RBCC Red Blood Cell Collection

MPO [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Myeloperoxidase; MPO; 1.11.2.2; Myeloperoxidase; 89 kDa myeloperoxidase; 84 kDa myeloperoxidase; Myeloperoxidase light chain; Myeloperoxidase heavy chain; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

Comments
Isoform P05164-3 was detected.

UniProt P05164
ID PERM_HUMAN Reviewed; 745 AA.
AC P05164; A1L4B8; Q14862; Q4PJH5; Q9UCL7;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-AUG-1987, sequence version 1.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Myeloperoxidase;
DE Short=MPO;
DE EC=1.11.2.2;
DE Contains:
DE RecName: Full=Myeloperoxidase;
DE Contains:
DE RecName: Full=89 kDa myeloperoxidase;
DE Contains:
DE RecName: Full=84 kDa myeloperoxidase;
DE Contains:
DE RecName: Full=Myeloperoxidase light chain;
DE Contains:
DE RecName: Full=Myeloperoxidase heavy chain;
DE Flags: Precursor;
GN Name=MPO;
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 H17).
RX PubMed=3029127;
RA Morishita K., Kubota N., Asano S., Kaziro Y., Nagata S.;
RT "Molecular cloning and characterization of cDNA for human
RT myeloperoxidase.";
RL J. Biol. Chem. 262:3844-3851(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2444596;
RA Morishita K., Tsuchiya M., Asano S., Kaziro Y., Nagata S.;
RT "Chromosomal gene structure of human myeloperoxidase and regulation of
RT its expression by granulocyte colony-stimulating factor.";
RL J. Biol. Chem. 262:15208-15213(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM H17).
RX PubMed=3654979; DOI=10.1172/JCI113181;
RA Seto P., Hirayu H., Magnusson R.P., Gestautas J., Portmann L.,
RA Degroot L.J., Rapoport B.;
RT "Isolation of a complementary DNA clone for thyroid microsomal
RT antigen. Homology with the gene for thyroid peroxidase.";
RL J. Clin. Invest. 80:1205-1208(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM H17).
RX PubMed=3031585; DOI=10.1093/nar/15.5.2013;
RA Johnson K.R., Nauseef W.M., Care A., Wheelock M.J., Shane S.,
RA Hudson S., Koeffler H.P., Selsted M., Miller C., Rovera G.;
RT "Characterization of cDNA clones for human myeloperoxidase: predicted
RT amino acid sequence and evidence for multiple mRNA species.";
RL Nucleic Acids Res. 15:2013-2028(1987).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS H7; H14 AND H17),
RP AND PROTEIN SEQUENCE OF 165-183; 216-222; 295-304; 311-331; 464-479;
RP 662-676 AND 766-776.
RC TISSUE=Leukemia;
RX PubMed=2903767; DOI=10.1021/bi00416a013;
RA Hashinaka K., Nishio C., Hur S.-J., Sakiyama F., Tsunasawa S.,
RA Yamada M.;
RT "Multiple species of myeloperoxidase messenger RNAs produced by
RT alternative splicing and differential polyadenylation.";
RL Biochemistry 27:5906-5914(1988).
RN [6]
RP ERRATUM.
RA Hashinaka K., Nishio C., Hur S.-J., Sakiyama F., Tsunasawa S.,
RA Yamada M.;
RL Biochemistry 27:9226-9226(1988).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2552418; DOI=10.1093/nar/17.19.7985;
RA Johnson K.R., Gemperlein I., Hudson S., Shane S., Rovera G.;
RT "Complete nucleotide sequence of the human myeloperoxidase gene.";
RL Nucleic Acids Res. 17:7985-7986(1989).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM H17).
RX PubMed=8383257;
RA Hosokawa Y., Kawaguchi R., Hikiji K., Yamada M., Suzuki K.,
RA Nakagawa T., Yoshihara T., Yamaguchi K.;
RT "Cloning and characterization of four types of cDNA encoding
RT myeloperoxidase from human monocytic leukemia cell line, SKM-1.";
RL Leukemia 7:441-445(1993).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PHE-53; CYS-604;
RP GLN-683 AND VAL-717.
RG NIEHS SNPs program;
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM H17).
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 [12]
RP PROTEIN SEQUENCE OF 49-66.
RX PubMed=2154223; DOI=10.1016/0006-291X(90)90888-T;
RA Yamada M., Hur S.-J., Toda H.;
RT "Isolation and characterization of extracellular myeloperoxidase
RT precursor in HL-60 cell cultures.";
RL Biochem. Biophys. Res. Commun. 166:852-859(1990).
RN [13]
RP PROTEIN SEQUENCE OF 49-53, SUBUNIT, GLYCOSYLATION AT ASN-323; ASN-355;
RP ASN-391; ASN-483 AND ASN-729, AND MASS SPECTROMETRY.
RX PubMed=20332087; DOI=10.1074/jbc.M109.089748;
RA Van Antwerpen P., Slomianny M.C., Boudjeltia K.Z., Delporte C.,
RA Faid V., Calay D., Rousseau A., Moguilevsky N., Raes M., Vanhamme L.,
RA Furtmueller P.G., Obinger C., Vanhaeverbeek M., Neve J.,
RA Michalski J.C.;
RT "Glycosylation pattern of mature dimeric leukocyte and recombinant
RT monomeric myeloperoxidase: glycosylation is required for optimal
RT enzymatic activity.";
RL J. Biol. Chem. 285:16351-16359(2010).
RN [14]
RP PROTEIN SEQUENCE OF 279-424.
RC TISSUE=Leukocyte;
RX PubMed=1334087;
RA Taylor K.L., Pohl J., Kinkade J.M. Jr.;
RT "Unique autolytic cleavage of human myeloperoxidase. Implications for
RT the involvement of active site MET409.";
RL J. Biol. Chem. 267:25282-25288(1992).
RN [15]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 548-629.
RX PubMed=8390465;
RA Yamada M., Yoshida M., Hashinaka K.;
RT "Identification of transcriptional cis-elements in introns 7 and 9 of
RT the myeloperoxidase gene.";
RL J. Biol. Chem. 268:13479-13485(1993).
RN [16]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 588-745.
RX PubMed=2884926; DOI=10.1016/0003-9861(87)90304-3;
RA Yamada M., Hur S.-J., Hashinaka K., Tsuneoka K., Saeki T., Nishio C.,
RA Sakiyama F., Tsunasawa S.;
RT "Isolation and characterization of a cDNA coding for human
RT myeloperoxidase.";
RL Arch. Biochem. Biophys. 255:147-155(1987).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-139 AND ASN-483, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-323 AND ASN-483, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-355 AND ASN-391, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [20]
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 [21]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 167-744, AND SUBUNIT.
RX PubMed=10766826; DOI=10.1074/jbc.275.16.11964;
RA Fiedler T.J., Davey C.A., Fenna R.E.;
RT "X-ray crystal structure and characterization of halide-binding sites
RT of human myeloperoxidase at 1.8-A resolution.";
RL J. Biol. Chem. 275:11964-11971(2000).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 167-744.
