Full text data of CP
CP
[Confidence: low (only semi-automatic identification from reviews)]
Ceruloplasmin; 1.16.3.1 (Ferroxidase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ceruloplasmin; 1.16.3.1 (Ferroxidase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P00450
ID CERU_HUMAN Reviewed; 1065 AA.
AC P00450; Q14063; Q2PP18; Q9UKS4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-AUG-1987, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Ceruloplasmin;
DE EC=1.16.3.1;
DE AltName: Full=Ferroxidase;
DE Flags: Precursor;
GN Name=CP;
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].
RX PubMed=2873574; DOI=10.1073/pnas.83.14.5086;
RA Koschinsky M.L., Funk W.D., van Oost B.A., McGillivray R.T.A.;
RT "Complete cDNA sequence of human preceruloplasmin.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5086-5090(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-1006.
RX PubMed=7702601; DOI=10.1006/bbrc.1995.1437;
RA Daimon M., Yamatani K., Igarashi M., Fukase N., Kawanami T., Kato T.,
RA Tominaga M., Sasaki H.;
RT "Fine structure of the human ceruloplasmin gene.";
RL Biochem. Biophys. Res. Commun. 208:1028-1035(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-40; 549-599; 784-829 AND 919-952.
RX PubMed=3755405; DOI=10.1016/0014-5793(86)80739-6;
RA Mercer J.F.B., Grimes A.;
RT "Isolation of a human ceruloplasmin cDNA clone that includes the N-
RT terminal leader sequence.";
RL FEBS Lett. 203:185-190(1986).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RA Bingle C.D.;
RT "Cloning and functional analysis of the human ceruloplasmin gene
RT minimal promoter.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 218-1065.
RX PubMed=3486416; DOI=10.1073/pnas.83.10.3257;
RA Yang F., Naylor S.L., Lum J.B., Cutshaw S., McCombs J.L.,
RA Naberhaus K.H., McGill J.R., Adrian G.S., Moore C.M., Barnett D.R.,
RA Bowman B.H.;
RT "Characterization, mapping, and expression of the human ceruloplasmin
RT gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:3257-3261(1986).
RN [7]
RP PROTEIN SEQUENCE OF 20-1065.
RX PubMed=6582496; DOI=10.1073/pnas.81.2.390;
RA Takahashi N., Ortel T.L., Putnam F.W.;
RT "Single-chain structure of human ceruloplasmin: the complete amino
RT acid sequence of the whole molecule.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:390-394(1984).
RN [8]
RP PROTEIN SEQUENCE OF 158-333; 518-724 AND 858-1065.
RX PubMed=6571985; DOI=10.1073/pnas.80.1.115;
RA Takahashi N., Bauman R.A., Ortel T.L., Dwulet F.E., Wang C.-C.,
RA Putnam F.W.;
RT "Internal triplication in the structure of human ceruloplasmin.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:115-119(1983).
RN [9]
RP PROTEIN SEQUENCE OF 501-905.
RX PubMed=6940148; DOI=10.1073/pnas.78.2.790;
RA Dwulet F.E., Putnam F.W.;
RT "Complete amino acid sequence of a 50,000-dalton fragment of human
RT ceruloplasmin.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:790-794(1981).
RN [10]
RP PROTEIN SEQUENCE OF 907-1065.
RX PubMed=6987229;
RA Kingston I.B., Kingston B.L., Putnam F.W.;
RT "Primary structure of a histidine-rich proteolytic fragment of human
RT ceruloplasmin. I. Amino acid sequence of the cyanogen bromide
RT peptides.";
RL J. Biol. Chem. 255:2878-2885(1980).
RN [11]
RP PROTEIN SEQUENCE OF 907-1065.
RX PubMed=6987230;
RA Kingston I.B., Kingston B.L., Putnam F.W.;
RT "Primary structure of a histidine-rich proteolytic fragment of human
RT ceruloplasmin. II. Amino acid sequence of the tryptic peptides.";
RL J. Biol. Chem. 255:2886-2896(1980).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1007-1061.
RX PubMed=2355023;
RA Yang F.M., Friedrichs W.E., Cupples R.L., Banifacio M.J.,
RA Sanford J.A., Horton W.A., Bowman B.H.;
RT "Human ceruloplasmin. Tissue-specific expression of transcripts
RT produced by alternative splicing.";
RL J. Biol. Chem. 265:10780-10785(1990).
RN [13]
RP REVIEW.
RX PubMed=12055353; DOI=10.1146/annurev.nutr.22.012502.114457;
RA Hellman N.E., Gitlin J.D.;
RT "Ceruloplasmin metabolism and function.";
RL Annu. Rev. Nutr. 22:439-458(2002).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-397 AND ASN-762,
RP AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-358; ASN-397;
RP ASN-588; ASN-762 AND ASN-926, AND MASS 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 [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-358; ASN-397 AND
RP ASN-762, AND MASS 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 [18]
RP GLYCOSYLATION AT ASN-138; ASN-358; ASN-397 AND ASN-762.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-358 AND ASN-397,
RP STRUCTURE OF CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS), DISULFIDE BONDS, AND
RP METAL-BINDING SITES.
RA Zaitseva I., Zaitsev V., Card G., Moshkov K., Bax B., Ralph A.,
RA Lindley P.;
RT "The X-ray structure of human serum ceruloplasmin at 3.1 A: nature of
RT the copper centres.";
RL J. Biol. Inorg. Chem. 1:15-23(1996).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS), METAL-BINDING SITES, AND
RP DISULFIDE BONDS.
RX PubMed=17242517; DOI=10.1107/S090744490604947X;
RA Bento I., Peixoto C., Zaitsev V.N., Lindley P.F.;
RT "Ceruloplasmin revisited: structural and functional roles of various
RT metal cation-binding sites.";
RL Acta Crystallogr. D 63:240-248(2007).
RN [22]
RP VARIANTS THR-63; LEU-477; GLU-544; ILE-551; HIS-793 AND ARG-841.
RX PubMed=15557511;
RA Hochstrasser H., Bauer P., Walter U., Behnke S., Spiegel J., Csoti I.,
RA Zeiler B., Bornemann A., Pahnke J., Becker G., Riess O., Berg D.;
RT "Ceruloplasmin gene variations and substantia nigra hyperechogenicity
RT in Parkinson disease.";
RL Neurology 63:1912-1917(2004).
RN [23]
RP CHARACTERIZATION OF VARIANTS THR-63; GLU-544 AND HIS-793.
RX PubMed=16150804; DOI=10.1096/fj.04-3486fje;
RA Hochstrasser H., Tomiuk J., Walter U., Behnke S., Spiegel J.,
RA Krueger R., Becker G., Riess O., Berg D.;
RT "Functional relevance of ceruloplasmin mutations in Parkinson's
RT disease.";
RL FASEB J. 19:1851-1853(2005).
CC -!- FUNCTION: Ceruloplasmin is a blue, copper-binding (6-7 atoms per
CC molecule) glycoprotein. It has ferroxidase activity oxidizing
CC Fe(2+) to Fe(3+) without releasing radical oxygen species. It is
CC involved in iron transport across the cell membrane. Provides
CC Cu(2+) ions for the ascorbate-mediated deaminase degradation of
CC the heparan sulfate chains of GPC1. May also play a role in fetal
CC lung development or pulmonary antioxidant defense (By similarity).
CC -!- CATALYTIC ACTIVITY: 4 Fe(2+) + 4 H(+) + O(2) = 4 Fe(3+) + 2 H(2)O.
CC -!- COFACTOR: Binds 6 copper ions per monomer.
CC -!- SUBCELLULAR LOCATION: Secreted. Note=Colocalizes with GCP1 in
CC secretory intracellular compartments (By similarity).
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- DISEASE: Aceruloplasminemia (ACERULOP) [MIM:604290]: An autosomal
CC recessive disorder of iron metabolism characterized by iron
CC accumulation in the brain as well as visceral organs. Clinical
CC features consist of the triad of retinal degeneration, diabetes
CC mellitus and neurological disturbances. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=Ceruloplasmin levels are decreased in Wilson
CC disease, in which copper cannot be incorporated into ceruloplasmin
CC in liver because of defects in the copper-transporting ATPase 2.
CC -!- SIMILARITY: Belongs to the multicopper oxidase family.
CC -!- SIMILARITY: Contains 3 F5/8 type A domains.
CC -!- SIMILARITY: Contains 6 plastocyanin-like domains.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CP";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ceruloplasmin entry;
CC URL="http://en.wikipedia.org/wiki/Ceruloplasmin";
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DR EMBL; M13699; AAA51976.1; -; mRNA.
DR EMBL; DQ314867; ABC40726.1; -; Genomic_DNA.
