RBCC Red Blood Cell Collection

ABCG2 (ABCP, BCRP, BCRP1, MXR) [Confidence: high (a blood group or CD marker)]
ATP-binding cassette sub-family G member 2 (Breast cancer resistance protein; CDw338; Mitoxantrone resistance-associated protein; Placenta-specific ATP-binding cassette transporter; Urate exporter; CD338)

hRBCD IPI00298214
IPI00298214 ATP-binding cassette, sub-family G, member 2 ATP-binding cassette, sub-family G, member 2 membrane n/a n/a n/a n/a 1 n/a n/a n/a 3 n/a 2 1 n/a n/a n/a 2 1 n/a 1 n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight

BGMUT jr
1450 jr ABCG2 ABCG2 1017delCTC 1017-1019 delCTC S340 del exon 1 to 16 in gDNA + flanking regions Jr(a-) rare 23438071 not available Hue-Roye et al. Transfusion 2013 53 online Feb.25 Blumenfeld OO. 2013-03-26 14:28:24.107 NA

Comments
Isoform Q9UNQ0-2 was detected.

UniProt Q9UNQ0
ID ABCG2_HUMAN Reviewed; 655 AA.
AC Q9UNQ0; A0A1W3; A8K1T5; O95374; Q4W5I3; Q53ZQ1; Q569L4; Q5YLG4;
read moreAC Q86V64; Q8IX16; Q96LD6; Q96TA8; Q9BY73; Q9NUS0;
DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2005, sequence version 3.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=ATP-binding cassette sub-family G member 2;
DE AltName: Full=Breast cancer resistance protein;
DE AltName: Full=CDw338;
DE AltName: Full=Mitoxantrone resistance-associated protein;
DE AltName: Full=Placenta-specific ATP-binding cassette transporter;
DE AltName: Full=Urate exporter;
DE AltName: CD_antigen=CD338;
GN Name=ABCG2; Synonyms=ABCP, BCRP, BCRP1, MXR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS GLU-166 AND SER-208,
RP AND TISSUE SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=9850061;
RA Allikmets R., Schriml L.M., Hutchinson A., Romano-Spica V., Dean M.;
RT "A human placenta-specific ATP-binding cassette gene (ABCP) on
RT chromosome 4q22 that is involved in multidrug resistance.";
RL Cancer Res. 58:5337-5339(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Mammary cancer;
RX PubMed=9861027; DOI=10.1073/pnas.95.26.15665;
RA Doyle L.A., Yang W., Abruzzo L.V., Krogmann T., Gao Y., Rishi A.K.,
RA Ross D.D.;
RT "A multidrug resistance transporter from human MCF-7 breast cancer
RT cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:15665-15670(1998).
RN [3]
RP ERRATUM.
RA Doyle L.A., Yang W., Abruzzo L.V., Krogmann T., Gao Y., Rishi A.K.,
RA Ross D.D.;
RL Proc. Natl. Acad. Sci. U.S.A. 96:2569-2569(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Kage K., Tsukahara S., Sugiyama T., Asada S., Ishikawa E., Tsuruo T.,
RA Sugimoto Y.;
RT "Breast cancer resistance protein constitutes a 140-kDa complex as a
RT homodimer.";
RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11306452;
RA Komatani H., Kotani H., Hara Y., Nakagawa R., Matsumoto M.,
RA Arakawa H., Nishimura S.;
RT "Identification of breast cancer resistant protein/mitoxantrone
RT resistance/placenta-specific, ATP-binding cassette transporter as a
RT transporter of NB-506 and J-107088, topoisomerase I inhibitors with an
RT indolocarbazole structure.";
RL Cancer Res. 61:2827-2832(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11533706; DOI=10.1038/nm0901-1028;
RA Zhou S., Schuetz J.D., Bunting K.D., Colapietro A.M., Sampath J.,
RA Morris J.J., Lagutina I., Grosveld G.C., Osawa M., Nakauchi H.,
RA Sorrentino B.P.;
RT "The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of
RT stem cells and is a molecular determinant of the side-population
RT phenotype.";
RL Nat. Med. 7:1028-1034(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND VARIANTS GLU-166
RP AND SER-208.
RC TISSUE=Brain endothelium;
RX PubMed=12958161; DOI=10.1096/fj.02-1131fje;
RA Zhang W., Mojsilovic-Petrovic J., Andrade M.F., Zhang H., Ball M.,
RA Stanimirovic D.B.;
RT "The expression and functional characterization of ABCG2 in brain
RT endothelial cells and vessels.";
RL FASEB J. 17:2085-2087(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT LYS-141.
RA Yoshikawa M., Yabuuchi H., Ikegami Y., Ishikawa T.;
RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT PRO-316.
RA Sudarikov A., Makarik T., Andreeff M.;
RT "Cell line K562 resistant to Hoechst 33342.";
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Hippocampus, and Placenta;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS MET-12; LYS-141;
RP HIS-296 AND THR-528.
RG SeattleSNPs variation discovery resource;
RL Submitted (SEP-2006) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP LYS-141.
RC TISSUE=Pancreas, and PNS;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 294-655 (ISOFORM 1).
RX PubMed=9892175;
RA Miyake K., Mickley L., Litman T., Zhan Z., Robey R.W., Cristensen B.,
RA Brangi M., Greenberger L., Dean M., Fojo T., Bates S.E.;
RT "Molecular cloning of cDNAs which are highly overexpressed in
RT mitoxantrone-resistant cells: demonstration of homology to ABC
RT transport genes.";
RL Cancer Res. 59:8-13(1999).
RN [15]
RP REVIEW.
RX PubMed=11590207;
RA Schmitz G., Langmann T., Heimerl S.;
RT "Role of ABCG1 and other ABCG family members in lipid metabolism.";
RL J. Lipid Res. 42:1513-1520(2001).
RN [16]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=15001581; DOI=10.1074/jbc.M310785200;
RA Xu J., Liu Y., Yang Y., Bates S., Zhang J.T.;
RT "Characterization of oligomeric human half-ABC transporter ATP-binding
RT cassette G2.";
RL J. Biol. Chem. 279:19781-19789(2004).
RN [17]
RP SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-596, AND MUTAGENESIS OF
RP ASN-418; ASN-557 AND ASN-596.
RX PubMed=15807535; DOI=10.1021/bi0479858;
RA Diop N.K., Hrycyna C.A.;
RT "N-linked glycosylation of the human ABC transporter ABCG2 on
RT asparagine 596 is not essential for expression, transport activity, or
RT trafficking to the plasma membrane.";
RL Biochemistry 44:5420-5429(2005).
RN [18]
RP MUTAGENESIS OF ARG-482.
RX PubMed=15670731; DOI=10.1016/j.bbamem.2004.11.005;
RA Oezvegy-Laczka C., Koebloes G., Sarkadi B., Varadi A.;
RT "Single amino acid (482) variants of the ABCG2 multidrug transporter:
RT major differences in transport capacity and substrate recognition.";
RL Biochim. Biophys. Acta 1668:53-63(2005).
RN [19]
RP MUTAGENESIS OF LYS-86, SUBCELLULAR LOCATION, AND HOMODIMERIZATION.
RX PubMed=15769853; DOI=10.1242/jcs.01729;
RA Henriksen U., Gether U., Litman T.;
RT "Effect of Walker A mutation (K86M) on oligomerization and surface
RT targeting of the multidrug resistance transporter ABCG2.";
RL J. Cell Sci. 118:1417-1426(2005).
RN [20]
RP SUBUNIT, AND DISULFIDE BONDS.
RX PubMed=17686774; DOI=10.1074/jbc.C700133200;
RA Wakabayashi K., Nakagawa H., Tamura A., Koshiba S., Hoshijima K.,
RA Komada M., Ishikawa T.;
RT "Intramolecular disulfide bond is a critical check point determining
RT degradative fates of ATP-binding cassette (ABC) transporter ABCG2
RT protein.";
RL J. Biol. Chem. 282:27841-27846(2007).
RN [21]
RP INVOLVEMENT IN UAQTL1 AND GOUT.
RX PubMed=18834626; DOI=10.1016/S0140-6736(08)61343-4;
RA Dehghan A., Kottgen A., Yang Q., Hwang S.J., Kao W.L., Rivadeneira F.,
RA Boerwinkle E., Levy D., Hofman A., Astor B.C., Benjamin E.J.,
RA van Duijn C.M., Witteman J.C., Coresh J., Fox C.S.;
RT "Association of three genetic loci with uric acid concentration and
RT risk of gout: a genome-wide association study.";
RL Lancet 372:1953-1961(2008).
RN [22]
RP INVOLVEMENT IN UAQTL1, ASSOCIATION OF VARIANT LYS-141 WITH GOUT, AND
RP CHARACTERIZATION OF VARIANT LYS-141.
RX PubMed=19506252; DOI=10.1073/pnas.0901249106;
RA Woodward O.M., Kottgen A., Coresh J., Boerwinkle E., Guggino W.B.,
RA Kottgen M.;
RT "Identification of a urate transporter, ABCG2, with a common
RT functional polymorphism causing gout.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:10338-10342(2009).
RN [23]
RP INVOLVEMENT IN UAQTL1, AND ASSOCIATION OF VARIANT LYS-141 WITH GOUT.
RX PubMed=20368174; DOI=10.1126/scitranslmed.3000237;
RA Matsuo H., Takada T., Ichida K., Nakamura T., Nakayama A.,
RA Ikebuchi Y., Ito K., Kusanagi Y., Chiba T., Tadokoro S., Takada Y.,
RA Oikawa Y., Inoue H., Suzuki K., Okada R., Nishiyama J., Domoto H.,