RX PubMed=7840679; DOI=10.1006/abbi.1995.1086;
RA Fenna R.E., Zeng J., Davey C.;
RT "Structure of the green heme in myeloperoxidase.";
RL Arch. Biochem. Biophys. 316:653-656(1995).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 167-744.
RX PubMed=11705390; DOI=10.1021/bi0111808;
RA Blair-Johnson M., Fiedler T., Fenna R.;
RT "Human myeloperoxidase: structure of a cyanide complex and its
RT interaction with bromide and thiocyanate substrates at 1.9 A
RT resolution.";
RL Biochemistry 40:13990-13997(2001).
RN [24]
RP VARIANT MPOD TRP-569.
RX PubMed=8142659;
RA Kizaki M., Miller C.W., Selsted M.E., Koeffler H.P.;
RT "Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency.";
RL Blood 83:1935-1940(1994).
RN [25]
RP VARIANT MPOD TRP-569.
RX PubMed=7904599;
RA Nauseef W.M., Brigham S., Cogley M.;
RT "Hereditary myeloperoxidase deficiency due to a missense mutation of
RT arginine 569 to tryptophan.";
RL J. Biol. Chem. 269:1212-1216(1994).
RN [26]
RP CHARACTERIZATION OF VARIANT MPOD TRP-569.
RX PubMed=8621627; DOI=10.1074/jbc.271.16.9546;
RA Nauseef W., Cogley M., McCormick S.;
RT "Effect of the R569W missense mutation on the biosynthesis of
RT myeloperoxidase.";
RL J. Biol. Chem. 271:9546-9549(1996).
RN [27]
RP VARIANT MPOD CYS-173, AND CHARACTERIZATION OF VARIANT MPOD CYS-173.
RX PubMed=9637725; DOI=10.1172/JCI2649;
RA DeLeo F.R., Goedken M., McCormick S.J., Nauseef W.M.;
RT "A novel form of hereditary myeloperoxidase deficiency linked to
RT endoplasmic reticulum/proteasome degradation.";
RL J. Clin. Invest. 101:2900-2909(1998).
RN [28]
RP VARIANT MPOD THR-251.
RX PubMed=9354683;
RA Romano M., Dri P., Dadalt L., Patriarca P., Baralle F.E.;
RT "Biochemical and molecular characterization of hereditary
RT myeloperoxidase deficiency.";
RL Blood 90:4126-4134(1997).
RN [29]
RP VARIANT [LARGE SCALE ANALYSIS] GLN-447.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Part of the host defense system of polymorphonuclear
CC leukocytes. It is responsible for microbicidal activity against a
CC wide range of organisms. In the stimulated PMN, MPO catalyzes the
CC production of hypohalous acids, primarily hypochlorous acid in
CC physiologic situations, and other toxic intermediates that greatly
CC enhance PMN microbicidal activity.
CC -!- CATALYTIC ACTIVITY: Cl(-) + H(2)O(2) + H(+) = HClO + H(2)O.
CC -!- CATALYTIC ACTIVITY: Cl(-) + H(2)O(2) = HOCl + 2 H(2)O.
CC -!- COFACTOR: Binds 1 calcium ion per monomer.
CC -!- COFACTOR: Binds 1 heme B (iron-protoporphyrin IX) group covalently
CC per monomer.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Each monomer consists of a
CC light and a heavy chain.
CC -!- SUBCELLULAR LOCATION: Lysosome.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=H17; Synonyms=B;
CC IsoId=P05164-1; Sequence=Displayed;
CC Name=H14;
CC IsoId=P05164-2; Sequence=VSP_007206;
CC Name=H7; Synonyms=A;
CC IsoId=P05164-3; Sequence=VSP_007207;
CC -!- DISEASE: Myeloperoxidase deficiency (MPOD) [MIM:254600]: A
CC disorder characterized by decreased myeloperoxidase activity in
CC neutrophils and monocytes that results in disseminated
CC candidiasis. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peroxidase family. XPO subfamily.
CC -!- WEB RESOURCE: Name=MPObase; Note=MPO mutation db;
CC URL="http://bioinf.uta.fi/MPObase/";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mpo/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Myeloperoxidase entry;
CC URL="http://en.wikipedia.org/wiki/Myeloperoxidase";
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DR EMBL; J02694; AAA59896.1; -; mRNA.
DR EMBL; M17176; AAA60346.1; -; Genomic_DNA.
DR EMBL; M17170; AAA60346.1; JOINED; Genomic_DNA.
DR EMBL; M17171; AAA60346.1; JOINED; Genomic_DNA.
DR EMBL; M17172; AAA60346.1; JOINED; Genomic_DNA.
DR EMBL; M17173; AAA60346.1; JOINED; Genomic_DNA.
DR EMBL; M17174; AAA60346.1; JOINED; Genomic_DNA.
DR EMBL; M17175; AAA60346.1; JOINED; Genomic_DNA.
DR EMBL; X04876; CAA28565.1; -; mRNA.
DR EMBL; M19507; AAA59863.1; -; mRNA.
DR EMBL; M19508; AAA59864.1; -; Genomic_DNA.
DR EMBL; M19508; AAA59865.1; -; Genomic_DNA.
DR EMBL; X15377; CAA33438.1; -; Genomic_DNA.
DR EMBL; S56200; AAB25582.1; -; mRNA.
DR EMBL; DQ088846; AAY68218.1; -; Genomic_DNA.
DR EMBL; CH471109; EAW94470.1; -; Genomic_DNA.
DR EMBL; BC130476; AAI30477.1; -; mRNA.
DR EMBL; D14466; BAA03362.1; -; Genomic_DNA.
DR PIR; A29467; OPHUM.
DR PIR; B28894; B28894.
DR PIR; D28894; D28894.
DR RefSeq; NP_000241.1; NM_000250.1.
DR UniGene; Hs.458272; -.
DR PDB; 1CXP; X-ray; 1.80 A; A/B=167-270, C/D=279-744.
DR PDB; 1D2V; X-ray; 1.75 A; A/B=167-270, C/D=279-744.
DR PDB; 1D5L; X-ray; 1.90 A; A/B=167-270, C/D=279-744.
DR PDB; 1D7W; X-ray; 1.90 A; A/B=167-270, C/D=279-744.
DR PDB; 1DNU; X-ray; 1.85 A; A/B=167-270, C/D=279-744.
DR PDB; 1DNW; X-ray; 1.90 A; A/B=167-270, C/D=279-744.
DR PDB; 1MHL; X-ray; 2.25 A; A/B=165-272, C/D=279-744.
DR PDB; 1MYP; X-ray; 3.00 A; A/B=165-272, C/D=279-744.
DR PDB; 3F9P; X-ray; 2.93 A; A/B=165-278, C/D=279-745.
DR PDB; 3ZS0; X-ray; 2.30 A; A/B=165-272, C/D=279-745.
DR PDB; 3ZS1; X-ray; 2.60 A; A/B=165-278, C/D=279-745.
DR PDB; 4C1M; X-ray; 2.00 A; A/B=165-272, C/D=279-745.
DR PDB; 4DL1; X-ray; 2.00 A; A/B/E/F/I/J/M/N=167-270, C/D/G/H/K/L/O/P=279-744.
DR PDB; 4EJX; X-ray; 4.69 A; B=165-278, D=279-745.
DR PDBsum; 1CXP; -.
DR PDBsum; 1D2V; -.
DR PDBsum; 1D5L; -.
DR PDBsum; 1D7W; -.
DR PDBsum; 1DNU; -.
DR PDBsum; 1DNW; -.
DR PDBsum; 1MHL; -.
DR PDBsum; 1MYP; -.
DR PDBsum; 3F9P; -.
DR PDBsum; 3ZS0; -.
DR PDBsum; 3ZS1; -.
DR PDBsum; 4C1M; -.
DR PDBsum; 4DL1; -.
DR PDBsum; 4EJX; -.
DR ProteinModelPortal; P05164; -.
DR SMR; P05164; 157-744.
DR IntAct; P05164; 3.
DR MINT; MINT-1522833; -.
DR STRING; 9606.ENSP00000225275; -.
DR BindingDB; P05164; -.
DR ChEMBL; CHEMBL2439; -.
DR DrugBank; DB00535; Cefdinir.
DR PeroxiBase; 3315; HsMPO.
DR PhosphoSite; P05164; -.
DR UniCarbKB; P05164; -.
DR DMDM; 129825; -.
DR PaxDb; P05164; -.
DR PRIDE; P05164; -.
DR DNASU; 4353; -.
DR Ensembl; ENST00000225275; ENSP00000225275; ENSG00000005381.
DR Ensembl; ENST00000340482; ENSP00000344419; ENSG00000005381.
DR GeneID; 4353; -.
DR KEGG; hsa:4353; -.
DR UCSC; uc002ivu.1; human.
DR CTD; 4353; -.
DR GeneCards; GC17M056347; -.
DR H-InvDB; HIX0039242; -.
DR HGNC; HGNC:7218; MPO.
DR HPA; CAB000059; -.
