GUC1A_HUMAN
ID GUC1A_HUMAN Reviewed; 201 AA.
AC P43080; B3KWT4; Q7Z6T1; Q9NU14;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Guanylyl cyclase-activating protein 1;
DE Short=GCAP 1;
DE AltName: Full=Guanylate cyclase activator 1A;
GN Name=GUCA1A; Synonyms=C6orf131, GCAP, GCAP1, GUCA1;
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 [GENOMIC DNA / MRNA].
RC TISSUE=Retina;
RX PubMed=7983048; DOI=10.1016/s0021-9258(18)47393-0;
RA Subbaraya I., Ruiz C.C., Helekar B.S., Zhao X., Gorczyca W.A.,
RA Pettenati M.J., Rao P.N., Palczewski K., Baehr W.;
RT "Molecular characterization of human and mouse photoreceptor guanylate
RT cyclase-activating protein (GCAP) and chromosomal localization of the human
RT gene.";
RL J. Biol. Chem. 269:31080-31089(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=9620085;
RA Cuenca N., Lopez S., Howes K., Kolb H.;
RT "The localization of guanylyl cyclase-activating proteins in the mammalian
RT retina.";
RL Invest. Ophthalmol. Vis. Sci. 39:1243-1250(1998).
RN [7]
RP VARIANT COD3 CYS-99.
RX PubMed=9425234; DOI=10.1093/hmg/7.2.273;
RA Payne A.M., Downes S.M., Bessant D.A.R., Taylor R., Holder G.E.,
RA Warren M.J., Bird A.C., Bhattacharya S.S.;
RT "A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal
RT dominant cone dystrophy pedigree mapping to a new locus on chromosome
RT 6p21.1.";
RL Hum. Mol. Genet. 7:273-277(1998).
RN [8]
RP CHARACTERIZATION OF VARIANTS COD3 LEU-50 AND CYS-99.
RX PubMed=11108966; DOI=10.1016/s0167-4889(00)00099-9;
RA Sokal I., Li N., Verlinde C.L.M.J., Haeseleer F., Baehr W., Palczewski K.;
RT "Ca(2+)-binding proteins in the retina: from discovery to etiology of human
RT disease.";
RL Biochim. Biophys. Acta 1498:233-251(2000).
RN [9]
RP VARIANTS COD3 LEU-50 AND CYS-99.
RX PubMed=11146732;
RA Downes S.M., Holder G.E., Fitzke F.W., Payne A.M., Warren M.J.,
RA Bhattacharya S.S., Bird A.C.;
RT "Autosomal dominant cone and cone-rod dystrophy with mutations in the
RT guanylate cyclase activator 1A gene-encoding guanylate cyclase activating
RT protein-1.";
RL Arch. Ophthalmol. 119:96-105(2001).
RN [10]
RP VARIANT COD3 GLY-155.
RX PubMed=11484154; DOI=10.1086/323265;
RA Wilkie S.E., Li Y., Deery E.C., Newbold R.J., Garibaldi D., Bateman J.B.,
RA Zhang H., Lin W., Zack D.J., Bhattacharya S.S., Warren M.J., Hunt D.M.,
RA Zhang K.;
RT "Identification and functional consequences of a new mutation (E155G) in
RT the gene for GCAP1 that causes autosomal dominant cone dystrophy.";
RL Am. J. Hum. Genet. 69:471-480(2001).
RN [11]
RP VARIANT COD3 ILE-143 DELINS ASN-THR, AND VARIANT ILE-114.
RX PubMed=15505030; DOI=10.1167/iovs.04-0590;
RA Nishiguchi K.M., Sokal I., Yang L., Roychowdhury N., Palczewski K.,
RA Berson E.L., Dryja T.P., Baehr W.;
RT "A novel mutation (I143NT) in guanylate cyclase-activating protein 1
RT (GCAP1) associated with autosomal dominant cone degeneration.";
RL Invest. Ophthalmol. Vis. Sci. 45:3863-3870(2004).