RA Watanabe S., Fujita M., Morimoto Y., Naito M., Nishio K., Hishida A.,
RA Wakai K., Asai Y., Niwa K., Kamakura K., Nonoyama S., Sakurai Y.,
RA Hosoya T., Kanai Y., Suzuki H., Hamajima N., Shinomiya N.;
RT "Common defects of ABCG2, a high-capacity urate exporter, cause gout:
RT a function-based genetic analysis in a Japanese population.";
RL Sci. Transl. Med. 1:5ra11-5ra11(2009).
RN [24]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF HIS-583; CYS-603 AND TYR-605.
RX PubMed=20705604; DOI=10.1074/jbc.M110.139170;
RA Desuzinges-Mandon E., Arnaud O., Martinez L., Huche F., Di Pietro A.,
RA Falson P.;
RT "ABCG2 transports and transfers heme to albumin through its large
RT extracellular loop.";
RL J. Biol. Chem. 285:33123-33133(2010).
RN [25]
RP FUNCTION.
RX PubMed=22132962; DOI=10.1080/15257770.2011.633953;
RA Nakayama A., Matsuo H., Takada T., Ichida K., Nakamura T.,
RA Ikebuchi Y., Ito K., Hosoya T., Kanai Y., Suzuki H., Shinomiya N.;
RT "ABCG2 is a high-capacity urate transporter and its genetic impairment
RT increases serum uric acid levels in humans.";
RL Nucleosides Nucleotides Nucleic Acids 30:1091-1097(2011).
RN [26]
RP REVIEW.
RX PubMed=22509477;
RA Mo W., Zhang J.T.;
RT "Human ABCG2: structure, function, and its role in multidrug
RT resistance.";
RL Int. J. Biochem. Mol. Biol. 3:1-27(2012).
RN [27]
RP INVOLVEMENT IN JR, AND VARIANT MET-12.
RX PubMed=22246507; DOI=10.1038/ng.1075;
RA Zelinski T., Coghlan G., Liu X.Q., Reid M.E.;
RT "ABCG2 null alleles define the Jr(a-) blood group phenotype.";
RL Nat. Genet. 44:131-132(2012).
RN [28]
RP INVOLVEMENT IN JR.
RX PubMed=22246505; DOI=10.1038/ng.1070;
RA Saison C., Helias V., Ballif B.A., Peyrard T., Puy H., Miyazaki T.,
RA Perrot S., Vayssier-Taussat M., Waldner M., Le Pennec P.Y.,
RA Cartron J.P., Arnaud L.;
RT "Null alleles of ABCG2 encoding the breast cancer resistance protein
RT define the new blood group system Junior.";
RL Nat. Genet. 44:174-177(2012).
RN [29]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23189181; DOI=10.1371/journal.pone.0050082;
RA Kobuchi H., Moriya K., Ogino T., Fujita H., Inoue K., Shuin T.,
RA Yasuda T., Utsumi K., Utsumi T.;
RT "Mitochondrial localization of ABC transporter ABCG2 and its function
RT in 5-aminolevulinic acid-mediated protoporphyrin IX accumulation.";
RL PLoS ONE 7:E50082-E50082(2012).
RN [30]
RP VARIANTS MET-12 AND LYS-141.
RX PubMed=12111378; DOI=10.1007/s100380200041;
RA Iida A., Saito S., Sekine A., Mishima C., Kitamura Y., Kondo K.,
RA Harigae S., Osawa S., Nakamura Y.;
RT "Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes
RT encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8,
RT ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and
RT ABCG8.";
RL J. Hum. Genet. 47:285-310(2002).
RN [31]
RP VARIANTS LEU-431 AND LEU-489.
RX PubMed=15618737; DOI=10.2133/dmpk.18.212;
RA Itoda M., Saito Y., Shirao K., Minami H., Ohtsu A., Yoshida T.,
RA Saijo N., Suzuki H., Sugiyama Y., Ozawa S., Sawada J.;
RT "Eight novel single nucleotide polymorphisms in ABCG2/BCRP in Japanese
RT cancer patients administered irinotacan.";
RL Drug Metab. Pharmacokinet. 18:212-217(2003).
RN [32]
RP VARIANTS MET-12; LYS-141; LEU-206 AND TYR-590.
RX PubMed=12544509; DOI=10.1097/00008571-200301000-00004;
RA Zamber C.P., Lamba J.K., Yasuda K., Farnum J., Thummel K.,
RA Schuetz J.D., Schuetz E.G.;
RT "Natural allelic variants of breast cancer resistance protein (BCRP)
RT and their relationship to BCRP expression in human intestine.";
RL Pharmacogenetics 13:19-28(2003).
RN [33]
RP CHARACTERIZATION OF VARIANTS MET-12; LYS-141 AND ASN-620.
RX PubMed=15838659; DOI=10.1007/s00280-004-0931-x;
RA Morisaki K., Robey R.W., Oezvegy-Laczka C., Honjo Y., Polgar O.,
RA Steadman K., Sarkadi B., Bates S.E.;
RT "Single nucleotide polymorphisms modify the transporter activity of
RT ABCG2.";
RL Cancer Chemother. Pharmacol. 56:161-172(2005).
RN [34]
RP VARIANTS MET-12; LEU-13; LYS-141; GLN-160; ARG-354; LEU-431; ASN-441
RP AND LEU-489.
RX PubMed=16702730; DOI=10.2133/dmpk.21.109;
RA Maekawa K., Itoda M., Sai K., Saito Y., Kaniwa N., Shirao K.,
RA Hamaguchi T., Kunitoh H., Yamamoto N., Tamura T., Minami H.,
RA Kubota K., Ohtsu A., Yoshida T., Saijo N., Kamatani N., Ozawa S.,
RA Sawada J.;
RT "Genetic variation and haplotype structure of the ABC transporter gene
RT ABCG2 in a Japanese population.";
RL Drug Metab. Pharmacokinet. 21:109-121(2006).
CC -!- FUNCTION: High-capacity urate exporter functioning in both renal
CC and extrarenal urate excretion. Plays a role in porphyrin
CC homeostasis as it is able to mediates the export of protoporhyrin
CC IX (PPIX) both from mitochondria to cytosol and from cytosol to
CC extracellular space, and cellular export of hemin, and heme.
CC Xenobiotic transporter that may play an important role in the
CC exclusion of xenobiotics from the brain. Appears to play a major
CC role in the multidrug resistance phenotype of several cancer cell
CC lines. Implicated in the efflux of numerous drugs and xenobiotics:
CC mitoxantrone, the photosensitizer pheophorbide, camptothecin,
CC methotrexate, azidothymidine (AZT), and the anthracyclines
CC daunorubicin and doxorubicin.
CC -!- SUBUNIT: Monomer under reducing conditions, the minimal functional
CC units is a homodimer; disulfide-linked, but the major oligomeric
CC form in plasma membranes is a homotetramer with possibility of
CC higher order oligomerization up to homododecamers.
CC -!- INTERACTION:
CC P11309-1:PIM1; NbExp=9; IntAct=EBI-1569435, EBI-1018629;
CC P0CG48:UBC; NbExp=2; IntAct=EBI-1569435, EBI-3390054;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC Mitochondrion membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UNQ0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UNQ0-2; Sequence=VSP_014232, VSP_014233;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Highly expressed in placenta. Low expression
CC in small intestine, liver and colon.
CC -!- INDUCTION: Up-regulated in brain tumors.
CC -!- DOMAIN: The extracellular loop 3 (ECL3) is involved in binding
CC porphyrins and transfer them to other carriers, probably albumin.
CC -!- PTM: Glycosylation-deficient ABCG2 is normally expressed and
CC functional.
CC -!- POLYMORPHISM: Genetic variations in ABCG2 define the blood group
CC Junior system (JR) [MIM:614490]. Individuals with Jr(a-) blood
CC group lack the Jr(a) antigen on their red blood cells. These
CC individuals may have anti-Jr(a) antibodies in their serum, which
CC can cause transfusion reactions or hemolytic disease of the fetus
CC or newborn. Although the clinical significance of the Jr(a-) blood
CC group has been controversial, severe fatal hemolytic disease of
CC the newborn has been reported. The Jr(a-) phenotype has a higher
CC frequency in individuals of Asian descent, compared to those of
CC European descent. The Jr(a-) phenotype is inherited as an
CC autosomal recessive trait.
CC -!- POLYMORPHISM: Genetic variations in ABCG2 influence the variance
CC in serum uric acid concentrations and define the serum uric acid
CC concentration quantitative trait locus 1 (UAQTL1) [MIM:138900].
CC Excess serum accumulation of uric acid can lead to the development
CC of gout, a common disorder characterized by tissue deposition of
CC monosodium urate crystals as a consequence of hyperuricemia.
CC -!- MISCELLANEOUS: When overexpressed, the transfected cells become
CC resistant to mitoxantrone, daunorubicin and doxorubicin.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCG
CC family. Eye pigment precursor importer (TC 3.A.1.204) subfamily.
CC -!- SIMILARITY: Contains 1 ABC transmembrane type-2 domain.
CC -!- SIMILARITY: Contains 1 ABC transporter domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AF093771; Type=Frameshift; Positions=486, 586;
CC Sequence=AF093772; Type=Frameshift; Positions=386, 502, 586;
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/abcg2/";
CC -!- WEB RESOURCE: Name=ABCMdb; Note=Database for mutations in ABC
CC proteins;
CC URL="http://abcmutations.hegelab.org/proteinDetails?uniprot_id=Q9UNQ0";