DR HPA; HPA021147; -.
DR MIM; 254600; phenotype.
DR MIM; 606989; gene.
DR neXtProt; NX_P05164; -.
DR Orphanet; 2587; Myeloperoxidase deficiency.
DR PharmGKB; PA243; -.
DR eggNOG; NOG262194; -.
DR HOGENOM; HOG000016084; -.
DR HOVERGEN; HBG000071; -.
DR KO; K10789; -.
DR OMA; QDKYRTI; -.
DR OrthoDB; EOG7M0NQW; -.
DR BioCyc; MetaCyc:HS00140-MONOMER; -.
DR ChiTaRS; MPO; human.
DR EvolutionaryTrace; P05164; -.
DR GeneWiki; Myeloperoxidase; -.
DR GenomeRNAi; 4353; -.
DR NextBio; 17126; -.
DR PMAP-CutDB; P05164; -.
DR PRO; PR:P05164; -.
DR ArrayExpress; P05164; -.
DR Bgee; P05164; -.
DR CleanEx; HS_MPO; -.
DR Genevestigator; P05164; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005764; C:lysosome; TAS:ProtInc.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; TAS:ProtInc.
DR GO; GO:0030141; C:secretory granule; IDA:MGI.
DR GO; GO:0003682; F:chromatin binding; TAS:ProtInc.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0008201; F:heparin binding; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004601; F:peroxidase activity; IDA:BHF-UCL.
DR GO; GO:0006952; P:defense response; TAS:ProtInc.
DR GO; GO:0050832; P:defense response to fungus; IEA:Ensembl.
DR GO; GO:0042744; P:hydrogen peroxide catabolic process; IDA:BHF-UCL.
DR GO; GO:0002149; P:hypochlorous acid biosynthetic process; IEA:Ensembl.
DR GO; GO:0034374; P:low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:ProtInc.
DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
DR GO; GO:0019430; P:removal of superoxide radicals; IEA:Ensembl.
DR GO; GO:0002679; P:respiratory burst involved in defense response; IEA:Ensembl.
DR GO; GO:0001878; P:response to yeast; IEA:Ensembl.
DR Gene3D; 1.10.640.10; -; 2.
DR InterPro; IPR010255; Haem_peroxidase.
DR InterPro; IPR002007; Haem_peroxidase_animal.
DR InterPro; IPR019791; Haem_peroxidase_animal_subgr.
DR Pfam; PF03098; An_peroxidase; 1.
DR PRINTS; PR00457; ANPEROXIDASE.
DR SUPFAM; SSF48113; SSF48113; 1.
DR PROSITE; PS00435; PEROXIDASE_1; 1.
DR PROSITE; PS00436; PEROXIDASE_2; FALSE_NEG.
DR PROSITE; PS50292; PEROXIDASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Heme; Hydrogen peroxide; Iron; Lysosome; Metal-binding;
KW Oxidation; Oxidoreductase; Peroxidase; Polymorphism;
KW Reference proteome; Signal.
FT SIGNAL 1 48
FT CHAIN 49 745 89 kDa myeloperoxidase.
FT /FTId=PRO_0000023651.
FT CHAIN 155 745 84 kDa myeloperoxidase.
FT /FTId=PRO_0000023653.
FT CHAIN 165 745 Myeloperoxidase.
FT /FTId=PRO_0000023654.
FT CHAIN 165 278 Myeloperoxidase light chain.
FT /FTId=PRO_0000023655.
FT CHAIN 279 745 Myeloperoxidase heavy chain.
FT /FTId=PRO_0000023656.
FT ACT_SITE 261 261 Proton acceptor.
FT METAL 262 262 Calcium.
FT METAL 334 334 Calcium.
FT METAL 336 336 Calcium; via carbonyl oxygen.
FT METAL 338 338 Calcium.
FT METAL 340 340 Calcium.
FT METAL 502 502 Iron (heme axial ligand).
FT BINDING 260 260 Heme (covalent; via 3 links).
FT BINDING 408 408 Heme (covalent; via 3 links).
FT BINDING 409 409 Heme (covalent; via 3 links).
FT SITE 405 405 Transition state stabilizer.
FT MOD_RES 316 316 Cysteine sulfenic acid (-SOH).
FT CARBOHYD 139 139 N-linked (GlcNAc...).
FT CARBOHYD 323 323 N-linked (GlcNAc...).
FT CARBOHYD 355 355 N-linked (GlcNAc...).
FT CARBOHYD 391 391 N-linked (GlcNAc...).
FT CARBOHYD 483 483 N-linked (GlcNAc...).
FT /FTId=CAR_000220.
FT CARBOHYD 729 729 N-linked (GlcNAc...).
FT DISULFID 167 180
FT DISULFID 281 291
FT DISULFID 285 309
FT DISULFID 319 319 Interchain.
FT DISULFID 387 398
FT DISULFID 606 663
FT DISULFID 704 730
FT VAR_SEQ 1 95 Missing (in isoform H14).
FT /FTId=VSP_007206.
FT VAR_SEQ 182 182 N -> NRCGWLGVAAGTGLREASRTPQASRCQRPVLPC
FT (in isoform H7).
FT /FTId=VSP_007207.
FT VARIANT 53 53 V -> F (in dbSNP:rs7208693).
FT /FTId=VAR_023995.
FT VARIANT 173 173 Y -> C (in MPOD; affects proteolytic
FT processing and secretion;
FT dbSNP:rs78950939).
FT /FTId=VAR_015377.
FT VARIANT 251 251 M -> T (in MPOD; dbSNP:rs56378716).
FT /FTId=VAR_015378.
FT VARIANT 447 447 R -> Q (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036517.
FT VARIANT 569 569 R -> W (in MPOD; suppress post-
FT translational processing).
FT /FTId=VAR_015379.
FT VARIANT 604 604 R -> C (in dbSNP:rs35670089).
FT /FTId=VAR_023996.
FT VARIANT 683 683 E -> Q (in dbSNP:rs35702888).
FT /FTId=VAR_023997.
FT VARIANT 717 717 I -> V (in dbSNP:rs2759).
FT /FTId=VAR_012066.
FT CONFLICT 36 36 L -> V (in Ref. 4; CAA28565 and 7;
FT CAA33438).
FT STRAND 181 185
FT TURN 186 189
FT STRAND 191 194
FT STRAND 206 208
FT STRAND 218 223
FT HELIX 227 234
FT HELIX 239 241
FT STRAND 244 249
FT HELIX 250 263
FT TURN 281 283
FT STRAND 317 319
FT STRAND 323 325
FT STRAND 329 331
FT STRAND 335 338
FT HELIX 340 343
FT HELIX 347 353
FT STRAND 357 360
FT STRAND 371 374
FT HELIX 387 390
FT TURN 392 394
FT STRAND 401 403
FT TURN 404 407
FT HELIX 410 433
FT HELIX 439 460
FT HELIX 463 475
FT HELIX 492 497
FT HELIX 498 504
FT STRAND 507 510
FT STRAND 516 518
FT STRAND 523 526
FT HELIX 527 529
FT TURN 530 532
FT HELIX 534 539
FT HELIX 543 552
FT STRAND 553 556
FT HELIX 566 569
FT HELIX 574 576
FT STRAND 577 579
FT HELIX 583 593
FT HELIX 599 605
FT HELIX 614 621
FT HELIX 624 634
FT HELIX 637 639
FT HELIX 642 648
FT STRAND 655 657
FT HELIX 659 674
FT TURN 683 685
FT HELIX 688 694
FT HELIX 699 706
FT STRAND 711 713
FT TURN 717 719
FT TURN 723 726
FT STRAND 727 729
FT HELIX 730 732
FT HELIX 739 741
SQ SEQUENCE 745 AA; 83869 MW; 348B1CE0A11038B4 CRC64;
MGVPFFSSLR CMVDLGPCWA GGLTAEMKLL LALAGLLAIL ATPQPSEGAA PAVLGEVDTS
LVLSSMEEAK QLVDKAYKER RESIKQRLRS GSASPMELLS YFKQPVAATR TAVRAADYLH
VALDLLERKL RSLWRRPFNV TDVLTPAQLN VLSKSSGCAY QDVGVTCPEQ DKYRTITGMC
NNRRSPTLGA SNRAFVRWLP AEYEDGFSLP YGWTPGVKRN GFPVALARAV SNEIVRFPTD
QLTPDQERSL MFMQWGQLLD HDLDFTPEPA ARASFVTGVN CETSCVQQPP CFPLKIPPND
PRIKNQADCI PFFRSCPACP GSNITIRNQI NALTSFVDAS MVYGSEEPLA RNLRNMSNQL
GLLAVNQRFQ DNGRALLPFD NLHDDPCLLT NRSARIPCFL AGDTRSSEMP ELTSMHTLLL
REHNRLATEL KSLNPRWDGE RLYQEARKIV GAMVQIITYR DYLPLVLGPT AMRKYLPTYR
SYNDSVDPRI ANVFTNAFRY GHTLIQPFMF RLDNRYQPME PNPRVPLSRV FFASWRVVLE
GGIDPILRGL MATPAKLNRQ NQIAVDEIRE RLFEQVMRIG LDLPALNMQR SRDHGLPGYN
AWRRFCGLPQ PETVGQLGTV LRNLKLARKL MEQYGTPNNI DIWMGGVSEP LKRKGRVGPL
LACIIGTQFR KLRDGDRFWW ENEGVFSMQQ RQALAQISLP RIICDNTGIT TVSKNNIFMS
NSYPRDFVNC STLPALNLAS WREAS
//