DR EMBL; D45045; BAA08085.1; -; Genomic_DNA.
DR EMBL; D00025; BAA00019.1; -; mRNA.
DR EMBL; X04135; CAA27752.1; -; mRNA.
DR EMBL; X04136; CAA27753.1; -; mRNA.
DR EMBL; X04137; CAA27754.1; -; mRNA.
DR EMBL; X04138; CAA27755.1; -; mRNA.
DR EMBL; AF132978; AAF02483.1; -; Genomic_DNA.
DR EMBL; M13536; AAA51975.1; -; mRNA.
DR EMBL; J05506; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; A25443; KUHU.
DR RefSeq; NP_000087.1; NM_000096.3.
DR UniGene; Hs.558314; -.
DR PDB; 1KCW; X-ray; 3.00 A; A=20-1065.
DR PDB; 2J5W; X-ray; 2.80 A; A=1-1065.
DR PDB; 4EJX; X-ray; 4.69 A; A=1-1065.
DR PDB; 4ENZ; X-ray; 2.60 A; A=1-1065.
DR PDBsum; 1KCW; -.
DR PDBsum; 2J5W; -.
DR PDBsum; 4EJX; -.
DR PDBsum; 4ENZ; -.
DR ProteinModelPortal; P00450; -.
DR IntAct; P00450; 5.
DR STRING; 9606.ENSP00000264613; -.
DR DrugBank; DB00055; Drotrecogin alfa.
DR PhosphoSite; P00450; -.
DR UniCarbKB; P00450; -.
DR DMDM; 116117; -.
DR DOSAC-COBS-2DPAGE; P00450; -.
DR SWISS-2DPAGE; P00450; -.
DR PaxDb; P00450; -.
DR PeptideAtlas; P00450; -.
DR PRIDE; P00450; -.
DR Ensembl; ENST00000264613; ENSP00000264613; ENSG00000047457.
DR GeneID; 1356; -.
DR KEGG; hsa:1356; -.
DR UCSC; uc003ewy.4; human.
DR CTD; 1356; -.
DR GeneCards; GC03M148880; -.
DR HGNC; HGNC:2295; CP.
DR HPA; CAB008591; -.
DR HPA; HPA001834; -.
DR MIM; 117700; gene.
DR MIM; 604290; phenotype.
DR neXtProt; NX_P00450; -.
DR Orphanet; 48818; Aceruloplasminemia.
DR PharmGKB; PA26815; -.
DR eggNOG; NOG276067; -.
DR HOGENOM; HOG000231499; -.
DR HOVERGEN; HBG003674; -.
DR InParanoid; P00450; -.
DR KO; K13624; -.
DR BioCyc; MetaCyc:HS00590-MONOMER; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR SABIO-RK; P00450; -.
DR EvolutionaryTrace; P00450; -.
DR GeneWiki; Ceruloplasmin; -.
DR GenomeRNAi; 1356; -.
DR NextBio; 5493; -.
DR PMAP-CutDB; P00450; -.
DR PRO; PR:P00450; -.
DR ArrayExpress; P00450; -.
DR Bgee; P00450; -.
DR CleanEx; HS_CP; -.
DR Genevestigator; P00450; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; IEA:Ensembl.
DR GO; GO:0004322; F:ferroxidase activity; TAS:ProtInc.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0006825; P:copper ion transport; IEA:UniProtKB-KW.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR Gene3D; 2.60.40.420; -; 6.
DR InterPro; IPR027150; CP.
DR InterPro; IPR001117; Cu-oxidase.
DR InterPro; IPR011706; Cu-oxidase_2.
DR InterPro; IPR011707; Cu-oxidase_3.
DR InterPro; IPR002355; Cu_oxidase_Cu_BS.
DR InterPro; IPR008972; Cupredoxin.
DR PANTHER; PTHR10127:SF89; PTHR10127:SF89; 1.
DR Pfam; PF00394; Cu-oxidase; 1.
DR Pfam; PF07731; Cu-oxidase_2; 1.
DR Pfam; PF07732; Cu-oxidase_3; 2.
DR SUPFAM; SSF49503; SSF49503; 6.
DR PROSITE; PS00079; MULTICOPPER_OXIDASE1; 3.
DR PROSITE; PS00080; MULTICOPPER_OXIDASE2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Copper; Copper transport;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Ion transport; Metal-binding; Oxidoreductase; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal; Transport.
FT SIGNAL 1 19
FT CHAIN 20 1065 Ceruloplasmin.
FT /FTId=PRO_0000002912.
FT DOMAIN 20 357 F5/8 type A 1.
FT DOMAIN 20 200 Plastocyanin-like 1.
FT DOMAIN 209 357 Plastocyanin-like 2.
FT DOMAIN 370 718 F5/8 type A 2.
FT DOMAIN 370 560 Plastocyanin-like 3.
FT DOMAIN 570 718 Plastocyanin-like 4.
FT DOMAIN 730 1061 F5/8 type A 3.
FT DOMAIN 730 900 Plastocyanin-like 5.
FT DOMAIN 908 1061 Plastocyanin-like 6.
FT METAL 120 120 Copper 1; type 2.
FT METAL 122 122 Copper 2; type 3.
FT METAL 180 180 Copper 2; type 3.
FT METAL 182 182 Copper 3; type 3.
FT METAL 295 295 Copper 4; type 1.
FT METAL 338 338 Copper 4; type 1.
FT METAL 343 343 Copper 4; type 1.
FT METAL 656 656 Copper 5; type 1.
FT METAL 699 699 Copper 5; type 1.
FT METAL 704 704 Copper 5; type 1.
FT METAL 709 709 Copper 5; type 1.
FT METAL 994 994 Copper 6; type 1.
FT METAL 997 997 Copper 1; type 2.
FT METAL 999 999 Copper 3; type 3.
FT METAL 1039 1039 Copper 3; type 3.
FT METAL 1040 1040 Copper 6; type 1.
FT METAL 1041 1041 Copper 2; type 3.
FT METAL 1045 1045 Copper 6; type 1.
FT METAL 1050 1050 Copper 6; type 1.
FT CARBOHYD 138 138 N-linked (GlcNAc...) (complex).
FT CARBOHYD 358 358 N-linked (GlcNAc...) (complex).
FT CARBOHYD 397 397 N-linked (GlcNAc...) (complex).
FT CARBOHYD 588 588 N-linked (GlcNAc...).
FT CARBOHYD 762 762 N-linked (GlcNAc...) (complex).
FT CARBOHYD 926 926 N-linked (GlcNAc...).
FT DISULFID 174 200 Probable.
FT DISULFID 276 357 Probable.
FT DISULFID 534 560 Probable.
FT DISULFID 637 718 Probable.
FT DISULFID 874 900 Probable.
FT VARIANT 63 63 I -> T (retained in the ER due to
FT impaired N-glycosylation; may present a
FT vulnerability factor for iron induced
FT oxidative stress in Parkinson disease).
FT /FTId=VAR_025655.
FT VARIANT 367 367 R -> C (in dbSNP:rs34624984).
FT /FTId=VAR_032815.
FT VARIANT 477 477 P -> L (in dbSNP:rs35331711).
FT /FTId=VAR_025656.
FT VARIANT 544 544 D -> E (reduced ferroxidase activity; may
FT present a vulnerability factor for iron
FT induced oxidative stress in Parkinson
FT disease; dbSNP:rs701753).
FT /FTId=VAR_025657.
FT VARIANT 551 551 T -> I.
FT /FTId=VAR_025658.
FT VARIANT 793 793 R -> H.
FT /FTId=VAR_025659.
FT VARIANT 841 841 T -> R (in dbSNP:rs56033670).
FT /FTId=VAR_025660.
FT CONFLICT 1060 1060 E -> EGEYP (in Ref. 6; AAA51975).