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CC -----------------------------------------------------------------------
DR EMBL; AF103796; AAD09188.1; -; mRNA.
DR EMBL; AF098951; AAC97367.1; -; mRNA.
DR EMBL; AB056867; BAB39212.1; -; mRNA.
DR EMBL; AB051855; BAB46933.1; -; mRNA.
DR EMBL; AY017168; AAG52982.1; -; mRNA.
DR EMBL; AY289766; AAP44087.1; -; mRNA.
DR EMBL; AY288307; AAP31310.1; -; mRNA.
DR EMBL; AF463519; AAO14617.1; -; mRNA.
DR EMBL; AY333755; AAQ92941.1; -; mRNA.
DR EMBL; AY333756; AAQ92942.1; -; mRNA.
DR EMBL; AK002040; BAA92050.1; -; mRNA.
DR EMBL; AK290000; BAF82689.1; -; mRNA.
DR EMBL; DQ996467; ABI97388.1; -; Genomic_DNA.
DR EMBL; AC084732; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC097484; AAY40902.1; -; Genomic_DNA.
DR EMBL; BC021281; AAH21281.1; -; mRNA.
DR EMBL; BC092408; AAH92408.1; -; mRNA.
DR EMBL; AF093771; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AF093772; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_001244315.1; NM_001257386.1.
DR RefSeq; NP_004818.2; NM_004827.2.
DR RefSeq; XP_005263411.1; XM_005263354.1.
DR RefSeq; XP_005263412.1; XM_005263355.1.
DR UniGene; Hs.480218; -.
DR ProteinModelPortal; Q9UNQ0; -.
DR SMR; Q9UNQ0; 37-337.
DR DIP; DIP-29162N; -.
DR IntAct; Q9UNQ0; 3.
DR MINT; MINT-2840423; -.
DR BindingDB; Q9UNQ0; -.
DR ChEMBL; CHEMBL5393; -.
DR DrugBank; DB00619; Imatinib.
DR DrugBank; DB01204; Mitoxantrone.
DR DrugBank; DB00622; Nicardipine.
DR DrugBank; DB01054; Nitrendipine.
DR DrugBank; DB01098; Rosuvastatin.
DR DrugBank; DB01232; Saquinavir.
DR DrugBank; DB01030; Topotecan.
DR TCDB; 3.A.1.204.2; the atp-binding cassette (abc) superfamily.
DR PhosphoSite; Q9UNQ0; -.
DR DMDM; 67462103; -.
DR PaxDb; Q9UNQ0; -.
DR PRIDE; Q9UNQ0; -.
DR DNASU; 9429; -.
DR Ensembl; ENST00000237612; ENSP00000237612; ENSG00000118777.
DR Ensembl; ENST00000515655; ENSP00000426917; ENSG00000118777.
DR GeneID; 9429; -.
DR KEGG; hsa:9429; -.
DR UCSC; uc003hrf.3; human.
DR CTD; 9429; -.
DR GeneCards; GC04M089011; -.
DR HGNC; HGNC:74; ABCG2.
DR HPA; CAB037299; -.
DR MIM; 138900; phenotype.
DR MIM; 603756; gene.
DR MIM; 614490; phenotype.
DR neXtProt; NX_Q9UNQ0; -.
DR PharmGKB; PA390; -.
DR eggNOG; COG1131; -.
DR HOVERGEN; HBG050441; -.
DR InParanoid; Q9UNQ0; -.
DR KO; K05681; -.
DR OMA; FYKETKA; -.
DR OrthoDB; EOG7HXCR2; -.
DR PhylomeDB; Q9UNQ0; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR ChiTaRS; ABCG2; human.
DR GeneWiki; ABCG2; -.
DR GenomeRNAi; 9429; -.
DR NextBio; 35322; -.
DR PRO; PR:Q9UNQ0; -.
DR ArrayExpress; Q9UNQ0; -.
DR Bgee; Q9UNQ0; -.
DR Genevestigator; Q9UNQ0; -.
DR GO; GO:0016021; C:integral to membrane; TAS:ProtInc.
DR GO; GO:0016020; C:membrane; IEA:InterPro.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; TAS:ProtInc.
DR GO; GO:0016887; F:ATPase activity; IEA:InterPro.
DR GO; GO:0015232; F:heme transporter activity; TAS:Reactome.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:BHF-UCL.
DR GO; GO:0008559; F:xenobiotic-transporting ATPase activity; TAS:ProtInc.
DR GO; GO:0006200; P:ATP catabolic process; IEA:GOC.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0046415; P:urate metabolic process; IMP:UniProtKB.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR013525; ABC_2_trans.
DR InterPro; IPR003439; ABC_transporter-like.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF01061; ABC2_membrane; 1.
DR Pfam; PF00005; ABC_tran; 1.
DR SMART; SM00382; AAA; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS51012; ABC_TM2; FALSE_NEG.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; FALSE_NEG.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cell membrane; Complete proteome;
KW Disulfide bond; Glycoprotein; Membrane; Mitochondrion;
KW Nucleotide-binding; Polymorphism; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1 655 ATP-binding cassette sub-family G member
FT 2.
FT /FTId=PRO_0000093386.
FT TOPO_DOM 1 395 Cytoplasmic (Potential).
FT TRANSMEM 396 416 Helical; (Potential).
FT TOPO_DOM 417 428 Extracellular (Potential).
FT TRANSMEM 429 449 Helical; (Potential).
FT TOPO_DOM 450 477 Cytoplasmic (Potential).
FT TRANSMEM 478 498 Helical; (Potential).
FT TOPO_DOM 499 506 Extracellular (Potential).
FT TRANSMEM 507 527 Helical; (Potential).
FT TOPO_DOM 528 535 Cytoplasmic (Potential).
FT TRANSMEM 536 556 Helical; (Potential).
FT TOPO_DOM 557 630 Extracellular (Potential).
FT TRANSMEM 631 651 Helical; (Potential).
FT TOPO_DOM 652 655 Cytoplasmic (Potential).
FT DOMAIN 37 286 ABC transporter.
FT DOMAIN 389 651 ABC transmembrane type-2.
FT NP_BIND 80 87 ATP (Potential).
FT SITE 418 418 Not glycosylated.
FT SITE 557 557 Not glycosylated.
FT CARBOHYD 596 596 N-linked (GlcNAc...).
FT DISULFID 592 608
FT DISULFID 603 603 Interchain.
FT VAR_SEQ 550 611 IFSGLLVNLTTIASWLSWLQYFSIPRYGFTALQHNEFLGQN
FT FCPGLNATGNNPCNYATCTGE -> VCWSISQPLHLGCHGF
FT STSAFHDMDLRLCSIMNFWDKTSAQDSMQQETILVTMQHVL
FT AKNIW (in isoform 2).
FT /FTId=VSP_014232.
FT VAR_SEQ 612 655 Missing (in isoform 2).
FT /FTId=VSP_014233.
FT VARIANT 12 12 V -> M (found in Jr(a-) blood group
FT phenotype; dbSNP:rs2231137).
FT /FTId=VAR_020779.
FT VARIANT 13 13 S -> L.
FT /FTId=VAR_067363.
FT VARIANT 141 141 Q -> K (polymorphism associated with high
FT serum levels of uric acid and increased
FT risk of gout; results in lower urate
FT transport rates compared to wild-type;
FT dbSNP:rs2231142).
FT /FTId=VAR_020780.
FT VARIANT 160 160 R -> Q.
FT /FTId=VAR_067364.
FT VARIANT 166 166 Q -> E (in dbSNP:rs1061017).
FT /FTId=VAR_022704.
FT VARIANT 206 206 I -> L.
FT /FTId=VAR_022705.
FT VARIANT 208 208 F -> S (in dbSNP:rs1061018).
FT /FTId=VAR_022706.
FT VARIANT 248 248 S -> P (in dbSNP:rs3116448).
FT /FTId=VAR_022707.
FT VARIANT 296 296 D -> H (in dbSNP:rs41282401).
FT /FTId=VAR_030357.
FT VARIANT 316 316 T -> P.
FT /FTId=VAR_022443.
FT VARIANT 354 354 G -> R (in dbSNP:rs138606116).
FT /FTId=VAR_067365.
FT VARIANT 431 431 F -> L.
FT /FTId=VAR_018349.
FT VARIANT 441 441 S -> N.
FT /FTId=VAR_067366.
FT VARIANT 489 489 F -> L (in dbSNP:rs192169063).
FT /FTId=VAR_018350.
FT VARIANT 528 528 A -> T (in dbSNP:rs45605536).
FT /FTId=VAR_030358.
FT VARIANT 571 571 F -> I (in dbSNP:rs9282571).
FT /FTId=VAR_022708.
FT VARIANT 590 590 N -> Y (in dbSNP:rs34264773).
FT /FTId=VAR_035355.
FT VARIANT 620 620 D -> N (in dbSNP:rs34783571).
FT /FTId=VAR_022709.
FT MUTAGEN 86 86 K->M: Inactive and altered subcellular
FT location.
FT MUTAGEN 418 418 N->Q: No effect.
FT MUTAGEN 482 482 R->D: Decreases ATPase activity.
FT MUTAGEN 482 482 R->G,N,S,T: Increases ATPase activity.
FT MUTAGEN 482 482 R->K,I,M,Y: No change in ATPase activity.
FT MUTAGEN 482 482 R->T,Y: Decreases transport activity.
FT MUTAGEN 557 557 N->Q: No effect.
FT MUTAGEN 583 583 H->A: Strongly reduced binding to hemin
FT but not to PPIX.
FT MUTAGEN 596 596 N->Q: Loss of glycosylation.
FT MUTAGEN 603 603 C->A: Strongly reduced binding to hemin
FT but not to PPIX.
FT MUTAGEN 605 605 Y->A: No effect on hemin binding.
FT CONFLICT 24 24 A -> V (in Ref. 1; AAD09188 and 7;
FT AAP44087).
FT CONFLICT 315 316 Missing (in Ref. 10; BAA92050).
FT CONFLICT 390 390 G -> V (in Ref. 13; AAH92408).
FT CONFLICT 482 482 R -> G (in Ref. 14; AF093771/AF093772).
FT CONFLICT 482 482 R -> T (in Ref. 2; AAC97367).
FT CONFLICT 484 485 LP -> FT (in Ref. 14; AF093772).
FT CONFLICT 501 501 P -> A (in Ref. 6; AAG52982).
SQ SEQUENCE 655 AA; 72314 MW; A8AF66B96034C5A8 CRC64;
MSSSNVEVFI PVSQGNTNGF PATASNDLKA FTEGAVLSFH NICYRVKLKS GFLPCRKPVE
KEILSNINGI MKPGLNAILG PTGGGKSSLL DVLAARKDPS GLSGDVLING APRPANFKCN
SGYVVQDDVV MGTLTVRENL QFSAALRLAT TMTNHEKNER INRVIQELGL DKVADSKVGT
QFIRGVSGGE RKRTSIGMEL ITDPSILFLD EPTTGLDSST ANAVLLLLKR MSKQGRTIIF
SIHQPRYSIF KLFDSLTLLA SGRLMFHGPA QEALGYFESA GYHCEAYNNP ADFFLDIING
DSTAVALNRE EDFKATEIIE PSKQDKPLIE KLAEIYVNSS FYKETKAELH QLSGGEKKKK
ITVFKEISYT TSFCHQLRWV SKRSFKNLLG NPQASIAQII VTVVLGLVIG AIYFGLKNDS
TGIQNRAGVL FFLTTNQCFS SVSAVELFVV EKKLFIHEYI SGYYRVSSYF LGKLLSDLLP
MRMLPSIIFT CIVYFMLGLK PKADAFFVMM FTLMMVAYSA SSMALAIAAG QSVVSVATLL
MTICFVFMMI FSGLLVNLTT IASWLSWLQY FSIPRYGFTA LQHNEFLGQN FCPGLNATGN
NPCNYATCTG EEYLVKQGID LSPWGLWKNH VALACMIVIF LTIAYLKLLF LKKYS
//

