RBCC Red Blood Cell Collection

GPI [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Glucose-6-phosphate isomerase; GPI; 5.3.1.9 (Autocrine motility factor; AMF; Neuroleukin; NLK; Phosphoglucose isomerase; PGI; Phosphohexose isomerase; PHI; Sperm antigen 36; SA-36)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P06744
ID G6PI_HUMAN Reviewed; 558 AA.
AC P06744; B4DG39; Q9BRD3; Q9BSK5; Q9UHE6;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Glucose-6-phosphate isomerase;
DE Short=GPI;
DE EC=5.3.1.9;
DE AltName: Full=Autocrine motility factor;
DE Short=AMF;
DE AltName: Full=Neuroleukin;
DE Short=NLK;
DE AltName: Full=Phosphoglucose isomerase;
DE Short=PGI;
DE AltName: Full=Phosphohexose isomerase;
DE Short=PHI;
DE AltName: Full=Sperm antigen 36;
DE Short=SA-36;
GN Name=GPI;
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).
RA Gurney M.E.;
RL Submitted (MAR-1987) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=10727272;
RA Yakirevich E., Naot Y.;
RT "Cloning of a glucose phosphate isomerase/neuroleukin-like sperm
RT antigen involved in sperm agglutination.";
RL Biol. Reprod. 62:1016-1023(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT THR-208.
RG NIEHS SNPs program;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Amygdala;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-71.
RX PubMed=2387591; DOI=10.1016/0888-7543(90)90212-D;
RA Walker J.I.H., Faik P., Morgan M.J.;
RT "Characterization of the 5' end of the gene for human glucose
RT phosphate isomerase (GPI).";
RL Genomics 7:638-643(1990).
RN [8]
RP PROTEIN SEQUENCE OF 2-12; 58-73; 97-104; 181-226; 424-438 AND 455-461,
RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND MASS
RP SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (OCT-2004) to UniProtKB.
RN [9]
RP IDENTITY OF NEUROLEUKIN AS PGI.
RX PubMed=3352745; DOI=10.1038/332455a0;
RA Faik P., Walker J.I.H., Redmill A.A.M., Morgan M.J.;
RT "Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3'
RT sequences.";
RL Nature 332:455-456(1988).
RN [10]
RP FUNCTION, AND PHOSPHORYLATION AT SER-185.
RX PubMed=11004567; DOI=10.1016/S0167-4838(00)00075-3;
RA Haga A., Niinaka Y., Raz A.;
RT "Phosphohexose isomerase/autocrine motility
RT factor/neuroleukin/maturation factor is a multifunctional
RT phosphoprotein.";
RL Biochim. Biophys. Acta 1480:235-244(2000).
RN [11]
RP SUBCELLULAR LOCATION, AND CYTOKINE AND ANGIOGENIC FUNCTIONS.
RX PubMed=11437381; DOI=10.1006/bbrc.2001.5135;
RA Funasaka T., Haga A., Raz A., Nagase H.;
RT "Tumor autocrine motility factor is an angiogenic factor that
RT stimulates endothelial cell motility.";
RL Biochem. Biophys. Res. Commun. 285:118-128(2001).
RN [12]
RP SPECIES SPECIFICITY OF THE CYTOKINE FUNCTION.
RX PubMed=12163179; DOI=10.1016/S0014-5793(02)03072-7;
RA Amraei M., Nabi I.R.;
RT "Species specificity of the cytokine function of phosphoglucose
RT isomerase.";
RL FEBS Lett. 525:151-155(2002).
RN [13]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [14]
RP PHOSPHORYLATION AT SER-185, AND MUTAGENESIS OF SER-185.
RX PubMed=15637053; DOI=10.1074/jbc.M409457200;
RA Yanagawa T., Funasaka T., Tsutsumi S., Raz T., Tanaka N., Raz A.;
RT "Differential regulation of phosphoglucose isomerase/autocrine
RT motility factor activities by protein kinase CK2 phosphorylation.";
RL J. Biol. Chem. 280:10419-10426(2005).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-109, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-109, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-12 AND LYS-142, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP MALONYLATION AT LYS-454.
RX PubMed=21908771; DOI=10.1074/mcp.M111.012658;
RA Peng C., Lu Z., Xie Z., Cheng Z., Chen Y., Tan M., Luo H., Zhang Y.,
RA He W., Yang K., Zwaans B.M., Tishkoff D., Ho L., Lombard D., He T.C.,
RA Dai J., Verdin E., Ye Y., Zhao Y.;
RT "The first identification of lysine malonylation substrates and its
RT regulatory enzyme.";
RL Mol. Cell. Proteomics 10:M111.012658.01-M111.012658.12(2011).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS), SUBUNIT, AND ACTIVE SITE.
RX PubMed=11371164; DOI=10.1006/jmbi.2001.4680;
RA Read J., Pearce J., Li X., Muirhead H., Chirgwin J., Davies C.;
RT "The crystal structure of human phosphoglucose isomerase at 1.6 A
RT resolution: implications for catalytic mechanism, cytokine activity
RT and haemolytic anaemia.";
RL J. Mol. Biol. 309:447-463(2001).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) ALONE AND IN COMPLEX WITH
RP INHIBITOR.
RX PubMed=12054796; DOI=10.1016/S0022-2836(02)00186-9;
RA Tanaka N., Haga A., Uemura H., Akiyama H., Funasaka T., Nagase H.,
RA Raz A., Nakamura K.T.;
RT "Inhibition mechanism of cytokine activity of human autocrine motility
RT factor examined by crystal structure analyses and site-directed
RT mutagenesis studies.";
RL J. Mol. Biol. 318:985-997(2002).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.51 ANGSTROMS) IN COMPLEX WITH INHIBITOR, AND
RP ACTIVE SITE.
RX PubMed=12777791; DOI=10.1107/S0907444903007352;
RA Davies C., Muirhead H., Chirgwin J.;
RT "The structure of human phosphoglucose isomerase complexed with a
RT transition-state analogue.";
RL Acta Crystallogr. D 59:1111-1113(2003).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS), AND ACTIVE SITE.
RX PubMed=12573240; DOI=10.1016/S1570-9639(02)00464-8;
RA Cordeiro A.T., Godoi P.H., Silva C.H., Garratt R.C., Oliva G.,
RA Thiemann O.H.;
RT "Crystal structure of human phosphoglucose isomerase and analysis of
RT the initial catalytic steps.";
RL Biochim. Biophys. Acta 1645:117-122(2003).
RN [25]
RP VARIANTS HA-GPID SER-159; HIS-347 AND THR-525.
RX PubMed=8499925; DOI=10.1093/hmg/2.3.327;
RA Walker J.I.H., Layton D.M., Bellingham A.J., Morgan M.J., Faik P.;
RT "DNA sequence abnormalities in human glucose 6-phosphate isomerase
