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Not curated in GtoImmuPdb
Target id: 189
Nomenclature: ADGRV1
Family: Adhesion Class GPCRs
Annotation status:
Annotated and reviewed, awaiting update
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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 | 6306 | 5q14.3 | ADGRV1 | adhesion G protein-coupled receptor V1 | 9,15,21 |
| Mouse | 7 | 6298 | 13 42.18 cM | Adgrv1 | adhesion G protein-coupled receptor V1 | |
| Rat | 7 | - | 2q11 | Adgrv1 | adhesion G protein-coupled receptor V1 | |
| Previous and Unofficial Names |
| FEB4 | MASS1 | USH2C | VLGR1 | very large G protein-coupled receptor 1 | GPR98 (G protein-coupled receptor 98) |
| Database Links |
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| Specialist databases | |
| GPCRdb | gpr98_mouse (Mm) |
| Other databases | |
| Alphafold | Q8WXG9 (Hs), Q8VHN7 (Mm) |
| Ensembl Gene | ENSG00000164199 (Hs), ENSMUSG00000069170 (Mm) |
| Entrez Gene | 84059 (Hs), 110789 (Mm), 685383 (Rn) |
| Human Protein Atlas | ENSG00000164199 (Hs) |
| KEGG Gene | hsa:84059 (Hs), mmu:110789 (Mm), rno:685383 (Rn) |
| OMIM | 602851 (Hs) |
| Orphanet | ORPHA122270 (Hs) |
| Pharos | Q8WXG9 (Hs) |
| RefSeq Nucleotide | NM_032119 (Hs), NM_054053 (Mm) |
| RefSeq Protein | NP_115495 (Hs), NP_473394 (Mm) |
| UniProtKB | Q8WXG9 (Hs), Q8VHN7 (Mm) |
| Wikipedia | ADGRV1 (Hs) |
| Associated Protein Comments | ||
| Intracellular interactors: harmonin [22], whirlin [26]. |
| Agonist Comments | ||
| No ligands identified: orphan receptor. |
| Tissue Distribution
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| Expression Datasets |
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| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Xenobiotics Influencing 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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| Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other mutations in humans that are probably pathogenic are: D1929N, H3399P, R4707Y [3]. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||||||
| Several isoforms of Adgrv1 were identified [17]: Vlgr1a, b, c, d, e (recently also f-o were postulated) and MASS1.1, MASS1.2, MASS1.3. The Vlgr1a isoform is presumably restricted to humans. The antibodies used to study Adgrv1 expression are usually not isoform specific and only limited information is available by RT-PCR experiments differentiating between isoforms. Therefore, the biological significance of single isoforms remains to be elucidated. |
| General Comments |
| ADGRV1 (adhesion G protein-coupled receptor V1, formerly known as VLGR: very large G protein coupled receptor 1 and GPR98) is an orphan receptor belonging to Family IX Adhesion-GPCRs [2]. The full-length isoform VLGR1b is by far the largest GPCR with a molecular weight of ~700 kDa. Its extracellular domain contains 35 CalX-beta motifs, which are homologous to the calcium binding domains found in Na+/Ca2+ exchangers. Further extracellular domains are the LamG/TspN/PTX domain and the EAR domain that is possibly associated with epilepsy. The PDZ binding motif, located at the extreme carboxy-terminus of VLGR1b, mediates the interaction with intracellular PDZ domain-containing proteins, e.g. the two scaffold proteins whirlin and harmonin. Mutations in the ADGRV1 gene are causative for the human Usher syndrome (USH) type 2. USH is the most common form of combined hereditary deaf-blindness. It is an autosomal recessive disorder characterized by retinal dystophy (retinitis pigmentosa) and hearing loss, which can be associated with vestibular dysfunctions. ADGRV1 is expressed in most adult tissues, with the highest expression found in the developing nervous system and in tissues affected in USH patients, namely the inner ear and neuronal retina. In the inner ear