MIM 138900
*RECORD*
*FIELD* NO
138900
*FIELD* TI
#138900 URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1; UAQTL1
;;GOUT SUSCEPTIBILITY 1; GOUT1
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that serum
uric acid concentration and susceptibility to gout can be conferred by
variation in the ABCG2 gene (603756) on chromosome 4q22.

DESCRIPTION

Gout is a common disorder resulting from tissue deposition of monosodium
urate crystals as a consequence of hyperuricemia. Patients with gout
experience very painful attacks caused by precipitation of urate in
joints, which triggers subsequent inflammation. Elevated serum uric acid
concentration is a key risk factor for gout (summary from Matsuo et al.,
2009 and Woodward et al., 2011).

- Genetic Heterogeneity of Serum Uric Acid Concentration Quantitative
Trait Loci

See also UAQTL2 (see 612076), conferred by variation in the SLC2A9 gene
(606142) on chromosome 4p; UAQTL4 (612671), conferred by variation in
the SLC17A3 gene (611034) on chromosome 6p21; UAQTL5 (614746),
associated with a SNP on chromosome 19q13; and UAQTL6 (614747),
associated with a SNP on chromosome 1.

MAPPING

The Pacific Austronesian population, including Taiwanese aborigines, has
a remarkably high prevalence of hyperuricemia and gout, suggesting a
founder effect across the Pacific region. Cheng et al. (2004) reported a
genomewide linkage study of 21 multiplex pedigrees with gout from an
aboriginal tribe in Taiwan. From observations of familial clustering,
early onset of gout, and clinically severe manifestations, they
hypothesized that a major gene plays a role in this trait. A highly
significant linkage for gout at marker D4S2623 was found on 4q25. When
alcohol consumption was included as a covariate in the model, the lod
score increased to 5.66.

By genomewide linkage analysis of 7,699 participants in the Framingham
cohort and in 4,148 participants in a Rotterdam cohort, Dehghan et al.
(2008) found a significant association between serum uric acid
concentration and a gln141-to-lys (Q141K; 603756.0007) substitution
(dbSNP rs2231142) in the ABCG2 gene on chromosome 4q22 (p = 9.0 x
10(-20) and p = 3.3 x 10(-9), respectively). The findings were
replicated in the ARIC cohort of 11,024 white and 3,843 black
individuals, yielding p values of 9.7 x 10(-30) and 9.8 x 10(-4),
respectively. The combined p value for white individuals from all 3
cohorts was 2.5 x 10(-60), and further analysis showed that the SNP was
direction-consistent with the development of gout in white participants
(OR of 1.74; p = 3.3 x 10(-15)).

PATHOGENESIS

Martinon et al. (2006) showed that monosodium urate (MSU) and calcium
pyrophosphate dihydrate (CPPD), both crystals found in gout, engage the
caspase-1 (CASP1; 147678)-activating NALP3 (606416) inflammasome,
resulting in the production of active interleukin (IL1)-1-beta (IL1B;
147720) and IL18 (IL18; 600953). Macrophages from mice deficient in
various components of the inflammasome such as CASP1, ASC (606838), and
NALP3 are defective in crystal-induced IL1B activation. Moreover, an
impaired neutrophil influx was found in an in vivo model of
crystal-induced peritonitis in inflammasome-deficient mice or mice
deficient in the IL1B receptor (IL1R; 147810). Martinon et al. (2006)
concluded that their findings provide insight into the molecular
processing underlying the inflammatory conditions of gout and
pseudogout, and further support a pivotal role of the inflammasome in
several autoinflammatory diseases.

INHERITANCE

Gout is a disorder in which, as in essential hypertension, diabetes
mellitus, and hypercholesterolemia, there is room for debate as to
whether polygenic or monomeric inheritance is its genetic basis.
Although numerous other genetic and environmental factors influence the
level of serum uric acid and although the phenotype gout can probably be
produced by nongenetic elevations of serum uric acid, classic familial
gout may be a monomeric dominantly inherited disorder. Certainly there
is genetic heterogeneity in gout as in the other phenotypes listed
above. This heterogeneity is documented by the definition of X-linked
forms of gout (e.g., 300323). Evidence for both an increased rate of
uric acid synthesis and an impaired net elimination of uric acid by the
kidney has been advanced. In some reported families with both parents
affected, children have been affected unusually early and severely and
may represent homozygotes (Emmerson, 1960).

The view on the polygenic inheritance of gout was stated by Neel et al.
(1965) and by Wyngaarden and Kelley (1972). Hyperuricemia in Filipinos
has been shown to result from interplay of environmental and genetic
factors (Healey et al., 1967). Morton (1979) analyzed the family data of
Hauge and Harvald (1955) and of Neel et al. (1965) and concluded that
hyperuricemia ascertained through a gouty proband is rarely due to a
major gene.

MOLECULAR GENETICS

Among 90 Japanese patients with increased serum uric acid levels, Matsuo
et al. (2009) identified 6 nonsynonymous changes in the ABCG2 gene. Two
polymorphic variants occurred at high frequencies and were studied in
more detail: Q126X (603756.0002) and Q141K (603756.0007). In vitro
cellular studies showed that ATP-dependent urate transport was reduced
by 46.7% in cells expressing a Q141K mutation and was nearly eliminated
in cells expressing a Q126X mutation, consistent with a loss of
function. Both of these variants showed a significant association with
hyperuricemia and with gout in a larger cohort of 228 Japanese men,
including 161 with gout, and 871 controls. The Q126X allele was
associated with a significantly increased risk of hyperuricemia (odds
ratio (OR) of 3.61; p = 2.91 x 10(-7)) and gout (OR of 4.25, p = 3.04 x
10(-8)). The Q141K allele was associated with a significantly increased
risk of hyperuricemia (OR of 2.06, p = 1.53 x 10(-11)) and gout (OR of
2.23; p = 5.54 x 10(-11)). These 2 variants were assigned to different
risk haplotypes, and combinations of these haplotypes conferred
different disease risks (up to an odds ratio of 25.8). Matsuo et al.
(2009) concluded that loss-of-function variants in the ABCG2 gene impair
urate excretion, resulting in hyperuricemia and gout.

- Genomewide Association Studies

Kottgen et al. (2013) reported the identification and replication of 28
genomewide-significant urate concentration-associated loci, 18 of which
were novel, using genomewide association study (GWAS) (26 loci) and
pathway (2 loci) approaches. The study combined data from more than
140,000 individuals of European ancestry within the Global Urate
Genetics Consortium (GUGC).

NOMENCLATURE

The locus on chromosome 4q22 identified by Dehghan et al. (2008) was
previously designated 'UAQTL3,' but is now believed to represent the
same UAQTL1 locus on 4q25 identified by Cheng et al. (2004) (Matsuo et
al., 2009).

*FIELD* RF
1. Cheng, L. S.-C.; Chiang, S.-L.; Tu, H.-P.; Chang, S.-J.; Wang,
T.-N.; Ko, A. M.-J.; Chakraborty, R.; Ko, Y.-C.: Genomewide scan
for gout in Taiwanese Aborigines reveals linkage to chromosome 4q25. Am.
J. Hum. Genet. 75: 498-503, 2004.

2. Dehghan, A.; Kottgen, A.; Yang, Q.; Hwang, S.-J.; Kao, W. H. L.;
Rivadeneira, F.; Boerwinkle, E.; Levy, D.; Hofman, A.; Astor, B. C.;
Benjamin, E. J.; van Duijn, C. M.; Witteman, J. C.; Coresh, J.; Fox,
C. S.: Association of three genetic loci with uric acid concentration
and risk of gout: a genome-wide association study. Lancet 372: 1953-1961,
2008.