RT deficiency.";
RL Hum. Mol. Genet. 2:327-329(1993).
RN [26]
RP VARIANTS HA-GPID TRP-83; MET-224; HIS-273; LEU-278; CYS-347; PHE-487
RP AND LYS-495.
RX PubMed=7989588; DOI=10.1172/JCI117597;
RA Xu W., Beutler E.;
RT "The characterization of gene mutations for human glucose phosphate
RT isomerase deficiency associated with chronic hemolytic anemia.";
RL J. Clin. Invest. 94:2326-2329(1994).
RN [27]
RP VARIANTS HA-GPID MET-101; ILE-195; ARG-343 AND THR-525.
RX PubMed=8822952;
RA Baronciani L., Zanella A., Bianchi P., Zappa M., Alfinito F.,
RA Iolascon A., Tannoia N., Beutler E., Sirchia G.;
RT "Study of the molecular defects in glucose phosphate isomerase-
RT deficient patients affected by chronic hemolytic anemia.";
RL Blood 88:2306-2310(1996).
RN [28]
RP VARIANTS HA-GPID ILE-5; MET-224; ARG-343; ARG-375 AND ASN-539.
RX PubMed=8822954;
RA Kanno H., Fujii H., Hirono A., Ishida Y., Ohga S., Fukumoto Y.,
RA Matsuzawa K., Ogawa S., Miwa S.;
RT "Molecular analysis of glucose phosphate isomerase deficiency
RT associated with hereditary hemolytic anemia.";
RL Blood 88:2321-2325(1996).
RN [29]
RP VARIANTS HA-GPID GLY-75; PRO-300; CYS-347 AND HIS-472.
RX PubMed=9446754; DOI=10.1006/bcmd.1997.0157;
RA Beutler E., West C., Britton H.A., Harris J., Forman L.;
RT "Glucosephosphate isomerase (GPI) deficiency mutations associated with
RT hereditary nonspherocytic hemolytic anemia (HNSHA).";
RL Blood Cells Mol. Dis. 23:402-409(1997).
RN [30]
RP VARIANTS HA-GPID PRO-20; PRO-339; ARG-389 AND VAL-517.
RX PubMed=9856489; DOI=10.1007/s004390050849;
RA Kugler W., Breme K., Laspe P., Muirhead H., Davies C., Winkler H.,
RA Schroter W., Lakomek M.;
RT "Molecular basis of neurological dysfunction coupled with haemolytic
RT anaemia in human glucose-6-phosphate isomerase (GPI) deficiency.";
RL Hum. Genet. 103:450-454(1998).
CC -!- FUNCTION: Besides it's role as a glycolytic enzyme, mammalian GPI
CC can function as a tumor-secreted cytokine and an angiogenic factor
CC (AMF) that stimulates endothelial cell motility. GPI is also a
CC neurotrophic factor (Neuroleukin) for spinal and sensory neurons.
CC -!- CATALYTIC ACTIVITY: D-glucose 6-phosphate = D-fructose 6-
CC phosphate.
CC -!- PATHWAY: Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-
CC phosphate and glycerone phosphate from D-glucose: step 2/4.
CC -!- SUBUNIT: Homodimer in the catalytically active form, monomer in
CC the secreted form.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P06744-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P06744-2; Sequence=VSP_043475, VSP_043476;
CC Note=No experimental confirmation available;
CC -!- PTM: Phosphorylation at Ser-185 by CK2 has been shown to decrease
CC enzymatic activity and may contribute to secretion by a non-
CC classical secretory pathway.
CC -!- PTM: ISGylated.
CC -!- DISEASE: Hemolytic anemia, non-spherocytic, due to glucose
CC phosphate isomerase deficiency (HA-GPID) [MIM:613470]: A form of
CC anemia in which there is no abnormal hemoglobin or spherocytosis.
CC It is caused by glucose phosphate isomerase deficiency. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the GPI family.
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=GPI";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Phosphoglucose isomerase entry;
CC URL="http://en.wikipedia.org/wiki/Phosphoglucose_isomerase";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/gpi/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; K03515; AAA36368.1; -; mRNA.
DR EMBL; AF187554; AAF22645.1; -; mRNA.
DR EMBL; AY324386; AAP72966.1; -; Genomic_DNA.
DR EMBL; AK294396; BAG57650.1; -; mRNA.
DR EMBL; AC010504; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC092073; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004982; AAH04982.1; -; mRNA.
DR EMBL; AH002710; AAA52593.1; -; Genomic_DNA.
DR PIR; A35333; A35333.
DR RefSeq; NP_000166.2; NM_000175.3.
DR RefSeq; NP_001171651.1; NM_001184722.1.
DR RefSeq; XP_005258821.1; XM_005258764.1.
DR UniGene; Hs.466471; -.
DR PDB; 1IAT; X-ray; 1.62 A; A=2-558.
DR PDB; 1IRI; X-ray; 2.40 A; A/B/C/D=1-558.
DR PDB; 1JIQ; X-ray; 1.90 A; A/B/C/D=1-558.
DR PDB; 1JLH; X-ray; 2.10 A; A/B/C/D=1-558.
DR PDB; 1NUH; X-ray; 2.51 A; A=1-558.
DR PDBsum; 1IAT; -.
DR PDBsum; 1IRI; -.
DR PDBsum; 1JIQ; -.
DR PDBsum; 1JLH; -.
DR PDBsum; 1NUH; -.
DR ProteinModelPortal; P06744; -.
DR SMR; P06744; 2-557.
DR IntAct; P06744; 4.
DR MINT; MINT-4999095; -.
DR STRING; 9606.ENSP00000348877; -.
DR PhosphoSite; P06744; -.
DR DMDM; 17380385; -.
DR PaxDb; P06744; -.
DR PeptideAtlas; P06744; -.
DR PRIDE; P06744; -.
DR DNASU; 2821; -.
DR Ensembl; ENST00000356487; ENSP00000348877; ENSG00000105220.
DR Ensembl; ENST00000415930; ENSP00000405573; ENSG00000105220.
DR GeneID; 2821; -.
DR KEGG; hsa:2821; -.
DR UCSC; uc002nvf.3; human.
DR CTD; 2821; -.
DR GeneCards; GC19P034855; -.
DR HGNC; HGNC:4458; GPI.
DR HPA; CAB018655; -.
DR HPA; CAB040563; -.
DR HPA; HPA024305; -.
DR MIM; 172400; gene.
DR MIM; 613470; phenotype.
DR neXtProt; NX_P06744; -.
DR Orphanet; 712; Hemolytic anemia due to glucophosphate isomerase deficiency.
DR PharmGKB; PA28841; -.
DR eggNOG; COG0166; -.
DR HOGENOM; HOG000261371; -.
DR HOVERGEN; HBG002877; -.
DR InParanoid; P06744; -.
DR KO; K01810; -.
DR OMA; RLKYFAA; -.
DR OrthoDB; EOG7FXZXV; -.
DR PhylomeDB; P06744; -.
DR BioCyc; MetaCyc:HS02693-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P06744; -.
DR UniPathway; UPA00109; UER00181.
DR ChiTaRS; GPI; human.
DR EvolutionaryTrace; P06744; -.
DR GeneWiki; Glucose-6-phosphate_isomerase; -.
DR GenomeRNAi; 2821; -.
DR NextBio; 11117; -.
DR PRO; PR:P06744; -.
DR ArrayExpress; P06744; -.
DR Bgee; P06744; -.
DR CleanEx; HS_GPI; -.
DR Genevestigator; P06744; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004347; F:glucose-6-phosphate isomerase activity; TAS:Reactome.
