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Gene and Protein Information  |
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| Adhesion G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 1017 | Xp22.13 | ADGRG2 | adhesion G protein-coupled receptor G2 | 16 |
| Mouse | 7 | 1009 | X F4 | Adgrg2 | adhesion G protein-coupled receptor G2 | 15 |
| Rat | 7 | 1013 | Xq14 | Adgrg2 | adhesion G protein-coupled receptor G2 | 15 |
| Previous and Unofficial Names |
| GPR64 (G protein-coupled receptor 64) | HE6 (human epididymal 6) | TM7LN2 |
| Database Links |
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| Specialist databases | |
| GPCRdb | agrg2_human (Hs), agrg2_mouse (Mm), agrg2_rat (Rn) |
| Other databases | |
| Alphafold | Q8IZP9 (Hs), Q8CJ12 (Mm), Q8CJ11 (Rn) |
| ChEMBL Target | CHEMBL4523893 (Hs) |
| Ensembl Gene | ENSG00000173698 (Hs), ENSMUSG00000031298 (Mm), ENSRNOG00000032472 (Rn) |
| Entrez Gene | 10149 (Hs), 237175 (Mm), 266735 (Rn) |
| Human Protein Atlas | ENSG00000173698 (Hs) |
| KEGG Gene | hsa:10149 (Hs), mmu:237175 (Mm), rno:266735 (Rn) |
| OMIM | 300572 (Hs) |
| Pharos | Q8IZP9 (Hs) |
| RefSeq Nucleotide | NM_001079859 (Hs), NM_001079858 (Hs), NM_001079860 (Hs), NM_005756 (Hs), NM_001184833 (Hs), NM_001184834 (Hs), NM_001184835 (Hs), NM_001184836 (Hs), NM_178712 (Mm), NM_181366 (Rn) |
| RefSeq Protein | NP_001171762 (Hs), NP_001073328 (Hs), NP_005747 (Hs), NP_001171764 (Hs), NP_001073329 (Hs), NP_001171765 (Hs), NP_001073327 (Hs), NP_001171763 (Hs), NP_848827 (Mm), NP_852031 (Rn) |
| UniProtKB | Q8IZP9 (Hs), Q8CJ12 (Mm), Q8CJ11 (Rn) |
| Wikipedia | ADGRG2 (Hs) |
| Selected 3D Structures |
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| Endogenous agonists |
| Peptides derived from the Stachel sequence: TSFGVLLDLSRTSLPP [5] |
| Agonist Comments | ||
| Peptides derived from the Stachel sequence: TSFGVLLDLSRTSLPP [5]. |
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gs family | Adenylyl cyclase stimulation |
| Comments: This pathway applies to the recombinant expression of human ADGRG2 protein in Xenopus melanophores [7]. There is a brief note in the literature that the receptor will activate G proteins Gs and Gq when overexpressed in Xenopus melanophores (C. Jayawickreme, pers. communication, cited in [7]) which couple to adenylate cyclase and phospholipase C, respectively (see below). | |
| References: 5,11 | |
| Secondary Transduction Mechanisms |
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| Transducer | Effector/Response |
| Gq/G11 family | Phospholipase C stimulation |
| Comments: This pathway also applies to the recombinant expression of human ADGRG2 protein in Xenopus melanophores [1] (see above). | |
| References: 5,22 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| ADGRG2 is also specific to certain cell types, namely the non-ciliated principal cells in the ductuli efferentes [12]. It is not expressed in the neighbouring ciliated cells. In the Ductuli efferentes and proximal epididymal duct, the mature receptor is a heterodimeric membrane protein of the apical epithelial membrane domain [15]. | ||||||||
| Expression Datasets |
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| Functional Assays
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| Physiological Functions
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| Physiological Functions Comments | ||||||||
| KO mice show a downregulation of the following genes: Enpp2/autotaxin, the lipocalins 8 and 9, the beta-defensin Defb42, cystatins 8 and 12, as well as the membrane proteins ADAM (a disintegrin and metalloprotease) 28, claudin-10, EAAC1, and Me9 (Teddm1). In contrast, clusterin/ApoJ and osteopontin/Spp1 mRNAsare are upregulated in KO tissue [4]. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||||||
| The human ADGRG2 gene was assigned to the X chromosome (Xp22.13) in a region which is syntenic to the mouse [15]. Three DNA variants (single nucleotide polymorphisms) of the human gene sequence have been reported [20] which are listed in the LOVD X-chromosome gene database. 10 transcripts exist in human [6,15-16]. The transcripts affect predominantly the open reading frame in the N-terminal part immediately following the signal peptide. Nine of the transcripts encode proteins which differ in length. |
| General Comments |
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ADGRG2 (adhesion G protein-coupled receptor G2, formerly GPR64) is an orphan receptor belonging to Family VIII Adhesion-GPCRs together with ADGRG1 and ADGRG3-7 [8]. The gene is localized on human chromosome X and mouse chromosome 8. The long extracellular ectosubunit of ADGRG2 is highly glycosylated [15], showing similarity to mucin-like cell-surface molecules. Gene product appears to be cleaved shortly before the first transmembrane domain to produce a large, highly glycoslylated (approximately 180 kDa) amino terminal domain and carboxly terminal domain containing seven transmemberane domains (40 kDa in human) [15]. The putative cysteine-rich cleavage site, GPS (GPCR proteolysis site), is found in several other class B GPCRs [9]. Full coding sequence human cDNA is publicly available, IMAGE:7447877 [13] in mammalian expression vector pCDNA3.1. |