3. Emmerson, B. T.: Heredity in primary gout. Aust. Ann. Med. 9:
168-175, 1960.

4. Hauge, M.; Harvald, B.: Heredity in gout and hyperuricemia. Acta
Med. Scand. 152: 247-257, 1955.

5. Healey, L. A.; Skeith, M. D.; Decker, J. L.; Bayani-Sioson, P.
S.: Hyperuricemia in Filipinos: interaction of heredity and environment. Am.
J. Hum. Genet. 19: 81-85, 1967.

6. Kottgen, A.; Albrecht, E.; Teumer, A.; Vitart, V.; Krumsiek, J.;
Hundertmark, C.; Pistis, G.; Ruggiero, D.; Seaghdha, C. M.; Haller,
T.; Yang, Q.; Tanaka, T.; and 218 others: Genome-wide association
analyses identify 18 new loci associated with serum urate concentrations. Nature
Genet. 45: 145-154, 2013.

7. Martinon, F.; Petrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J.
: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:
237-241, 2006.

8. Matsuo, H.; Takada, T.; Ichida, K.; Nakamura, T.; Nakayama, A.;
Ikebuchi, Y.; Ito, K.; Kusanagi, Y.; Chiba, T.; Tadokoro, S.; Takada,
Y.; Oikawa, Y.; and 22 others: Common defects of ABCG2, a high-capacity
urate exporter, cause gout: a function-based genetic analysis in a
Japanese population. Sci. Transl. Med. 1: 5ra11, 2009. Note: Electronic
Article.

9. Morton, N. E.: Genetics of hyperuricemia in families with gout. Am.
J. Med. Genet. 4: 103-106, 1979.

10. Neel, J. V.; Rakic, M. T.; Davidson, R. T.; Valkenburg, H. A.;
Mikkelson, W. M.: Studies on hyperuricemia. II. A reconsideration
of the distribution of serum uric acid values in the families of Smyth,
Cotterman, and Freyburg. Am. J. Hum. Genet. 17: 14-22, 1965.

11. Woodward, O, M.; Kottgen, A.; Kottgen, M.: ABCG transporters
and disease. FEBS J. 278: 3215-3225, 2011.

12. Wyngaarden, J. B.; Kelley, W. N.: Gout.In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.: The Metabolic Basis of Inherited Disease.
New York: McGraw-Hill (pub.) (3rd ed.): 1972. Pp. 889-968.

*FIELD* CS

Joints:
Arthritis

Skin:
Urate tophi

Lab:
Increased rate of uric acid synthesis;
Impaired net elimination of uric acid by the kidney;
Hyperuricemia

Inheritance:
? Autosomal dominant form

*FIELD* CN
Ada Hamosh - updated: 04/11/2013
Cassandra L. Kniffin - updated: 2/22/2012
Ada Hamosh - updated: 5/8/2008
Ada Hamosh - updated: 12/6/2006
Victor A. McKusick - updated: 9/8/2004

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 04/11/2013
joanna: 3/18/2013
carol: 8/10/2012
ckniffin: 8/7/2012
alopez: 7/27/2012
terry: 7/23/2012
carol: 2/24/2012
ckniffin: 2/22/2012
ckniffin: 3/18/2009
alopez: 5/21/2008
terry: 5/8/2008
alopez: 12/15/2006
terry: 12/6/2006
alopez: 9/10/2004
alopez: 9/9/2004
terry: 9/8/2004
carol: 5/20/1999
mimadm: 9/24/1994
davew: 8/1/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988

MIM 603756
*RECORD*
*FIELD* NO
603756
*FIELD* TI
*603756 ATP-BINDING CASSETTE, SUBFAMILY G, MEMBER 2; ABCG2
;;ATP-BINDING CASSETTE TRANSPORTER, PLACENTA-SPECIFIC; ABCP;;
read moreBREAST CANCER RESISTANCE PROTEIN; BCRP;;
MITOXANTRONE-RESISTANCE PROTEIN; MRX
*FIELD* TX

DESCRIPTION

The ABCG2 gene encodes a membrane transporter belonging to the
ATP-binding cassette (ABC) superfamily of membrane transporters, which
are involved in the trafficking of biologic molecules across cell
membranes. ABCG2 was initially found to be a xenobiotic transporter that
plays a role in the multidrug resistance phenotype of a specific human
breast cancer (Doyle et al., 1998) and has since been shown to confer
multidrug resistance in several cancer cells by actively exporting a
wide variety of drugs across the plasma membrane. The ABCG2 protein is
also a high capacity transporter for uric acid excretion in the kidney,
liver, and gut (summary from Matsuo et al., 2009 and Saison et al.,
2012).

For general information on the ABC superfamily, see ABCA4 (601691).

CLONING

Allikmets et al. (1998) characterized an ABC transporter gene, which
they designated ABCP, that is highly expressed in the placenta. The ABCP
gene produces 2 transcripts that differ at the 5-prime end and encode
the same 655-amino acid protein. The predicted protein is closely
related to the Drosophila White and the yeast ADP1 proteins.

MCF-7/AdrVp is a multidrug-resistant human breast cancer subline that
displays an ATP-dependent reduction in the intracellular accumulation of
anthracycline anticancer drugs in the absence of overexpression of known
multidrug resistance transporters such as P-glycoprotein (PGY1; 171050).
By RNA fingerprinting, Doyle et al. (1998) identified a 2.4-kb mRNA that
is overexpressed in these cells of the subline relative to parental
MCF-7 cells. The mRNA encodes a 665-amino acid member of the ATP-binding
cassette superfamily of transporters, which Doyle et al. (1998) termed
the transporter breast cancer resistance protein (BCRP).

Miyake et al. (1999) cloned 2 cDNAs for ABCG2, which they called MRX1
and MRX2, that were overexpressed in human colon carcinoma cells
selected for mitoxantrone resistance. Northern blot analysis confirmed
marked overexpression of mRNA between 2.89 and 3.4 kb in the resistant
cells. Using porcine brain capillary endothelial cells as a model for
the blood-brain barrier, Eisenblatter and Galla (2002) identified
porcine ABCG2 mRNA overexpressed in hydrocortisone-treated cultures.
Northern blot analysis revealed expression in brain, with predominant
localization within endothelial cells isolated from porcine brain
capillaries.

GENE FUNCTION

Doyle et al. (1998) found that enforced expression of the full-length
BCRP cDNA in MCF-7 breast cancer cells confers resistance to
mitoxantrone, doxorubicin, and daunorubicin, reduces daunorubicin
accumulation and retention, and causes an ATP-dependent enhancement of
the efflux or rhodamine-123 in the cloned transfected cells. Thus, BCRP
is a xenobiotic transporter that appears to play a major role in the
multidrug resistance phenotype of a specific human breast cancer.

Ozvegy et al. (2001) expressed ABCG2 as an underglycosylated recombinant
protein in Sf9 insect cells. In vitro assays of isolated membrane
preparations revealed a high-capacity, vanadate-sensitive ATPase
activity associated with ABCG2 expression that was stimulated by
compounds known to be transported by this protein. Ozvegy et al. (2001)
concluded that ABCG2 is likely functioning as a homodimer or
homooligomer in this expression system since it is unlikely that
putative Sf9 transport partners would be overexpressed at similarly high
levels.

Ozvegy et al. (2002) expressed wildtype human ABCG2, ABCG2 with
mutations identified in drug-selected tumor cells (arg482 to gly (R482G)
or arg482 to thr (R482T)), and ABCG2 with a catalytic center mutation
(K86M) in Sf9 insect cells. The K86M mutant had no transport or ATP
hydrolytic activity, although its ability to bind ATP was retained.
Wildtype ABCG2 and the R482G and R482T mutants showed characteristically
different drug and dye transport activities, but transport in each was
blocked by the specific inhibitor fumitremorgin C. All variants showed
high basal ATPase activity and vanadate-dependent adenine nucleotide
trapping under nonhydrolytic conditions. However, only the R482G and
R482T mutants showed ATPase activity that was stimulated in a
drug-dependent manner and nucleotide trapping that was stimulated by
transported compounds.

Jonker et al. (2002) showed that mice lacking Abcg2 became extremely
sensitive to the dietary chlorophyll-breakdown product pheophorbide-a,
resulting in severe, sometimes lethal phototoxic lesions on
light-exposed skin. Abcg2 transports pheophorbide-a, which occurs in
various plant-derived foods and food supplements and is highly efficient
in limiting its uptake from ingested food. Homozygous deficient mice
also displayed a novel type of protoporphyria (see 177000). Erythrocyte
levels of the heme precursor and phototoxin protoporphyrin IX, which is
structurally related to pheophorbide-a, were increased 10-fold.
Transplantation with wildtype bone marrow cured the protoporphyria and
reduced the phototoxin sensitivity of Abcg2 -/- mice. These results
indicated that humans or animals with low or absent ABCG2 activity may
be at increased risk for developing protoporphyria and diet-dependent
phototoxicity and illustrated the importance of drug transporters in
protection from toxicity of normal food constituents.

Accumulation of heme can lead to production of cell-damaging reactive
oxygen species, and accumulation of heme/porphyrin can lead to collapse
of mitochondrial function. Thus, regulation of intracellular porphyrin
levels is fundamental to cell survival, particularly under conditions of
low oxygen, when the cellular concentration of heme may increase.
Krishnamurthy et al. (2004) showed that hematopoietic cells from
Bcrp-null mice had increased sensitivity to hypoxia and accumulated
heme. The hypoxia sensitivity of these cells was rescued by inhibition
of heme biosynthesis. Krishnamurthy et al. (2004) found that Bcrp bound
heme and that the presence of heme modified Bcrp-mediated transport.
Bcrp expression was upregulated by hypoxia, and this upregulation
involved the hypoxia-inducible transcription factor complex Hif1 (see
603348). Krishnamurthy et al. (2004) concluded that cells can, upon
hypoxic demand, use BCRP to reduce heme or porphyrin accumulation.