FT STRAND 21 36
FT TURN 49 52
FT HELIX 53 56
FT STRAND 58 61
FT STRAND 65 79
FT STRAND 82 84
FT HELIX 88 90
FT STRAND 97 100
FT STRAND 104 111
FT STRAND 113 115
FT STRAND 120 125
FT HELIX 128 130
FT HELIX 141 144
FT HELIX 145 147
FT STRAND 154 160
FT STRAND 173 180
FT HELIX 185 190
FT STRAND 194 200
FT STRAND 205 210
FT STRAND 214 225
FT HELIX 226 228
FT HELIX 232 239
FT HELIX 243 245
FT HELIX 251 257
FT STRAND 258 262
FT STRAND 274 276
FT STRAND 280 287
FT STRAND 295 301
FT STRAND 304 306
FT STRAND 309 312
FT STRAND 321 327
FT STRAND 332 338
FT HELIX 341 344
FT TURN 345 347
FT STRAND 349 355
FT STRAND 367 385
FT TURN 392 394
FT STRAND 401 403
FT HELIX 406 409
FT STRAND 412 414
FT STRAND 418 427
FT STRAND 429 435
FT HELIX 444 446
FT STRAND 453 456
FT STRAND 459 471
FT STRAND 476 481
FT HELIX 484 486
FT STRAND 514 520
FT TURN 523 525
FT STRAND 529 531
FT STRAND 533 540
FT STRAND 542 544
FT HELIX 545 551
FT STRAND 554 560
FT STRAND 575 580
FT STRAND 582 586
FT HELIX 587 589
FT HELIX 593 600
FT HELIX 604 606
FT HELIX 612 617
FT STRAND 619 623
FT STRAND 635 637
FT STRAND 642 647
FT STRAND 656 660
FT STRAND 665 667
FT STRAND 670 677
FT STRAND 682 687
FT STRAND 693 699
FT HELIX 702 706
FT STRAND 710 716
FT STRAND 729 745
FT HELIX 750 759
FT TURN 766 768
FT TURN 771 773
FT STRAND 777 789
FT HELIX 800 805
FT STRAND 812 815
FT STRAND 818 826
FT STRAND 828 830
FT STRAND 835 838
FT STRAND 842 844
FT STRAND 854 860
FT HELIX 863 865
FT STRAND 869 871
FT STRAND 873 880
FT HELIX 885 890
FT STRAND 894 900
FT STRAND 913 924
FT HELIX 925 927
FT HELIX 931 938
FT HELIX 942 944
FT HELIX 950 955
FT STRAND 957 961
FT STRAND 973 975
FT STRAND 979 986
FT STRAND 994 998
FT STRAND 1003 1006
FT HELIX 1007 1009
FT STRAND 1011 1018
FT STRAND 1023 1028
FT STRAND 1034 1040
FT HELIX 1043 1047
FT STRAND 1051 1057
SQ SEQUENCE 1065 AA; 122205 MW; 2F2F1294E2D30F58 CRC64;
MKILILGIFL FLCSTPAWAK EKHYYIGIIE TTWDYASDHG EKKLISVDTE HSNIYLQNGP
DRIGRLYKKA LYLQYTDETF RTTIEKPVWL GFLGPIIKAE TGDKVYVHLK NLASRPYTFH
SHGITYYKEH EGAIYPDNTT DFQRADDKVY PGEQYTYMLL ATEEQSPGEG DGNCVTRIYH
SHIDAPKDIA SGLIGPLIIC KKDSLDKEKE KHIDREFVVM FSVVDENFSW YLEDNIKTYC
SEPEKVDKDN EDFQESNRMY SVNGYTFGSL PGLSMCAEDR VKWYLFGMGN EVDVHAAFFH
GQALTNKNYR IDTINLFPAT LFDAYMVAQN PGEWMLSCQN LNHLKAGLQA FFQVQECNKS
SSKDNIRGKH VRHYYIAAEE IIWNYAPSGI DIFTKENLTA PGSDSAVFFE QGTTRIGGSY
KKLVYREYTD ASFTNRKERG PEEEHLGILG PVIWAEVGDT IRVTFHNKGA YPLSIEPIGV
RFNKNNEGTY YSPNYNPQSR SVPPSASHVA PTETFTYEWT VPKEVGPTNA DPVCLAKMYY
SAVDPTKDIF TGLIGPMKIC KKGSLHANGR QKDVDKEFYL FPTVFDENES LLLEDNIRMF
TTAPDQVDKE DEDFQESNKM HSMNGFMYGN QPGLTMCKGD SVVWYLFSAG NEADVHGIYF
SGNTYLWRGE RRDTANLFPQ TSLTLHMWPD TEGTFNVECL TTDHYTGGMK QKYTVNQCRR
QSEDSTFYLG ERTYYIAAVE VEWDYSPQRE WEKELHHLQE QNVSNAFLDK GEFYIGSKYK
KVVYRQYTDS TFRVPVERKA EEEHLGILGP QLHADVGDKV KIIFKNMATR PYSIHAHGVQ
TESSTVTPTL PGETLTYVWK IPERSGAGTE DSACIPWAYY STVDQVKDLY SGLIGPLIVC
RRPYLKVFNP RRKLEFALLF LVFDENESWY LDDNIKTYSD HPEKVNKDDE EFIESNKMHA
INGRMFGNLQ GLTMHVGDEV NWYLMGMGNE IDLHTVHFHG HSFQYKHRGV YSSDVFDIFP
GTYQTLEMFP RTPGIWLLHC HVTDHIHAGM ETTYTVLQNE DTKSG
//
ID CERU_HUMAN Reviewed; 1065 AA.
AC P00450; Q14063; Q2PP18; Q9UKS4;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-AUG-1987, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Ceruloplasmin;
DE EC=1.16.3.1;
DE AltName: Full=Ferroxidase;
DE Flags: Precursor;
GN Name=CP;
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].
RX PubMed=2873574; DOI=10.1073/pnas.83.14.5086;
RA Koschinsky M.L., Funk W.D., van Oost B.A., McGillivray R.T.A.;
RT "Complete cDNA sequence of human preceruloplasmin.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5086-5090(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-1006.
RX PubMed=7702601; DOI=10.1006/bbrc.1995.1437;
RA Daimon M., Yamatani K., Igarashi M., Fukase N., Kawanami T., Kato T.,
RA Tominaga M., Sasaki H.;
RT "Fine structure of the human ceruloplasmin gene.";
RL Biochem. Biophys. Res. Commun. 208:1028-1035(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-40; 549-599; 784-829 AND 919-952.
RX PubMed=3755405; DOI=10.1016/0014-5793(86)80739-6;
RA Mercer J.F.B., Grimes A.;
RT "Isolation of a human ceruloplasmin cDNA clone that includes the N-
RT terminal leader sequence.";
RL FEBS Lett. 203:185-190(1986).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RA Bingle C.D.;
RT "Cloning and functional analysis of the human ceruloplasmin gene
RT minimal promoter.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 218-1065.
RX PubMed=3486416; DOI=10.1073/pnas.83.10.3257;
RA Yang F., Naylor S.L., Lum J.B., Cutshaw S., McCombs J.L.,
RA Naberhaus K.H., McGill J.R., Adrian G.S., Moore C.M., Barnett D.R.,
RA Bowman B.H.;
RT "Characterization, mapping, and expression of the human ceruloplasmin
RT gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:3257-3261(1986).
RN [7]
RP PROTEIN SEQUENCE OF 20-1065.
RX PubMed=6582496; DOI=10.1073/pnas.81.2.390;
RA Takahashi N., Ortel T.L., Putnam F.W.;
RT "Single-chain structure of human ceruloplasmin: the complete amino
RT acid sequence of the whole molecule.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:390-394(1984).
RN [8]
RP PROTEIN SEQUENCE OF 158-333; 518-724 AND 858-1065.
RX PubMed=6571985; DOI=10.1073/pnas.80.1.115;
RA Takahashi N., Bauman R.A., Ortel T.L., Dwulet F.E., Wang C.-C.,
RA Putnam F.W.;
RT "Internal triplication in the structure of human ceruloplasmin.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:115-119(1983).
RN [9]
RP PROTEIN SEQUENCE OF 501-905.
RX PubMed=6940148; DOI=10.1073/pnas.78.2.790;
RA Dwulet F.E., Putnam F.W.;
RT "Complete amino acid sequence of a 50,000-dalton fragment of human
RT ceruloplasmin.";
RL Proc. Natl. Acad. Sci. U.S.A. 78:790-794(1981).
RN [10]
RP PROTEIN SEQUENCE OF 907-1065.
RX PubMed=6987229;
RA Kingston I.B., Kingston B.L., Putnam F.W.;
RT "Primary structure of a histidine-rich proteolytic fragment of human
RT ceruloplasmin. I. Amino acid sequence of the cyanogen bromide
RT peptides.";
RL J. Biol. Chem. 255:2878-2885(1980).
RN [11]
RP PROTEIN SEQUENCE OF 907-1065.
RX PubMed=6987230;
RA Kingston I.B., Kingston B.L., Putnam F.W.;
RT "Primary structure of a histidine-rich proteolytic fragment of human
RT ceruloplasmin. II. Amino acid sequence of the tryptic peptides.";
RL J. Biol. Chem. 255:2886-2896(1980).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1007-1061.
RX PubMed=2355023;
RA Yang F.M., Friedrichs W.E., Cupples R.L., Banifacio M.J.,
RA Sanford J.A., Horton W.A., Bowman B.H.;
RT "Human ceruloplasmin. Tissue-specific expression of transcripts
RT produced by alternative splicing.";
RL J. Biol. Chem. 265:10780-10785(1990).