VLGR1b is an essential component of the ankle links, which are important for the proper development of the mechano-sensitive hair bundles of auditory hair cells. In photoreceptor cells VLGR1b forms fibrous structures linking the membranes of the apical inner segment and the connecting cilium. It was also identified as an essential component of the periciliary USH protein network, crucial for cargo transport to the photoreceptor cilium. In both types of sensory cells VLGR1b is additionally expressed in the synaptic region, where it is present in the post-synaptic terminals. |
1. Besnard T, Vaché C, Baux D, Larrieu L, Abadie C, Blanchet C, Odent S, Blanchet P, Calvas P, Hamel C et al.. (2012) Non-USH2A mutations in USH2 patients. Hum Mutat, 33 (3): 504-10. [PMID:22147658]
2. Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics, 84 (1): 23-33. [PMID:15203201]
3. Bonnet C, Grati M, Marlin S, Levilliers J, Hardelin JP, Parodi M, Niasme-Grare M, Zelenika D, Délépine M, Feldmann D et al.. (2011) Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis, 6: 21. [PMID:21569298]
4. Carroll N, Hughes L, McEntee G, Parle-McDermott A. (2012) Investigation of the molecular response to folate metabolism inhibition. J Nutr Biochem, 23 (11): 1531-6. [PMID:22402366]
5. Ebermann I, Wiesen MH, Zrenner E, Lopez I, Pigeon R, Kohl S, Löwenheim H, Koenekoop RK, Bolz HJ. (2009) GPR98 mutations cause Usher syndrome type 2 in males. J Med Genet, 46 (4): 277-80. [PMID:19357117]
6. Goodyear R, Richardson G. (1999) The ankle-link antigen: an epitope sensitive to calcium chelation associated with the hair-cell surface and the calycal processes of photoreceptors. J Neurosci, 19 (10): 3761-72. [PMID:10234008]
7. Goodyear RJ, Richardson GP. (2003) A novel antigen sensitive to calcium chelation that is associated with the tip links and kinocilial links of sensory hair bundles. J Neurosci, 23 (12): 4878-87. [PMID:12832510]
8. Hilgert N, Kahrizi K, Dieltjens N, Bazazzadegan N, Najmabadi H, Smith RJ, Van Camp G. (2009) A large deletion in GPR98 causes type IIC Usher syndrome in male and female members of an Iranian family. J Med Genet, 46 (4): 272-6. [PMID:19357116]
9. Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. (1998) Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res, 5 (3): 169-76. [PMID:9734811]
10. Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Roman AJ, Gardner LM, Prosser HM, Mishra M, Bech-Hansen NT, Herrera W, Schwartz SB, Liu XZ, Kimberling WJ, Steel KP, Williams DS. (2008) Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Hum Mol Genet, 17 (15): 2405-15. [PMID:18463160]
11. Le Quesne Stabej P, Saihan Z, Rangesh N, Steele-Stallard HB, Ambrose J, Coffey A, Emmerson J, Haralambous E, Hughes Y, Steel KP et al.. (2012) Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet, 49 (1): 27-36. [PMID:22135276]
12. Maerker T, van Wijk E, Overlack N, Kersten FF, McGee J, Goldmann T, Sehn E, Roepman R, Walsh EJ, Kremer H et al.. (2008) A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum Mol Genet, 17 (1): 71-86. [PMID:17906286]
13. Malm E, Ponjavic V, Möller C, Kimberling WJ, Andréasson S. (2011) Phenotypes in defined genotypes including siblings with Usher syndrome. Ophthalmic Genet, 32 (2): 65-74. [PMID:21174530]
14. McGee J, Goodyear RJ, McMillan DR, Stauffer EA, Holt JR, Locke KG, Birch DG, Legan PK, White PC, Walsh EJ et al.. (2006) The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles. J Neurosci, 26 (24): 6543-53. [PMID:16775142]
15. McMillan DR, Kayes-Wandover KM, Richardson JA, White PC. (2002) Very large G protein-coupled receptor-1, the largest known cell surface protein, is highly expressed in the developing central nervous system. J Biol Chem, 277 (1): 785-92. [PMID:11606593]