Jonker et al. (2005) found high alveolar expression of ABCG2 in
lactating but not virgin or nonlactating mammary glands of mice, cows,
and humans. Clinically and toxicologically important substrates such as
the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
(PhIP), the anticancer drug topotecan, and the antiulcer drug cimetidine
were highly concentrated in the milk of wildtype mice, but active
secretion of these compounds was abolished in Abcg2 -/- mice. Jonker et
al. (2005) concluded that ABCG2 is a major factor in the concentrative
transfer of drugs, carcinogens, and dietary toxins to the milk of mice,
cows, and humans.

Sims-Mourtada et al. (2007) showed that inhibition of Sonic hedgehog
(SHH; 600725) signaling increased the response of human cancer cell
lines to multiple structurally unrelated chemotherapies. SHH activation
induced chemoresistance in part by increasing drug efflux in an ABC
transporter-dependent manner. SHH signaling regulated expression of
ABCB1 (171050) and ABCG2, and targeted knockdown of ABCB1 and ABCG2
expression by small interfering RNA partially reversed SHH-induced
chemoresistance.

In Xenopus oocytes, Woodward et al. (2009) demonstrated that the human
ABCG2 gene encodes a uric acid efflux transporter. In mammals, the
proximal renal tubule is the major site of renal urate handling. ABCG2
was also found to be expressed at the apical brush border membrane in
polarized renal epithelial cells, indicating that it is a secretory
urate transporter in the proximal tubule. Thus, mutations in the ABCG2
gene that increase serum urate concentrations must be loss-of-function
mutations.

In HEK293 cells, Matsuo et al. (2009) demonstrated that ABCG2 is a
high-capacity, low-affinity exporter of uric acid.

Wang et al. (2010) identified ABCG2 as a target of microRNA-520H
(MIR520H; 614755). Expression of an MIR520H mimic in PANC-1 human
pancreatic cancer cells reduced ABCG2 mRNA and protein expression.

GENE STRUCTURE

Bailey-Dell et al. (2001) determined that the ABCG2 gene contains 16
exons and spans over 66 kb. Sequence analysis indicated that the
promoter region has a CCAAT box but no TATA box, a potential CpG island,
and putative binding sites for SP1 (189906), AP1 (see 165160), and AP2
(TFAP2A; 107580). The promoter does not have a serum response element,
suggesting that ABCG2 is not a lipid transporter. Assays of reporter
gene activity with truncation mutants in the ABCG2 promoter suggested
the presence of positive and negative regulatory elements.

MAPPING

By radiation hybrid analysis, Allikmets et al. (1998) mapped the ABCG2
gene to human chromosome 4q22, between markers D4S2462 and D4S1557. By
the same method, they mapped the mouse Abcg2 gene to chromosome 6, 28 to
29 cM from the centromere.

MOLECULAR GENETICS

- Association with Increased Uric Acid Levels

Among 90 Japanese patients with increased serum uric acid levels
(UAQTL1; 138900), Matsuo et al. (2009) identified 6 nonsynonymous
changes in the ABCG2 gene. Three variants occurred at high frequencies
and were studied in more detail: Q126X (603756.0002), Q141K
(603756.0007), and V12M (603756.0003). In vitro cellular studies showed
that ATP-dependent urate transport was reduced by 46.7% in cells
expressing a Q141K mutation and was nearly eliminated in cells
expressing a Q126X mutation, consistent with a loss of function. Both of
these variants showed a significant association with hyperuricemia and
with gout in a larger cohort of 228 Japanese men and 871 controls. These
2 variants were assigned to different risk haplotypes, and combinations
of these haplotypes conferred different disease risks (up to an odds
ratio of 25.8). The V12M substitution appeared to offer a protective
effect and was found on a nonrisk haplotype.

- Junior (Jr) Blood Group Antigen

By SNP haplotype analysis of 4 probands with Jr(a) antibodies to red
blood cells, indicating that their red blood cells were of the Jr(a-)
phenotype (614490), Zelinski et al. (2012) identified a shared
homozygous region on chromosome 4q22 including the ABCG2 gene. Analysis
of coding exons identified 4 different mutations in the ABCG2 gene
(603756.0001-603756.0004) in the homozygous or compound heterozygous
state. Three of the mutations caused null alleles, and erythrocytes from
all individuals did not display the Jr antigen. One woman and her
blood-group compatible sister were Caucasian, another woman and her
blood-group compatible brother were Asian, and 2 further unrelated
individuals were Asian. The findings indicated that the Jr(a-) blood
group phenotype is defined by ABCG2 null alleles.

In 18 unrelated women with the Jr(a-) blood type, Saison et al. (2012)
identified 8 different null mutations in the ABCG2 gene (see, e.g.,
603756.0004-603756.0006). All mutations occurred in the homozygous or
compound heterozygous state, indicating autosomal recessive inheritance.
All women were identified during pregnancy after having developed
anti-Jr(a) antibodies. Protein blot and flow cytometric analysis
confirmed absence of the ABCG2 transporter on red blood cells of Jr(a-)
individuals. Six women belonging to Gypsy communities of southwestern
Europe were homozygous for the same mutation (R236X; 603756.0004),
consistent with a founder effect. Because of the possible role of the
ABCG2 protein as a uric acid transporter, Saison et al. (2012) measured
plasma samples from pregnant Jr(a-) women, but urate levels were not
significantly increased compared to controls. However, plasma porphyrin
was significantly decreased and red blood cell porphyrin significantly
increased in pregnant Jr(a-) women, suggesting a role for ABCG2 in
exporting excess porphyrin from red blood cells. These individuals
showed no symptoms of porphyria, but the aberrations in porphyrin
transport may place them at risk under certain conditions.

*FIELD* AV
.0001
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE
ABCG2, ARG246TER

In 2 Caucasian sisters with the Jr(a-) blood group phenotype (614490),
Zelinski et al. (2012) identified a homozygous 736C-T transition in exon
7 of the ABCG2 gene, resulting in an arg246-to-ter (R246X) substitution
in the ATP-binding domain. One of the women had Jr(a)-specific
antibodies to red blood cells.

.0002
URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE, INCLUDED
ABCG2, GLN126TER (dbSNP rs72552713)

Matsuo et al. (2009) identified a heterozygous gln126-to-ter (Q126X)
substitution in exon 4 of the ABCG2 gene in 10 of 90 Japanese
individuals with increased serum uric acid (UAQTL1; 138900), yielding an
allele frequency of 5.56% in this group. The allele frequency in the
Japanese population was estimated at either 2.8% (Maekawa et al., 2006)
or 5.5%, depending on the method used. Additional genotyping of 228
Japanese men with hyperuricemia, including 161 with gout, and 871
controls showed that presence of the Q126X allele increased the risk of
hyperuricemia (odds ratio (OR) of 3.61; p = 2.91 x 10(-7)) and the risk
of gout (OR of 4.25, p = 3.04 x 10(-8)). In vitro functional expression
studies showed that the Q126X mutation nearly eliminated ATP-dependent
urate transport, and Western blot analysis showed no detectable protein
on membrane vesicles, consistent with a loss of function.

In an Asian sister and brother and an unrelated Asian woman with the
Jr(a-) blood group phenotype (614490), Zelinski et al. (2012) identified
a homozygous 376C-T transition in exon 4 of the ABCG2 gene (dbSNP
rs72552713), resulting in a gln126-to-ter substitution in the
ATP-binding domain. The 2 women had Jr(a)-specific antibodies to red
blood cells.

Saison et al. (2012) identified homozygosity for the Q126X mutation in 3
unrelated Korean women with the Jr(a-) phenotype and Jr(a) antibodies.
They stated that the allele frequency in Japan ranged between 1.6 and
2.4%.

.0003
URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE, INCLUDED
ABCG2, VAL12MET (dbSNP rs2231137)

Among 90 Japanese individuals with increased serum uric acid (138900),
Matsuo et al. (2009) found that 23 and 3 individuals, respectively,
carried a heterozygous or homozygous V12M substitution, yielding an
allele frequency of 16.11% in this group. The allele frequency in the
Japanese population was estimated at either 19.2% (Maekawa et al., 2006)
or 34.7%, depending on the method used. Additional genotyping of 228
Japanese men with hyperuricemia, including 161 with gout, and 871
controls suggested that the presence of the V12M allele was associated
with a decreased risk of hyperuricemia (OR of 0.67, p = 0.005) and gout
(OR of 0.68; p = 0.020). However, in vitro functional expression assays
demonstrated that the V12M substitution did not result in any changes in
urate transport or ABCG2 protein levels compared to wildtype.

In an Asian woman with the Jr(a-) blood group phenotype (614490),
Zelinski et al. (2012) identified 3 mutations in the ABCG2 gene:
homozygosity for a 34G-A transition in exon 2 (dbSNP rs2231137),
resulting in a val12-to-met (V12M) substitution, and heterozygosity for
R236X (603756.0004). She had Jr(a)-specific antibodies to red blood
cells, suggesting that her erythrocytes did not display the Jr(a)
antigen.

.0004
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE
ABCG2, ARG236TER (dbSNP rs140207606)

In 7 unrelated women with the Jr(a-) blood group phenotype (614990),
Saison et al. (2012) identified a homozygous 706C-T transition in exon 7
of the ABCG2 gene, resulting in an arg236-to-ter (R236X) substitution.
Six of the 7 woman belonged to Gypsy communities in southwestern Europe
and shared a common haplotype, consistent with a founder effect.
However, 2 additional individuals not of Gypsy origin also carried
R236X, suggesting that this mutation had arisen independently. Protein
blot and flow cytometric analysis confirmed absence of the ABCG2
transporter on red blood cells of Jr(a-) individuals.