RN [12]
RP VARIANT CORD14 PHE-151.
RX PubMed=15790869; DOI=10.1167/iovs.04-1431;
RA Sokal I., Dupps W.J., Grassi M.A., Brown J. Jr., Affatigato L.M.,
RA Roychowdhury N., Yang L., Filipek S., Palczewski K., Stone E.M., Baehr W.;
RT "A novel GCAP1 missense mutation (L151F) in a large family with autosomal
RT dominant cone-rod dystrophy (adCORD).";
RL Invest. Ophthalmol. Vis. Sci. 46:1124-1132(2005).
RN [13]
RP VARIANT COD3 PHE-151.
RX PubMed=15735604;
RA Jiang L., Katz B.J., Yang Z., Zhao Y., Faulkner N., Hu J., Baird J.,
RA Baehr W., Creel D.J., Zhang K.;
RT "Autosomal dominant cone dystrophy caused by a novel mutation in the GCAP1
RT gene (GUCA1A).";
RL Mol. Vis. 11:143-151(2005).
RN [14]
RP VARIANT COD3 LYS-104, CHARACTERIZATION OF VARIANT COD3 LYS-104, AND
RP FUNCTION.
RX PubMed=18706439; DOI=10.1016/j.visres.2008.07.016;
RA Jiang L., Wheaton D., Bereta G., Zhang K., Palczewski K., Birch D.G.,
RA Baehr W.;
RT "A novel GCAP1(N104K) mutation in EF-hand 3 (EF3) linked to autosomal
RT dominant cone dystrophy.";
RL Vision Res. 48:2425-2432(2008).
RN [15]
RP VARIANTS COD3 LYS-89; GLU-100; PHE-151 AND VAL-159, CHARACTERIZATION OF
RP VARIANTS COD3 LYS-89; GLU-100 AND VAL-159, AND FUNCTION.
RX PubMed=19459154; DOI=10.1002/humu.21055;
RA Kitiratschky V.B.D., Behnen P., Kellner U., Heckenlively J.R., Zrenner E.,
RA Jaegle H., Kohl S., Wissinger B., Koch K.-W.;
RT "Mutations in the GUCA1A gene involved in hereditary cone dystrophies
RT impair calcium-mediated regulation of guanylate cyclase.";
RL Hum. Mutat. 30:E782-E796(2009).
RN [16]
RP VARIANTS CORD14 PHE-84 AND THR-107.
RX PubMed=24024198; DOI=10.1155/2013/517570;
RA Kamenarova K., Corton M., Garcia-Sandoval B., Fernandez-San Jose P.,
RA Panchev V., Avila-Fernandez A., Lopez-Molina M.I., Chakarova C., Ayuso C.,
RA Bhattacharya S.S.;
RT "Novel GUCA1A mutations suggesting possible mechanisms of pathogenesis in
RT cone, cone-rod, and macular dystrophy patients.";
RL Biomed. Res. Int. 2013:517570-517570(2013).
RN [17]
RP VARIANT CORD14 GLY-100.
RX PubMed=24352742; DOI=10.1007/s10633-013-9420-z;
RA Nong E., Lee W., Merriam J.E., Allikmets R., Tsang S.H.;
RT "Disease progression in autosomal dominant cone-rod dystrophy caused by a
RT novel mutation (D100G) in the GUCA1A gene.";
RL Doc. Ophthalmol. 128:59-67(2014).
RN [18]
RP CHARACTERIZATION OF VARIANTS CORD14 PHE-84 AND THR-107.
RX PubMed=26358777; DOI=10.1093/hmg/ddv370;
RA Marino V., Scholten A., Koch K.W., Dell'Orco D.;
RT "Two retinal dystrophy-associated missense mutations in GUCA1A with
RT distinct molecular properties result in a similar aberrant regulation of
RT the retinal guanylate cyclase.";
RL Hum. Mol. Genet. 24:6653-6666(2015).
