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Gene and Protein Information | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 4 | 467 | 15q12 | GABRG3 | gamma-aminobutyric acid type A receptor subunit gamma3 | 5,7 |
Mouse | 4 | 467 | 7 33.48 cM | Gabrg3 | gamma-aminobutyric acid type A receptor, subunit gamma 3 | 22 |
Rat | 4 | 467 | 1q22 | Gabrg3 | gamma-aminobutyric acid type A receptor subunit gamma 3 | 12 |
Gene and Protein Information Comments | ||||||
The data for tabulated are for the full length isoform of the human β3 subunit. A shorter alternatively spliced isoform lacks six amino acid residues and a consensus sequence for phosphorylation by PKC in the large intracellular M3-M4 loop [18]. |
Database Links | |
Alphafold | Q99928 (Hs), P27681 (Mm), P28473 (Rn) |
CATH/Gene3D | 2.70.170.10 |
ChEMBL Target | CHEMBL3885573 (Hs), CHEMBL3885577 (Hs), CHEMBL2094133 (Mm), CHEMBL1907607 (Rn) |
DrugBank Target | Q99928 (Hs), Q99928 (Hs) |
Ensembl Gene | ENSG00000182256 (Hs), ENSMUSG00000055026 (Mm), ENSRNOG00000014862 (Rn) |
Entrez Gene | 2567 (Hs), 14407 (Mm), 79211 (Rn) |
Human Protein Atlas | ENSG00000182256 (Hs) |
KEGG Gene | hsa:2567 (Hs), mmu:14407 (Mm), rno:79211 (Rn) |
OMIM | 600233 (Hs) |
Pharos | Q99928 (Hs) |
RefSeq Nucleotide | NM_033223 (Hs), NM_008074 (Mm), NM_024370 (Rn) |
RefSeq Protein | NP_150092 (Hs), NP_032100 (Mm), NP_077346 (Rn) |
UniProtKB | Q99928 (Hs), P27681 (Mm), P28473 (Rn) |
Wikipedia | GABRG3 (Hs) |
Natural/Endogenous Ligands |
GABA |
Download all structure-activity data for this target as a CSV file
Channel Blockers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Tissue Distribution | ||||||||||
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Tissue Distribution Comments | ||||||||||
The protein sequences tabulated above represent immature polypeptides that include a 17 AA signal peptide that is absent in the mature polypeptide |
Physiological Consequences of Altering Gene Expression | ||||||||||
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Physiological Consequences of Altering Gene Expression Comments | ||||||||||
The specific contribution of the GABRG3 gene deletion to autism and autism spectrum disorder phenotypes associated with chromosome 15q11-q13 copy number variations is currently not known. Loss of paternally or maternally inherited deletions of the same chromosomal region lead to Prader-Willi and Angelman syndrome, respectivley, which are principally attributed to loss of function of the UBE3A gene in this same chromosmal segement. |
Clinically-Relevant Mutations and Pathophysiology | ||||||||||||||||||||||||||||
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Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||||
Autism and autism spectrum disorder are associated with copy number variation and epigenetic dysregulation of the 15q11-q13 gene cluster [10]. In particular, the expression of non-imprinted GABAA receptor subunit genes is significantly reduced specifically in the female 15q11-13 dupication brain without detectable methylation differences [2,4,9]. Whether alterations specifically of the GABRG3 gene dosage contribute to the behavioral disease phenotype is not known currently. |
Biologically Significant Variants | ||||||||||||||
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Biologically Significant Variant Comments | ||||||||||||||
Human transcript variant 2 represents a minor (<1%) alternatively spliced form of the GABRG3 gene. It reflects usage of an alternative spliced donor site that result in extension of exon nine by six amino acids and adds the consensus sequence of a PKC phosphorylation site. This extension maps to the cytoplasmic loop region between the 3rd and 4th transmembrane domain of the gamma 3 subunit [18]. Amino acid numbers tabulated include a 17 AA signal sequence that is absent in the mature polypeptides. |
General Comments |
The γ3 subunit is most abundant in the developing brain. Although there is significant γ3 subunit immunoreactivity detectable in brain of adult mice, the loss of 94% of benzodiazepine binding sites in Gabrg3 KO mice [6] and estimates that approx 80% of GABAA receptors are sensitive to benzodizepines, indicates that the γ3 subunit contributes to less than 5% of postnatal GABAA receptors. The same conclusion can be drawn from immunoaffinity purification experiments of γ3 subunit containing GABAA receptors[20]. |
1. Baer K, Essrich C, Benson JA, Benke D, Bluethmann H, Fritschy JM, Lüscher B. (1999) Postsynaptic clustering of gamma-aminobutyric acid type A receptors by the gamma3 subunit in vivo. Proc Natl Acad Sci USA, 96 (22): 12860-5. [PMID:10536013]