MIM 254600
*RECORD*
*FIELD* NO
254600
*FIELD* TI
#254600 MYELOPEROXIDASE DEFICIENCY; MPOD
;;MPO DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because myeloperoxidase
read moredeficiency is caused by mutation in the myeloperoxidase gene (MPO;
606989) on chromosome 17q23.

CLINICAL FEATURES

Lehrer and Cline (1969) found no detectable activity of the lysosomal
enzyme myeloperoxidase in neutrophils and monocytes of a patient with
disseminated candidiasis. Other granule-associated enzymes were normal.
Leukocytes from one of the proband's sisters also showed no MPO
activity. Leukocytes from the proband's 4 sons showed about one-third
normal levels. The proband and his relatives had not experienced
frequent or unusual bacterial infections. The incidence of candidiasis
may be increased in persons with myeloperoxidase deficiency, and the
ability of the leukocytes of affected persons to resist Candida in vitro
may be reduced.

Salmon et al. (1970) demonstrated immunologically the absence of MPO
protein, or at least the absence of cross-reacting material, in
homozygotes. Eosinophil peroxidase (EPX; 131399), which is chemically
distinct from MPO, was normal. Kitahara et al. (1981) found partial
deficiency in heterozygotes; only 2 of these had serious infections
(recurrent streptococcal cellulitis and aseptic meningitis).

INHERITANCE

Variable expression in families makes it difficult to interpret the
genetics of the disorder (Cech et al., 1979). In the 17 cases reported
by Cramer et al. (1982), autosomal recessive inheritance was proved in 7
cases and was considered likely in at least 8 others because of the
presence of 2 or 3 deficient persons in the family.

Eosinophil peroxidase contributes to the peroxidase activity of blood
leukocytes. Because EPX expression is normal in MPO-deficient subjects,
eosinophil contamination can significantly contribute to peroxidase
activity in leukocytes from family members of an MPO-deficient subject
and thereby undermine correct interpretation of the inheritance pattern.
To avoid this potential problem, Nauseef et al. (1998) used
cytochemical, immunochemical, and genetic techniques to assess the
inheritance pattern of MPO deficiency in 16 individuals from 5 unrelated
kindreds. Each kindred had an index case with MPO deficiency caused by
the R569W missense mutation (606989.0001). The analysis demonstrated
that MPO deficiency was not inherited as a simple autosomal recessive
trait. Most subjects were compound heterozygotes with respect to the
R569W mutation and demonstrated a spectrum of phenotypes. The data
demonstrated the broad phenotypic impact of compound heterozygosity on
the expression and function of a multimeric protein such as MPO.

CLINICAL MANAGEMENT

The defective cellular immunity in this condition was restored to normal
by transfusion of HLA identical leukocytes from a healthy brother
(Valdimarsson et al., 1972). Immune responses remained normal after 17
months. Persistence of functionally competent grafted cells was
considered the likely mechanism.

POPULATION GENETICS

Although previously considered to be rare, MPO deficiency was found by
Parry et al. (1981), using automated flow cytometry, to have a frequency
of 1 in several thousand.

Cramer et al. (1982) found reports of 17 cases of apparently primary MPO
deficiency and reported a high frequency in the Friuli-Venezia Giulia
region of northeastern Italy. A screening method identified 45 suspected
subjects.