RN [19]
RP VARIANT COD3 LEU-120.
RX PubMed=28125083; DOI=10.1038/gim.2016.217;
RA Chen X., Sheng X., Zhuang W., Sun X., Liu G., Shi X., Huang G., Mei Y.,
RA Li Y., Pan X., Liu Y., Li Z., Zhao Q., Yan B., Zhao C.;
RT "GUCA1A mutation causes maculopathy in a five-generation family with a wide
RT spectrum of severity.";
RL Genet. Med. 19:945-954(2017).
RN [20]
RP VARIANT PHE-176, AND CHARACTERIZATION OF VARIANT PHE-176.
RX PubMed=28025326; DOI=10.1093/hmg/ddw374;
RA Vocke F., Weisschuh N., Marino V., Malfatti S., Jacobson S.G., Reiff C.M.,
RA Dell'Orco D., Koch K.W.;
RT "Dysfunction of cGMP signalling in photoreceptors by a macular dystrophy-
RT related mutation in the calcium sensor GCAP1.";
RL Hum. Mol. Genet. 26:133-144(2017).
RN [21]
RP VARIANT VAL-101 DEL, AND VARIANT COD3 GLU-148.
RX PubMed=28442884;
RA Manes G., Mamouni S., Herald E., Richard A.C., Senechal A., Aouad K.,
RA Bocquet B., Meunier I., Hamel C.P.;
RT "Cone dystrophy or macular dystrophy associated with novel autosomal
RT dominant GUCA1A mutations.";
RL Mol. Vis. 23:198-209(2017).
RN [22]
RP VARIANT CORD14 VAL-111, CHARACTERIZATION OF VARIANT CORD14 VAL-111,
RP FUNCTION, AND SUBUNIT.
RX PubMed=30184081; DOI=10.1093/hmg/ddy311;
RA Marino V., Dal Cortivo G., Oppici E., Maltese P.E., D'Esposito F.,
RA Manara E., Ziccardi L., Falsini B., Magli A., Bertelli M., Dell'Orco D.;
RT "A novel p.(Glu111Val) missense mutation in GUCA1A associated with cone-rod
RT dystrophy leads to impaired calcium sensing and perturbed second messenger
RT homeostasis in photoreceptors.";
RL Hum. Mol. Genet. 27:4204-4217(2018).
RN [23]
RP VARIANT CORD14 ARG-86, CHARACTERIZATION OF VARIANT CORD14 ARG-86, AND
RP FUNCTION.
RX PubMed=30622141; DOI=10.1074/jbc.ra118.006180;
RA Peshenko I.V., Cideciyan A.V., Sumaroka A., Olshevskaya E.V., Scholten A.,
RA Abbas S., Koch K.W., Jacobson S.G., Dizhoor A.M.;
RT "A G86R mutation in the calcium-sensor protein GCAP1 alters regulation of
RT retinal guanylyl cyclase and causes dominant cone-rod degeneration.";
RL J. Biol. Chem. 294:3476-3488(2019).
RN [24]
RP VARIANT COD3 GLY-144, AND CHARACTERIZATION OF VARIANT COD3 GLY-144.
RX PubMed=32025184;
RA Tang S., Xia Y., Dai Y., Liu Y., Li J., Pan X., Chen P.;
RT "Functional characterization of a novel GUCA1A missense mutation (D144G) in
RT autosomal dominant cone dystrophy: A novel pathogenic GUCA1A variant in
RT COD.";
RL Mol. Vis. 25:921-921(2019).
RN [25]
RP VARIANTS COD3 ILE-42; GLU-68; ILE-80; ASN-99; SER-99; PHE-151 AND ARG-184.