Zelinski et al. (2012) found that an Asian woman with the Jr(a-)
phenotype was compound heterozygous for R236X and homozygous for another
substitution in the ABCG2 gene (V12M; 603756.0003). Zelinski et al.
(2012) noted that 706C-T (dbSNP rs140207606) occurs in the ATP-binding
domain.

.0005
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE
ABCG2, 2-BP DEL, 791TT

In 2 unrelated women, believed to be of Turkish origin, with the Jr(a-)
blood group phenotype (614490), Saison et al. (2012) identified a
homozygous 2-bp deletion (791delTT) in exon 7 of the ABCG2 gene,
predicted to result in a frameshift and premature termination. Both
women developed anti-Jr(a) antibodies during pregnancy. Two additional
patients from France were compound heterozygous for this mutation and
another truncating mutation in the ABCG2 gene.

.0006
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE
ABCG2, 2-BP DEL, 1111AC

In a Pakistani woman with the Jr(a-) blood group phenotype (614490) who
developed anti-Jr(a) antibodies during pregnancy, Saison et al. (2012)
identified a homozygous 2-bp deletion (1111delAC) in exon 9 of the ABCG2
gene, resulting in a frameshift and premature termination.

.0007
URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1
JUNIOR BLOOD GROUP SYSTEM, JR(a-) PHENOTYPE, INCLUDED
ABCG2, GLN141LYS (dbSNP rs2231142)

By genomewide linkage analysis of 7,699 participants in the Framingham
cohort and in 4,148 participants in a Rotterdam cohort, Dehghan et al.
(2008) found a significant association between serum uric acid
concentration (138900) and a G-to-T transversion in the ABCG2 gene
(dbSNP rs2231142), resulting in a gln141-to-lys (Q141K) substitution (p
= 9.0 x 10(-20) and p = 3.3 x 10(-9), respectively). The findings were
replicated in the ARIC cohort of 11,024 white and 3,843 black
individuals, yielding p values of 9.7 x 10(-30) and 9.8 x 10(-4),
respectively. The combined p value for white individuals from all 3
cohorts was 2.5 x 10(-60), and further analysis showed that the SNP was
direction-consistent with the development of gout in white participants
(OR of 1.74; p = 3.3 x 10(-15)).

Woodward et al. (2009) noted that the Q141K substitution occurs in a
highly conserved residue in the intracellular nucleotide-binding domain.
In vitro functional expression studies in Xenopus oocytes showed that
the mutant Q141K protein caused a 54% reduction in urate transport
compared to wildtype, consistent with a loss of function. Among 8,092
white individuals, the T allele was significantly associated with
increased serum uric acid levels (p = 4 x 10(-27)). Among a larger
cohort of 14,783 individuals including both blacks and whites, the T
allele showed more significant associations with uric acid in whites (p
= 10(-30)) compared to blacks (p = 10(-4)), owing to the lesser overall
frequency of this allele among blacks. The effect was more pronounced in
men compared to women. The frequency of Q141K is about 30% in Asian
populations, 11% in white populations, and 3% in black populations.

Among 90 Japanese individuals with increased serum uric acid, Matsuo et
al. (2009) found that 47 and 14 individuals, respectively, carried a
heterozygous and homozygous Q141K substitution, yielding an allele
frequency of 41.67% in this patient group. The frequency of Q141K in the
general Japanese population was estimated to be 31.9% (Maekawa et al.,
2006) or 53.6%, depending on the method used. Additional genotyping of
228 Japanese men with hyperuricemia, including 161 with gout, and 871
controls showed that the presence of the Q141K allele was associated
with a significantly increased risk of hyperuricemia (OR of 2.06, p =
1.53 x 10(-11)) and gout (OR of 2.23; p = 5.54 x 10(-11)). In vitro
functional expression studies showed that the Q141K mutation reduced the
ATP-dependent transport of urate by 46.7%, consistent with a partial
loss of function.

*FIELD* RF
1. Allikmets, R.; Schriml, L. M.; Hutchinson, A.; Romano-Spica, V.;
Dean, M.: A human placenta-specific ATP-binding cassette gene (ABCP)
on chromosome 4q22 that is involved in multidrug resistance. Cancer
Res. 58: 5337-5339, 1998.

2. Bailey-Dell, K. J.; Hassel, B.; Doyle, L. A.; Ross, D. D.: Promoter
characterization and genomic organization of the human breast cancer
resistance protein (ATP-binding cassette transporter G2) gene. Biochim.
Biophys. Acta 1520: 234-241, 2001.

3. Dehghan, A.; Kottgen, A.; Yang, Q.; Hwang, S.-J.; Kao, W. H. L.;
Rivadeneira, F.; Boerwinkle, E.; Levy, D.; Hofman, A.; Astor, B. C.;
Benjamin, E. J.; van Duijn, C. M.; Witteman, J. C.; Coresh, J.; Fox,
C. S.: Association of three genetic loci with uric acid concentration
and risk of gout: a genome-wide association study. Lancet 372: 1953-1961,
2008.

4. Doyle, L. A.; Yang, W.; Abruzzo, L. V.; Krogmann, T.; Gao, Y.;
Rishi, A. K.; Ross, D. D.: A multidrug resistance transporter from
human MCF-7 breast cancer cells. Proc. Nat. Acad. Sci. 95: 15665-15670,
1998. Note: Erratum: Proc. Nat. Acad. Sci. 96: 2569 only, 1999.

5. Eisenblatter, T.; Galla, H.-J.: A new multidrug resistance protein
at the blood-brain barrier. Biochem. Biophys. Res. Commun. 293:
1273-1278, 2002.

6. Jonker, J. W.; Buitelaar, M.; Wagenaar, E.; van der Valk, M. A.;
Scheffer, G. L.; Scheper, R. J.; Plosch, T.; Kuipers, F.; Oude Elferink,
R. P. J.; Rosing, H.; Beijnen, J. H.; Schinkel, A. H.: The breast
cancer resistance protein protects against a major chlorophyll-derived
dietary phototoxin and protoporphyria. Proc. Nat. Acad. Sci. 99:
15649-15654, 2002.

7. Jonker, J. W.; Merino, G.; Musters, S.; van Herwaarden, A. E.;
Bolscher, E.; Wagenaar, E.; Mesman, E.; Dale, T. C.; Schinkel, A.
H.: The breast cancer resistance protein BCRP (ABCG2) concentrates
drugs and carcinogenic xenotoxins into milk. Nature Med. 11: 127-129,
2005.

8. Krishnamurthy, P.; Ross, D. D.; Nakanishi, T.; Bailey-Dell, K.;
Zhou, S.; Mercer, K. E.; Sarkadi, B.; Sorrentino, B. P.; Schuetz,
J. D.: The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival
through interactions with heme. J. Biol. Chem. 279: 24218-24225,
2004.

9. Maekawa, K.; Itoda, M.; Sai, K.; Saito, Y.; Kaniwa, N.; Shirao,
K.; Hamaguchi, T.; Kunitoh, H.; Yamamoto, N.; Tamura, T.; Minami,
H.; Kubota, K.; Ohtsu, A.; Yoshida, T.; Saijo, N.; Kamatani, N.; Ozawa,
S.; Sawada, J.: Genetic variation and haplotype structure of the
ABC transporter gene ABCG2 in a Japanese population. Drug Metab.
Pharmacokinet. 21: 109-121, 2006.

10. Matsuo, H.; Takada, T.; Ichida, K.; Nakamura, T.; Nakayama, A.;
Ikebuchi, Y.; Ito, K.; Kusanagi, Y.; Chiba, T.; Tadokoro, S.; Takada,
Y.; Oikawa, Y.; and 22 others: Common defects of ABCG2, a high-capacity
urate exporter, cause gout: a function-based genetic analysis in a
Japanese population. Sci. Transl. Med. 1: 5ra11, 2009. Note: Electronic
Article.

11. Miyake, K.; Mickley, L.; Litman, T.; Zhan, Z.; Robey, R.; Cristensen,
B.; Brangi, M.; Greenberger, L.; Dean, M.; Fojo, T.; Bates, S. E.
: Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant
cells: demonstration of homology to ABC transport genes. Cancer Res. 59:
8-13, 1999.

12. Ozvegy, C.; Litman, T.; Szakacs, G.; Nagy, Z.; Bates, S.; Varadi,
A.; Sarkadi, B.: Functional characterization of the human multidrug
transporter, ABCG2, expressed in insect cells. Biochem. Biophys.
Res. Commun. 285: 111-117, 2001.

13. Ozvegy, C.; Varadi, A.; Sarkadi, B.: Characterization of drug
transport, ATP hydrolysis, and nucleotide trapping by the human ABCG2
multidrug transporter: modulation of substrate specificity by a point
mutation. J. Biol. Chem. 277: 47980-47990, 2002.

14. Saison, C.; Helias, V.; Ballif, B. A.; Peyrard, T.; Puy, H.; Miyazaki,
T.; Perrot, S.; Vayssier-Taussat, M.; Waldner, M.; Le Pennec, P.-Y.;
Cartron, J.-P.; Arnaud, L.: Null alleles of ABCG2 encoding the breast
cancer resistance protein define the new blood group system Junior. Nature
Genet. 44: 174-177, 2012.

15. Sims-Mourtada, J.; Izzo, J. G.; Ajani, J.; Chao, K. S. C.: Sonic
hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26:
5674-5679, 2007.

16. Wang, F.; Xue, X.; Wei, J.; An, Y.; Yao, J.; Cai, H.; Wu, J.;
Dai, C.; Qian, Z.; Xu, Z.; Miao, Y.: hsa-miR-520h downregulates ABCG2
in pancreatic cancer cells to inhibit migration, invasion, and side
populations. Brit. J. Cancer 103: 567-574, 2010.