DR GO; GO:0016866; F:intramolecular transferase activity; IEA:Ensembl.
DR GO; GO:0048029; F:monosaccharide binding; IEA:Ensembl.
DR GO; GO:0046185; P:aldehyde catabolic process; IEA:Ensembl.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0006094; P:gluconeogenesis; TAS:Reactome.
DR GO; GO:0051156; P:glucose 6-phosphate metabolic process; IEA:Ensembl.
DR GO; GO:0006096; P:glycolysis; TAS:Reactome.
DR GO; GO:0007599; P:hemostasis; TAS:ProtInc.
DR GO; GO:0006959; P:humoral immune response; TAS:ProtInc.
DR GO; GO:0007611; P:learning or memory; IEA:Ensembl.
DR GO; GO:0019242; P:methylglyoxal biosynthetic process; IEA:Ensembl.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 1.10.1390.10; -; 1.
DR InterPro; IPR001672; G6P_Isomerase.
DR InterPro; IPR023096; G6P_Isomerase_C.
DR InterPro; IPR018189; Phosphoglucose_isomerase_CS.
DR PANTHER; PTHR11469; PTHR11469; 1.
DR Pfam; PF00342; PGI; 1.
DR PRINTS; PR00662; G6PISOMERASE.
DR PROSITE; PS00765; P_GLUCOSE_ISOMERASE_1; 1.
DR PROSITE; PS00174; P_GLUCOSE_ISOMERASE_2; 1.
DR PROSITE; PS51463; P_GLUCOSE_ISOMERASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Angiogenesis;
KW Complete proteome; Cytokine; Cytoplasm; Direct protein sequencing;
KW Disease mutation; Gluconeogenesis; Glycolysis; Growth factor;
KW Hereditary hemolytic anemia; Isomerase; Phosphoprotein; Polymorphism;
KW Reference proteome; Secreted; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 558 Glucose-6-phosphate isomerase.
FT /FTId=PRO_0000180537.
FT ACT_SITE 358 358 Proton donor.
FT ACT_SITE 389 389
FT ACT_SITE 519 519
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 12 12 N6-acetyllysine.
FT MOD_RES 109 109 Phosphothreonine.
FT MOD_RES 142 142 N6-acetyllysine.
FT MOD_RES 185 185 Phosphoserine; by CK2.
FT MOD_RES 454 454 N6-malonyllysine.
FT VAR_SEQ 1 1 M -> MVALCSLQHLGSSDPRALPTLPTATSGQRPAKRRRK
FT SPAM (in isoform 2).
FT /FTId=VSP_043475.
FT VAR_SEQ 135 162 Missing (in isoform 2).
FT /FTId=VSP_043476.
FT VARIANT 5 5 T -> I (in HA-GPID; GPI Matsumoto).
FT /FTId=VAR_002516.
FT VARIANT 20 20 H -> P (in HA-GPID; severe form with
FT neurological deficits; GPI Homburg).
FT /FTId=VAR_002517.
FT VARIANT 75 75 R -> G (in HA-GPID; GPI Elyria).
FT /FTId=VAR_002518.
FT VARIANT 83 83 R -> W (in HA-GPID).
FT /FTId=VAR_002519.
FT VARIANT 101 101 V -> M (in HA-GPID; GPI Sarcina).
FT /FTId=VAR_002521.
FT VARIANT 159 159 G -> S (in HA-GPID).
FT /FTId=VAR_002520.
FT VARIANT 195 195 T -> I (in HA-GPID; GPI Bari and Mola).
FT /FTId=VAR_002522.
FT VARIANT 208 208 I -> T (in dbSNP:rs8191371).
FT /FTId=VAR_018816.
FT VARIANT 224 224 T -> M (in HA-GPID; GPI Iwate;
FT dbSNP:rs61754634).
FT /FTId=VAR_002523.
FT VARIANT 273 273 R -> H (in HA-GPID).
FT /FTId=VAR_002524.
FT VARIANT 278 278 S -> L (in HA-GPID; dbSNP:rs34306618).
FT /FTId=VAR_002525.
FT VARIANT 300 300 A -> P (in HA-GPID).
FT /FTId=VAR_002526.
FT VARIANT 308 308 R -> H (in dbSNP:rs2230294).
FT /FTId=VAR_033943.
FT VARIANT 339 339 L -> P (in HA-GPID; severe form with
FT neurological deficits; GPI Homburg).
FT /FTId=VAR_002527.
FT VARIANT 343 343 Q -> R (in HA-GPID; GPI Narita and
FT Morcone).
FT /FTId=VAR_002528.
FT VARIANT 347 347 R -> C (in HA-GPID; GPI Mount Scopus).
FT /FTId=VAR_002529.
FT VARIANT 347 347 R -> H (in HA-GPID).
FT /FTId=VAR_002530.
FT VARIANT 375 375 T -> R (in HA-GPID; GPI Kinki).
FT /FTId=VAR_002531.
FT VARIANT 389 389 H -> R (in HA-GPID; severe form; GPI
FT Calden).
FT /FTId=VAR_002532.
FT VARIANT 472 472 R -> H (in HA-GPID).
FT /FTId=VAR_002533.
FT VARIANT 487 487 L -> F (in HA-GPID).
FT /FTId=VAR_002534.
FT VARIANT 495 495 E -> K (in HA-GPID).
FT /FTId=VAR_002535.
FT VARIANT 517 517 L -> V (in HA-GPID; severe form; GPI
FT Calden).
FT /FTId=VAR_002536.
FT VARIANT 525 525 I -> T (in HA-GPID).
FT /FTId=VAR_002537.
FT VARIANT 539 539 D -> N (in HA-GPID; GPI Fukuoka and
FT Kinki).
FT /FTId=VAR_002538.
FT MUTAGEN 185 185 S->A: Retained full enzymatic activity.
FT MUTAGEN 185 185 S->E: Decreased enzymatic activity.
FT CONFLICT 158 158 G -> V (in Ref. 1; AAA36368).
FT CONFLICT 426 426 L -> V (in Ref. 2; AAF22645).
FT CONFLICT 436 436 L -> V (in Ref. 2; AAF22645).
FT HELIX 3 6
FT HELIX 8 20
FT HELIX 21 23
FT HELIX 26 32
FT HELIX 36 39
FT STRAND 41 45
FT STRAND 50 54
FT STRAND 57 59
FT HELIX 62 74
FT HELIX 77 85
FT TURN 92 95
FT HELIX 100 103
FT STRAND 116 118
FT HELIX 119 137
FT STRAND 151 155
FT HELIX 158 160
FT HELIX 162 170
FT HELIX 172 174
FT STRAND 180 184
FT HELIX 189 196
FT HELIX 201 203
FT STRAND 204 209
FT STRAND 211 213
FT HELIX 216 233
FT HELIX 236 238
FT HELIX 239 242
FT STRAND 243 248
FT HELIX 250 256
FT HELIX 260 262
FT STRAND 263 265
FT HELIX 272 274
FT TURN 276 278
FT HELIX 279 281
FT HELIX 282 288
FT HELIX 290 309
FT HELIX 312 314
FT HELIX 316 329
FT STRAND 335 341
FT HELIX 343 345
FT HELIX 348 360
FT STRAND 378 380
FT HELIX 386 389
FT HELIX 392 397
FT STRAND 398 400
FT STRAND 404 411
FT HELIX 416 419
FT HELIX 420 438
FT HELIX 442 451
FT HELIX 456 462
FT HELIX 463 466
FT STRAND 474 481
FT HELIX 484 505
FT HELIX 513 515
FT HELIX 516 528
FT STRAND 530 532
FT HELIX 540 552
SQ SEQUENCE 558 AA; 63147 MW; 7C8E95277BDC79A6 CRC64;
MAALTRDPQF QKLQQWYREH RSELNLRRLF DANKDRFNHF SLTLNTNHGH ILVDYSKNLV
TEDVMRMLVD LAKSRGVEAA RERMFNGEKI NYTEGRAVLH VALRNRSNTP ILVDGKDVMP
EVNKVLDKMK SFCQRVRSGD WKGYTGKTIT DVINIGIGGS DLGPLMVTEA LKPYSSGGPR
VWYVSNIDGT HIAKTLAQLN PESSLFIIAS KTFTTQETIT NAETAKEWFL QAAKDPSAVA
KHFVALSTNT TKVKEFGIDP QNMFEFWDWV GGRYSLWSAI GLSIALHVGF DNFEQLLSGA
HWMDQHFRTT PLEKNAPVLL ALLGIWYINC FGCETHAMLP YDQYLHRFAA YFQQGDMESN
GKYITKSGTR VDHQTGPIVW GEPGTNGQHA FYQLIHQGTK MIPCDFLIPV QTQHPIRKGL
HHKILLANFL AQTEALMRGK STEEARKELQ AAGKSPEDLE RLLPHKVFEG NRPTNSIVFT
KLTPFMLGAL VAMYEHKIFV QGIIWDINSF DQWGVELGKQ LAKKIEPELD GSAQVTSHDA
STNGLINFIK QQREARVQ
//