RX PubMed=31728034; DOI=10.1038/s41598-019-52660-1;
RA Mizobuchi K., Hayashi T., Katagiri S., Yoshitake K., Fujinami K., Yang L.,
RA Kuniyoshi K., Shinoda K., Machida S., Kondo M., Ueno S., Terasaki H.,
RA Matsuura T., Tsunoda K., Iwata T., Nakano T.;
RT "Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy:
RT low prevalence among Japanese patients with inherited retinal
RT dystrophies.";
RL Sci. Rep. 9:16851-16851(2019).
RN [26]
RP CHARACTERIZATION OF VARIANT CORD14 ARG-86.
RX PubMed=31979372; DOI=10.3390/ijms21030752;
RA Abbas S., Marino V., Bielefeld L., Koch K.W., Dell'Orco D.;
RT "Constitutive activation of guanylate cyclase by the G86R GCAP1 variant is
RT due to 'locking' cation-pi interactions that impair the activator-to-
RT inhibitor structural transition.";
RL Int. J. Mol. Sci. 21:0-0(2020).
CC -!- FUNCTION: Stimulates retinal guanylyl cyclase when free calcium ions
CC concentration is low and inhibits guanylyl cyclase when free calcium
CC ions concentration is elevated (PubMed:19459154, PubMed:30622141,
CC PubMed:18706439, PubMed:30184081). This Ca(2+)-sensitive regulation of
CC retinal guanylyl cyclase is a key event in recovery of the dark state
CC of rod photoreceptors following light exposure (By similarity). May be
CC involved in cone photoreceptor light response and recovery of response
CC in bright light (By similarity). {ECO:0000250|UniProtKB:P43081,
CC ECO:0000250|UniProtKB:P46065, ECO:0000269|PubMed:18706439,
CC ECO:0000269|PubMed:30184081, ECO:0000269|PubMed:30622141}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:30184081}.
CC -!- INTERACTION:
CC P43080; O95994: AGR2; NbExp=3; IntAct=EBI-6873005, EBI-712648;
CC P43080; Q9BXJ0: C1QTNF5; NbExp=3; IntAct=EBI-6873005, EBI-19947914;
CC P43080; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-6873005, EBI-742054;
CC P43080; Q96PH6: DEFB118; NbExp=3; IntAct=EBI-6873005, EBI-17250528;
CC P43080; O15499: GSC2; NbExp=3; IntAct=EBI-6873005, EBI-19954058;
CC P43080; Q9BW62: KATNAL1; NbExp=3; IntAct=EBI-6873005, EBI-743591;
CC P43080; P31321: PRKAR1B; NbExp=3; IntAct=EBI-6873005, EBI-2805516;
CC -!- SUBCELLULAR LOCATION: Membrane; Lipid-anchor
CC {ECO:0000250|UniProtKB:P46065}. Photoreceptor inner segment
CC {ECO:0000269|PubMed:9620085}. Cell projection, cilium, photoreceptor
CC outer segment {ECO:0000269|PubMed:9620085}. Note=Present at higher
CC levels in cone than in rod outer segments (PubMed:9620085). Subcellular
CC location is not affected by light or dark conditions.
CC {ECO:0000269|PubMed:9620085}.
CC -!- TISSUE SPECIFICITY: In the retina, it is expressed in rod and cone
CC photoreceptors. {ECO:0000269|PubMed:9620085}.
CC -!- DOMAIN: Binds three calcium ions (via EF-hands 2, 3 and 4) when calcium
CC levels are high. Binds Mg(2+) when calcium levels are low.
CC {ECO:0000250|UniProtKB:P46065}.
CC -!- DISEASE: Cone dystrophy 3 (COD3) [MIM:602093]: An autosomal dominant
CC cone dystrophy. Cone dystrophies are retinal dystrophies characterized
CC by progressive degeneration of the cone photoreceptors with
CC preservation of rod function, as indicated by electroretinogram.
CC However, some rod involvement may be present in some cone dystrophies,
CC particularly at late stage. Affected individuals suffer from
CC photophobia, loss of visual acuity, color vision and central visual
CC field. Another sign is the absence of macular lesions for many years.