17. Woodward, O. M.; Kottgen, A.; Coresh, J.; Boerwinkle, E.; Guggino,
W. B.; Kottgen, M.: Identification of a urate transporter, ABCG2,
with a common functional polymorphism causing gout. Proc. Nat. Acad.
Sci. 106: 10338-10342, 2009.

18. Zelinski, T.; Coghlan, G.; Liu, X.-Q.; Reid, M. E.: ABCG2 null
alleles define the Jr(a-) blood group phenotype. Nature Genet. 44:
131-132, 2012.

*FIELD* CN
Patricia A. Hartz - updated: 8/6/2012
Cassandra L. Kniffin - updated: 2/22/2012
Patricia A. Hartz - updated: 5/27/2008
Patricia A. Hartz - updated: 10/25/2007
Marla J. F. O'Neill - updated: 3/29/2005
Victor A. McKusick - updated: 1/14/2003
Patricia A. Hartz - updated: 6/20/2002

*FIELD* CD
Victor A. McKusick: 4/20/1999

*FIELD* ED
carol: 10/22/2013
tpirozzi: 10/1/2013
carol: 9/24/2013
mgross: 3/18/2013
terry: 3/12/2013
carol: 8/17/2012
mgross: 8/6/2012
terry: 8/6/2012
carol: 2/28/2012
carol: 2/24/2012
ckniffin: 2/22/2012
terry: 10/8/2008
mgross: 6/13/2008
terry: 5/27/2008
mgross: 10/30/2007
terry: 10/25/2007
wwang: 3/29/2005
carol: 1/23/2003
tkritzer: 1/21/2003
terry: 1/14/2003
carol: 6/20/2002
terry: 6/20/2002
carol: 11/11/1999
carol: 4/20/1999

MIM 614490
*RECORD*
*FIELD* NO
614490
*FIELD* TI
#614490 BLOOD GROUP, JUNIOR SYSTEM; JR
*FIELD* TX
A number sign (#) is used with this entry because the Junior(a-) blood
read moregroup phenotype is caused by homozygous or compound heterozygous
mutation in the ABCG2 gene (603756) on chromosome 4q22.

DESCRIPTION

Individuals with Jr(a-) blood group lack the Jr(a) antigen on their red
blood cells. These individuals may have anti-Jr(a) antibodies in their
serum, which can cause transfusion reactions or hemolytic disease of the
fetus or newborn. Although the clinical significance of the Jr(a-) blood
group has been controversial, severe fatal hemolytic disease of the
newborn has been reported. The Jr(a-) phenotype has a higher frequency
in individuals of Asian descent, compared to those of European descent
(summary by Kim et al., 2010 and Zelinski et al., 2012).

CLINICAL FEATURES

Nakajima and Ito (1978) reported a 30-year-old Japanese woman with no
history of blood transfusion whose child developed hemolytic disease of
the newborn. The infant became jaundiced within 3 days of birth, and
blood showed a strongly positive direct antiglobulin reaction. The
maternal serum was found to contain anti-Jr(a) IgG antibodies. Red cells
of the baby and the father carried the Jr(a) antigen, whereas those of
the mother did not. The mother had a previous history of spontaneous
abortion at 3 months' gestation.

Peyrard et al. (2008) reported fatal hemolytic disease of the fetus and
newborn associated with anti-Jr(a) antibodies. Prenatal ultrasound of a
28-year-old Caucasian woman of Gypsy Spanish origin at 29 weeks'
gestation pregnancy showed fetal cardiomegaly and hepatomegaly. She had
a history of 2 abortions and 1 full-term pregnancy, as well as a history
of massive transfusion with Jr(a)-positive blood. In this pregnancy, an
emergency cesarean section was performed at 36 weeks' gestation; the
newborn was hydropic with severe anemia and died 30 hours after birth.
The mother was found to have the Jr(a-) phenotype with anti-Jr(a)
antibodies. Peyrard et al. (2008) stated that this was the first
documented case of fatal hemolytic disease of the fetus or newborn due
to anti-Jr(a), which provided new information about the clinical
significance of anti-Jr(a).

Kim et al. (2010) reported a 33-year-old nulliparous Korean woman with
no history of transfusion who had the Jr(a-) red blood cell phenotype
and anti-Jr(a) IgG antibodies. She delivered male twins with the Jr(a)
phenotype, and circulating maternal Jr(a) antibodies were detected in
the babies' serum. The twins had mild hemolytic disease of the newborn,
which was successfully treated with phototherapy; they had no further
complications.

INHERITANCE

The Jr(a-) phenotype is inherited as an autosomal recessive trait
(Zelinski et al., 2012).

DIAGNOSIS

Miyazaki et al. (1994) developed a human monoclonal IgG3 antibody
against the Jr(a) antigen using EBV-transformed lymphocytes derived from
a Japanese woman with serum anti-Jr(a) antibodies hybridized with a
mouse myeloma cell line. Studies on a panel of red cells demonstrated
the specificity of the antibody for the Jr(a) antigen. Screening of
28,744 Japanese blood donor samples using the antibody detected 19
(0.07%) agglutination-negative samples, which were confirmed as Jr(a-)
by conventional anti-Jr(a) antisera.

MOLECULAR GENETICS

By SNP haplotype analysis of 4 probands with Jr(a) antibodies to red
blood cells, indicating that their red blood cells were of the Jr(a-)
phenotype, Zelinski et al. (2012) identified a shared homozygous region
on chromosome 4q22 including the ABCG2 gene. Analysis of coding exons
identified 4 different mutations in the ABCG2 gene
(603756.0001-603756.0004) in the homozygous or compound heterozygous
state. Three of the mutations caused null alleles, and erythrocytes from
all individuals did not display the Jr antigen. One woman and her
blood-group compatible sister were Caucasian, another woman and her
blood-group compatible brother were Asian, and 2 further unrelated
individuals were Asian. The findings indicated that the Jr(a-) blood
group phenotype is defined by ABCG2 null alleles.

In 18 unrelated women with the Jr(a-) blood type, Saison et al. (2012)
identified 8 different null mutations in the ABCG2 gene (see, e.g.,
603756.0004-603756.0006). All mutations occurred in the homozygous or
compound heterozygous state, indicating autosomal recessive inheritance.
All women were identified during pregnancy after having developed
anti-Jr(a) antibodies. Protein blot and flow cytometric analysis
confirmed absence of the ABCG2 transporter on red blood cells of Jr(a-)
individuals. Six women belonging to Gypsy communities of southwestern
Europe were homozygous for the same mutation (R236X; 603756.0004),
consistent with a founder effect. Because of the possible role of the
ABCG2 protein as a uric acid transporter, Saison et al. (2012) measured
plasma samples from pregnant Jr(a-) women, but urate levels were not
significantly increased compared to controls. However, plasma porphyrin
was significantly decreased and red blood cell porphyrin significantly
increased in pregnant Jr(a-) women, suggesting a role for ABCG2 in
exporting excess porphyrin from red blood cells. These individuals
showed no symptoms of porphyria, but the aberrations in porphyrin
transport may place them at risk under certain conditions. The mutation
was found after identifying the orthologous protein on cat erythrocytes.

POPULATION GENETICS

Nakajima and Ito (1978) determined that the frequency of the Jr(a-)
phenotype is about 0.026% in Japan.

Miyazaki et al. (1994) found that the frequency of the Jr(a-) phenotype
was 0.07% in Japan.

Zelinski et al. (2012) noted that the Jr(a-) phenotype is rare in
European and North Americans of European descent, but is more common in
Japan, where the incidence has been reported to range from a high of 1
in 60 in the Niigata area to a low of 1 in 3,800 in the Tokyo area.

*FIELD* RF
1. Kim, H.; Park, M.-J.; Sung, T.-J.; Choi, J. S.; Hyun, J.; Park,
K. U.; Han, K.-S.: Hemolytic disease of the newborn associated with
anti-Jr(a) alloimmunization in a twin pregnancy: the first case report
in Korea. Korean J. Lab. Med. 30: 511-515, 2010.

2. Miyazaki, T.; Kwon, K. W.; Yamamoto, K.; Tone, Y.; Ihara, H.; Kato,
T.; Ikeda, H.; Sekiguchi, S.: A human monoclonal antibody to high-frequency
red cell antigen Jr(a). Vox Sang. 66: 51-54, 1994.

3. Nakajima, H.; Ito, K.: An example of anti-Jr(a) causing hemolytic
disease of the newborn and frequency of Jr(a) antigen in the Japanese
population. Vox Sang. 35: 265-267, 1978.

4. Peyrard, T.; Pham, B.-N.; Arnaud, L.; Fleutiaux, S.; Brossard,
Y.; Guerin, B.; Desmoulins, I.; Rouger, P.; Le Pennec, P.-Y.: Fatal
hemolytic disease of the fetus and newborn associated with anti-Jr(a). Transfusion 48:
1906-1911, 2008.

5. Saison, C.; Helias, V.; Ballif, B. A.; Peyrard, T.; Puy, H.; Miyazaki,
T.; Perrot, S.; Vayssier-Taussat, M.; Waldner, M.; Le Pennec, P.-Y.;
Cartron, J.-P.; Arnaud, L.: Null alleles of ABCG2 encoding the breast
cancer resistance protein define the new blood group system Junior. Nature
Genet. 44: 174-177, 2012.

6. Zelinski, T.; Coghlan, G.; Liu, X.-Q.; Reid, M. E.: ABCG2 null
alleles define the Jr(a-) blood group phenotype. Nature Genet. 44:
131-132, 2012.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/7/2013

*FIELD* CD
Cassandra L. Kniffin: 2/21/2012

*FIELD* ED
carol: 03/12/2013
ckniffin: 3/7/2013
terry: 3/5/2012
terry: 2/24/2012
carol: 2/24/2012
ckniffin: 2/22/2012