RN [13]
RP REVIEW.
RX PubMed=12055353; DOI=10.1146/annurev.nutr.22.012502.114457;
RA Hellman N.E., Gitlin J.D.;
RT "Ceruloplasmin metabolism and function.";
RL Annu. Rev. Nutr. 22:439-458(2002).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-397 AND ASN-762,
RP AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-358; ASN-397;
RP ASN-588; ASN-762 AND ASN-926, AND MASS 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 [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-358; ASN-397 AND
RP ASN-762, AND MASS 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 [18]
RP GLYCOSYLATION AT ASN-138; ASN-358; ASN-397 AND ASN-762.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-138; ASN-358 AND ASN-397,
RP STRUCTURE OF CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS), DISULFIDE BONDS, AND
RP METAL-BINDING SITES.
RA Zaitseva I., Zaitsev V., Card G., Moshkov K., Bax B., Ralph A.,
RA Lindley P.;
RT "The X-ray structure of human serum ceruloplasmin at 3.1 A: nature of
RT the copper centres.";
RL J. Biol. Inorg. Chem. 1:15-23(1996).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS), METAL-BINDING SITES, AND
RP DISULFIDE BONDS.
RX PubMed=17242517; DOI=10.1107/S090744490604947X;
RA Bento I., Peixoto C., Zaitsev V.N., Lindley P.F.;
RT "Ceruloplasmin revisited: structural and functional roles of various
RT metal cation-binding sites.";
RL Acta Crystallogr. D 63:240-248(2007).
RN [22]
RP VARIANTS THR-63; LEU-477; GLU-544; ILE-551; HIS-793 AND ARG-841.
RX PubMed=15557511;
RA Hochstrasser H., Bauer P., Walter U., Behnke S., Spiegel J., Csoti I.,
RA Zeiler B., Bornemann A., Pahnke J., Becker G., Riess O., Berg D.;
RT "Ceruloplasmin gene variations and substantia nigra hyperechogenicity
RT in Parkinson disease.";
RL Neurology 63:1912-1917(2004).
RN [23]
RP CHARACTERIZATION OF VARIANTS THR-63; GLU-544 AND HIS-793.
RX PubMed=16150804; DOI=10.1096/fj.04-3486fje;
RA Hochstrasser H., Tomiuk J., Walter U., Behnke S., Spiegel J.,
RA Krueger R., Becker G., Riess O., Berg D.;
RT "Functional relevance of ceruloplasmin mutations in Parkinson's
RT disease.";
RL FASEB J. 19:1851-1853(2005).
CC -!- FUNCTION: Ceruloplasmin is a blue, copper-binding (6-7 atoms per
CC molecule) glycoprotein. It has ferroxidase activity oxidizing
CC Fe(2+) to Fe(3+) without releasing radical oxygen species. It is
CC involved in iron transport across the cell membrane. Provides
CC Cu(2+) ions for the ascorbate-mediated deaminase degradation of
CC the heparan sulfate chains of GPC1. May also play a role in fetal
CC lung development or pulmonary antioxidant defense (By similarity).
CC -!- CATALYTIC ACTIVITY: 4 Fe(2+) + 4 H(+) + O(2) = 4 Fe(3+) + 2 H(2)O.
CC -!- COFACTOR: Binds 6 copper ions per monomer.
CC -!- SUBCELLULAR LOCATION: Secreted. Note=Colocalizes with GCP1 in
CC secretory intracellular compartments (By similarity).
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- DISEASE: Aceruloplasminemia (ACERULOP) [MIM:604290]: An autosomal
CC recessive disorder of iron metabolism characterized by iron
CC accumulation in the brain as well as visceral organs. Clinical
CC features consist of the triad of retinal degeneration, diabetes
CC mellitus and neurological disturbances. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=Ceruloplasmin levels are decreased in Wilson
CC disease, in which copper cannot be incorporated into ceruloplasmin
CC in liver because of defects in the copper-transporting ATPase 2.
CC -!- SIMILARITY: Belongs to the multicopper oxidase family.
CC -!- SIMILARITY: Contains 3 F5/8 type A domains.
CC -!- SIMILARITY: Contains 6 plastocyanin-like domains.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CP";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ceruloplasmin entry;
CC URL="http://en.wikipedia.org/wiki/Ceruloplasmin";
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DR EMBL; M13699; AAA51976.1; -; mRNA.
DR EMBL; DQ314867; ABC40726.1; -; Genomic_DNA.
DR EMBL; D45045; BAA08085.1; -; Genomic_DNA.
DR EMBL; D00025; BAA00019.1; -; mRNA.
DR EMBL; X04135; CAA27752.1; -; mRNA.
DR EMBL; X04136; CAA27753.1; -; mRNA.
DR EMBL; X04137; CAA27754.1; -; mRNA.
DR EMBL; X04138; CAA27755.1; -; mRNA.
DR EMBL; AF132978; AAF02483.1; -; Genomic_DNA.
DR EMBL; M13536; AAA51975.1; -; mRNA.
DR EMBL; J05506; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; A25443; KUHU.
DR RefSeq; NP_000087.1; NM_000096.3.
DR UniGene; Hs.558314; -.
DR PDB; 1KCW; X-ray; 3.00 A; A=20-1065.
DR PDB; 2J5W; X-ray; 2.80 A; A=1-1065.
DR PDB; 4EJX; X-ray; 4.69 A; A=1-1065.
DR PDB; 4ENZ; X-ray; 2.60 A; A=1-1065.
DR PDBsum; 1KCW; -.
DR PDBsum; 2J5W; -.
DR PDBsum; 4EJX; -.
DR PDBsum; 4ENZ; -.
DR ProteinModelPortal; P00450; -.
DR IntAct; P00450; 5.
DR STRING; 9606.ENSP00000264613; -.
DR DrugBank; DB00055; Drotrecogin alfa.
DR PhosphoSite; P00450; -.
DR UniCarbKB; P00450; -.
DR DMDM; 116117; -.
DR DOSAC-COBS-2DPAGE; P00450; -.
DR SWISS-2DPAGE; P00450; -.
DR PaxDb; P00450; -.
DR PeptideAtlas; P00450; -.
DR PRIDE; P00450; -.
DR Ensembl; ENST00000264613; ENSP00000264613; ENSG00000047457.
DR GeneID; 1356; -.
DR KEGG; hsa:1356; -.
DR UCSC; uc003ewy.4; human.
DR CTD; 1356; -.
DR GeneCards; GC03M148880; -.
DR HGNC; HGNC:2295; CP.
DR HPA; CAB008591; -.
DR HPA; HPA001834; -.
DR MIM; 117700; gene.
DR MIM; 604290; phenotype.
DR neXtProt; NX_P00450; -.
DR Orphanet; 48818; Aceruloplasminemia.
DR PharmGKB; PA26815; -.
DR eggNOG; NOG276067; -.
DR HOGENOM; HOG000231499; -.
DR HOVERGEN; HBG003674; -.
DR InParanoid; P00450; -.
DR KO; K13624; -.
DR BioCyc; MetaCyc:HS00590-MONOMER; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR SABIO-RK; P00450; -.
DR EvolutionaryTrace; P00450; -.
DR GeneWiki; Ceruloplasmin; -.
DR GenomeRNAi; 1356; -.
DR NextBio; 5493; -.
DR PMAP-CutDB; P00450; -.
DR PRO; PR:P00450; -.
DR ArrayExpress; P00450; -.
DR Bgee; P00450; -.
DR CleanEx; HS_CP; -.
DR Genevestigator; P00450; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; IEA:Ensembl.
DR GO; GO:0004322; F:ferroxidase activity; TAS:ProtInc.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0006825; P:copper ion transport; IEA:UniProtKB-KW.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR Gene3D; 2.60.40.420; -; 6.
DR InterPro; IPR027150; CP.
DR InterPro; IPR001117; Cu-oxidase.
DR InterPro; IPR011706; Cu-oxidase_2.
DR InterPro; IPR011707; Cu-oxidase_3.
DR InterPro; IPR002355; Cu_oxidase_Cu_BS.
DR InterPro; IPR008972; Cupredoxin.
DR PANTHER; PTHR10127:SF89; PTHR10127:SF89; 1.
DR Pfam; PF00394; Cu-oxidase; 1.
DR Pfam; PF07731; Cu-oxidase_2; 1.
DR Pfam; PF07732; Cu-oxidase_3; 2.
DR SUPFAM; SSF49503; SSF49503; 6.
DR PROSITE; PS00079; MULTICOPPER_OXIDASE1; 3.