CC Cone dystrophies are distinguished from the cone-rod dystrophies in
CC which some loss of peripheral vision also occurs.
CC {ECO:0000269|PubMed:11108966, ECO:0000269|PubMed:11146732,
CC ECO:0000269|PubMed:11484154, ECO:0000269|PubMed:15505030,
CC ECO:0000269|PubMed:15735604, ECO:0000269|PubMed:18706439,
CC ECO:0000269|PubMed:19459154, ECO:0000269|PubMed:28125083,
CC ECO:0000269|PubMed:28442884, ECO:0000269|PubMed:31728034,
CC ECO:0000269|PubMed:32025184, ECO:0000269|PubMed:9425234}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Cone-rod dystrophy 14 (CORD14) [MIM:602093]: An autosomal
CC dominant form of cone-rod dystrophy, a retinal disease characterized by
CC retinal pigment deposits visible on fundus examination, predominantly
CC in the macular region, and initial loss of cone photoreceptors followed
CC by rod degeneration. This leads to decreased visual acuity and
CC sensitivity in the central visual field, followed by loss of peripheral
CC vision. Severe loss of vision occurs earlier than in retinitis
CC pigmentosa, due to cone photoreceptors degenerating at a higher rate
CC than rod photoreceptors. {ECO:0000269|PubMed:15790869,
CC ECO:0000269|PubMed:24024198, ECO:0000269|PubMed:24352742,
CC ECO:0000269|PubMed:26358777, ECO:0000269|PubMed:30184081,
CC ECO:0000269|PubMed:30622141, ECO:0000269|PubMed:31979372}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- WEB RESOURCE: Name=Mutations of the GUCA1A gene; Note=Retina
CC International's Scientific Newsletter;
CC URL="https://www.retina-international.org/files/sci-news/gcmut.htm";
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DR EMBL; L36859; AAA60541.1; -; mRNA.
DR EMBL; L36861; AAA60542.1; -; Genomic_DNA.
DR EMBL; AK125780; BAG54246.1; -; mRNA.
DR EMBL; AL096814; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471081; EAX04084.1; -; Genomic_DNA.
DR EMBL; BC031663; AAH31663.1; -; mRNA.
DR CCDS; CCDS4864.1; -.
DR PIR; C55331; C55331.
DR RefSeq; NP_000400.2; NM_000409.4.
DR RefSeq; NP_001305990.1; NM_001319061.1.
DR RefSeq; NP_001305991.1; NM_001319062.1.
DR RefSeq; XP_011512839.1; XM_011514537.2.
DR RefSeq; XP_011512841.1; XM_011514539.1.
DR AlphaFoldDB; P43080; -.
DR SMR; P43080; -.
DR BioGRID; 109233; 8.
DR IntAct; P43080; 8.
DR STRING; 9606.ENSP00000377784; -.
DR DrugBank; DB08231; Myristic acid.
DR BioMuta; GUCA1A; -.
DR DMDM; 46577585; -.
DR MassIVE; P43080; -.
DR PaxDb; P43080; -.
DR PeptideAtlas; P43080; -.
DR PRIDE; P43080; -.
DR ProteomicsDB; 55577; -.
DR Antibodypedia; 30136; 193 antibodies from 29 providers.
DR DNASU; 2978; -.
DR Ensembl; ENST00000372958.2; ENSP00000362049.1; ENSG00000048545.17.
DR Ensembl; ENST00000654459.1; ENSP00000499539.1; ENSG00000048545.17.
DR GeneID; 118142757; -.
DR GeneID; 2978; -.
DR KEGG; hsa:118142757; -.
DR MANE-Select; ENST00000372958.2; ENSP00000362049.1; NM_001384910.1; NP_001371839.1.
DR UCSC; uc003orx.4; human.
DR CTD; 2978; -.
DR DisGeNET; 2978; -.
DR GeneCards; GUCA1A; -.
DR HGNC; HGNC:4678; GUCA1A.
DR HPA; ENSG00000048545; Tissue enriched (retina).