MIM 172400
*RECORD*
*FIELD* NO
172400
*FIELD* TI
*172400 GLUCOSE-6-PHOSPHATE ISOMERASE; GPI
;;GLUCOSE PHOSPHATE ISOMERASE;;
PHOSPHOHEXOSE ISOMERASE; PHI;;
read morePHOSPHOGLUCOSE ISOMERASE; PGI;;
AUTOCRINE MOTILITY FACTOR; AMF;;
NEUROLEUKIN; NLK
*FIELD* TX

DESCRIPTION

The GPI gene encodes glucose phosphate isomerase (GPI; EC 5.3.1.9), also
known as phosphohexose isomerase (PHI; D-glucose-6-phosphate
ketol-isomerase) and phosphoglucose isomerase (PGI). GPI catalyzes the
interconversion of glucose-6-phosphate and fructose-6-phosphate, the
second step of the Embden-Meyerhof glycolytic pathway. GPI is also
referred to as neuroleukin (NLK) and autocrine motility factor (AMF)
(Niinaka et al., 1998).

CLONING

Chaput et al. (1988) cloned the gene for pig muscle phosphohexose
isomerase and found 90% homology to the sequence of mouse neuroleukin.
In a similar study, Faik et al. (1988) isolated a mouse phosphoglucose
isomerase cDNA clone and found complete identity between 759 nucleotides
at the 3-prime end of this clone and the sequence of mouse neuroleukin.
Thus it seemed likely that the molecule previously described as
neuroleukin was in fact glucose phosphate isomerase. Gurney (1988) found
that mouse and human neuroleukin cDNAs expressed GPI enzyme activity
when transfected into monkey COS cells.

Neuroleukin is a lymphokine produced by lectin-stimulated T cells. It
induces immunoglobulin secretion by cultured human peripheral blood
mononuclear cells. Neuroleukin acts early in the in vitro response that
leads to formation of antibody-secreting cells. Continued production of
immunoglobulin by differentiated antibody-secreting cells is
neuroleukin-independent. NLK is not directly mitogenic; however,
cellular proliferation is a late component of the response to this
lymphokine. Gurney et al. (1986) found that NLK had no B-cell growth
factor (BCGF) or B-cell differentiation factor (BCDF) activity in
defined assays. Its induction of immunoglobulin secretion was found to
be both monocyte- and T-cell-dependent. Gurney et al. (1986) found NLK
in mouse salivary gland. It is a 56,000-dalton growth factor which is a
neurotrophic factor as well as a lymphokine. It promotes the survival in
culture of a subpopulation of embryonic spinal neurons that probably
includes skeletal motor neurons. It also supports the survival of
cultured sensory neurons that are insensitive to nerve growth factor but
it has no effect on sympathetic or parasympathetic neurons. Gurney et
al. (1986) found that the amino acid sequence of NLK is partly
homologous to a highly conserved region of the external envelope protein
of HTLV-III-LAV, the retrovirus that causes acquired immune deficiency
syndrome (AIDS).

Niinaka et al. (1998) used protein microsequencing to show that the
55-kD autocrine motility factor (AMF) is NLK. Although AMF, NLK, and GPI
have different assigned functions, they are the products of a single
gene. Niinaka et al. (1998) cloned the human AMF cDNA. The gene encodes
a 558-amino acid polypeptide. Niinaka et al. (1998) showed that the
different sizes of AMF observed in normal versus cancerous cells are not
the result of alternative splicing; the mRNAs are identical.
Immunofluorescence studies showed that AMF is localized primarily in
tubular vesicles in the cytoplasm. AMF and its receptor (AMFR; 603243)
partially colocalize on the malignant cell surface.

GENE STRUCTURE

Walker et al. (1995) and Xu et al. (1995) found that the GPI gene spans
more than 40 kb and consists of 18 exons ranging in size from 44 to 153
bp. All splice sites conformed to the GT/AG rule.

MAPPING

Ritter et al. (1971) suggested that the PGI locus may be linked to the
ABO locus. However, Hamerton et al. (1973) and McMorris et al. (1973)
showed by somatic cell hybridization that the PGI locus is on chromosome
19. The SRO of 19cen-q13.2 was arrived at by data collated at HGM8
(Naylor et al., 1985). Lusis et al. (1985) assigned GPI to the long arm
of chromosome 19. By study of human-mouse hybrid cells, Kaneda et al.
(1987) narrowed the assignment of GPI to 19cen-q12.

Gurney (1988) reported that the cDNA encoding human neuroleukin maps to
the same region as GPI on the long arm of chromosome 19.

In the mouse the hemoglobin beta chain locus is loosely linked to that
for glucosephosphate isomerase (recombination fraction, 32%) on
chromosome 7. GPI and PEPD, which are on chromosome 19 in man, are on
chromosome 9 of the Chinese hamster, and TPI, which is on chromosome 12
of man, is on Chinese hamster chromosome 8 (Siciliano et al., 1983).