DR PROSITE; PS00080; MULTICOPPER_OXIDASE2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Copper; Copper transport;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Ion transport; Metal-binding; Oxidoreductase; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal; Transport.
FT SIGNAL 1 19
FT CHAIN 20 1065 Ceruloplasmin.
FT /FTId=PRO_0000002912.
FT DOMAIN 20 357 F5/8 type A 1.
FT DOMAIN 20 200 Plastocyanin-like 1.
FT DOMAIN 209 357 Plastocyanin-like 2.
FT DOMAIN 370 718 F5/8 type A 2.
FT DOMAIN 370 560 Plastocyanin-like 3.
FT DOMAIN 570 718 Plastocyanin-like 4.
FT DOMAIN 730 1061 F5/8 type A 3.
FT DOMAIN 730 900 Plastocyanin-like 5.
FT DOMAIN 908 1061 Plastocyanin-like 6.
FT METAL 120 120 Copper 1; type 2.
FT METAL 122 122 Copper 2; type 3.
FT METAL 180 180 Copper 2; type 3.
FT METAL 182 182 Copper 3; type 3.
FT METAL 295 295 Copper 4; type 1.
FT METAL 338 338 Copper 4; type 1.
FT METAL 343 343 Copper 4; type 1.
FT METAL 656 656 Copper 5; type 1.
FT METAL 699 699 Copper 5; type 1.
FT METAL 704 704 Copper 5; type 1.
FT METAL 709 709 Copper 5; type 1.
FT METAL 994 994 Copper 6; type 1.
FT METAL 997 997 Copper 1; type 2.
FT METAL 999 999 Copper 3; type 3.
FT METAL 1039 1039 Copper 3; type 3.
FT METAL 1040 1040 Copper 6; type 1.
FT METAL 1041 1041 Copper 2; type 3.
FT METAL 1045 1045 Copper 6; type 1.
FT METAL 1050 1050 Copper 6; type 1.
FT CARBOHYD 138 138 N-linked (GlcNAc...) (complex).
FT CARBOHYD 358 358 N-linked (GlcNAc...) (complex).
FT CARBOHYD 397 397 N-linked (GlcNAc...) (complex).
FT CARBOHYD 588 588 N-linked (GlcNAc...).
FT CARBOHYD 762 762 N-linked (GlcNAc...) (complex).
FT CARBOHYD 926 926 N-linked (GlcNAc...).
FT DISULFID 174 200 Probable.
FT DISULFID 276 357 Probable.
FT DISULFID 534 560 Probable.
FT DISULFID 637 718 Probable.
FT DISULFID 874 900 Probable.
FT VARIANT 63 63 I -> T (retained in the ER due to
FT impaired N-glycosylation; may present a
FT vulnerability factor for iron induced
FT oxidative stress in Parkinson disease).
FT /FTId=VAR_025655.
FT VARIANT 367 367 R -> C (in dbSNP:rs34624984).
FT /FTId=VAR_032815.
FT VARIANT 477 477 P -> L (in dbSNP:rs35331711).
FT /FTId=VAR_025656.
FT VARIANT 544 544 D -> E (reduced ferroxidase activity; may
FT present a vulnerability factor for iron
FT induced oxidative stress in Parkinson
FT disease; dbSNP:rs701753).
FT /FTId=VAR_025657.
FT VARIANT 551 551 T -> I.
FT /FTId=VAR_025658.
FT VARIANT 793 793 R -> H.
FT /FTId=VAR_025659.
FT VARIANT 841 841 T -> R (in dbSNP:rs56033670).
FT /FTId=VAR_025660.
FT CONFLICT 1060 1060 E -> EGEYP (in Ref. 6; AAA51975).
FT STRAND 21 36
FT TURN 49 52
FT HELIX 53 56
FT STRAND 58 61
FT STRAND 65 79
FT STRAND 82 84
FT HELIX 88 90
FT STRAND 97 100
FT STRAND 104 111
FT STRAND 113 115
FT STRAND 120 125
FT HELIX 128 130
FT HELIX 141 144
FT HELIX 145 147
FT STRAND 154 160
FT STRAND 173 180
FT HELIX 185 190
FT STRAND 194 200
FT STRAND 205 210
FT STRAND 214 225
FT HELIX 226 228
FT HELIX 232 239
FT HELIX 243 245
FT HELIX 251 257
FT STRAND 258 262
FT STRAND 274 276
FT STRAND 280 287
FT STRAND 295 301
FT STRAND 304 306
FT STRAND 309 312
FT STRAND 321 327
FT STRAND 332 338
FT HELIX 341 344
FT TURN 345 347
FT STRAND 349 355
FT STRAND 367 385
FT TURN 392 394
FT STRAND 401 403
FT HELIX 406 409
FT STRAND 412 414
FT STRAND 418 427
FT STRAND 429 435
FT HELIX 444 446
FT STRAND 453 456
FT STRAND 459 471
FT STRAND 476 481
FT HELIX 484 486
FT STRAND 514 520
FT TURN 523 525
FT STRAND 529 531
FT STRAND 533 540
FT STRAND 542 544
FT HELIX 545 551
FT STRAND 554 560
FT STRAND 575 580
FT STRAND 582 586
FT HELIX 587 589
FT HELIX 593 600
FT HELIX 604 606
FT HELIX 612 617
FT STRAND 619 623
FT STRAND 635 637
FT STRAND 642 647
FT STRAND 656 660
FT STRAND 665 667
FT STRAND 670 677
FT STRAND 682 687
FT STRAND 693 699
FT HELIX 702 706
FT STRAND 710 716
FT STRAND 729 745
FT HELIX 750 759
FT TURN 766 768
FT TURN 771 773
FT STRAND 777 789
FT HELIX 800 805
FT STRAND 812 815
FT STRAND 818 826
FT STRAND 828 830
FT STRAND 835 838
FT STRAND 842 844
FT STRAND 854 860
FT HELIX 863 865
FT STRAND 869 871
FT STRAND 873 880
FT HELIX 885 890
FT STRAND 894 900
FT STRAND 913 924
FT HELIX 925 927
FT HELIX 931 938
FT HELIX 942 944
FT HELIX 950 955
FT STRAND 957 961
FT STRAND 973 975
FT STRAND 979 986
FT STRAND 994 998
FT STRAND 1003 1006
FT HELIX 1007 1009
FT STRAND 1011 1018
FT STRAND 1023 1028
FT STRAND 1034 1040
FT HELIX 1043 1047
FT STRAND 1051 1057
SQ SEQUENCE 1065 AA; 122205 MW; 2F2F1294E2D30F58 CRC64;
MKILILGIFL FLCSTPAWAK EKHYYIGIIE TTWDYASDHG EKKLISVDTE HSNIYLQNGP
DRIGRLYKKA LYLQYTDETF RTTIEKPVWL GFLGPIIKAE TGDKVYVHLK NLASRPYTFH
SHGITYYKEH EGAIYPDNTT DFQRADDKVY PGEQYTYMLL ATEEQSPGEG DGNCVTRIYH
SHIDAPKDIA SGLIGPLIIC KKDSLDKEKE KHIDREFVVM FSVVDENFSW YLEDNIKTYC
SEPEKVDKDN EDFQESNRMY SVNGYTFGSL PGLSMCAEDR VKWYLFGMGN EVDVHAAFFH
GQALTNKNYR IDTINLFPAT LFDAYMVAQN PGEWMLSCQN LNHLKAGLQA FFQVQECNKS
SSKDNIRGKH VRHYYIAAEE IIWNYAPSGI DIFTKENLTA PGSDSAVFFE QGTTRIGGSY
KKLVYREYTD ASFTNRKERG PEEEHLGILG PVIWAEVGDT IRVTFHNKGA YPLSIEPIGV
RFNKNNEGTY YSPNYNPQSR SVPPSASHVA PTETFTYEWT VPKEVGPTNA DPVCLAKMYY
SAVDPTKDIF TGLIGPMKIC KKGSLHANGR QKDVDKEFYL FPTVFDENES LLLEDNIRMF
TTAPDQVDKE DEDFQESNKM HSMNGFMYGN QPGLTMCKGD SVVWYLFSAG NEADVHGIYF
SGNTYLWRGE RRDTANLFPQ TSLTLHMWPD TEGTFNVECL TTDHYTGGMK QKYTVNQCRR
QSEDSTFYLG ERTYYIAAVE VEWDYSPQRE WEKELHHLQE QNVSNAFLDK GEFYIGSKYK
KVVYRQYTDS TFRVPVERKA EEEHLGILGP QLHADVGDKV KIIFKNMATR PYSIHAHGVQ
TESSTVTPTL PGETLTYVWK IPERSGAGTE DSACIPWAYY STVDQVKDLY SGLIGPLIVC
RRPYLKVFNP RRKLEFALLF LVFDENESWY LDDNIKTYSD HPEKVNKDDE EFIESNKMHA
INGRMFGNLQ GLTMHVGDEV NWYLMGMGNE IDLHTVHFHG HSFQYKHRGV YSSDVFDIFP
GTYQTLEMFP RTPGIWLLHC HVTDHIHAGM ETTYTVLQNE DTKSG
//
MIM
117700
*RECORD*
*FIELD* NO
117700
*FIELD* TI
*117700 CERULOPLASMIN; CP
;;FERROXIDASE
*FIELD* TX
DESCRIPTION
Ceruloplasmin (also known as ferroxidase; iron (II):oxygen
read moreoxidoreductase, EC 1.16.3.1) is a blue alpha-2-glycoprotein that binds
90 to 95% of plasma copper and has 6 or 7 cupric ions per molecule. It
is involved in peroxidation of Fe(II) transferrin to form Fe(III)
transferrin. Like transferrin (TF; 190000), ceruloplasmin is a plasma
metalloprotein.
