ID GUC2D_HUMAN Reviewed; 1103 AA. AC Q02846; Q6LEA7; DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1996, sequence version 2. DT 24-JAN-2024, entry version 232. DE RecName: Full=Retinal guanylyl cyclase 1; DE Short=RETGC-1; DE EC=4.6.1.2 {ECO:0000269|PubMed:15123990, ECO:0000269|PubMed:21928830, ECO:0000269|PubMed:26100624, ECO:0000269|PubMed:30319355, ECO:0000269|PubMed:7912093, ECO:0000269|PubMed:9600905}; DE AltName: Full=CG-E {ECO:0000303|PubMed:30319355}; DE AltName: Full=Guanylate cyclase 2D, retinal; DE AltName: Full=Rod outer segment membrane guanylate cyclase; DE Short=ROS-GC; DE Flags: Precursor; GN Name=GUCY2D; GN Synonyms=CORD6, GUC1A4, GUC2D {ECO:0000303|PubMed:7806240}, RETGC, GN RETGC1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Retina; RX PubMed=1356371; DOI=10.1016/0896-6273(92)90035-c; RA Shyjan A.W., de Sauvage F.J., Gillett N.A., Goeddel D.V., Lowe D.G.; RT "Molecular cloning of a retina-specific membrane guanylyl cyclase."; RL Neuron 9:727-737(1992). RN [2] RP SEQUENCE REVISION. RA Lowe D.G.; RL Submitted (JAN-1995) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Perrault I.; RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1009-1088. RX PubMed=7806240; DOI=10.1006/geno.1994.1415; RA Oliveira L., Miniou P., Viegas-Pequignot E., Rozet J.-M., Dollfus H., RA Pittler S.J.; RT "Human retinal guanylate cyclase (GUC2D) maps to chromosome 17p13.1."; RL Genomics 22:478-481(1994). RN [5] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY. RX PubMed=7912093; DOI=10.1016/0896-6273(94)90449-9; RA Dizhoor A.M., Lowe D.G., Olshevskaya E.V., Laura R.P., Hurley J.B.; RT "The human photoreceptor membrane guanylyl cyclase, RetGC, is present in RT outer segments and is regulated by calcium and a soluble activator."; RL Neuron 12:1345-1352(1994). RN [6] RP MUTAGENESIS OF GLU-925 AND CYS-997, CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=9600905; DOI=10.1073/pnas.95.11.5993; RA Tucker C.L., Hurley J.H., Miller T.R., Hurley J.B.; RT "Two amino acid substitutions convert a guanylyl cyclase, RetGC-1, into an RT adenylyl cyclase."; RL Proc. Natl. Acad. Sci. U.S.A. 95:5993-5997(1998). RN [7] RP 3D-STRUCTURE MODELING OF 871-1028. RX PubMed=9391039; DOI=10.1073/pnas.94.25.13414; RA Liu Y., Ruoho A.E., Rao V.D., Hurley J.H.; RT "Catalytic mechanism of the adenylyl and guanylyl cyclases: modeling and RT mutational analysis."; RL Proc. Natl. Acad. Sci. U.S.A. 94:13414-13419(1997). RN [8] RP VARIANT LCA1 SER-52. RX PubMed=8944027; DOI=10.1038/ng1296-461; RA Perrault I., Rozet J.-M., Calvas P., Gerber S., Camuzat A., Dollfus H., RA Chatelin S., Souied E., Ghazi I., Leowski C., Bonnemaison M., RA le Paslier D., Frezal J., Dufier J.-L., Pittler S., Munnich A., Kaplan J.; RT "Retinal-specific guanylate cyclase gene mutations in Leber's congenital RT amaurosis."; RL Nat. Genet. 14:461-464(1996). RN [9] RP VARIANT CORD6 837-GLU--THR-839 DELINS ASP-CYS-MET. RX PubMed=9683616; DOI=10.1086/301985; RA Perrault I., Rozet J.-M., Gerber S., Kelsell R.E., Souied E., Cabot A., RA Hunt D.M., Munnich A., Kaplan J.; RT "A retGC-1 mutation in autosomal dominant cone-rod dystrophy."; RL Am. J. Hum. Genet. 63:651-654(1998). RN [10] RP VARIANTS CORD6 ASP-837 AND CYS-838. RX PubMed=9618177; DOI=10.1093/hmg/7.7.1179; RA Kelsell R.E., Gregory-Evans K., Payne A.M., Perrault I., Kaplan J., RA Yang R.-B., Garbers D.L., Bird A.C., Moore A.T., Hunt D.M.; RT "Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant RT cone-rod dystrophy."; RL Hum. Mol. Genet. 7:1179-1184(1998). RN [11] RP CHARACTERIZATION OF VARIANT LCA1 SER-565. RX PubMed=9888789; DOI=10.1021/bi9824137; RA Duda T., Venkataraman V., Goraczniak R., Lange C., Koch K.-W., Sharma R.K.; RT "Functional consequences of a rod outer segment membrane guanylate cyclase RT (ROS-GC1) gene mutation linked with Leber's congenital amaurosis."; RL Biochemistry 38:509-515(1999). RN [12] RP VARIANTS LCA1 TYR-105; PRO-325 AND SER-858. RX PubMed=11035546; DOI=10.1076/1381-6810(200009)21:3;1-z;ft135; RA Dharmaraj S.R., Silva E.R., Pina A.-L., Li Y.Y., Yang J.M., Carter C.R., RA Loyer M.K., El-Hilali H.K., Traboulsi E.K., Sundin O.K., Zhu D.K., RA Koenekoop R.K., Maumenee I.H.; RT "Mutational analysis and clinical correlation in Leber congenital RT amaurosis."; RL Ophthalmic Genet. 