GENE FUNCTION

In a T-cell receptor transgenic mouse model, an inflammatory arthritis
that resembles human rheumatoid arthritis (RA; 180300), is initiated by
T cells but is sustained by antibodies to GPI. Using ELISA analysis,
Schaller et al. (2001) detected high levels of antibody to GPI,
independent of the presence of rheumatoid factor, in serum and synovial
fluid of most RA patients; antibody to GPI was rare in controls and in
patients with Lyme arthritis or Sjogren syndrome. In addition, the
authors identified high levels of GPI in sera and synovial fluid and the
presence of GPI-containing immune complexes in RA synovial fluid.
Immunohistochemical analysis and confocal microscopy demonstrated
intense expression of GPI on the surface of endothelial cells of
synovial arterioles and some capillaries, but not venules or in other
tissues. Intense patchy expression was observed on the surface lining of
hypertrophic synovium, particularly where the hypertrophic villus
formed; this expression pattern resembled that for vascular permeability
factor (VEGF/VPF; 192240). Schaller et al. (2001) suggested that GPI may
be presented to the immune system either on endothelial cell surfaces or
as a soluble protein in synovial fluid of inflamed RA joints, leading to
antibody binding or to immune complex formation with complement
activation, respectively. In either case, they concluded that there is a
role for autoantibody in the pathology of RA and that there may be scope
for antibody treatments for the disease.

MOLECULAR GENETICS

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

Mohrenweiser and Neel (1981) identified thermolabile variants of lactate
dehydrogenase B, glucosephosphate isomerase, and glucose-6-phosphate
dehydrogenase. None was detectable as a variant by standard
electrophoretic techniques. All were inherited.

In a patient with chronic hemolytic anemia associated with severe
deficiency of red cell glucose phosphate isomerase (613470), Walker et
al. (1993) identified compound heterozygosity for 2 mutations in the GLI
gene (172400.0001-172400.0002).

Schroter et al. (1985) described a GPI mutant called GPI Homburg
(172400.0006) characterized by severe enzyme deficiency in red cells,
granulocytes and muscle. The mutant enzyme had nearly normal stability,
normal kinetic properties, and decreased electrophoretic mobility. The
proband was a boy with transfusion-requiring, recurrent, spontaneous
hemolytic crises beginning at the age of 3 and relieved by splenectomy
at age 5 years. At age 13, however, he still had mild hemolytic anemia
and moderate icterus and showed several pigment gallstones. Involvement
of the neuromuscular system was indicated by muscle weakness, a mixed
sensory and cerebellar ataxia, and mental retardation. Although
granulocyte function appeared not to be altered in vivo, in vitro they
showed decreased production of superoxide anion and reduced bactericidal
activity. Although red cell enzymopathies are well-recognized causes of
hemolytic anemia in the newborn, rarely have they been implicated in
hydrops fetalis or even in immediate neonatal death.

*FIELD* AV
.0001
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, GLY158SER

In a patient with chronic nonspherocytic hemolytic anemia associated
with severe deficiency of red cell glucose phosphate isomerase (613470),
Walker et al. (1993) demonstrated compound heterozygosity for a
transition converting codon 158 from GGC (gly) to AGC (ser) and codon
346 from CGC (arg) to CAC (his) (172400.0002).

.0002
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, ARG346HIS

See 172400.0001 and Walker et al. (1993).

.0003
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, ILE524THR

In a patient with chronic hemolytic anemia and severe deficiency of
glucose phosphate isomerase (613470), Walker et al. (1993) demonstrated
a T-to-C transition converting codon 524 from ATA (ile) to ACA (thr).

.0004
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, ASP539ASN

Kanno et al. (1996) reported a case of GPI deficiency associated with
hemolytic anemia (613470) in a 3-year-old girl who presented in an acute
hemolytic crisis after a history of prolonged neonatal jaundice. Red
blood cell GPI activity was decreased to 11.8% of normal. Homozygosity
for an asp539-to-asn missense mutation (GPI Fukuoka) was found.

.0005
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, THR224MET

Kanno et al. (1996) reported a case of GPI deficiency associated with
hemolytic anemia (613470) in a 54-year-old man with chronic active
hepatitis and compensated hemolysis. GPI activity was 18.8% of normal.
Homozygosity for a thr224-to-met (GPI Iwate) missense mutation was
found.

.0006
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, AND NEUROLOGIC DEFICITS, DUE TO
GLUCOSE PHOSPHATE ISOMERASE DEFICIENCY
GPI, HIS20PRO

Kugler et al. (1998) found that the patient with severe GPI deficiency
and neurologic deficits (613470) described as GPI Homburg (Schroter et
al., 1985) was a compound heterozygote for 2 missense mutations: an
A-to-C transversion at nucleotide 59 causing a his-to-pro substitution
at codon 20, and a T-to-C transition at nucleotide 1016 causing a
leu-to-pro substitution at codon 339 (172400.0007). Kugler et al. (1998)
proposed that the proline substitutions lead to incorrect folding, which
would destroy both the catalytic (GPI) and neurotrophic (NLK)
activities. Another patient they described with 2 missense mutations had
no neurologic deficits; the mutations occurred in the catalytic site and
should not have affected folding, supporting their hypothesis.

.0007
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, AND NEUROLOGIC DEFICITS, DUE TO
GLUCOSE PHOSPHATE ISOMERASE DEFICIENCY
GPI, LEU339PRO

See 172400.0006 and Kugler et al. (1998).

.0008
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, GLN343ARG

Kanno et al. (1996) reported a Japanese patient with nonspherocytic
hemolytic anemia and GPI deficiency (613470) who was homozygous for a
gln343-to-arg (GPI Narita) mutation in the GLI gene.

.0009
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, THR5ILE

Kanno et al. (1996) reported a Japanese patient with nonspherocytic
hemolytic anemia and GPI deficiency (613470) who was homozygous for a
thr5-to-ile (GPI Matsumoto) mutation in the GLI gene.

.0010
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, THR375ARG

Kanno et al. (1996) reported a Japanese patient with nonspherocytic
hemolytic anemia and GPI deficiency (613470) who was compound
heterozygous for a 2 mutations in the GLI gene: thr375 to arg and asp539
to asn (172400.0011). This variant was designated GPI Kinki.

.0011
HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
GPI, ASP539ASN

See 172400.0010 and Kanno et al. (1996).

*FIELD* SA
Kahn et al. (1977); Krone et al. (1970); Mohrenweiser et al. (1987);
Satoh and Mohrenweiser (1979); Schroter et al. (1974); Tariverdian
et al. (1970); Terrenato et al. (1972); Welch (1973)
*FIELD* RF
1. Chaput, M.; Claes, V.; Portetelle, D.; Cludts, I.; Cravador, A.;
Burny, A.; Gras, H.; Tartar, A.: The neurotrophic factor neuroleukin
is 90% homologous with phosphohexose isomerase. (Letter) Nature 332:
454-455, 1988.

2. Faik, P.; Walker, J. I. H.; Redmill, A. A. M.; Morgan, M. J.:
Mouse glucose-6-phosphate isomerase and neuroleukin have identical
3-prime sequences. (Letter) Nature 332: 455-457, 1988.

3. Gurney, M. E.: Reply to letters of Chaput et al. (1988) and Faik
et al. (1988) [loc. cit.]. (Letter) Nature 332: 456-457, 1988.

4. Gurney, M. E.; Apatoff, B. R.; Spear, G. T.; Baumel, M. J.; Antel,
J. P.; Bania, M. B.; Reder, A. T.: Neuroleukin: a lymphokine product
of lectin-stimulated T cells. Science 234: 574-581, 1986.

5. Gurney, M. E.; Heinrich, S. P.; Lee, M. R.; Yin, H.: Molecular
cloning and expression of neuroleukin, a neurotrophic factor for spinal
and sensory neurons. Science 234: 566-574, 1986.