DR MalaCards; GUCA1A; -.
DR MIM; 600364; gene.
DR MIM; 602093; phenotype.
DR neXtProt; NX_P43080; -.
DR OpenTargets; ENSG00000048545; -.
DR Orphanet; 75377; Central areolar choroidal dystrophy.
DR Orphanet; 1872; Cone rod dystrophy.
DR Orphanet; 1871; Progressive cone dystrophy.
DR PharmGKB; PA29062; -.
DR VEuPathDB; HostDB:ENSG00000048545; -.
DR eggNOG; KOG0044; Eukaryota.
DR GeneTree; ENSGT00940000160607; -.
DR HOGENOM; CLU_072366_4_1_1; -.
DR InParanoid; P43080; -.
DR OMA; IRTINPC; -.
DR OrthoDB; 1271942at2759; -.
DR PhylomeDB; P43080; -.
DR TreeFam; TF333971; -.
DR PathwayCommons; P43080; -.
DR Reactome; R-HSA-2514859; Inactivation, recovery and regulation of the phototransduction cascade.
DR SignaLink; P43080; -.
DR BioGRID-ORCS; 2978; 11 hits in 1068 CRISPR screens.
DR ChiTaRS; GUCA1A; human.
DR GeneWiki; GUCA1A; -.
DR GenomeRNAi; 2978; -.
DR Pharos; P43080; Tbio.
DR PRO; PR:P43080; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; P43080; protein.
DR Bgee; ENSG00000048545; Expressed in nucleus accumbens and 44 other tissues.
DR Genevisible; P43080; HS.
DR GO; GO:0120199; C:cone photoreceptor outer segment; IDA:UniProtKB.
DR GO; GO:0097381; C:photoreceptor disc membrane; TAS:Reactome.
DR GO; GO:0001917; C:photoreceptor inner segment; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0008048; F:calcium sensitive guanylate cyclase activator activity; ISS:UniProtKB.
DR GO; GO:0030249; F:guanylate cyclase regulator activity; IMP:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; ISS:UniProtKB.
DR GO; GO:0007602; P:phototransduction; IEA:Ensembl.
DR GO; GO:0010753; P:positive regulation of cGMP-mediated signaling; IEA:Ensembl.
DR GO; GO:0031284; P:positive regulation of guanylate cyclase activity; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; NAS:ProtInc.
DR GO; GO:0007601; P:visual perception; IBA:GO_Central.
DR CDD; cd00051; EFh; 2.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR033022; GUCA1A.
DR InterPro; IPR028846; Recoverin.
DR PANTHER; PTHR23055; PTHR23055; 1.
DR PANTHER; PTHR23055:SF13; PTHR23055:SF13; 1.
DR Pfam; PF13499; EF-hand_7; 1.
DR Pfam; PF13833; EF-hand_8; 1.
DR SMART; SM00054; EFh; 3.
DR SUPFAM; SSF47473; SSF47473; 1.
DR PROSITE; PS00018; EF_HAND_1; 3.
DR PROSITE; PS50222; EF_HAND_2; 4.
