GPR98 explained

ADGRV1, also known as G protein-coupled receptor 98 (GPR98) or Very Large G-protein coupled receptor 1 (VLGR1), is a protein that in humans is encoded by the GPR98 gene.^[1] Several alternatively spliced transcripts have been described.

The adhesion GPCR VLGR1 is the largest GPCR known, with a size of 6300 amino acids and consisting of 90 exons.^[2] There are 8 splice variants of VlgR1, named VlgR1a-1e and Mass1.1-1.3. The N-terminus consists of 5800 amino acids containing 35 Calx-beta domains, one pentraxin domain, and one epilepsy associated repeat. Mutations of VlgR1 have been shown to result in Usher's syndrome. Knockouts of Vlgr1 in mice have been shown to phenocopy Usher's syndrome and lead to audiogenic seizures.

Function

This gene encodes a member of the adhesion-GPCR family of receptors.^[3] The protein binds calcium and is expressed in the central nervous system. It is also known as very large G-protein coupled receptor 1 because it is 6300 residues long. It contains a C-terminal 7-transmembrane receptor domain, whereas the large N-terminal segment (5900 residues) includes 35 calcium binding Calx-beta domains, and 6 EAR domains.

Evolution

The sea urchin genome has a homolog of VLGR1 in it.^[4]

Clinical significance

Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures.

Further reading

• Staub E, Pérez-Tur J, Siebert R, etal . The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders. . Trends Biochem. Sci. . 27 . 9 . 441–4 . 2002 . 12217514 . 10.1016/S0968-0004(02)02163-1 .
• Ishikawa K, Nagase T, Suyama M, etal . 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 . 1998 . 9734811 . 10.1093/dnares/5.3.169 . free .
• Nakayama J, Hamano K, Iwasaki N, etal . Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. . Hum. Mol. Genet. . 9 . 1 . 87–91 . 2000 . 10587582 . 10.1093/hmg/9.1.87 . free .
• Pieke-Dahl S, Möller CG, Kelley PM, etal . Genetic heterogeneity of Usher syndrome type II: localisation to chromosome 5q. . J. Med. Genet. . 37 . 4 . 256–62 . 2000 . 10745043 . 10.1136/jmg.37.4.256 . 1734554 .
• Nikkila H, McMillan DR, Nunez BS, etal . 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 . 2001 . 10976914 . 10.1210/me.14.9.1351 .
• Wiemann S, Weil B, Wellenreuther R, etal . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. . Genome Res. . 11 . 3 . 422–35 . 2001 . 11230166 . 10.1101/gr.GR1547R . 311072 .
• Skradski SL, Clark AM, Jiang H, etal . A novel gene causing a mendelian audiogenic mouse epilepsy. . Neuron . 31 . 4 . 537–44 . 2001 . 11545713 . 10.1016/S0896-6273(01)00397-X . 14468960 . free .
• McMillan DR, Kayes-Wandover KM, Richardson JA, White PC . 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 . 2002 . 11606593 . 10.1074/jbc.M108929200 . free .
• Nagase T, Kikuno R, Ohara O . Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. . DNA Res. . 8 . 6 . 319–27 . 2002 . 11853319 . 10.1093/dnares/8.6.319 .
• Nakayama J, Fu YH, Clark AM, etal . A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. . Ann. Neurol. . 52 . 5 . 654–7 . 2002 . 12402266 . 10.1002/ana.10347 . 36357793 .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Weston MD, Luijendijk MW, Humphrey KD, etal . 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 . 2004 . 14740321 . 10.1086/381685 . 1181933 .
• Bjarnadóttir TK, Fredriksson R, Höglund PJ, etal . The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. . Genomics . 84 . 1 . 23–33 . 2005 . 15203201 . 10.1016/j.ygeno.2003.12.004 .
• Fu GK, Wang JT, Yang J, etal . Circular rapid amplification of cDNA ends for high-throughput extension cloning of partial genes. . Genomics . 84 . 1 . 205–10 . 2005 . 15203218 . 10.1016/j.ygeno.2004.01.011 .
• Schwartz SB, Aleman TS, Cideciyan AV, etal . Disease expression in Usher syndrome caused by VLGR1 gene mutation (USH2C) and comparison with USH2A phenotype. . Invest. Ophthalmol. Vis. Sci. . 46 . 2 . 734–43 . 2005 . 15671307 . 10.1167/iovs.04-1136 .
• Kimura K, Wakamatsu A, Suzuki Y, etal . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129 .

External links

• GeneReviews/NCBI/NIH/UW entry on Usher Syndrome Type II

Notes and References

1. Web site: Entrez Gene: GPR98 G protein-coupled receptor 98.
2. Sun . JP . Li . R . Ren . HZ . Xu . AT . Yu . X . Xu . ZG . May 2013 . The very large g protein coupled receptor (vlgr1) in hair cells . J Mol Neurosci . 50 . 1. 204–14 . 10.1007/s12031-012-9911-5 . 23180093 . 16730555 .
3. Book: Stacey M, Yona S . AdhesionGPCRs: Structure to Function (Advances in Experimental Medicine and Biology) . Springer . Berlin . 2011 . 978-1-4419-7912-4 .
4. Whittakera . Charles A. . Bergerone . Karl-Frederik . Whittlec . James . Bruce . P. . 2006 . Brandhorste, Robert D. Burked, Richard O. Hynes. The echinoderm adhesome . Developmental Biology . 300 . 1. 252–266 . 10.1016/j.ydbio.2006.07.044 . 16950242 . 3565218.