Nauseef (1988) reviewed the studies on the frequency of myeloperoxidase
deficiency in apparently healthy populations, pointing out that this
information was an unexpected dividend of the technology for performing
differential counts automatically. The prevalence in the U.S. is on the
order of 1 in 2,000.

PATHOGENESIS

By immunoautoradiography and other methods, Nauseef et al. (1983) found
that partial MPO deficiency is characterized by the presence of
electrophoretically and immunologically normal MPO in amounts about half
that seen in PMNs of normal subjects. Completely MPO-deficient PMNs
lacked MPO peptides; no CRM was found in the 5 unrelated subjects
studied. Purified MPO is composed of 2 peptide subunits of 60,000 and
12,000 Da. Nauseef et al. (1983) concluded that since deficiency is
associated with the absence of more than 1 peptide, the genetic defect
may involve (a) failure to synthesize a single precursor peptide; (b)
defective regulation of the synthesis of 2 separate peptides; or (c) an
aberration in postsynthetic processing or packaging into azurophilic
granules.

Stendahl et al. (1984) pointed out that patients lacking myeloperoxidase
usually do not show any increased susceptibility to infection or altered
inflammatory response. In a patient with generalized pustular psoriasis
and complete MPO deficiency, they found that MPO-deficient neutrophils
showed enhanced phagocytosis and exaggerated superoxide production on
stimulation in vitro. They suggested that apart from being a potent
antimicrobial system, the oxidizing activity of the MPO-H2O2-halide
system may modulate the inflammatory response which otherwise could
elicit inflammatory reactions and tissue injury.

MOLECULAR GENETICS

Using a cDNA probe for MPO in studies of 3 completely and 2 partially
MPO-deficient persons, Nauseef (1989) found no evidence of major
deletion or rearrangement of the MPO gene. Myeloid precursors in 1
patient contained normal amounts of an mRNA that was the same size as
that for MPO in normal persons. Two different endonuclease digestion
patterns were found in MPO-deficient subjects who were biochemically and
phenotypically identical.

In a patient with myeloperoxidase deficiency, Nauseef et al. (1994)
identified an arg569-to-trp mutation in the myeloperoxidase gene
(606989.0001).

*FIELD* SA
Klebanoff and Pincus (1971); Ross and Kaplow (1985)
*FIELD* RF
1. Cech, P.; Stalder, H. S.; Widmann, J. J.; Rohrer, A.; Miescher,
P. A.: Leukocyte myeloperoxidase deficiency and diabetes mellitus
associated with Candida albicans liver abscess. Am. J. Med. 66:
149-153, 1979.

2. Cramer, R.; Soranzo, M. R.; Dri, P.; Rottini, G. D.; Bramezza,
M.; Cirielli, S.; Patriarca, P.: Incidence of myeloperoxidase deficiency
in an area of northern Italy: histochemical, biochemical and functional
studies. Brit. J. Haemat. 51: 81-87, 1982.

3. Kitahara, M.; Eyre, H. J.; Simonian, Y.; Atkin, C. L.; Hasstedt,
S. J.: Hereditary myeloperoxidase deficiency. Blood 57: 888-893,
1981.

4. Klebanoff, S. J.; Pincus, S. H.: Hydrogen peroxide utilization
in myeloperoxidase-deficient leukocytes: a possible microbicidal control
mechanism. J. Clin. Invest. 50: 2226-2229, 1971.

5. Lehrer, R. I.; Cline, M. J.: Leukocyte myeloperoxidase deficiency
and disseminated candidiasis: the role of myeloperoxidase in resistance
to Candida infection. J. Clin. Invest. 48: 1478-1488, 1969.

6. Nauseef, W. M.: Myeloperoxidase deficiency. Hemat. Oncol. Clin.
North Am. 2: 135-158, 1988.

7. Nauseef, W. M.: Aberrant restriction endonuclease digests of DNA
from subjects with hereditary myeloperoxidase deficiency. Blood 73:
290-295, 1989.

8. Nauseef, W. M.; Brigham, S.; Cogley, M.: Hereditary myeloperoxidase
deficiency due to a missense mutation of arginine 569 to tryptophan. J.
Biol. Chem. 269: 1212-1216, 1994.

9. Nauseef, W. M.; Cogley, M.; Bock, S.; Petrides, P. E.: Pattern
of inheritance in hereditary myeloperoxidase deficiency associated
with the R569W missense mutation. J. Leukoc. Biol. 63: 264-269,
1998.

10. Nauseef, W. M.; Root, R. K.; Malech, H. L.: Biochemical and immunologic
analysis of hereditary myeloperoxidase deficiency. J. Clin. Invest. 71:
1297-1307, 1983.

11. Parry, M. F.; Root, R. K.; Metcalf, J. A.; Delaney, K. K.; Kaplow,
L. S.; Richar, W. J.: Myeloperoxidase deficiency: prevalence and
clinical significance. Ann. Intern. Med. 95: 293-301, 1981.

12. Ross, D. W.; Kaplow, L. S.: Myeloperoxidase deficiency: increased
sensitivity for immunocytochemical compared to cytochemical detection
of enzyme. Arch. Path. Lab. Med. 109: 1005-1006, 1985.

13. Salmon, S. E.; Cline, M. J.; Schultz, J.; Lehrer, R. I.: Myeloperoxidase
deficiency: immunologic study of a genetic leukocyte defect. New
Eng. J. Med. 282: 250-253, 1970.

14. Stendahl, O.; Coble, B.-I.; Dahlgren, C.; Hed, J.; Molin, L.:
Myeloperoxidase modulates the phagocytic activity of polymorphonuclear
neutrophil leukocytes: studies with cells from a myeloperoxidase-deficient
patient. J. Clin. Invest. 73: 366-373, 1984.

15. Valdimarsson, H.; Moss, P. D.; Holt, P. J. L.; Hobbs, J. R.:
Treatment of chronic mucocutaneous candidiasis with leukocytes from
HL-A compatible sibling. Lancet 299: 469-472, 1972. Note: Originally
Volume I.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEMATOLOGY:
Decreased myeloperoxidase activity in neutrophils and monocytes

IMMUNOLOGY:
Disseminated candidiasis

LABORATORY ABNORMALITIES:
Absence of peroxidase staining in neutrophils and monocytes;
Normal eosinophil peroxidase activity

MISCELLANEOUS:
Estimated frequency 1/2000-1/4000 individuals;
Majority of individuals are healthy

MOLECULAR BASIS:
Caused by mutations in the myeloperoxidase gene (MPO, 606989.0001).

*FIELD* CN
Kelly A. Przylepa - updated: 06/22/2006
Cassandra L. Kniffin - revised: 5/30/2002

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

*FIELD* ED
joanna: 06/22/2006
ckniffin: 5/30/2002

*FIELD* CN
Cassandra L. Kniffin - reorganized: 5/29/2002
Victor A. McKusick - updated: 3/12/1999
Victor A. McKusick - updated: 1/20/1999
Victor A. McKusick - updated: 9/3/1998
Victor A. McKusick - updated: 6/21/1997
Jon B. Obray - updated: 6/29/1996

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

*FIELD* ED
carol: 06/16/2011
terry: 3/13/2009
carol: 5/29/2002
ckniffin: 5/29/2002
carol: 3/15/1999
terry: 3/12/1999
carol: 1/21/1999
terry: 1/20/1999
alopez: 9/14/1998
carol: 9/3/1998
terry: 6/24/1997
terry: 6/21/1997
carol: 6/29/1996
mimman: 2/8/1996
mark: 8/25/1995
carol: 5/24/1994
mimadm: 3/29/1994
carol: 3/26/1992
supermim: 3/17/1992
carol: 3/3/1992

MIM 606989
*RECORD*
*FIELD* NO
606989
*FIELD* TI
*606989 MYELOPEROXIDASE; MPO
*FIELD* TX

DESCRIPTION

The MPO gene encodes myeloperoxidase (EC 1.11.1.7), a lysosomal
read morehemoprotein located in the azurophilic granules of polymorphonuclear
(PMN) leukocytes and monocytes. In response to stimulation, MPO is
activated into a transient intermediate with potent antimicrobial
oxidizing abilities (Goedken et al., 2007).