6. Hamerton, J. L.; Douglas, G. R.; Gee, P. A.; Richardson, B. J.
: The association of glucose phosphate isomerase expression with human
chromosome 19 using somatic cell hybrids. Cytogenet. Cell Genet. 12:
128-135, 1973.

7. Kahn, A.; van Biervliet, J. P. G. M.; Vives-Corrons, J. L.; Cottreau,
D.; Staal, G. E. J.: Genetic and molecular mechanisms of the congenital
defects in glucose phosphate isomerase activity: studies of four families. Pediat.
Res. 11: 1123-1129, 1977.

8. Kaneda, Y.; Hayes, H.; Uchida, T.; Yoshida, M. C.; Okada, Y.:
Regional assignment of five genes on human chromosome 19. Chromosoma 95:
8-12, 1987.

9. Kanno, H.; Fujii, H.; Hirono, A.; Ishida, Y.; Ohga, S.; Fukumoto,
Y.; Matsuzawa, K.; Ogawa, S.; Miwa, S.: Molecular analysis of glucose
phosphate isomerase deficiency associated with hereditary hemolytic
anemia. Blood 88: 2321-2325, 1996.

10. Krone, W.; Schneider, G.; Schulz, D.; Arnold, H.; Blume, K. G.
: Detection of phosphohexose isomerase: deficiency in human fibroblast
cultures. Humangenetik 10: 224-230, 1970.

11. Kugler, W.; Breme, K.; Laspe, P.; Muirhead, H.; Davies, C.; Winkler,
H.; Schroter, W.; Lakomek, M.: Molecular basis of neurological dysfunction
coupled with haemolytic anaemia in human glucose-6-phosphate isomerase
(GPI) deficiency. Hum. Genet. 103: 450-454, 1998.

12. Lusis, A. J.; Heinzmann, C.; Sparkes, R. S.; Geller, R.; Sparkes,
M. C.; Mohandas, T.: Regional mapping on human chromosome 19: apolipoprotein
E, apolipoprotein CII, low density lipoprotein (LDL) receptor, peptidase
D, glucose phosphate isomerase. (Abstract) Cytogenet. Cell Genet. 40:
683 only, 1985.

13. McMorris, F. A.; Chen, T.-R.; Ricciuti, F.; Tischfield, J.; Creagan,
R.; Ruddle, F. H.: Chromosome assignments in man of the genes for
two hexosephosphate isomerases. Science 179: 1129-1131, 1973.

14. Mohrenweiser, H. W.; Neel, J. V.: Frequency of thermostability
variants: estimation of total 'rare' variant frequency in human populations. Proc.
Nat. Acad. Sci. 78: 5729-5733, 1981.

15. Mohrenweiser, H. W.; Wade, P. T.; Wurzinger, K. H.: Characterization
of a series of electrophoretic and enzyme activity variants of human
glucose-phosphate isomerase. Hum. Genet. 75: 28-31, 1987.

16. Naylor, S.; Lalouel, J.-M.; Shaw, D. J.: Report of the committee
on the genetic constitution of chromosomes 17, 18 and 19. Cytogenet.
Cell Genet. 40: 242-267, 1985.

17. Niinaka, Y.; Paku, S.; Haga, A.; Watanabe, H.; Raz, A.: Expression
and secretion of neuroleukin/phosphohexose isomerase/maturation factor
as autocrine motility factor by tumor cells. Cancer Res. 58: 2667-2674,
1998.

18. Ritter, H.; Tariverdian, G.; Arnold, H.; Blume, K. G.; Schroter,
W.; Wendt, G. G.: Evidence for linkage between the locus for the
ABO-system and the locus for phosphoglucoseisomerase (PGI). Humangenetik 11:
349-350, 1971.

19. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.

20. Satoh, C.; Mohrenweiser, H. W.: Genetic heterogeneity within
an electrophoretic phenotype of phosphoglucose isomerase in a Japanese
population. Ann. Hum. Genet. 42: 283-292, 1979.

21. Schaller, M.; Burton, D. R.; Ditzel, H. J.: Autoantibodies to
GPI in rheumatoid arthritis: linkage between an animal model and human
disease. Nature Immun. 2: 746-753, 2001.

22. Schroter, W.; Eber, S. W.; Bardosi, A.; Gahr, M.; Gabriel, M.;
Sitzmann, F. C.: Generalised glucosephosphate isomerase (GPI) deficiency
causing haemolytic anaemia, neuromuscular symptoms and impairment
of granulocytic function: a new syndrome due to a new stable GPI variant
with diminished specific activity (GPI Homburg). Europ. J. Pediat. 144:
301-305, 1985.

23. Schroter, W.; Koch, H. H.; Wonneberger, B.; Kalinowsky, W.: Glucose
phosphate isomerase deficiency with congenital nonspherocytic hemolytic
anemia: a new variant (type Nordhorn). I. Clinical and genetic studies. Pediat.
Res. 8: 18-25, 1974.

24. Siciliano, M. J.; Stallings, R. L.; Adair, G. M.; Humphrey, R.
M.; Siciliano, J.: Provisional assignment of TPI, GPI, and PEPD to
Chinese hamster autosomes 8 and 9: a cytogenetic basis for functional
haploidy of an autosomal linkage group in CHO cells. Cytogenet. Cell
Genet. 35: 15-20, 1983.

25. Tariverdian, G.; Arnold, H.; Blume, K. G.; Lenkeit, U.; Lohr,
G. W.: Zur Formalgenetik der Phosphoglucoseisomerase (EC: 5.3.1.9).
Untersuchung einer Sippe mit Pgi-Defizienz. Humangenetik 10: 218-223,
1970.

26. Terrenato, L.; Santolamazza, C.; Piacentini, E.; Ulizzi, L.; Stirati,
G.: Two human red cell phosphohexose isomerase variants in a sample
from the population of Rome. Humangenetik 14: 162-163, 1972.

27. Walker, J. I. H.; Layton, D. M.; Bellingham, A. J.; Morgan, M.
J.; Faik, P.: DNA sequence abnormalities in human glucose 6-phosphate
isomerase deficiency. Hum. Molec. Genet. 2: 327-329, 1993.

28. Walker, J. I. H.; Morgan, M. J.; Faik, P.: Structure and organization
of the human glucose phosphate isomerase gene (GPI). Genomics 29:
261-265, 1995.

29. Welch, S. G.: An immunological approach to the study of inherited
differences in the activity of human erythrocyte phosphoglucose isomerase. Hum.
Hered. 23: 164-174, 1973.

30. Xu, W.; Lee, P.; Beutler, E.: Human glucose phosphate isomerase:
exon mapping and gene structure. Genomics 29: 732-739, 1995.

*FIELD* CN
Paul J. Converse - updated: 12/11/2001
Ada Hamosh - updated: 3/9/1999
Jennifer P. Macke - updated: 11/2/1998
Cynthia K. Ewing - updated: 10/22/1996
Alan F. Scott - updated: 11/8/1995

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 03/10/2011
carol: 7/6/2010
joanna: 3/24/2010
carol: 1/13/2010
mgross: 1/7/2002
terry: 12/11/2001
alopez: 3/11/1999
alopez: 3/9/1999
carol: 11/3/1998
alopez: 11/2/1998
mark: 7/1/1997
mark: 10/2/1995
mimadm: 1/14/1995
pfoster: 1/5/1995
warfield: 3/4/1994
carol: 12/16/1993

MIM 613470
*RECORD*
*FIELD* NO
613470
*FIELD* TI
#613470 HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO GLUCOSE PHOSPHATE ISOMERASE
DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because nonspherocytic
hemolytic anemia can be caused by homozygous or compound heterozygous
mutation in the gene encoding glucose phosphate isomerase (GPI; 172400),
also known as phosphoglucose isomerase (PHI).