21:135-150(2000). RN [13] RP VARIANT LCA1 PRO-954. RX PubMed=12365911; DOI=10.1001/archopht.120.10.1325; RA Koenekoop R.K., Fishman G.A., Iannaccone A., Ezzeldin H., Ciccarelli M.L., RA Baldi A., Sunness J.S., Lotery A.J., Jablonski M.M., Pittler S.J., RA Maumenee I.; RT "Electroretinographic abnormalities in parents of patients with Leber RT congenital amaurosis who have heterozygous GUCY2D mutations."; RL Arch. Ophthalmol. 120:1325-1330(2002). RN [14] RP VARIANTS CORD6 CYS-838 AND HIS-838, AND DISCUSSION OF PHENOTYPIC RP VARIABILITY. RX PubMed=12552567; DOI=10.1002/humu.9109; RA Udar N., Yelchits S., Chalukya M., Yellore V., Nusinowitz S., RA Silva-Garcia R., Vrabec T., Hussles Maumenee I., Donoso L., Small K.W.; RT "Identification of GUCY2D gene mutations in CORD5 families and evidence of RT incomplete penetrance."; RL Hum. Mutat. 21:170-171(2003). RN [15] RP INVOLVEMENT IN CORD6. RX PubMed=15111605; DOI=10.1167/iovs.03-0315; RA Ito S., Nakamura M., Nuno Y., Ohnishi Y., Nishida T., Miyake Y.; RT "Novel complex GUCY2D mutation in Japanese family with cone-rod RT dystrophy."; RL Invest. Ophthalmol. Vis. Sci. 45:1480-1485(2004). RN [16] RP CHARACTERIZATION OF VARIANTS LCA1 TYR-105; PRO-325; SER-858 AND PRO-954, RP CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=15123990; RA Tucker C.L., Ramamurthy V., Pina A.-L., Loyer M., Dharmaraj S., Li Y., RA Maumenee I.H., Hurley J.B., Koenekoop R.K.; RT "Functional analyses of mutant recessive GUCY2D alleles identified in Leber RT congenital amaurosis patients: protein domain comparisons and dominant RT negative effects."; RL Mol. Vis. 10:297-303(2004). RN [17] RP POSSIBLE INVOLVEMENT OF VARIANT SER-701 IN LEBER CONGENITAL AMAUROSIS. RX PubMed=16123401; DOI=10.1167/iovs.05-0111; RA Zernant J., Kulm M., Dharmaraj S., den Hollander A.I., Perrault I., RA Preising M.N., Lorenz B., Kaplan J., Cremers F.P., Maumenee I., RA Koenekoop R.K., Allikmets R.; RT "Genotyping microarray (disease chip) for Leber congenital amaurosis: RT detection of modifier alleles."; RL Invest. Ophthalmol. Vis. Sci. 46:3052-3059(2005). RN [18] RP VARIANTS LCA1 TRP-768 AND GLN-795, VARIANTS ARG-325 AND SER-701, AND RP POSSIBLE INVOLVEMENT OF VARIANT SER-701 IN LEBER CONGENITAL AMAUROSIS. RX PubMed=17724218; DOI=10.1167/iovs.07-0068; RA Simonelli F., Ziviello C., Testa F., Rossi S., Fazzi E., Bianchi P.E., RA Fossarello M., Signorini S., Bertone C., Galantuomo S., Brancati F., RA Valente E.M., Ciccodicola A., Rinaldi E., Auricchio A., Banfi S.; RT "Clinical and molecular genetics of Leber's congenital amaurosis: a RT multicenter study of Italian patients."; RL Invest. Ophthalmol. Vis. Sci. 48:4284-4290(2007). RN [19] RP VARIANTS [LARGE SCALE ANALYSIS] VAL-328; ASP-431; MET-507; GLU-693; SER-701 RP AND HIS-782. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [20] RP INVOLVEMENT IN CORD6. RX PubMed=18332321; DOI=10.1001/archopht.126.3.397; RA Small K.W., Silva-Garcia R., Udar N., Nguyen E.V., Heckenlively J.R.; RT "New mutation, P575L, in the GUCY2D gene in a family with autosomal RT dominant progressive cone degeneration."; RL Arch. Ophthalmol. 126:397-403(2008). RN [21] RP INVOLVEMENT IN CORD6, AND VARIANTS CORD6 CYS-838; HIS-838 AND GLY-838. RX PubMed=18487367; DOI=10.1167/iovs.08-1901; RA Kitiratschky V.B., Wilke R., Renner A.B., Kellner U., Vadala M., RA Birch D.G., Wissinger B., Zrenner E., Kohl S.; RT "Mutation analysis identifies GUCY2D as the major gene responsible for RT autosomal dominant progressive cone degeneration."; RL Invest. Ophthalmol. Vis. Sci. 49:5015-5023(2008). RN [22] RP INVOLVEMENT IN CORD6, AND VARIANT CORD6 THR-949. RX PubMed=20517349; DOI=10.1038/ejhg.2010.81; RA Ugur Iseri S.A., Durlu Y.K., Tolun A.; RT "A novel recessive GUCY2D mutation causing cone-rod dystrophy and not RT Leber's congenital amaurosis."; RL Eur. J. Hum. Genet. 