CLONING

Morishita et al. (1987) determined a partial amino acid sequence for
human myeloperoxidase and chemically synthesized a 41-base
oligonucleotide containing deoxyinosines at 4 positions. By using the
oligonucleotide as a probe, cDNA clones for MPO were isolated. The
sequence was found to contain an open reading frame encoding a deduced
745-amino acid protein. The heavy chain of MPO, consisting of 467 amino
acids, was located on the COOH terminus half of the protein. The results
of Southern hybridization analysis of human genomic DNA suggested that
there are 1 or 2 genes for MPO in the human haploid genome. Yamada et
al. (1987) isolated and characterized a cDNA coding for human
myeloperoxidase. Weil et al. (1987) identified cDNA clones of human MPO.

MPO is a dimeric protein and each dimer contains a 60-kD heavy unit and
a 12-kD light subunit. The primary translation product is a single 80-kD
protein that undergoes cotranslational glycosylation, proteolytic
processing, and lysosomal targeting during the promyelocytic stage of
myeloid development (Nauseef et al., 1988).

GENE STRUCTURE

Johnson et al. (1989) determined that the MPO gene contains 12 exons and
spans about 13 kb. It has 2 polyadenylation signals.

MAPPING

Using an MPO cDNA for Southern blot analysis of DNA from a somatic cell
hybrid clone panel, Chang et al. (1987) showed that MPO segregated with
chromosome 17. In situ hybridization localized the gene to 17q22-q24.
Kudoh et al. (1987) and Le Beau et al. (1987) assigned the MPO gene to
chromosome 17. The latter group sublocalized the MPO gene to 17q11-q21
by in situ hybridization. Since the MPO gene was translocated to
chromosome 15 in 5 cases of t(15;17), Le Beau et al. (1987) concluded
that the MPO gene is located at 17q12-q21. See also Liang et al. (1988).
Using a regional mapping panel of somatic cell hybrids containing
various deleted or translocated segments of chromosome 17, and by in
situ hybridization, van Tuinen et al. (1987) assigned MPO to 17q22-q23.
Kudoh et al. (1988) confirmed the location of MPO on chromosome 17 by
use of a cDNA clone for Southern blot hybridization experiments with DNA
from a panel of human-mouse cell hybrids and for DNA spot-blot
hybridization using flow-sorted human chromosomes. Miki et al. (1988)
found linkage of MPO to markers on 17q, with MPO being closest to the
growth hormone cluster at 17q22-q24.

By in situ hybridization, Weil et al. (1988) assigned the MPO gene to
17q12-q21. Inazawa et al. (1989) also mapped MPO to 17q21.3-q23 by in
situ hybridization. Zaki et al. (1990) assigned the MPO gene to
17q21-q22 by in situ hybridization using oligonucleotide probes. Law et
al. (1995) refined the assignment of the MPO gene to 17q23.1,
demonstrating that it is located within a YAC contig containing the
ZNF147 (600453) gene, which in 2 independent studies by fluorescence in
situ hybridization had been assigned to 17q23.1.

Using a rat/mouse somatic cell hybrid that contained chromosome 11 as
the only mouse material, Robinson et al. (1990) mapped Mpo to mouse
chromosome 11. A regional assignment of the gene by in situ
hybridization placed the locus in the region C-E1, with a peak at band
11C.

GENE FUNCTION

Myeloperoxidase is part of the host defense system of human
polymorphonuclear leukocytes, responsible for microbicidal activity
against a wide range of organisms. In the stimulated PMN, MPO catalyzes
the production of hypohalous acids, primarily hypochlorous acid in
physiologic situations, and other toxic intermediates that greatly
enhance PMN microbicidal activity (Klebanoff, 1999). Murao et al. (1988)
found that MPO is located in the nucleus as well as in the cytoplasm.
Intranuclear MPO may help to protect DNA against damage resulting from
oxygen radicals produced during myeloid cell maturation and function.
Borregaard and Cowland (1997) gave a comprehensive review of the
granules of human neutrophilic polymorphonuclear leukocytes. The primary
step in the classification of granules in neutrophils is according to
content of MPO. Peroxidase-positive (azurophilic or primary) granules
may be further divided based on their content of defensins (see 125220)
into large, defensin-rich granules and smaller defensin-poor granules.

Eiserich et al. (2002) found that MPO modulates the vasodilatory and
vascular signaling functions of nitric oxide (NO). By
immunohistochemical visualization of MPO in a rodent model of acute
inflammation, they found that the enzyme localizes in and around
vascular endothelial cells, presumably following secretion by activated
leukocytes. Vascular relaxation was compromised in these animals and
also in isolated rat aortic segments treated with MPO and hydrogen
peroxide. Biochemical analysis of human MPO, performed in human blood
plasma containing ascorbate and other physiologic substrates, revealed
consumption of NO until ascorbate levels were depleted, after which the
concentration of NO returned to steady state levels. Eiserich et al.
(2002) concluded that altered vascular responsiveness in the presence of
high MPO levels is due to catalytic consumption of NO by substrate
radicals generated by MPO.

Inflammation is linked to adverse outcomes in acute coronary syndromes.
Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit
lesions that have fissured or ruptured in patients with sudden death
from cardiac causes. Brennan et al. (2003) showed that in 604
sequentially ascertained patients presenting with chest pain, a single
initial measurement of plasma myeloperoxidase was an independent early
predictor of myocardial infarction, as well as the risk of major adverse
cardiac events in ensuing 30-day and 6-month periods. In contrast to
troponin T (191045), creatine kinase MB isoform (123310), and C-reactive
protein (123260) levels, myeloperoxidase levels identified patients at
risk for cardiac events in the absence of myocardial necrosis.

- Role in Acute Promyelocytic Leukemia

Weil et al. (1988) found that the MPO gene was translocated to
chromosome 15 in all cases of acute promyelocytic leukemia (subtype M3),
which is consistently associated with the chromosomal translocation
t(15;17)(q22;q11.2). In 2 of 4 cases examined by genomic blot analysis,
rearrangement of the MPO gene was detected in leukemia cells. Weil et
al. (1988) also suggested that MPO may be pivotal in the pathogenesis of
APL. According to HGM10, the MPO gene is located at a distance from the
breakpoint in APL, and the gene itself is probably usually not
rearranged in APL.