2. Cook EH, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E. (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet, 60 (4): 928-34. [PMID:9106540]
3. Culiat CT, Stubbs LJ, Montgomery CS, Russell LB, Rinchik EM. (1994) Phenotypic consequences of deletion of the gamma 3, alpha 5, or beta 3 subunit of the type A gamma-aminobutyric acid receptor in mice. Proc Natl Acad Sci USA, 91 (7): 2815-8. [PMID:8146195]
4. Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA et al.. (2003) Mitochondrial dysfunction in autistic patients with 15q inverted duplication. Ann Neurol, 53 (6): 801-4. [PMID:12783428]
5. Greger V, Knoll JH, Woolf E, Glatt K, Tyndale RF, DeLorey TM, Olsen RW, Tobin AJ, Sikela JM, Nakatsu Y. (1995) The gamma-aminobutyric acid receptor gamma 3 subunit gene (GABRG3) is tightly linked to the alpha 5 subunit gene (GABRA5) on human chromosome 15q11-q13 and is transcribed in the same orientation. Genomics, 26 (2): 258-64. [PMID:7601451]
6. Günther U, Benson J, Benke D, Fritschy JM, Reyes G, Knoflach F, Crestani F, Aguzzi A, Arigoni M, Lang Y. (1995) Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci USA, 92 (17): 7749-53. [PMID:7644489]
7. Hadingham KL, Wafford KA, Thompson SA, Palmer KJ, Whiting PJ. (1995) Expression and pharmacology of human GABAA receptors containing gamma 3 subunits. Eur J Pharmacol, 291 (3): 301-9. [PMID:8719414]
8. Herb A, Wisden W, Lüddens H, Puia G, Vicini S, Seeburg PH. (1992) The third gamma subunit of the gamma-aminobutyric acid type A receptor family. Proc Natl Acad Sci USA, 89 (4): 1433-7. [PMID:1311098]
9. Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO, Schanen NC, LaSalle JM. (2009) Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet, 46 (2): 86-93. [PMID:18835857]
10. Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM. (2007) 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet, 16 (6): 691-703. [PMID:17339270]
11. Itsara A, Cooper GM, Baker C, Girirajan S, Li J, Absher D, Krauss RM, Myers RM, Ridker PM, Chasman DI et al.. (2009) Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet, 84 (2): 148-61. [PMID:19166990]
12. Knoflach F, Rhyner T, Villa M, Kellenberger S, Drescher U, Malherbe P, Sigel E, Möhler H. (1991) The gamma 3-subunit of the GABAA-receptor confers sensitivity to benzodiazepine receptor ligands. FEBS Lett, 293 (1-2): 191-4. [PMID:1660002]
13. Laurie DJ, Wisden W, Seeburg PH. (1992) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci, 12 (11): 4151-72. [PMID:1331359]
14. Miller AD, Blaha CD. (2005) Midbrain muscarinic receptor mechanisms underlying regulation of mesoaccumbens and nigrostriatal dopaminergic transmission in the rat. Eur J Neurosci, 21 (7): 1837-46. [PMID:15869479]
15. Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ et al.. (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet, 46 (4): 242-8. [PMID:18805830]
16. Nakatsu Y, Tyndale RF, DeLorey TM, Durham-Pierre D, Gardner JM, McDanel HJ, Nguyen Q, Wagstaff J, Lalande M, Sikela JM. (1993) A cluster of three GABAA receptor subunit genes is deleted in a neurological mutant of the mouse p locus. Nature, 364 (6436): 448-50. [PMID:8392662]
17. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. (2000) GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience, 101 (4): 815-50. [PMID:11113332]
18. Poulsen CF, Christjansen KN, Hastrup S, Hartvig L. (2000) Identification and cloning of a gamma 3 subunit splice variant of the human GABA(A) receptor. Brain Res Mol Brain Res, 78 (1-2): 201-3. [PMID:10891602]
19. Thomas JA, Johnson J, Peterson Kraai TL, Wilson R, Tartaglia N, LeRoux J, Beischel L, McGavran L, Hagerman RJ. (2003) Genetic and clinical characterization of patients with an interstitial duplication 15q11-q13, emphasizing behavioral phenotype and response to treatment. Am J Med Genet A, 119A (2): 111-20. [PMID:12749048]
20. Tögel M, Mossier B, Fuchs K, Sieghart W. (1994) gamma-Aminobutyric acidA receptors displaying association of gamma 3-subunits with beta 2/3 and different alpha-subunits exhibit unique pharmacological properties. J Biol Chem, 269 (17): 12993-8. [PMID:8175718]
21. van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, Mercer CL, Fichera M et al.. (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet, 46 (8): 511-23. [PMID:19372089]
22. Wilson-Shaw D, Robinson M, Gambarana C, Siegel RE, Sikela JM. (1991) A novel gamma subunit of the GABAA receptor identified using the polymerase chain reaction. FEBS Lett, 284 (2): 211-5. [PMID:1647983]
23. Wisden W, Laurie DJ, Monyer H, Seeburg PH. (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci, 12 (3): 1040-62. [PMID:1312131]