CLONING
Human ceruloplasmin is composed of a single polypeptide chain of 1,046
amino acids, with a molecular mass of 132 kD (Takahashi et al., 1984).
Koschinsky et al. (1986) reported the nucleotide sequence of human
preceruloplasmin cDNA. The mRNA from human liver was found to be 3,700
nucleotides in size. Sequence homology with factor VIII was
demonstrated. The protein is synthesized in hepatocytes and secreted
into the serum with copper incorporated during biosynthesis. Failure to
incorporate copper during synthesis results in the secretion of an
apoprotein devoid of copper, termed apoceruloplasmin (Culotta and
Gitlin, 2001).
Yang et al. (1990) demonstrated 2 forms of CP which differed by the
presence or absence of 12 nucleotide bases encoding a deduced sequence
of gly-glu-tyr-pro in the C-terminal region of the molecule. Alternative
splicing was the apparent explanation, and differential expression of
the 2 transcripts in different tissues with production of isoforms from
a single gene was demonstrated.
Klomp and Gitlin (1996) analyzed ceruloplasmin gene expression in the
brain. In situ hybridization utilizing ceruloplasmin cDNA clones
revealed abundant expression in specific populations of glial cells
within the brain microvasculature, surrounding dopaminergic melanized
neurons in the substantia nigra, and within the inner nuclear layer of
the retina.
GENE STRUCTURE
Daimon et al. (1995) determined that the ceruloplasmin gene contains 19
exons and spans approximately 50 kb.
GENE FUNCTION
Klomp and Gitlin (1996) concluded that glial cell-specific ceruloplasmin
gene expression is essential for iron homeostasis and neuronal survival
in the human central nervous system.
Individuals with hereditary ceruloplasmin deficiency have profound iron
accumulation in most tissues, suggesting that ceruloplasmin is important
for normal release of cellular iron (Mukhopadhyay et al., 1998).
MAPPING
Weitkamp (1983) found a peak lod score of 3.5 at theta about 0.15 for
linkage of CP to TF, which is located at 3q21. Homology argues for this
linkage; TF and CP are linked in cattle with a lod score of 11.3 at 20%
recombination frequency in sires (Larsen, 1977). By Southern blot
analysis of human-mouse somatic cell hybrids, Naylor et al. (1985)
mapped the CP gene to chromosome 3. Royle et al. (1987) localized the CP
gene to 3q21-q24 by analysis of somatic cell hybrid DNAs and in situ
hybridization.
Riddell et al. (1987) identified a ceruloplasmin pseudogene on
chromosome 8. Koschinsky et al. (1987) isolated a processed gene for
human ceruloplasmin and mapped it to chromosome 8 by somatic cell
hybridization. Wang et al. (1988) localized the processed pseudogene
further to 8q21.13-q23.1 by in situ hybridization. They pointed out that
like all other processed pseudogenes described to date, the gene is
located on a chromosome different from the parent gene.
MOLECULAR GENETICS
Shreffler et al., 1967 identified at least 3 variants determined by
codominant alleles by starch gel electrophoresis. Mohrenweiser and
Decker (1982) identified several more electrophoretic variants of
ceruloplasmin.
In a Japanese patient reported by Miyajima et al. (1987) as a case of
familial apoceruloplasmin deficiency, Harris et al. (1995) identified a
mutation in the CP gene. Southern blot analysis of the patient's DNA was
normal, but PCR amplification of 18 of the 19 exons composing the CP
gene revealed a size difference in exon 7. Sequencing of this exon
uncovered a 5-bp insertion at amino acid 410 (117700.0002), resulting in
a frameshift mutation and a truncated open reading frame after 445 amino
acids. The patient's daughter was heterozygous for the 5-bp insertion.
In the Japanese family reported by Morita et al. (1992), Yoshida et al.
(1995) demonstrated a homozygous mutation in the ceruloplasmin gene
(117700.0001) in 4 sibs with aceruloplasminemia, 3 of whom showed
extrapyramidal disorders, cerebellar ataxia, progressive dementia, and
diabetes mellitus.
In a patient with hereditary ceruloplasmin deficiency characterized by
systemic hemosiderosis, diabetes mellitus, pigment degeneration of the
retina, and neurologic abnormalities, Okamoto et al. (1996) reported a
novel homozygous mutation, a base insertion of adenine at position 184,
that produced a premature stop codon (117700.0005).
In the kindred reported by Takahashi et al. (1996), a G-to-A
substitution was identified in exon 15 of the CP gene, resulting in a
nonsense mutation at amino acid 858 (trp858 to ter; 117700.0003). The
homozygous mutation was found in the 45-year-old symptomatic proband as
well as in her younger asymptomatic brother. Thus, the authors found
that aceruloplasminemia appears to be a genetic cause of both diabetes
and neurologic disease.
In the 2 brothers reported by Logan et al. (1994), Harris et al. (1996)
found homozygosity for a single basepair deletion (2389G) in exon 13 of
the CP gene (117700.0004). The nucleotide sequence surrounded this
deletion site (TGGAGA) corresponded to a consensus sequence 'hotspot'
for nucleotide deletions (Krawczak and Cooper, 1991). The nucleotide
deletion resulted in a frameshift with change of 11 amino acids and a
premature stop codon at codon 789.
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
EVOLUTION
Internal duplication is a method of evolution of the genome illustrated
by ceruloplasmin (Dwulet and Putnam, 1981). From internal homology of
amino acid structure, Takahashi et al. (1983) concluded that the
ceruloplasmin molecule evolved by tandem triplication of ancestral
genes. From a computer search of the protein and nucleic acid sequence
data banks of the National Biomedical Research Foundation, Church et al.
(1984) found evidence that factor V (612309), factor VIII (300841), and
ceruloplasmin may have had a common evolutionary origin.
ANIMAL MODEL
To elucidate the role of ceruloplasmin in iron homeostasis, Harris et
al. (1999) created an animal model of aceruloplasminemia by disrupting
the murine Cp gene. Although normal at birth, Cp -/- mice demonstrated
progressive accumulation of iron such that by 1 year of age all animals
had a prominent elevation of serum keratin and a 3- to 6-fold increase
in the iron content of the liver and spleen. Histologic analysis of
affected tissues in these mice showed abundant iron stores within
reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp
+/+ and Cp -/- mice revealed equivalent rates of iron absorption and
plasma iron turnover, suggesting that iron accumulation results from
altered compartmentalization within the iron cycle. Consistent with this
concept, Cp -/- mice showed no abnormalities in cellular iron uptake but
a striking impairment in the movement of iron out of reticuloendothelial
cells and hepatocytes. The findings demonstrated an essential
physiologic role for ceruloplasmin in determining the rate of iron
efflux from cells with mobilizable iron stores.
Mechanisms of brain and retinal iron homeostasis became subjects of
increased interest after the discovery of elevated iron levels in brains
of patients with Alzheimer disease (104300) and retinas of patients with
age-related macular degeneration (603075). To determine whether Cp and
its homolog hephestin (HEPH; 300167) are important for retinal iron
homeostasis, Hahn et al. (2004) studied retinas from mice deficient in
ceruloplasmin and/or hephestin. In normal mice, Cp and Heph localized to
Muller glia and retinal pigment epithelium, a blood-brain barrier. Mice
deficient in both Cp and Heph, but not each individually, had a
striking, age-dependent increase in iron of the retinal pigment
epithelium and retina. The iron storage protein ferritin (see 134790)
was also increased in the doubly null retinas. After retinal iron levels
had increased, mice null for both Cp and Heph had age-dependent retinal
pigment epithelium hypertrophy, hypoplasia, and death, photoreceptor
degeneration, and subretinal neovascularization, providing a model of
some features of the human retinal diseases aceruloplasminemia and
age-related macular degeneration. These pathologic changes indicated
that ceruloplasmin and hephestin are critical for central nervous system
iron homeostasis and that loss of both in the mouse leads to
age-dependent retinal neurodegeneration, providing a model that can be
used to test therapeutic efficacy of iron chelators and antiangiogenic
agents.