CLINICAL FEATURES

Baughan et al. (1968) found deficiency of erythrocyte GPI in an
adolescent boy with lifelong nonspherocytic hemolytic anemia. The
autohemolysis pattern conformed to Dacie type I. Both parents, a sib,
and 5 other relatives showed intermediate enzyme levels. The proband
showed low enzyme in leukocytes and no detectable enzyme in plasma. The
deficiency occurs in leukocytes and plasma as well as in erythrocytes
but the only clinical manifestation is hemolytic anemia.

Paglia et al. (1969) found deficiency of red cell and leukocyte
glucosephosphate isomerase in 3 sibs with hemolytic anemia. The anemia
was ameliorated by splenectomy. Heterozygotes could be identified.

Detter et al. (1968) found that the parents of a patient with hemolytic
anemia had different electrophoretic variants of PHI, each associated
with reduced enzyme activity. Thus, the patient was a genetic compound.
Blume et al. (1972) also described a patient with hemolytic anemia who
was a genetic compound for 2 forms of GPI. The variant inherited from
the mother had no detectable activity. That inherited from the father
and designated GPI Los Angeles had residual activity and electrophoretic
and thermolability peculiarities. A patient homozygous for GPI Winnipeg
was also described. Nakashima et al. (1973) described 2 Japanese
families with nonspherocytic hemolytic anemia due to GPI deficiency.
Each family demonstrated a 'new' variety of mutant enzyme with
deficiency of catalytic function.

Beutler et al. (1974) described a 13-year-old girl with chronic
nonspherocytic hemolytic anemia who appeared to be homozygous for a
deficient GPI allele, which the authors designated GPI Elyria. The
girl's parents were related.

Schroter et al. (1985) described a patient with what they called GPI
Homburg characterized by severe enzyme deficiency in red cells,
granulocytes and muscle. The mutant enzyme had nearly normal stability,
normal kinetic properties, and decreased electrophoretic mobility. The
proband was a boy with transfusion-requiring, recurrent, spontaneous
hemolytic crises beginning at the age of 3 and relieved by splenectomy
at age 5 years. At age 13, however, he still had mild hemolytic anemia
and moderate icterus and showed several pigment gallstones. Involvement
of the neuromuscular system was indicated by muscle weakness, a mixed
sensory and cerebellar ataxia, and mental retardation. Although
granulocyte function appeared not to be altered in vivo, in vitro they
showed decreased production of superoxide anion and reduced bactericidal
activity.

Ravindranath et al. (1987) reported a consanguineous family from
southern India in which 5 of 6 pregnancies resulted either in stillbirth
or in early neonatal death (one with hydrops). The sixth child was
delivered early, noted to have hydrops fetalis, and successfully treated
with exchange transfusion in the immediate postnatal period. The
hemolytic anemia was subsequently shown to be due to GPI deficiency and
was clinically ameliorated by splenectomy at the age of 3 years.

Shalev et al. (1993) reported what they claimed to be the first instance
of GPI deficiency causing hereditary nonspherocytic hemolytic anemia in
an Ashkenazi Jew. The biophysical characteristics of the GPI variant,
which they called GPI Mount Scopus, were slow electrophoretic mobility,
presence of only 1 of the 2 electrophoretic bands normally present, and
extreme thermolability.

DIAGNOSIS

Blume and Beutler (1972) developed a simple screening test for GPI
deficiency.

MOLECULAR GENETICS

In a patient with chronic hemolytic anemia associated with severe
deficiency of red cell glucose phosphate isomerase, Walker et al. (1993)
identified compound heterozygosity for 2 mutations in the GLI gene
(172400.0001-172400.0002).

In the patient described by Schroter et al. (1985) with GPI Homburg
(172400.0006), Kugler et al. (1998) identified compound heterozygosity
for 2 mutations in the GLI gene (172400.0006-172400.0007).

ANIMAL MODEL

Merkle and Pretsch (1993) reported enzymatic and hematologic studies on
mice homozygous for one or the other of 2 mutations in the GPI gene
found in mutagenicity experiments.

*FIELD* SA
Arnold (1979); Arnold et al. (1983); Arnold et al. (1981); Arnold
et al. (1980); Bonne-Tamir et al. (1987); Galand et al. (1978); Hutton
(1969); Hutton and Chilcote (1974); Isacchi et al. (1979); Kahn et
al. (1978); Paglia et al. (1975); Paglia and Valentine (1974); Rotteveel
et al. (1977); van Biervliet et al. (1975); van Biervliet et al. (1975);
Whitelaw et al. (1979); Zanella et al. (1980); Zanella et al. (1978)
*FIELD* RF
1. Arnold, H.: Inherited glucosephosphate isomerase deficiency: a
review of known variants and some aspects of the pathomechanism of
the deficiency. Blut 39: 405-417, 1979.

2. Arnold, H.; Hasslinger, K.; Witt, I.: Glucosephosphate-isomerase
type Kaiserslautern: a new variant causing congenital nonspherocytic
hemolytic anemia. Blut 46: 271-277, 1983.

3. Arnold, H.; Lohr, G. W.; Hasslinger, K.; Ludwig, R.: Combined
erythrocyte glucosephosphate isomerase (GPI) and glucose-6-phosphate
dehydrogenase (G6PD) deficiency in an Italian family. Hum. Genet. 57:
226-229, 1981.

4. Arnold, H.; Lohr, G. W.; Hasslinger, K.; Podgajny, T.: Augsburg-type
glucosephosphate isomerase deficiency: a new variant causing congenital
nonspherocytic hemolytic anemia in a German family. Blut 40: 107-115,
1980.

5. Baughan, M. A.; Valentine, W. N.; Paglia, M. D.; Ways, P. O.; Simon,
E. R.; Demarsh, Q. B.: Hereditary hemolytic anemia associated with
glucosephosphate isomerase (GPI) deficiency--a new enzyme defect of
human erythrocytes. Blood 32: 236-249, 1968.

6. Beutler, E.; Sigalove, W. H.; Muir, W. A.; Matsumoto, B. S.; West,
C.: Glucosephosphate-isomerase (GPI) deficiency: GPI Elyria. Ann.
Intern. Med. 80: 730-732, 1974.

7. Blume, K. G.; Beutler, E.: Detection of glucose-phosphate isomerase
deficiency by a screening procedure. Blood 39: 685-687, 1972.

8. Blume, K. G.; Hryniuk, W.; Powars, D.; Trinidad, F.; West, C.;
Beutler, E.: Characterization of two new variants of glucose-phosphate-isomerase
deficiency with hereditary nonspherocytic hemolytic anemia. J. Lab.
Clin. Med. 79: 942-949, 1972.

