c.1238C-T, NM_000810.3) in the GABRA5 gene, resulting in a ser413-to-phe (S413F) substitution at a nonconserved residue in the intracellular N tail of the M4 domain. The mutation, which was found by next-generation sequencing of a targeted gene panel and confirmed by Sanger sequencing, was not found in the gnomAD database. Expression of the mutation into rat primary hippocampal neurons resulted in normal expression of the mutant protein at dendritic GABAergic synapses similar to wildtype. Functional studies in neurons and HEK293 cells showed that the mutation was associated with decreased GABA-evoked current amplitudes compared to wildtype. The S413F mutation also showed a dominant-negative effect by decreasing the trafficking of the partnering GABRB3 (137192) subunit to the cell surface, with no effect on other subunits. The patient had onset of epileptic spasms and focal and tonic seizures at 3 months of age.
Butler, K. M., Moody, O. A., Schuler, E., Coryell, J., Alexander, J. J., Jenkins, A., Escayg, A. De novo variations in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy. Brain 141: 2392-2405, 2018. [PubMed: 29961870] [Full Text: https://doi.org/10.1093/brain/awy171]
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]
Glatt, K. A., Sinnett, D., Lalande, M. Dinucleotide repeat polymorphism at the GABA-A receptor alpha-5 (GABRA5) locus at chromosome 15q11-q13. Hum. Molec. Genet. 1: 348 only, 1992. [PubMed: 1338907] [Full Text: https://doi.org/10.1093/hmg/1.5.348]
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]
Hernandez, C. C., XiangWei, W., Hu, N., Shen, D., Shen, W., Lagrange, A. H., Zhang, Y., Dai, L., Ding, C., Sun, Z., Hu, J., Zhu, H., Jiang, Y., Macdonald, R. L. Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies. Brain 142: 1938-1954, 2019. [PubMed: 31056671] [Full Text: https://doi.org/10.1093/brain/awz123]
Hogart, A., Nagarajan, R. P., Patzel, K. A., Yasui, D. H., Lasalle, J. M. 15q11-13 GABA(A) receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum. Molec. Genet. 16: 691-703, 2007. [PubMed: 17339270] [Full Text: https://doi.org/10.1093/hmg/ddm014]
Knoll, J. H. M., Sinnett, D., Wagstaff, J., Glatt, K., Wilcox, A. S., Whiting, P., Wingrove, P., Sikela, J., Lalande, M. FISH ordering of DNA markers within the Angelman/Prader-Willi chromosomal regions: mapping of a second GABA-A receptor subunit gene, GABRA5. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A9 only, 1992.
Papadimitriou, G. N., Dikeos, D. G., Karadima, G., Avramopoulos, D., Daskalopoulou, E. G., Vassilopoulos, D., Stefanis, C. N. Association between the GABA-A receptor alpha-5 subunit gene locus (GABRA5) and bipolar affective disorder. Am. J. Med. Genet. 81: 73-80, 1998. [PubMed: 9514592]
Ritchie, R. J., Mattei, M.-G., Lalande, M. A large polymorphic repeat in the pericentromeric region of human chromosome 15q contains three partial gene duplications. Hum. Molec. Genet. 7: 1253-1260, 1998. [PubMed: 9668167] [Full Text: https://doi.org/10.1093/hmg/7.8.1253]
Russek, S. J., Farb, D. H. Mapping of the beta-2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABA-A receptor isoform. Genomics 23: 528-533, 1994. [PubMed: 7851879] [Full Text: https://doi.org/10.1006/geno.1994.1539]
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]
Wingrove, P., Hadingham, K., Wafford, K., Kemp, J. A., Ragan, C. I., Whiting, P. Cloning and expression of a cDNA encoding the human GABA-A receptor alpha-5 subunit. Biochem. Soc. Trans. 20: 18S only, 1991.