Stasi et al. (2007) found that Cp mRNA and Cp protein were upregulated
in the retinas of glaucomatous DBA/2 mice. Upregulation of Cp occurred
at approximately the time of extensive retinal ganglion cell (RGC) death
and increased with increasing age in the retinas but not in the brains
of the animals. No age-related Cp upregulation was detected in the
reference normal mouse strain (C57BL/6), which could develop significant
nonglaucomatous RGC loss toward the end of the same time frame. Cp
upregulation was also detected in most eyes from patients with glaucoma.
Cp upregulation was localized to the Muller cells within the retinas and
in the area of the inner limiting membrane. Stasi et al. (2007)
concluded that the timing of this upregulation suggested that it may
represent a reactive change of the retina in response to a noxious
stimulus or to RGC death. Stasi et al. (2007) hypothesized that such Cp
upregulation might represent a protective mechanism within the retina.
*FIELD* AV
.0001
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
CP, IVSAS, G-A, -1
In a family with hypo- or aceruloplasminemia (604290) reported by Morita
et al. (1992), Yoshida et al. (1995) demonstrated a G-to-A transition at
the splice acceptor site, converting the canonical AG to AA immediately
before the exon beginning with nucleotide 3019 of the cDNA. The parents
were first cousins, thus indicating autosomal recessive inheritance,
which was supported by the demonstration of homozygosity in the affected
sibs. In this disorder, there is no copper overload. One of the 4
aceruloplasmic sibs was free of neurologic symptoms although he showed
iron deposition. The proband from whom information on the distribution
of iron deposits in the brain, liver, pancreas, heart, kidney, spleen,
and thyroid gland was obtained had died at the age of 60 years, having
shown dementia in the advanced stages of his disorder.
.0002
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
CP, 5-BP INS
After the cloning of the Wilson disease gene, ATP7B (606882), Harris et
al. (1995) investigated a number of patients referred for molecular
diagnosis with neurologic degeneration and low serum ceruloplasmin. In
the course of this analysis, they recognized several patients who did
not have Wilson disease. One such patient identified in Japan and
reported as a case of familial apoceruloplasmin deficiency (604290)
(Miyajima et al., 1987) was found to have a mutation in the CP gene. The
patient was a Japanese woman, 61 years old at the time of study, who had
had retinal degeneration and blepharospasm for the previous 10 years.
She had also developed cogwheel rigidity and dysarthria. Her younger
sister, who was asymptomatic at the time of the original presentation
despite undetectable CP, was 51 years old and had recent onset of
retinal degeneration and basal ganglia symptoms. In each case, the
absence of serum CP was associated with mild anemia, low serum iron, and
elevated serum ferritin. Magnetic resonance imaging studies demonstrated
changes in the basal ganglia suggestive of elevated iron content in the
brain. The patient's daughter was entirely asymptomatic but had a serum
CP concentration that was 50% of normal, consistent with an obligate
heterozygote. There was no consanguinity in the family. Liver biopsy
confirmed the presence of excess iron. Although Southern blot analysis
of the patient's DNA was normal, PCR amplification of 18 of the 19 exons
composing the CP gene revealed a size difference in exon 7. Sequencing
of this exon uncovered a 5-bp insertion at amino acid 410, resulting in
a frameshift mutation and a truncated open reading frame after 445 amino
acids. The patient's daughter was heterozygous for the 5-bp insertion.
The study by Harris et al. (1995) demonstrated the essential role of
ceruloplasmin in human biology and identified aceruloplasminemia as an
autosomal recessive disorder of iron metabolism. The findings supported
previous studies that identified ceruloplasmin as a ferroxidase (Osaki
et al., 1966) with a role in the ferric iron uptake by transferrin.
Consistent with this concept, the anemia that develops in
copper-deficient animals is unresponsive to iron but is correctable by
ceruloplasmin administration (Lee et al., 1968). It is also consistent
with the essential role of a homologous copper oxidase in iron
metabolism in yeast.
.0003
ACERULOPLASMINEMIA
HYPOCERULOPLASMINEMIA, INCLUDED
CP, TRP858TER
Takahashi et al. (1996) reported a ceruloplasmin mutation in a kindred
with aceruloplasminemia (604290) and expanded the information on the
clinical implications of the disorder. Their patient was a 45-year-old
woman who came to attention after a several-month history of difficulty
in walking and slurring of speech. She had previously been in excellent
health with the exception of insulin-dependent diabetes mellitus
beginning at age 31 years. Physical examination revealed ataxic gait,
scanning speech, and retinal degeneration. MRI of the brain was
consistent with increased basal ganglia iron content, and laboratory
studies revealed a low serum iron concentration and no detectable serum
ceruloplasmin. A homozygous G-to-A substitution in exon 15 resulted in a
nonsense mutation at amino acid 858 (trp858 to ter). The patient's
younger, neurologically asymptomatic brother was also found to be
homozygous for this mutation. Thus, the authors found that
aceruloplasminemia appears to be a genetic cause of both diabetes and
neurologic disease.
Miyajima et al. (2001) characterized 3 Japanese patients from 2 families
who had cerebellar ataxia with hypoceruloplasminemia. Onset was in the
fourth decade of life. Signs of cerebellar dysfunction included
relatively nondisabling gait ataxia and dysarthria, as well as
hyperreflexia. Brain and abdominal MRI showed cerebellar atrophy and no
low-signal intensities in the basal ganglia, thalamus, and liver. Direct
mutation analysis excluded 8 previously characterized forms of
cerebellar ataxia. The deficiency in serum ceruloplasmin was partial;
protein concentrations and ferroxidase activities ranged from 36 to 41%
of control values. The patients were heterozygous for the trp858-to-ter
mutation of the CP gene. Serum iron concentration and transferrin
saturation were normal. At autopsy, pathologic and biochemical
examinations showed marked loss of Purkinje cells, a large iron
deposition in the cerebellum, and small depositions in the basal
ganglia, thalamus, and liver. Cerebellar ataxia reflected the site of
iron deposition. The authors concluded that heterozygosity for mutation
of the CP gene can result in cerebellar ataxia.
.0004
ACERULOPLASMINEMIA
CERULOPLASMIN BELFAST
CP, 1-BP DEL, 2389G
In 2 brothers with aceruloplasminemia (604290) reported by Logan et al.
(1994), Harris et al. (1996) found homozygosity for a single basepair
deletion (2389G) in exon 13 of the CP gene. The nucleotide sequence
surrounded this deletion site (TGGAGA) corresponded to a consensus
sequence 'hotspot' for nucleotide deletions (Krawczak and Cooper, 1991).
The proband had been admitted to hospital at the age of 49 years with a
6-week history of thirst and polyuria and a 2-week history of
progressive confusion. Neurologic examination was normal. He was started
on a diabetic diet and oral sulfonylurea. At the age of 52, he suddenly
left his work one day and was found at home the next day sitting in a
chair with the appearance of not having been to bed. When asked why he
was not at work he replied, 'What work?' Dementia progressed thereafter,
confusion occurring episodically. The younger brother, who worked as a
railway laborer, developed diabetes and mental slowing at the age of 47
years. The symptoms seemed to have developed over a period of days and
were progressive thereafter. The abnormal ceruloplasmin in this case was
referred to as ceruloplasmin Belfast. The nucleotide deletion resulted
in a frameshift with change of 11 amino acids and a premature stop codon
at codon 789.
.0005
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
CP, 1-BP INS, 184A
In a patient with hereditary ceruloplasmin deficiency characterized by
systemic hemosiderosis, diabetes mellitus, pigment degeneration of the
retina, and neurologic abnormalities, Okamoto et al. (1996) reported a
novel homozygous mutation, a base insertion of adenine at position 184,
that produced a premature stop codon.