9. Bonne-Tamir, B.; Papiha, S. S.; Ashbel, S.; Brok-Simoni, F.; Kende,
G.; Ramot, B.: PGI*3(Israel), a new, unstable allele in the phosphoglucose
isomerase system. Hum. Genet. 77: 76-79, 1987.

10. Detter, J. C.; Ways, P. O.; Giblett, E. R.; Baughan, D. A.; Hopkinson,
D. A.; Povey, S.; Harris, H.: Inherited variations in human phosphohexose
isomerase. Ann. Hum. Genet. 31: 329-338, 1968.

11. Galand, C.; Torres, M.; Boivin, P.; Bourgeaud, J. P.: A new variant
of glucosephosphate isomerase deficiency with mild haemolytic anaemia
(GPI-MYTHO). Scand. J. Haemat. 20: 77-84, 1978.

12. Hutton, J. J.: Linkage analysis using biochemical variants in
mice: linkage of the hemoglobin beta-chain and glucosephosphate isomerase
loci. Biochem. Genet. 3: 507-515, 1969.

13. Hutton, J. J.; Chilcote, R. R.: Glucose phosphate isomerase deficiency
with hereditary nonspherocytic hemolytic anemia. J. Pediat. 85:
494-497, 1974.

14. Isacchi, G.; Cottreau, D.; Mandelli, F.; Papa, G.; Ciccone, F.;
Kahn, A.: 'GPI Roma,' a new glucose phosphate isomerase deficient
variant: in vivo occurrence of postsynthetic modifications of the
mutant enzyme. Hum. Genet. 46: 219-226, 1979.

15. Kahn, A.; Buc, H.-A.; Girot, R.; Cottreau, D.; Griscelli, C.:
Molecular and functional anomalies in two new mutant glucose-phosphate-isomerase
variants with enzyme deficiency and chronic hemolysis. Hum. Genet. 40:
293-304, 1978.

16. Kugler, W.; Breme, K.; Laspe, P.; Muirhead, H.; Davies, C.; Winkler,
H.; Schroter, W.; Lakomek, M.: Molecular basis of neurological dysfunction
coupled with haemolytic anaemia in human glucose-6-phosphate isomerase
(GPI) deficiency. Hum. Genet. 103: 450-454, 1998.

17. Merkle, S.; Pretsch, W.: Glucose-6-phosphate isomerase deficiency
associated with nonspherocytic hemolytic anemia in the mouse: an animal
model for the human disease. Blood 81: 206-213, 1993.

18. Nakashima, K.; Miwa, S.; Oda, S.; Oda, E.; Matsumoto, N.; Fukumoto,
Y.; Yamada, T.: Electrophoretic and kinetic studies of glucosephosphate
isomerase (GPI) in two different Japanese families with GPI deficiency. Am.
J. Hum. Genet. 25: 294-301, 1973.

19. Paglia, D. E.; Holland, P.; Baughan, M. A.; Valentine, W. N.:
Occurrence of defective hexosephosphate isomerization in human erythrocytes
and leukocytes. New Eng. J. Med. 280: 66-71, 1969.

20. Paglia, D. E.; Paredes, R.; Valentine, W. N.; Dorantes, S.; Konrad,
P. N.: Unique phenotypic expression of glucosephosphate isomerase
deficiency. Am. J. Hum. Genet. 27: 62-70, 1975.

21. Paglia, D. E.; Valentine, W. N.: Hereditary glucosephosphate
isomerase deficiency: a review. Am. J. Clin. Path. 62: 740-751,
1974.

22. Ravindranath, Y.; Paglia, D. E.; Warrier, I.; Valentine, W.; Nakatani,
M.; Brockway, R. A.: Glucose phosphate isomerase deficiency as a
cause of hydrops fetalis. New Eng. J. Med. 316: 258-261, 1987.

23. Rotteveel, J. J.; de Vaan, G. A. M.; Staal, G. E. J.; van Biervliet,
J. P. G. M.; Schretlen, E. D. A. M.: Glucosephosphate isomerase deficiency,
a new variant in a Dutch family. A case report. Europ. J. Pediat. 125:
21-28, 1977.

24. Schroter, W.; Eber, S. W.; Bardosi, A.; Gahr, M.; Gabriel, M.;
Sitzmann, F. C.: Generalised glucosephosphate isomerase (GPI) deficiency
causing haemolytic anaemia, neuromuscular symptoms and impairment
of granulocytic function: a new syndrome due to a new stable GPI variant
with diminished specific activity (GPI Homburg). Europ. J. Pediat. 144:
301-305, 1985.

25. Shalev, O.; Shalev, R. S.; Forman, L.; Beutler, E.: GPI Mount
Scopus--a variant of glucosephosphate isomerase deficiency. Ann.
Hemat. 67: 197-200, 1993.

26. van Biervliet, J. P. G. M.; van Milligen-Boersma, L.; Staal, G.
E. J.: A new variant of glucosephosphate isomerase deficiency (GPI-Utrecht). Clin.
Chim. Acta 65: 157-166, 1975.

27. van Biervliet, J. P. G. M.; Vlug, A.; Bartstra, H.; Rotteveel,
J. J.; de Vaan, G. A. M.: A new variant of glucosephosphate isomerase
deficiency. Humangenetik 30: 35-40, 1975.

28. Walker, J. I. H.; Layton, D. M.; Bellingham, A. J.; Morgan, M.
J.; Faik, P.: DNA sequence abnormalities in human glucose 6-phosphate
isomerase deficiency. Hum. Molec. Genet. 2: 327-329, 1993.

29. Whitelaw, A. G. L.; Rogers, P. A.; Hopkinson, D. A.; Gordon, H.;
Emerson, P. M.; Darley, J. H.; Reid, C.; Crawfurd, M. A.: Congenital
haemolytic anaemia resulting from glucose phosphate isomerase deficiency:
genetics, clinical picture, and prenatal diagnosis. J. Med. Genet. 16:
189-196, 1979.

30. Zanella, A.; Izzo, C.; Rebulla, P.; Perroni, L.; Mariani, M.;
Canestri, G.; Sansone, G.; Sirchia, G.: The first stable variant
of erythrocyte glucose-phosphate isomerase associated with severe
hemolytic anemia. Am. J. Hemat. 9: 1-11, 1980.

31. Zanella, A.; Rebulla, P.; Izzo, C.; Zanuso, F.; Kahane, I.; Molinari,
E.; Sirchia, G.: A new erythrocyte glucosephosphate isomerase (GPI)
associated with GSH abnormality. Am. J. Hemat. 5: 11-23, 1978.

*FIELD* CS
Heme:
Nonspherocytic hemolytic anemia;
Spontaneous hemolytic crises

Skin:
Jaundice

GI:
Pigment gallstones;
Splenomegaly;
Cholecystitis

Muscle:
Muscle weakness

Neuro:
Mixed sensory and cerebellar ataxia;
Mental retardation

Misc:
Response to splenectomy;
Stillbirth or early neonatal death ( ? recessive)

Lab:
Phosphohexose isomerase deficiency;
Glucosephosphate isomerase deficiency;
Normal osmotic fragility;
Reduced leukocyte superoxide anion production;
Reduced leukocyte bactericidal activity

Inheritance:
Autosomal recessive

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/08/2012

*FIELD* CD
Carol A. Bocchini: 7/6/2010

*FIELD* ED
carol: 09/03/2010
carol: 7/6/2010