18:1121-1126(2010). RN [23] RP INTERACTION WITH RD3. RX PubMed=21078983; DOI=10.1073/pnas.1010460107; RA Azadi S., Molday L.L., Molday R.S.; RT "RD3, the protein associated with Leber congenital amaurosis type 12, is RT required for guanylate cyclase trafficking in photoreceptor cells."; RL Proc. Natl. Acad. Sci. U.S.A. 107:21158-21163(2010). RN [24] RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, RP INTERACTION WITH RD3, AND FUNCTION. RX PubMed=21928830; DOI=10.1021/bi201342b; RA Peshenko I.V., Olshevskaya E.V., Azadi S., Molday L.L., Molday R.S., RA Dizhoor A.M.; RT "Retinal degeneration 3 (RD3) protein inhibits catalytic activity of RT retinal membrane guanylyl cyclase (RetGC) and its stimulation by activating RT proteins."; RL Biochemistry 50:9511-9519(2011). RN [25] RP INVOLVEMENT IN CACD1, AND VARIANT CACD1 ALA-933. RX PubMed=22695961; DOI=10.1167/iovs.12-10061; RA Hughes A.E., Meng W., Lotery A.J., Bradley D.T.; RT "A novel GUCY2D mutation, V933A, causes central areolar choroidal RT dystrophy."; RL Invest. Ophthalmol. Vis. Sci. 53:4748-4753(2012). RN [26] RP MUTAGENESIS OF ARG-822 AND MET-823, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=26100624; DOI=10.1074/jbc.m115.661371; RA Peshenko I.V., Olshevskaya E.V., Dizhoor A.M.; RT "Dimerization Domain of Retinal Membrane Guanylyl Cyclase 1 (RetGC1) Is an RT Essential Part of Guanylyl Cyclase-activating Protein (GCAP) Binding RT Interface."; RL J. Biol. Chem. 290:19584-19596(2015). RN [27] RP CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR LOCATION, VARIANT LCA1 LEU-902, RP CHARACTERIZATION OF VARIANT LCA1 VAL-710 AND LEU-902, VARIANT CORD6 RP ARG-873, AND CHARACTERIZATION OF VARIANTS CORD6 LYS-841; ASN-846 AND RP ARG-873. RX PubMed=30319355; DOI=10.3389/fnmol.2018.00348; RA Wimberg H., Lev D., Yosovich K., Namburi P., Banin E., Sharon D., RA Koch K.W.; RT "Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal RT Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis."; RL Front. Mol. Neurosci. 11:348-348(2018). RN [28] RP VARIANT CORD6 PRO-838. RX PubMed=21552474; RA Garcia-Hoyos M., Auz-Alexandre C.L., Almoguera B., Cantalapiedra D., RA Riveiro-Alvarez R., Lopez-Martinez M.A., Gimenez A., Blanco-Kelly F., RA Avila-Fernandez A., Trujillo-Tiebas M.J., Garcia-Sandoval B., Ramos C., RA Ayuso C.; RT "Mutation analysis at codon 838 of the Guanylate Cyclase 2D gene in Spanish RT families with autosomal dominant cone, cone-rod, and macular dystrophies."; RL Mol. Vis. 17:1103-1109(2011). RN [29] RP VARIANT CORD6 HIS-838. RX PubMed=22194653; RA Xiao X., Guo X., Jia X., Li S., Wang P., Zhang Q.; RT "A recurrent mutation in GUCY2D associated with autosomal dominant cone RT dystrophy in a Chinese family."; RL Mol. Vis. 17:3271-3278(2011). RN [30] RP VARIANTS LCA1 MET-55; VAL-103; MET-312; 405-LEU-ASP-406 DELINS PRO-ASN; RP CYS-438; LEU-640; GLN-660; HIS-728; ALA-734; TRP-768; ARG-784; LEU-1007 AND RP GLY-ILE-1027 INS, AND VARIANTS ARG-21; SER-52 AND SER-701. RX PubMed=21602930; DOI=10.1371/journal.pone.0019458; RA Li L., Xiao X., Li S., Jia X., Wang P., Guo X., Jiao X., Zhang Q., RA Hejtmancik J.F.; RT "Detection of variants in 15 genes in 87 unrelated Chinese patients with RT Leber congenital amaurosis."; RL PLoS ONE 6:E19458-E19458(2011). RN [31] RP VARIANT CORD6 ALA-849. RX PubMed=23734073; RA Zhao X., Ren Y., Zhang X., Chen C., Dong B., Li Y.; RT "A novel GUCY2D mutation in a Chinese family with dominant cone RT dystrophy."; RL Mol. Vis. 19:1039-1046(2013). RN [32] RP VARIANT CORD6 HIS-838. RX PubMed=24480840; DOI=10.1038/eye.2014.7; RA Mukherjee R., Robson A.G., Holder G.E., Stockman A., Egan C.A., Moore A.T., RA Webster A.R.; RT "A detailed phenotypic description of autosomal dominant cone dystrophy due RT to a de novo mutation in the GUCY2D gene."; RL Eye 28:481-487(2014). RN [33] RP VARIANTS CORD6 CYS-838; LYS-841 AND ASN-846. RX PubMed=25515582; DOI=10.1167/iovs.14-15647; RA Lazar C.H., Mutsuddi M., Kimchi A., Zelinger L., Mizrahi-Meissonnier L., RA Marks-Ohana D., Boleda A., Ratnapriya R., Sharon D., Swaroop A., Banin E.; RT "Whole exome sequencing reveals GUCY2D as a major gene associated with cone RT and cone-rod dystrophy in Israel."; RL Invest. Ophthalmol. Vis. Sci. 56:420-430(2014). RN [34] RP VARIANT LCA1 VAL-710. RX PubMed=27475985; DOI=10.1186/s12881-016-0314-2; RA Gradstein L., Zolotushko J., Sergeev Y.V., Lavy I., Narkis G., Perez Y., RA Guigui S., Sharon D., Banin E., Walter E., Lifshitz T., Birk O.S.; RT "Novel GUCY2D mutation causes phenotypic variability of Leber congenital RT amaurosis in a large kindred."; RL BMC Med. Genet. 