1. Aalto Y, El-Rifa W, Vilpo L, Ollila J, Nagy B, Vihinen M, Vilpo J, Knuutila S. (2001) Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion. Leukemia, 15 (11): 1721-8. [PMID:11681413]
2. Bjarnadóttir TK, Geirardsdóttir K, Ingemansson M, Mirza MA, Fredriksson R, Schiöth HB. (2007) Identification of novel splice variants of Adhesion G protein-coupled receptors. Gene, 387 (1-2): 38-48. [PMID:17056209]
3. Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U. (2004) Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol Cell Biol, 24 (19): 8642-8. [PMID:15367682]
4. Davies B, Behnen M, Cappallo-Obermann H, Spiess AN, Theuring F, Kirchhoff C. (2007) Novel epididymis-specific mRNAs downregulated by HE6/Gpr64 receptor gene disruption. Mol Reprod Dev, 74 (5): 539-53. [PMID:17034053]
5. Demberg LM, Rothemund S, Schöneberg T, Liebscher I. (2015) Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2. Biochem Biophys Res Commun, 464 (3): 743-7. [PMID:26188515]
6. Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S et al.. (2013) Ensembl 2013. Nucleic Acids Res, 41 (Database issue): D48-55. [PMID:23203987]
7. Foord SM, Jupe S, Holbrook J. (2002) Bioinformatics and type II G-protein-coupled receptors. Biochem Soc Trans, 30 (4): 473-9. [PMID:12196118]
8. Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB. (2003) There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini. Biochem Biophys Res Commun, 301 (3): 725-34. [PMID:12565841]
9. Fredriksson R, Lagerström MC, Höglund PJ, Schiöth HB. (2002) Novel human G protein-coupled receptors with long N-terminals containing GPS domains and Ser/Thr-rich regions. FEBS Lett, 531 (3): 407-14. [PMID:12435584]
10. Galligan CL, Baig E, Bykerk V, Keystone EC, Fish EN. (2007) Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity. Genes Immun, 8 (6): 480-91. [PMID:17568789]
11. Gottwald U, Davies B, Fritsch M, Habenicht UF. (2006) New approaches for male fertility control: HE6 as an example of a putative target. Mol Cell Endocrinol, 250 (1-2): 49-57. [PMID:16442214]
12. Kirchhoff C, Osterhoff C, Samalecos A. (2008) HE6/GPR64 adhesion receptor co-localizes with apical and subapical F-actin scaffold in male excurrent duct epithelia. Reproduction, 136 (2): 235-45. [PMID:18469038]
13. Lennon G, Auffray C, Polymeropoulos M, Soares MB. (1996) The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics, 33 (1): 151-2. [PMID:8617505]
14. Lin H, Xiao P, Bu RQ, Guo S, Yang Z, Yuan D, Zhu ZL, Zhang CX, He QT, Zhang C et al.. (2022) Structures of the ADGRG2-Gs complex in apo and ligand-bound forms. Nat Chem Biol, 18 (11): 1196-1203. [PMID:35982227]
15. Obermann H, Samalecos A, Osterhoff C, Schröder B, Heller R, Kirchhoff C. (2003) HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia. Mol Reprod Dev, 64 (1): 13-26. [PMID:12420295]
16. Osterhoff C, Ivell R, Kirchhoff C. (1997) Cloning of a human epididymis-specific mRNA, HE6, encoding a novel member of the seven transmembrane-domain receptor superfamily. DNA Cell Biol, 16 (4): 379-89. [PMID:9150425]
17. Pagin A, Bergougnoux A, Girodon E, Reboul MP, Willoquaux C, Kesteloot M, Raynal C, Bienvenu T, Humbert M, Lalau G et al.. (2020) Novel ADGRG2 truncating variants in patients with X-linked congenital absence of vas deferens. Andrology, 8 (3): 618-624. [PMID:31845523]
18. Patat O, Pagin A, Siegfried A, Mitchell V, Chassaing N, Faguer S, Monteil L, Gaston V, Bujan L, Courtade-Saïdi M et al.. (2016) Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens. Am J Hum Genet, 99 (2): 437-42. [PMID:27476656]
19. Richter GH, Fasan A, Hauer K, Grunewald TG, Berns C, Rössler S, Naumann I, Staege MS, Fulda S, Esposito I et al.. (2013) G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1. J Pathol, 230 (1): 70-81. [PMID:23338946]
20. Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A et al.. (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet, 41 (5): 535-43. [PMID:19377476]
21. Wu H, Gao Y, Ma C, Shen Q, Wang J, Lv M, Liu C, Cheng H, Zhu F, Tian S et al.. (2020) A novel hemizygous loss-of-function mutation in ADGRG2 causes male infertility with congenital bilateral absence of the vas deferens. J Assist Reprod Genet, 37 (6): 1421-1429. [PMID:32314195]
22. Zhang DL, Sun YJ, Ma ML, Wang YJ, Lin H, Li RR, Liang ZL, Gao Y, Yang Z, He DF et al.. (2018) Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. Elife, 7. [PMID:29393851]