PE 1: Evidence at protein level;
KW Calcium; Cell projection; Cone-rod dystrophy; Disease variant; Lipoprotein;
KW Membrane; Metal-binding; Myristate; Reference proteome; Repeat;
KW Sensory transduction; Vision.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000255"
FT CHAIN 2..201
FT /note="Guanylyl cyclase-activating protein 1"
FT /id="PRO_0000073803"
FT DOMAIN 31..49
FT /note="EF-hand 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT DOMAIN 51..86
FT /note="EF-hand 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT DOMAIN 87..122
FT /note="EF-hand 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT DOMAIN 131..166
FT /note="EF-hand 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 64
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 66
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 68
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 70
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 75
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 100
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 102
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 104
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 106
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 111
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 144
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 146
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 148
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 150
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 155
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT MOD_RES 3
FT /note="Deamidated asparagine"
FT /evidence="ECO:0000255"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250|UniProtKB:P46065"
FT VARIANT 42
FT /note="F -> I (in COD3; likely benign variant)"
FT /evidence="ECO:0000269|PubMed:31728034"
FT /id="VAR_083669"
FT VARIANT 50
FT /note="P -> L (in COD3; some subjects may present a
FT moderately severe cone-rod dystrophy; unknown pathological
FT significance; causes a decrease in the number of bound
FT calcium ions from 3 to 2, without changing the activity
FT profile; dbSNP:rs104893968)"
FT /evidence="ECO:0000269|PubMed:11108966,
FT ECO:0000269|PubMed:11146732"
FT /id="VAR_010648"
FT VARIANT 68
FT /note="D -> E (in COD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:31728034"
FT /id="VAR_083670"
FT VARIANT 80
FT /note="L -> I (in COD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:31728034"
FT /id="VAR_083671"
FT VARIANT 84
FT /note="L -> F (in CORD14; affects guanylate cyclase
FT regulator activity resulting in constitutive activation of
FT GUCY2D at physiologic calcium concentrations; altered
FT tertiary structure; no change of affinity for calcium ions;
FT increased affinity for magnesium ions)"
FT /evidence="ECO:0000269|PubMed:24024198,
FT ECO:0000269|PubMed:26358777"
FT /id="VAR_083672"
FT VARIANT 86
FT /note="G -> R (in CORD14; results in impaired guanylate
FT cyclase regulator activity; interferes with GCAP1 calcium-
FT dependent transition from activator to inhibitor of GUCY2D;
FT the mutant protein remains active at high calcium
FT concentrations causing persistent GUCY2D stimulation)"
FT /evidence="ECO:0000269|PubMed:30622141,
FT ECO:0000269|PubMed:31979372"
FT /id="VAR_083673"
FT VARIANT 89
FT /note="E -> K (in COD3; exhibits an about 6-fold shift of
FT ionic calcium concentration at which the guanylate cyclase
FT activity is halfmaximal)"
FT /evidence="ECO:0000269|PubMed:19459154"
FT /id="VAR_060802"
FT VARIANT 99
FT /note="Y -> C (in COD3; results in impaired guanylate
FT cyclase regulator activity; at high calcium ion
FT concentrations the mutant protein stimulates GUCY2D
FT activity while the wild-type inhibits it;
FT dbSNP:rs104893967)"
FT /evidence="ECO:0000269|PubMed:11108966,
FT ECO:0000269|PubMed:11146732, ECO:0000269|PubMed:9425234"
FT /id="VAR_001372"
FT VARIANT 99
FT /note="Y -> N (in COD3)"
FT /evidence="ECO:0000269|PubMed:31728034"
FT /id="VAR_083674"