17:52-52(2016). RN [35] RP INVOLVEMENT IN CSNB1I, AND VARIANT CSNB1I TRP-768. RX PubMed=29559409; DOI=10.1016/j.ajo.2018.03.021; RA Stunkel M.L., Brodie S.E., Cideciyan A.V., Pfeifer W.L., Kennedy E.L., RA Stone E.M., Jacobson S.G., Drack A.V.; RT "Expanded Retinal Disease Spectrum Associated With Autosomal Recessive RT Mutations in GUCY2D."; RL Am. J. Ophthalmol. 190:58-68(2018). CC -!- FUNCTION: Catalyzes the synthesis of cyclic GMP (cGMP) in rods and CC cones of photoreceptors. Plays an essential role in phototransduction, CC by mediating cGMP replenishment (PubMed:21928830, PubMed:30319355, CC PubMed:26100624, PubMed:9600905, PubMed:15123990). May also participate CC in the trafficking of membrane-asociated proteins to the photoreceptor CC outer segment membrane (By similarity). {ECO:0000250|UniProtKB:P52785, CC ECO:0000269|PubMed:15123990, ECO:0000269|PubMed:21928830, CC ECO:0000269|PubMed:26100624, ECO:0000269|PubMed:30319355, CC ECO:0000269|PubMed:9600905}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP = 3',5'-cyclic GMP + diphosphate; Xref=Rhea:RHEA:13665, CC ChEBI:CHEBI:33019, ChEBI:CHEBI:37565, ChEBI:CHEBI:57746; EC=4.6.1.2; CC Evidence={ECO:0000269|PubMed:15123990, ECO:0000269|PubMed:21928830, CC ECO:0000269|PubMed:26100624, ECO:0000269|PubMed:30319355, CC ECO:0000269|PubMed:7912093, ECO:0000269|PubMed:9600905}; CC -!- ACTIVITY REGULATION: Activated by GUCA1A when free calcium ions CC concentration is low, and inhibited by GUCA1A when free calcium ions CC concentration is high (By similarity). Negatively regulated by RD3; CC inhibits the basal and GUCA1A-stimulated guanylate cyclase activity CC (PubMed:21928830). {ECO:0000250|UniProtKB:P52785, CC ECO:0000269|PubMed:21928830}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.31 mM for GTP (in absence of RD3) {ECO:0000269|PubMed:21928830}; CC KM=1.57 mM for GTP (in presence of 30 nM of RD3) CC {ECO:0000269|PubMed:21928830}; CC KM=0.94 mM for GTP (in presence of 60 nM of RD3) CC {ECO:0000269|PubMed:21928830}; CC Vmax=3.5 nmol/min/mg enzyme (in absence of RD3) CC {ECO:0000269|PubMed:21928830}; CC Vmax=1.4 nmol/min/mg enzyme (in presence of 30 nM of RD3) CC {ECO:0000269|PubMed:21928830}; CC Vmax=0.7 nmol/min/mg enzyme (in presence of 60 nM of RD3) CC {ECO:0000269|PubMed:21928830}; CC -!- SUBUNIT: Homodimer; requires homodimerization for guanylyl cyclase CC activity (By similarity). Interacts with RD3; promotes the exit of CC GUCY2D from the endoplasmic reticulum and its trafficking to the CC photoreceptor outer segments (PubMed:21928830, PubMed:21078983). CC Interaction with RD3 negatively regulates guanylate cyclase activity CC (PubMed:21928830). {ECO:0000250|UniProtKB:P51840, CC ECO:0000269|PubMed:21078983, ECO:0000269|PubMed:21928830}. CC -!- INTERACTION: CC Q02846; Q7Z3Z2: RD3; NbExp=3; IntAct=EBI-1756902, EBI-10257497; CC -!- SUBCELLULAR LOCATION: Photoreceptor outer segment membrane CC {ECO:0000269|PubMed:7912093}; Single-pass type I membrane protein CC {ECO:0000255}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:30319355}; Single-pass type I membrane protein CC {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Retina. {ECO:0000269|PubMed:7912093}. CC -!- DISEASE: Leber congenital amaurosis 1 (LCA1) [MIM:204000]: A severe CC dystrophy of the retina, typically becoming evident in the first years CC of life. Visual function is usually poor and often accompanied by CC nystagmus, sluggish or near-absent pupillary responses, photophobia, CC high hyperopia and keratoconus. {ECO:0000269|PubMed:11035546, CC ECO:0000269|PubMed:12365911, ECO:0000269|PubMed:15123990, CC ECO:0000269|PubMed:17724218, ECO:0000269|PubMed:21602930, CC ECO:0000269|PubMed:27475985, ECO:0000269|PubMed:30319355, CC ECO:0000269|PubMed:8944027, ECO:0000269|PubMed:9888789}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Cone-rod dystrophy 6 (CORD6) [MIM:601777]: An inherited CC retinal dystrophy characterized by retinal pigment deposits visible on CC fundus examination, predominantly in the macular region, and initial CC loss of cone photoreceptors followed by rod degeneration. This leads to CC decreased visual acuity and