- Role in Alzheimer Disease

Myeloperoxidase has been detected in activated microglial macrophages
and within amyloid plaques in the central nervous system. Using
statistical analysis, Reynolds et al. (2000) examined the relationship
between APOE (107741) and MPO polymorphisms in the risk of Alzheimer
disease (AD; 104300) in a genetically homogeneous Finnish population.
They found that the presence of the MPO -463A allele (606989.0008) in
conjunction with APOE4 significantly increased the risk of AD in men,
but not in women (odds ratio for men with both alleles = 11.4 vs APOE4
alone = 3.0). Reynolds et al. (2000) also found that estrogen
receptor-alpha (133430) binds to the MPO A promoter, which may explain
the gender differences.

- Role in Atrial Fibrillation

Rudolph et al. (2010) pretreated Mpo-deficient mice with angiotensin II
(see 106150) to provoke leukocyte activation and observed lower atrial
tissue abundance of the Mpo product 3-chlorotyrosine, reduced activity
of matrix metalloproteinases, and blunted atrial fibrosis as compared to
wildtype mice. Upon right atrial electrophysiologic stimulation,
Mpo-deficient mice were protected from atrial fibrillation, which was
reversed when Mpo was restored. Rudolph et al. (2010) measured plasma
MPO levels and performed immunohistochemical studies of atrial tissue
from 27 patients undergoing coronary bypass surgery, 10 of whom had
atrial fibrillation (see 608583), and found higher plasma concentrations
of MPO and a larger MPO burden in right atrial tissue in the individuals
with concomitant atrial fibrillation. In the atria, MPO colocalized with
markedly increased formation of 3-chlorotyrosine. Rudolph et al. (2010)
concluded that MPO is a crucial prerequisite for structural remodeling
of the myocardium, leading to an increased vulnerability to atrial
fibrillation.

BIOCHEMICAL FEATURES

- Crystal Structure

Fiedler et al. (2000) characterized the crystalline structure of human
myeloperoxidase at a resolution of 1.8 angstroms. The results confirmed
that the heme is covalently attached to the protein.

MOLECULAR GENETICS

In 6 of 7 patients with complete MPO deficiency (254600), Nauseef et al.
(1994) identified an arg569-to-trp mutation (606989.0001) in the
myeloperoxidase gene.

Of approximately 40,000 individuals analyzed for MPO deficiency in
Italy, Marchetti et al. (2004) identified 7 with partial and 8 with
total MPO deficiency. Among these patients, 3 previously identified and
6 novel mutations in the MPO gene were identified. Of the 6 novel
mutations, 4 were missense (see 606989.0005-606989.0006), one was
deletion of an adenine in exon 3, and one was an A-to-C transversion in
the 3-prime splice site of intron 11 (606989.0007).

Makela et al. (2003) investigated the effect of long-term hormone
replacement therapy (HRT) on the progression of atherosclerosis in a
5-year follow-up study of postmenopausal women with different MPO
genotypes. The atherosclerosis severity score for abdominal aorta and
carotid arteries was determined by ultrasonography, and the MPO genotype
was analyzed. In subjects with the GG genotype of the -463G/A
polymorphism (606989.0008), the progression of atherosclerosis severity
score was significantly faster in the control group than in the HRT
group (genotype by time interaction, P = 0.042), whereas in A allele
carriers there were no significant differences in atherosclerosis
severity score progression between control and HRT. The authors
concluded that the effects of HRT on atherosclerosis progression in
subjects with the GG genotype seem to be especially beneficial compared
with controls with the same genotype but without HRT. They suggested
that these results may help understanding in greater detail the benefit
and possible risk of HRT in atherosclerotic diseases.

Taioli et al. (2007) found that the -463G/A polymorphism (606989.0008)
confers resistance to cancer among smokers.

CYTOGENETICS

Poland et al. (2009) reported a 10-year-old boy with acute myeloid
leukemia (AML; 601626) subtype M1 and an acquired translocation,
t(17;19)(q22;q13.32). The translocation breakpoint on chromosome 17 was
in the promoter/enhancer region of the MPO gene, and the breakpoint on
chromosome 19 was within the promoter region of the ZNF296 gene
(613226), which Poland et al. (2009) called ZNF342. The translocation
resulted in a derivative chromosome 17 containing the promoter/enhancer
region of the MPO gene fused to the promoter and coding region of the
ZNF296 gene, resulting in 90-fold upregulation of ZNF296 expression in
the patient's leukemia cells.

*FIELD* AV
.0001
MYELOPEROXIDASE DEFICIENCY
MPO, ARG569TRP

In 6 of 7 patients with complete MPO deficiency (254600), Nauseef et al.
(1994) described a C-to-T substitution at nucleotide 8089 in exon 10 of
the genomic sequence of MPO. At the amino acid level, the mutation
replaced arginine at codon 569 with tryptophan. One subject was
homozygous for the mutation, whereas the others were heterozygous. A
seventh patient was the only completely deficient subject without the
mutation.

Independently, Kizaki et al. (1994) reported a 65-year-old Hispanic
woman who was found to have MPO deficiency during routine blood
examination by automated flow cytometry. The patient had no history of
recurrent infections and was not taking medications known to interfere
with MPO activity. Additional family members were not available for
study. Granulocytes had no MPO activity and showed complete absence of
mature and precursor MPO protein by Western blotting. By Southern
blotting, a novel BglII fragment was detected. Direct sequencing of the
PCR product of exon 10 showed a C-to-T transition at codon 569,
resulting in an arginine (CGG)-to-tryptophan (TGG) substitution and
creating a new BglII site. The mutation was homozygous. It was not found
in 400 normal individuals.

Nauseef et al. (1996) examined the consequences of the arg569-to-trp
mutation on MPO biosynthesis and processing, using stably transfected
K562 cells expressing normal MPO or the arg562-to-trp mutation. The
authors concluded that the mutation results in a form of apopro-MPO that
does not undergo posttranslational processing to enzymatically active
MPO species.

.0002
MYELOPEROXIDASE DEFICIENCY
MPO, TYR173CYS

DeLeo et al. (1998) identified a tyr173-to-cys (Y173C) missense mutation
in the MPO gene that was associated with MPO deficiency (254600). They
assessed the impact of the mutation on MPO processing and targeting in
transfectants expressing normal or mutant proteins. Although the
precursor synthesized by cells expressing the Y173C mutation was
glycosylated, associated with the molecular chaperones calreticulin
(109091) and calnexin (114217), and acquired heme, it was neither
proteolytically processed to mature MPO subunits nor secreted. After
prolonged association with calreticulin and calnexin in the endoplasmic
reticulum, the mutant MPO was degraded.

.0003
MYELOPEROXIDASE DEFICIENCY
MPO, MET251THR

Romano et al. (1997) described a 5-year-old child with MPO deficiency
(254600). Her father also had MPO deficiency, whereas her mother had 24%
of MPO activity. Although the typical absorption spectrum of MPO was
absent in both the father and daughter, the father's neutrophils, but
not those of the daughter, contained material antigenically related to
MPO. The father was a compound heterozygote for MPO mutations: a T-to-C
transition causing the nonconservative replacement met251 to thr
(M251T), and a 14-bp deletion within exon 9. The M251T substitution
occurred in the C-terminal region of the light chain that is included in
the heme pocket. The daughter inherited the 14-bp deletion from her
father. Surprisingly, different mRNA phenotypes resulted from the 14-bp
deletion in the father and the daughter. The different behavior of the
14-bp deleted allele in the father and daughter might be the result of a
differentiation-stage dependent control of altered spliced mRNA. The
mRNA inherited from the mother had a wildtype sequence; no mutations
were found in the mother's MPO cDNA and MPO gene. The defect in the
mother might be a regulatory mutation.