16. McMillan DR, White PC. (2004) Loss of the transmembrane and cytoplasmic domains of the very large G-protein-coupled receptor-1 (VLGR1 or Mass1) causes audiogenic seizures in mice. Mol Cell Neurosci, 26 (2): 322-9. [PMID:15207856]
17. McMillan DR, White PC. (2010) Studies on the very large G protein-coupled receptor: from initial discovery to determining its role in sensorineural deafness in higher animals. Adv Exp Med Biol, 706: 76-86. [PMID:21618827]
18. Michalski N, Michel V, Bahloul A, Lefèvre G, Barral J, Yagi H, Chardenoux S, Weil D, Martin P, Hardelin JP et al.. (2007) Molecular characterization of the ankle-link complex in cochlear hair cells and its role in the hair bundle functioning. J Neurosci, 27 (24): 6478-88. [PMID:17567809]
19. Nakayama J, Fu YH, Clark AM, Nakahara S, Hamano K, Iwasaki N, Matsui A, Arinami T, Ptácek LJ. (2002) A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann Neurol, 52 (5): 654-7. [PMID:12402266]
20. Nakayama J, Hamano K, Iwasaki N, Nakahara S, Horigome Y, Saitoh H, Aoki T, Maki T, Kikuchi M, Migita T et al.. (2000) Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Hum Mol Genet, 9 (1): 87-91. [PMID:10587582]
21. Nikkila H, McMillan DR, Nunez BS, Pascoe L, Curnow KM, White PC. (2000) Sequence similarities between a novel putative G protein-coupled receptor and Na+/Ca2+ exchangers define a cation binding domain. Mol Endocrinol, 14 (9): 1351-64. [PMID:10976914]
22. Reiners J, van Wijk E, Märker T, Zimmermann U, Jürgens K, te Brinke H, Overlack N, Roepman R, Knipper M, Kremer H et al.. (2005) Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Hum Mol Genet, 14 (24): 3933-43. [PMID:16301216]
23. Sahly I, Dufour E, Schietroma C, Michel V, Bahloul A, Perfettini I, Pepermans E, Estivalet A, Carette D, Aghaie A et al.. (2012) Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice. J Cell Biol, 199 (2): 381-99. [PMID:23045546]
24. Skradski SL, Clark AM, Jiang H, White HS, Fu YH, Ptácek LJ. (2001) A novel gene causing a mendelian audiogenic mouse epilepsy. Neuron, 31: 537-544. [PMID:11545713]
25. Urano T, Shiraki M, Yagi H, Ito M, Sasaki N, Sato M, Ouchi Y, Inoue S. (2012) GPR98/Gpr98 gene is involved in the regulation of human and mouse bone mineral density. J Clin Endocrinol Metab, 97 (4): E565-74. [PMID:22419726]
26. van Wijk E, van der Zwaag B, Peters T, Zimmermann U, Te Brinke H, Kersten FF, Märker T, Aller E, Hoefsloot LH, Cremers CW et al.. (2006) The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum Mol Genet, 15 (5): 751-65. [PMID:16434480]
27. Weston MD, Luijendijk MW, Humphrey KD, Möller C, Kimberling WJ. (2004) Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II. Am J Hum Genet, 74 (2): 357-66. [PMID:14740321]
28. Yagi H, Takamura Y, Yoneda T, Konno D, Akagi Y, Yoshida K, Sato M. (2005) Vlgr1 knockout mice show audiogenic seizure susceptibility. J Neurochem, 92 (1): 191-202. [PMID:15606908]
29. Yagi H, Tokano H, Maeda M, Takabayashi T, Nagano T, Kiyama H, Fujieda S, Kitamura K, Sato M. (2007) Vlgr1 is required for proper stereocilia maturation of cochlear hair cells. Genes Cells, 12 (2): 235-50. [PMID:17295842]
30. Yang J, Liu X, Zhao Y, Adamian M, Pawlyk B, Sun X, McMillan DR, Liberman MC, Li T. (2010) Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PLoS Genet, 6 (5): e1000955. [PMID:20502675]
31. Zallocchi M, Delimont D, Meehan DT, Cosgrove D. (2012) Regulated vesicular trafficking of specific PCDH15 and VLGR1 variants in auditory hair cells. J Neurosci, 32 (40): 13841-59. [PMID:23035094]
32. Zallocchi M, Meehan DT, Delimont D, Rutledge J, Gratton MA, Flannery J, Cosgrove D. (2012) Role for a novel Usher protein complex in hair cell synaptic maturation. PLoS ONE, 7 (2): e30573. [PMID:22363448]
33. Zou J, Luo L, Shen Z, Chiodo VA, Ambati BK, Hauswirth WW, Yang J. (2011) Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Invest Ophthalmol Vis Sci, 52 (5): 2343-51. [PMID:21212183]