sensitivity in the central visual field, CC followed by loss of peripheral vision. Severe loss of vision occurs CC earlier than in retinitis pigmentosa, due to cone photoreceptors CC degenerating at a higher rate than rod photoreceptors. CC {ECO:0000269|PubMed:12552567, ECO:0000269|PubMed:15111605, CC ECO:0000269|PubMed:18332321, ECO:0000269|PubMed:18487367, CC ECO:0000269|PubMed:20517349, ECO:0000269|PubMed:21552474, CC ECO:0000269|PubMed:22194653, ECO:0000269|PubMed:23734073, CC ECO:0000269|PubMed:24480840, ECO:0000269|PubMed:25515582, CC ECO:0000269|PubMed:27475985, ECO:0000269|PubMed:30319355, CC ECO:0000269|PubMed:9618177, ECO:0000269|PubMed:9683616}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Choroidal dystrophy, central areolar, 1 (CACD1) [MIM:215500]: CC A form of central areolar choroidal dystrophy, a retinal disease that CC affects the macula and results in a well-demarcated circumscribed area CC of atrophy of the pigment epithelium and choriocapillaris. CACD1 CC inheritance is autosomal recessive. {ECO:0000269|PubMed:22695961}. CC Note=The disease may be caused by variants affecting the gene CC represented in this entry. CC -!- DISEASE: Night blindness, congenital stationary, 1I (CSNB1I) CC [MIM:618555]: A form of congenital stationary night blindness, a non- CC progressive retinal disorder characterized by impaired night vision or CC in dim light, with good vision only on bright days. CSNB1I patients CC present with night blindness from infancy or early childhood. Visual CC acuity is preserved, but some patients have color vision and/or visual CC field defects. Progression to mild retinitis pigmentosa may occur. CC CSNB1I inheritance is autosomal recessive. CC {ECO:0000269|PubMed:29559409}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: The gene names for receptor guanylyl cyclases are CC inconsistent between mouse and human. The ortholog of the mouse Gucy2d CC gene is a pseudogene in humans. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}. CC -!- WEB RESOURCE: Name=Mutations of the GUCY2D gene; Note=Retina CC International's Scientific Newsletter; CC URL="https://www.retina-international.org/files/sci-news/gcmut.htm"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M92432; AAA60547.1; -; mRNA. DR EMBL; AJ222657; CAA10914.1; -; Genomic_DNA. DR EMBL; L26921; AAA60366.1; -; Genomic_DNA. DR CCDS; CCDS11127.1; -. DR PIR; JH0717; JH0717. DR RefSeq; NP_000171.1; NM_000180.3. DR RefSeq; XP_011522118.1; XM_011523816.1. DR AlphaFoldDB; Q02846; -. DR SMR; Q02846; -. DR BioGRID; 109255; 17. DR IntAct; Q02846; 3. DR STRING; 9606.ENSP00000254854; -. DR TCDB; 8.A.85.1.3; the guanylate cyclase (gc) family. DR GlyCosmos; Q02846; 1 site, No reported glycans. DR GlyGen; Q02846; 1 site. DR iPTMnet; Q02846; -. DR PhosphoSitePlus; Q02846; -. DR BioMuta; GUCY2D; -. DR DMDM; 1345920; -. DR jPOST; Q02846; -. DR MassIVE; Q02846; -. DR MaxQB; Q02846; -. DR PaxDb; 9606-ENSP00000254854; -. DR PeptideAtlas; Q02846; -. DR ProteomicsDB; 58131; -. DR Antibodypedia; 12365; 275 antibodies from 29 providers. DR DNASU; 3000; -. DR Ensembl; ENST00000254854.5; ENSP00000254854.4; ENSG00000132518.7. DR GeneID; 3000; -. DR KEGG; hsa:3000; -. DR MANE-Select; ENST00000254854.5; ENSP00000254854.4; NM_000180.4; NP_000171.1. DR UCSC; uc002gjt.3; human. DR AGR; HGNC:4689; -. DR CTD; 3000; -. DR DisGeNET; 3000; -. DR GeneCards; GUCY2D; -. DR HGNC; HGNC:4689; GUCY2D. DR HPA; ENSG00000132518; Tissue enriched (retina). DR MalaCards; GUCY2D; -. DR MIM; 204000; phenotype. DR MIM; 215500; phenotype. DR MIM; 300071; phenotype. DR MIM; 600179; gene. DR MIM; 601777; phenotype. DR MIM; 618555; phenotype. DR neXtProt; NX_Q02846; -. DR OpenTargets; ENSG00000132518; -. DR Orphanet; 75377; Central areolar choroidal dystrophy. DR Orphanet; 1872; Cone rod dystrophy. DR Orphanet; 65; Leber congenital amaurosis. DR PharmGKB; PA187; -. DR VEuPathDB; HostDB:ENSG00000132518; -. DR eggNOG; KOG1023; Eukaryota. DR GeneTree; ENSGT00940000161326; -. DR HOGENOM; CLU_001072_1_0_1; -. DR InParanoid; Q02846; -. DR OMA; LPFDTIH; -. DR OrthoDB; 3683909at2759; -. DR PhylomeDB; Q02846; -. DR TreeFam; TF106338; -. DR BRENDA; 4.6.1.2; 2681. DR PathwayCommons; Q02846; -. DR Reactome; R-HSA-2514859; Inactivation, recovery and regulation of the phototransduction cascade. DR SignaLink; Q02846; -. DR BioGRID-ORCS; 3000; 12 hits in 1184 CRISPR screens. DR GenomeRNAi; 3000; -. DR Pharos; Q02846; Tbio. DR PRO; PR:Q02846; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q02846; Protein. DR Bgee; ENSG00000132518; Expressed in esophagus mucosa and 91 other cell types or tissues. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0005640; C:nuclear outer membrane; TAS:ProtInc. DR GO; GO:0097381; C:photoreceptor disc membrane; TAS:Reactome. DR GO; GO:0001750; C:photoreceptor outer segment; IDA:UniProtKB. DR GO; GO:0042622; C:photoreceptor outer segment membrane; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0004016; F:adenylate cyclase activity; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW. DR GO; GO:0004383; F:guanylate cyclase activity; IDA:UniProtKB. DR GO; GO:0001653; F:peptide receptor activity; IBA:GO_Central. DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; IEA:InterPro. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc. DR GO; GO:0006182; P:cGMP biosynthetic process; IBA:GO_Central. DR GO; GO:0019934; P:cGMP-mediated signaling; IEA:Ensembl. DR GO; GO:0007168; P:receptor guanylyl cyclase signaling pathway; IBA:GO_Central. DR GO; GO:0022400; P:regulation of rhodopsin mediated signaling pathway; TAS:Reactome. DR GO; GO:0007601; P:visual perception; TAS:ProtInc. DR CDD; cd07302; CHD; 1. DR CDD; cd06371; PBP1_sensory_GC_DEF-like; 1. DR CDD; cd14043; PK_GC-2D; 1. DR Gene3D; 3.40.50.2300; -; 1. DR Gene3D; 3.30.70.1230; Nucleotide cyclase; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR001054; A/G_cyclase. DR InterPro; IPR018297; A/G_cyclase_CS. DR InterPro; IPR001828; ANF_lig-bd_rcpt. DR InterPro; IPR011645; HNOB_dom_associated. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR029787; Nucleotide_cyclase. DR InterPro; IPR028082; Peripla_BP_I. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR PANTHER; PTHR11920; GUANYLYL CYCLASE; 1. DR PANTHER; PTHR11920:SF228; RETINAL GUANYLYL CYCLASE 1; 1. DR Pfam; PF01094; ANF_receptor; 1. DR Pfam; PF00211; Guanylate_cyc; 1. DR Pfam; PF07701; HNOBA; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR SMART; SM00044; CYCc; 1. DR SUPFAM; SSF55073; Nucleotide cyclase; 1. DR SUPFAM; SSF53822; Periplasmic binding protein-like I; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 1. DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; Q02846; HS. PE 1: Evidence at protein level; KW Cell projection; cGMP biosynthesis; Cone-rod dystrophy; KW Congenital stationary night blindness; Disease variant; Disulfide bond; KW Endoplasmic reticulum; Glycoprotein; GTP-binding; KW Leber congenital amaurosis; Lyase; Membrane; Nucleotide-binding; KW Reference proteome; Sensory transduction; Signal; Transmembrane; KW Transmembrane helix; Vision. FT SIGNAL 1..51 FT /evidence="ECO:0000250|UniProtKB:P55203" FT CHAIN 52..1103 FT /note="Retinal guanylyl cyclase 1" FT /id="PRO_0000012381" FT TOPO_DOM 52..462 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 463..487 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 488..1103 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 525..808 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 880..1010 FT /note="Guanylate cyclase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT REGION 1065..1103 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1085..1103 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 297 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 449 FT /note="Interchain" FT /evidence="ECO:0000305" FT DISULFID 457 FT /note="Interchain" FT /evidence="ECO:0000305" FT VARIANT 21 FT /note="W -> R (in dbSNP:rs9905402)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067168" FT VARIANT 52 FT /note="A -> S (in LCA1; uncertain significance; FT dbSNP:rs61749665)" FT /evidence="ECO:0000269|PubMed:21602930, FT ECO:0000269|PubMed:8944027" FT /id="VAR_003435" FT VARIANT 55 FT /note="T -> M (in LCA1; dbSNP:rs201414567)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067169" FT VARIANT 103 FT /note="E -> V (in LCA1)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067170" FT VARIANT 105 FT /note="C -> Y (in LCA1; does not