.0004
MYELOPEROXIDASE DEFICIENCY
MPO, 14-BP DEL

See 606989.0003 and Romano et al. (1997).

.0005
MYELOPEROXIDASE DEFICIENCY
MPO, ALA332VAL

In a patient with partial MPO deficiency (254600), Marchetti et al.
(2004) identified a heterozygous 995C-T transition in exon 7 of the MPO
gene, resulting in an ala332-to-val (A332V) mutation in the propeptide
sequence (A166V in the mature protein). In a patient with total MPO
deficiency, they identified the A332V mutation in compound heterozygous
state with a 1715T-G transversion in exon 10 of the MPO gene, resulting
in a leu572-to-trp mutation (L572W; 606989.0006) in the propeptide
sequence (L406W in the mature protein).

.0006
MYELOPEROXIDASE DEFICIENCY
MPO, LEU572TRP

See Marchetti et al. (2004) and 606989.0005.

.0007
MYELOPEROXIDASE DEFICIENCY
MPO, IVS11AS, A-C, -2, 109-BP DEL

In 2 patients with total MPO deficiency (254600), Marchetti et al.
(2004) identified homozygosity for a 2031A-C transversion in the 3-prime
splice site of intron 11 of the MPO gene (IVS11AS-2A-C). In a third
patient with total MPO deficiency, they identified the IVS11AS-2A-C
transversion in compound heterozygous state with a 14-bp deletion in
exon 9 of the MPO gene (606989.0004). Because of difficulty in obtaining
bone marrow samples from MPO-deficient subjects to study MPO mRNA
splicing in vivo, the authors set up a eukaryotic expression system to
investigate how the IVS11AS-2-A-C mutation alters MPO pre-mRNA splicing.
Activation of a cryptic 3-prime splice site located 109 bp upstream of
the authentic 3-prime splice site was observed. The 109-bp insertion
caused a frameshift, resulting in a premature stop codon and an abnormal
MPO precursor lacking enzymatic activity.

.0008
ALZHEIMER DISEASE, SUSCEPTIBILITY TO
LUNG CANCER, PROTECTION AGAINST, IN SMOKERS, INCLUDED
MPO, -463G-A

Reynolds et al. (2000) identified a -463G-A promoter polymorphism within
an Alu-encoded hormone response element in the MPO gene. The G allele is
associated with stronger promoter activity and gene expression, whereas
the A allele creates a binding site for a nuclear factor or receptor.
The G/G genotype is the most common. Reynolds et al. (2000) found that
the presence of the MPO -463A allele in conjunction with APOE4 (see
107741) significantly increased the risk of Alzheimer disease (104300)
in men, but not in women (odds ratio for men with both alleles = 11.4 vs
APOE4 alone = 3.0). Reynolds et al. (2000) also found that estrogen
receptor-alpha (133430) binds to the MPO A promoter, which may explain
the gender differences.

In a study of 148 patients from southern Italy with sporadic Alzheimer
disease, Zappia et al. (2004) found that having the G/G genotype
conferred an odds ratio of 1.65 for development of the disease. When
combined with an alpha-2-macroglobulin polymorphism genotype,
1000val/val (103950.0001), the odds ratio increased to 23.19. The
authors suggested that the synergistic effect of the 2 genotypes may
represent a facilitation of beta-amyloid deposition or a decrease in
amyloid clearance, and noted that MPO produces oxidizing conditions. The
findings were independent of APOE4 status.

Taioli et al. (2007) conducted a pooled analysis of individual data from
10 studies (3,688 cases and 3,874 controls) from the Genetic
Susceptibility to Environmental Carcinogens database. The odds ratio for
lung cancer (211980) was 0.88 (95% CI 0.80-0.97) for the A/G genotype of
myeloperoxidase -463G-A polymorphism and 0.71 (95% CI 0.57-0.88) for the
A/A genotype after adjusting for smoking, age, gender, and ethnicity.
The inverse association between lung cancer and myeloperoxidase -463G/A
polymorphism was equally found in males and females, without differences
in the association according to age in the 2 genders. The
myeloperoxidase -463G/A polymorphism was significantly protective in
ever smokers but not in never smokers.

.0009
MYELOPEROXIDASE DEFICIENCY
MPO, GLY501SER

In a Japanese patient with myeloperoxidase deficiency (254600), Ohashi
et al. (2004) identified a homozygous 1051G-A transition in exon 9 of
the MPO gene, resulting in a gly501-to-ser (G501S) substitution close to
his502, which is involved in heme binding. The patient's mother, who had
half-normal MPO activity, was heterozygous for the mutation. The proband
was asymptomatic and identified by automated flow hematocytochemistry
screening.

Using vitro functional expression studies, Goedken et al. (2007) found
that neither the G501S nor the R499C (606989.0010) MPO mutants had
peroxidase activity. Although both were translated into full-length MPO
precursor protein that entered the secretory pathway, neither underwent
proteolytic processing into subunits. Both mutations are present on the
proximal side of the heme pocket and both showed inefficient heme
acquisition.

.0010
MYELOPEROXIDASE DEFICIENCY
MPO, ARG499CYS

In a Japanese patient with myeloperoxidase deficiency (254600), Persad
et al. (2006) identified a mutation in the MPO gene, resulting in an
arg400-to-cys (R499C) substitution close to his502, which is involved in
heme binding. The patient was asymptomatic and identified by automated
flow hematocytochemistry screening.

In vitro functional expression studies by Goedken et al. (2007) showed
that the mutant protein had inefficient heme acquisition and lacked
enzyme activity (see 606989.0009).

*FIELD* SA
Liang et al. (1987)
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*FIELD* CN
Marla J. F. O'Neill - updated: 6/7/2010
Patricia A. Hartz - updated: 1/15/2010
Cassandra L. Kniffin - updated: 11/6/2007
Ada Hamosh - updated: 7/25/2007
John A. Phillips, III - updated: 10/13/2004
Cassandra L. Kniffin - updated: 6/22/2004
Victor A. McKusick - updated: 5/24/2004
Victor A. McKusick - updated: 11/3/2003
Patricia A. Hartz - updated: 7/10/2002
Cassandra L. Kniffin - updated: 6/19/2002

*FIELD* CD
Cassandra L. Kniffin: 5/28/2002

*FIELD* ED
wwang: 06/15/2010
terry: 6/7/2010
mgross: 1/19/2010
terry: 1/15/2010
terry: 11/15/2007
wwang: 11/12/2007
ckniffin: 11/6/2007
alopez: 7/31/2007
terry: 7/25/2007
alopez: 10/13/2004
tkritzer: 7/6/2004
tkritzer: 7/2/2004
ckniffin: 6/22/2004
tkritzer: 6/10/2004
terry: 5/24/2004
tkritzer: 11/6/2003
tkritzer: 11/4/2003
terry: 11/3/2003
tkritzer: 11/19/2002
carol: 7/10/2002
ckniffin: 6/19/2002
carol: 5/29/2002
ckniffin: 5/29/2002