FT VARIANT 99
FT /note="Y -> S (in COD3)"
FT /evidence="ECO:0000269|PubMed:31728034"
FT /id="VAR_083675"
FT VARIANT 100
FT /note="D -> E (in COD3; exhibits an about 28-fold shift of
FT ionic calcium concentration at which the guanylate cyclase
FT activity is halfmaximal)"
FT /evidence="ECO:0000269|PubMed:19459154"
FT /id="VAR_060803"
FT VARIANT 100
FT /note="D -> G (in CORD14)"
FT /evidence="ECO:0000269|PubMed:24352742"
FT /id="VAR_083676"
FT VARIANT 101
FT /note="Missing (found in a family with autosomal dominant
FT macular dystrophy; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:28442884"
FT /id="VAR_083677"
FT VARIANT 104
FT /note="N -> K (in COD3; results in impaired guanylate
FT cyclase regulator activity; at low calcium concentrations
FT the mutant protein stimulates GUCY2D less efficiently than
FT the wild-type but it remains active at high calcium
FT concentrations causing persistent GUCY2D stimulation)"
FT /evidence="ECO:0000269|PubMed:18706439"
FT /id="VAR_083678"
FT VARIANT 107
FT /note="I -> T (in CORD14; affects guanylate cyclase
FT regulator activity resulting in constitutive activation of
FT GUCY2D at physiologic calcium concentrations; 10-fold lower
FT affinity for calcium ions)"
FT /evidence="ECO:0000269|PubMed:24024198,
FT ECO:0000269|PubMed:26358777"
FT /id="VAR_083679"
FT VARIANT 111
FT /note="E -> V (in CORD14; results in impaired guanylate
FT cyclase regulator activity; at low calcium concentrations
FT the mutant protein stimulates GUCY2D as the wild-type while
FT at high calcium concentrations it does not fully inhibit
FT GUCY2D; decreased affinity for calcium ions)"
FT /evidence="ECO:0000269|PubMed:30184081"
FT /id="VAR_083680"
FT VARIANT 114
FT /note="T -> I (in a patient with an atypical form of
FT retinitis pigmentosa; unknown pathological significance;
FT dbSNP:rs771261841)"
FT /evidence="ECO:0000269|PubMed:15505030"
FT /id="VAR_060804"
FT VARIANT 120
FT /note="R -> L (in COD3)"
FT /evidence="ECO:0000269|PubMed:28125083"
FT /id="VAR_083681"
FT VARIANT 143
FT /note="I -> NT (in COD3)"
FT /evidence="ECO:0000269|PubMed:15505030"
FT /id="VAR_060805"
FT VARIANT 144
FT /note="D -> G (in COD3; results in impaired guanylate
FT cyclase regulator activity leading to increased GUCY2D
FT activity)"
FT /evidence="ECO:0000269|PubMed:32025184"
FT /id="VAR_083682"
FT VARIANT 148
FT /note="D -> E (in COD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:28442884"
FT /id="VAR_083683"
FT VARIANT 151
FT /note="L -> F (in COD3 and CORD14; dbSNP:rs121434631)"
FT /evidence="ECO:0000269|PubMed:15735604,
FT ECO:0000269|PubMed:15790869, ECO:0000269|PubMed:19459154,
FT ECO:0000269|PubMed:31728034"
FT /id="VAR_060806"
FT VARIANT 155
FT /note="E -> G (in COD3; constitutive activation of GUCY2D)"
FT /evidence="ECO:0000269|PubMed:11484154"
FT /id="VAR_012987"
FT VARIANT 159
FT /note="G -> V (in COD3; exhibits an about 18-fold shift of
FT ionic calcium concentration at which the guanylate cyclase
FT activity is halfmaximal)"
FT /evidence="ECO:0000269|PubMed:19459154"
FT /id="VAR_060807"
FT VARIANT 176
FT /note="L -> F (found in autosomal dominant macular
FT dystrophy; unknown pathological significance; affects
FT guanylate cyclase regulator activity resulting in a
FT constitutively active form at physiologic calcium
FT concentrations; no change of affinity for calcium ions;
FT increased affinity for magnesium ions)"
FT /evidence="ECO:0000269|PubMed:28025326"
FT /id="VAR_083684"
FT VARIANT 184
FT /note="Q -> R (in COD3; likely benign variant)"
FT /evidence="ECO:0000269|PubMed:31728034"
FT /id="VAR_083685"
FT CONFLICT 79
FT /note="A -> G (in Ref. 1; AAA60541/AAA60542)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 201 AA; 22920 MW; 063C6AD61BE44406 CRC64;
MGNVMEGKSV EELSSTECHQ WYKKFMTECP SGQLTLYEFR QFFGLKNLSP SASQYVEQMF
ETFDFNKDGY IDFMEYVAAL SLVLKGKVEQ KLRWYFKLYD VDGNGCIDRD ELLTIIQAIR
AINPCSDTTM TAEEFTDTVF SKIDVNGDGE LSLEEFIEGV QKDQMLLDTL TRSLDLTRIV
RRLQNGEQDE EGADEAAEAA G