affect basal guanylate FT cyclase activity; reduces GUCA1A-induced guanylate cyclase FT activity; dbSNP:rs61749669)" FT /evidence="ECO:0000269|PubMed:11035546, FT ECO:0000269|PubMed:15123990" FT /id="VAR_023770" FT VARIANT 312 FT /note="T -> M (in LCA1; dbSNP:rs61749673)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067171" FT VARIANT 325 FT /note="L -> P (in LCA1; does not affect basal guanylate FT cyclase activity; reduces GUCA1A-induced guanylate cyclase FT activity; dbSNP:rs61749675)" FT /evidence="ECO:0000269|PubMed:11035546, FT ECO:0000269|PubMed:15123990" FT /id="VAR_023771" FT VARIANT 325 FT /note="L -> R (found in a patient with LCA1)" FT /evidence="ECO:0000269|PubMed:17724218" FT /id="VAR_067172" FT VARIANT 328 FT /note="A -> V (in dbSNP:rs56280231)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042229" FT VARIANT 331 FT /note="R -> S (in dbSNP:rs34596269)" FT /id="VAR_049254" FT VARIANT 362 FT /note="A -> S (in LCA1; dbSNP:rs61749677)" FT /id="VAR_009129" FT VARIANT 405..406 FT /note="LD -> PN (in LCA1)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067173" FT VARIANT 431 FT /note="G -> D (in a metastatic melanoma sample; somatic FT mutation; dbSNP:rs1451501407)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042230" FT VARIANT 438 FT /note="R -> C (in LCA1; dbSNP:rs565948960)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067174" FT VARIANT 507 FT /note="V -> M (in dbSNP:rs746002871)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042231" FT VARIANT 565 FT /note="F -> S (in LCA1; loss of activity; FT dbSNP:rs61749755)" FT /evidence="ECO:0000269|PubMed:9888789" FT /id="VAR_009131" FT VARIANT 573 FT /note="I -> V (in LCA1; dbSNP:rs61749756)" FT /id="VAR_009130" FT VARIANT 602 FT /note="R -> W (in dbSNP:rs770740012)" FT /id="VAR_049255" FT VARIANT 640 FT /note="W -> L (in LCA1)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067175" FT VARIANT 660 FT /note="R -> Q (in LCA1; dbSNP:rs61750162)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067176" FT VARIANT 693 FT /note="A -> E (in dbSNP:rs35146471)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042232" FT VARIANT 701 FT /note="P -> S (in dbSNP:rs34598902)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:17724218, ECO:0000269|PubMed:21602930" FT /id="VAR_009132" FT VARIANT 710 FT /note="A -> V (in LCA1; loss of basal and GUCA1A-induced FT guanylate cyclase activity; does not affect endoplasmic FT reticulum membrane localization; dbSNP:rs781725943)" FT /evidence="ECO:0000269|PubMed:27475985, FT ECO:0000269|PubMed:30319355" FT /id="VAR_082624" FT VARIANT 722 FT /note="R -> W (in dbSNP:rs34331388)" FT /id="VAR_049256" FT VARIANT 728 FT /note="D -> H (in LCA1)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067177" FT VARIANT 734 FT /note="I -> A (in LCA1; requires 2 nucleotide FT substitutions)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067178" FT VARIANT 768 FT /note="R -> W (in LCA1 and CSNB1I; dbSNP:rs61750168)" FT /evidence="ECO:0000269|PubMed:17724218, FT ECO:0000269|PubMed:21602930, ECO:0000269|PubMed:29559409" FT /id="VAR_067179" FT VARIANT 782 FT /note="L -> H (in dbSNP:rs8069344)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_009133" FT VARIANT 784 FT /note="M -> R (in LCA1; dbSNP:rs375010731)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067180" FT VARIANT 795 FT /note="R -> Q (in LCA1; dbSNP:rs61750171)" FT /evidence="ECO:0000269|PubMed:17724218" FT /id="VAR_067181" FT VARIANT 837..839 FT /note="ERT -> DCM (in CORD6)" FT /evidence="ECO:0000269|PubMed:9683616" FT /id="VAR_003438" FT VARIANT 837 FT /note="E -> D (in CORD6; dbSNP:rs28933695)" FT /evidence="ECO:0000269|PubMed:9618177" FT /id="VAR_003436" FT VARIANT 838 FT /note="R -> C (in CORD6; dbSNP:rs61750172)" FT /evidence="ECO:0000269|PubMed:12552567, FT ECO:0000269|PubMed:18487367, ECO:0000269|PubMed:25515582, FT ECO:0000269|PubMed:9618177" FT /id="VAR_003437" FT VARIANT 838 FT /note="R -> G (in CORD6)" FT /evidence="ECO:0000269|PubMed:18487367" FT /id="VAR_071605" FT VARIANT 838 FT /note="R -> H (in CORD6; dbSNP:rs61750173)" FT /evidence="ECO:0000269|PubMed:12552567, FT ECO:0000269|PubMed:18487367, ECO:0000269|PubMed:22194653, FT ECO:0000269|PubMed:24480840" FT /id="VAR_015373" FT VARIANT 838 FT /note="R -> P (in CORD6; dbSNP:rs61750173)" FT /evidence="ECO:0000269|PubMed:21552474" FT /id="VAR_071606" FT VARIANT 841 FT /note="E -> K (in CORD6; decreases basal and GUCA1A-induced FT guanylate cyclase activity; inhibition by RD3 is less FT effective; does not affect endoplasmic reticulum membrane FT localization; dbSNP:rs1341592819)" FT /evidence="ECO:0000269|PubMed:25515582, FT ECO:0000269|PubMed:30319355" FT /id="VAR_082625" FT VARIANT 846 FT /note="K -> N (in CORD6; decreases basal and GUCA1A-induced FT guanylate cyclase activity; inhibition by RD3 is less FT effective; does not affect endoplasmic reticulum membrane FT localization; dbSNP:rs1598150539)" FT /evidence="ECO:0000269|PubMed:25515582, FT ECO:0000269|PubMed:30319355" FT /id="VAR_082626" FT VARIANT 849 FT /note="T -> A (in CORD6)" FT /evidence="ECO:0000269|PubMed:23734073" FT /id="VAR_071607" FT VARIANT 858 FT /note="P -> S (in LCA1; severely impairs basal and FT GUCA1A-induced guanylate cyclase activity; FT dbSNP:rs61750176)" FT /evidence="ECO:0000269|PubMed:11035546, FT ECO:0000269|PubMed:15123990" FT /id="VAR_009134" FT VARIANT 873 FT /note="P -> R (in CORD6; loss basal and GUCA1A-induced FT guanylate cyclase activity; does not affect endoplasmic FT reticulum membrane localization; dbSNP:rs1567961680)" FT /evidence="ECO:0000269|PubMed:30319355" FT /id="VAR_082627" FT VARIANT 902 FT /note="V -> L (in LCA1; increases basal and GUCA1A-induced FT guanylate cyclase activity; inhibition by RD3 is less FT effective; does not affect endoplasmic reticulum membrane FT localization; dbSNP:rs1598150793)" FT /evidence="ECO:0000269|PubMed:30319355" FT /id="VAR_082628" FT VARIANT 933 FT /note="V -> A (in CACD1; uncertain significance; FT dbSNP:rs1567961904)" FT /evidence="ECO:0000269|PubMed:22695961" FT /id="VAR_080484" FT VARIANT 949 FT /note="I -> T (in CORD6; dbSNP:rs267606857)" FT /evidence="ECO:0000269|PubMed:20517349" FT /id="VAR_071608" FT VARIANT 954 FT /note="L -> P (in LCA1; severely impairs basal and GUCA1A FT induced guanylate cyclase; dbSNP:rs61750182)" FT /evidence="ECO:0000269|PubMed:12365911, FT ECO:0000269|PubMed:15123990" FT /id="VAR_009135" FT VARIANT 1007 FT /note="S -> L (in LCA1)" FT /evidence="ECO:0000269|PubMed:21602930" FT /id="VAR_067182" FT VARIANT 1027 FT /note="I -> IGI (in LCA1)" FT /id="VAR_067183" FT MUTAGEN 822 FT /note="R->P: Fails to become activated by GUCA1A and by FT GUCA1B. Does not affect the binding to RP3." FT /evidence="ECO:0000269|PubMed:26100624" FT MUTAGEN 823 FT /note="M->R: Fails to become activated by GUCA1A and by FT GUCA1B. Does not affect the binding to RP3." FT /evidence="ECO:0000269|PubMed:26100624" FT MUTAGEN 925 FT /note="E->K: Changes the substrate specificity from GTP to FT ATP." FT /evidence="ECO:0000269|PubMed:9600905" FT MUTAGEN 997 FT /note="C->D: Changes the substrate specificity from GTP to FT ATP." FT /evidence="ECO:0000269|PubMed:9600905" SQ SEQUENCE 1103 AA; 120059 MW; 28631557E7CBDFA4 CRC64; MTACARRAGG LPDPGLCGPA WWAPSLPRLP RALPRLPLLL LLLLLQPPAL SAVFTVGVLG PWACDPIFSR ARPDLAARLA AARLNRDPGL AGGPRFEVAL LPEPCRTPGS LGAVSSALAR VSGLVGPVNP AACRPAELLA EEAGIALVPW GCPWTQAEGT TAPAVTPAAD ALYALLRAFG WARVALVTAP QDLWVEAGRS LSTALRARGL PVASVTSMEP LDLSGAREAL RKVRDGPRVT AVIMVMHSVL LGGEEQRYLL EAAEELGLTD GSLVFLPFDT IHYALSPGPE ALAALANSSQ LRRAHDAVLT LTRHCPSEGS VLDSLRRAQE RRELPSDLNL QQVSPLFGTI YDAVFLLARG VAEARAAAGG RWVSGAAVAR HIRDAQVPGF CGDLGGDEEP PFVLLDTDAA GDRLFATYML DPARGSFLSA GTRMHFPRGG SAPGPDPSCW FDPNNICGGG LEPGLVFLGF LLVVGMGLAG AFLAHYVRHR LLHMQMVSGP NKIILTVDDI TFLHPHGGTS RKVAQGSRSS LGARSMSDIR SGPSQHLDSP NIGVYEGDRV WLKKFPGDQH IAIRPATKTA FSKLQELRHE NVALYLGLFL ARGAEGPAAL WEGNLAVVSE HCTRGSLQDL LAQREIKLDW MFKSSLLLDL IKGIRYLHHR GVAHGRLKSR NCIVDGRFVL KITDHGHGRL LEAQKVLPEP PRAEDQLWTA PELLRDPALE RRGTLAGDVF SLAIIMQEVV CRSAPYAMLE LTPEEVVQRV RSPPPLCRPL VSMDQAPVEC ILLMKQCWAE QPELRPSMDH TFDLFKNINK GRKTNIIDSM LRMLEQYSSN LEDLIRERTE ELELEKQKTD RLLTQMLPPS VAEALKTGTP VEPEYFEQVT LYFSDIVGFT TISAMSEPIE VVDLLNDLYT LFDAIIGSHD VYKVETIGDA YMVASGLPQR NGQRHAAEIA NMSLDILSAV GTFRMRHMPE VPVRIRIGLH SGPCVAGVVG LTMPRYCLFG DTVNTASRME STGLPYRIHV NLSTVGILRA LDSGYQVELR GRTELKGKGA EDTFWLVGRR GFNKPIPKPP DLQPGSSNHG ISLQEIPPER RRKLEKARPG QFS //