*FIELD* SA
Decker and Mohrenweiser (1978); Kellermann and Walter (1972); McCombs
and Bowman (1969); McCombs et al. (1970); Poulik (1968); Schwartzman
et al. (1980); Shokeir and Shreffler (1970); Shokeir et al. (1967);
Stolc (1984)
*FIELD* RF
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*FIELD* CN
Jane Kelly - updated: 10/18/2007
Victor A. McKusick - updated: 11/24/2004
Cassandra L. Kniffin - reorganized: 7/3/2002
Victor A. McKusick - updated: 5/21/2002
Victor A. McKusick - updated: 11/10/1999
Victor A. McKusick - updated: 10/29/1999
Victor A. McKusick - updated: 1/26/1998
Victor A. McKusick - updated: 5/13/1997
Moyra Smith - updated: 1/28/1997
Moyra Smith - updated: 5/12/1996
Alan F. Scott - updated: 6/26/1995
*FIELD* CD
Victor A. McKusick: 6/24/1986
*FIELD* ED
carol: 04/07/2011
carol: 10/8/2008
carol: 10/18/2007
alopez: 12/6/2004
terry: 11/24/2004
carol: 7/3/2002
ckniffin: 7/3/2002
ckniffin: 6/12/2002
mgross: 6/4/2002
terry: 5/21/2002
carol: 4/29/2002
mgross: 11/11/1999
mgross: 11/10/1999
terry: 10/29/1999
carol: 1/13/1999
terry: 1/26/1998
terry: 7/7/1997
jenny: 5/13/1997
terry: 5/13/1997
terry: 5/7/1997
terry: 1/28/1997
mark: 1/27/1997
mark: 10/3/1996
terry: 9/9/1996
carol: 5/22/1996
carol: 5/12/1996
terry: 4/17/1996
mark: 3/7/1996
mark: 2/15/1996
terry: 2/8/1996
terry: 10/30/1995
mark: 3/17/1995
carol: 1/17/1995
mimadm: 6/25/1994
supermim: 3/16/1992
*RECORD*
*FIELD* NO
117700
*FIELD* TI
*117700 CERULOPLASMIN; CP
;;FERROXIDASE
*FIELD* TX
DESCRIPTION
Ceruloplasmin (also known as ferroxidase; iron (II):oxygen
read moreoxidoreductase, EC 1.16.3.1) is a blue alpha-2-glycoprotein that binds
90 to 95% of plasma copper and has 6 or 7 cupric ions per molecule. It
is involved in peroxidation of Fe(II) transferrin to form Fe(III)
transferrin. Like transferrin (TF; 190000), ceruloplasmin is a plasma
metalloprotein.
CLONING
Human ceruloplasmin is composed of a single polypeptide chain of 1,046
amino acids, with a molecular mass of 132 kD (Takahashi et al., 1984).
Koschinsky et al. (1986) reported the nucleotide sequence of human
preceruloplasmin cDNA. The mRNA from human liver was found to be 3,700
nucleotides in size. Sequence homology with factor VIII was
demonstrated. The protein is synthesized in hepatocytes and secreted
into the serum with copper incorporated during biosynthesis. Failure to
incorporate copper during synthesis results in the secretion of an
apoprotein devoid of copper, termed apoceruloplasmin (Culotta and
Gitlin, 2001).
Yang et al. (1990) demonstrated 2 forms of CP which differed by the
presence or absence of 12 nucleotide bases encoding a deduced sequence
of gly-glu-tyr-pro in the C-terminal region of the molecule. Alternative
splicing was the apparent explanation, and differential expression of
the 2 transcripts in different tissues with production of isoforms from
a single gene was demonstrated.
Klomp and Gitlin (1996) analyzed ceruloplasmin gene expression in the
brain. In situ hybridization utilizing ceruloplasmin cDNA clones
revealed abundant expression in specific populations of glial cells
within the brain microvasculature, surrounding dopaminergic melanized
neurons in the substantia nigra, and within the inner nuclear layer of
the retina.
GENE STRUCTURE
Daimon et al. (1995) determined that the ceruloplasmin gene contains 19
exons and spans approximately 50 kb.
GENE FUNCTION
Klomp and Gitlin (1996) concluded that glial cell-specific ceruloplasmin
gene expression is essential for iron homeostasis and neuronal survival
in the human central nervous system.
Individuals with hereditary ceruloplasmin deficiency have profound iron
accumulation in most tissues, suggesting that ceruloplasmin is important
for normal release of cellular iron (Mukhopadhyay et al., 1998).
MAPPING
Weitkamp (1983) found a peak lod score of 3.5 at theta about 0.15 for
linkage of CP to TF, which is located at 3q21. Homology argues for this
linkage; TF and CP are linked in cattle with a lod score of 11.3 at 20%
recombination frequency in sires (Larsen, 1977). By Southern blot
analysis of human-mouse somatic cell hybrids, Naylor et al. (1985)
mapped the CP gene to chromosome 3. Royle et al. (1987) localized the CP
gene to 3q21-q24 by analysis of somatic cell hybrid DNAs and in situ
hybridization.
Riddell et al. (1987) identified a ceruloplasmin pseudogene on
chromosome 8. Koschinsky et al. (1987) isolated a processed gene for
human ceruloplasmin and mapped it to chromosome 8 by somatic cell
hybridization. Wang et al. (1988) localized the processed pseudogene
further to 8q21.13-q23.1 by in situ hybridization. They pointed out that
like all other processed pseudogenes described to date, the gene is
located on a chromosome different from the parent gene.
MOLECULAR GENETICS
Shreffler et al., 1967 identified at least 3 variants determined by
codominant alleles by starch gel electrophoresis. Mohrenweiser and
Decker (1982) identified several more electrophoretic variants of
ceruloplasmin.
In a Japanese patient reported by Miyajima et al. (1987) as a case of
familial apoceruloplasmin deficiency, Harris et al. (1995) identified a
mutation in the CP gene. Southern blot analysis of the patient's DNA was
normal, but PCR amplification of 18 of the 19 exons composing the CP
gene revealed a size difference in exon 7. Sequencing of this exon
uncovered a 5-bp insertion at amino acid 410 (117700.0002), resulting in
a frameshift mutation and a truncated open reading frame after 445 amino
acids. The patient's daughter was heterozygous for the 5-bp insertion.
In the Japanese family reported by Morita et al. (1992), Yoshida et al.
(1995) demonstrated a homozygous mutation in the ceruloplasmin gene
(117700.0001) in 4 sibs with aceruloplasminemia, 3 of whom showed
extrapyramidal disorders, cerebellar ataxia, progressive dementia, and
diabetes mellitus.
In a patient with hereditary ceruloplasmin deficiency characterized by
systemic hemosiderosis, diabetes mellitus, pigment degeneration of the
retina, and neurologic abnormalities, Okamoto et al. (1996) reported a
novel homozygous mutation, a base insertion of adenine at position 184,
that produced a premature stop codon (117700.0005).
In the kindred reported by Takahashi et al. (1996), a G-to-A
substitution was identified in exon 15 of the CP gene, resulting in a
nonsense mutation at amino acid 858 (trp858 to ter; 117700.0003). The
homozygous mutation was found in the 45-year-old symptomatic proband as
well as in her younger asymptomatic brother. Thus, the authors found
that aceruloplasminemia appears to be a genetic cause of both diabetes
and neurologic disease.
In the 2 brothers reported by Logan et al. (1994), Harris et al. (1996)
found homozygosity for a single basepair deletion (2389G) in exon 13 of
the CP gene (117700.0004). The nucleotide sequence surrounded this
deletion site (TGGAGA) corresponded to a consensus sequence 'hotspot'
for nucleotide deletions (Krawczak and Cooper, 1991). The nucleotide
deletion resulted in a frameshift with change of 11 amino acids and a
premature stop codon at codon 789.
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
EVOLUTION
Internal duplication is a method of evolution of the genome illustrated
by ceruloplasmin (Dwulet and Putnam, 1981). From internal homology of
amino acid structure, Takahashi et al. (1983) concluded that the
ceruloplasmin molecule evolved by tandem triplication of ancestral
genes. From a computer search of the protein and nucleic acid sequence
data banks of the National Biomedical Research Foundation, Church et al.
(1984) found evidence that factor V (612309), factor VIII (300841), and
ceruloplasmin may have had a common evolutionary origin.
ANIMAL MODEL
To elucidate the role of ceruloplasmin in iron homeostasis, Harris et
al. (1999) created an animal model of aceruloplasminemia by disrupting
the murine Cp gene. Although normal at birth, Cp -/- mice demonstrated
progressive accumulation of iron such that by 1 year of age all animals
had a prominent elevation of serum keratin and a 3- to 6-fold increase
in the iron content of the liver and spleen. Histologic analysis of
affected tissues in these mice showed abundant iron stores within
reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp
+/+ and Cp -/- mice revealed equivalent rates of iron absorption and
plasma iron turnover, suggesting that iron accumulation results from
altered compartmentalization within the iron cycle. Consistent with this
concept, Cp -/- mice showed no abnormalities in cellular iron uptake but
a striking impairment in the movement of iron out of reticuloendothelial
cells and hepatocytes. The findings demonstrated an essential
physiologic role for ceruloplasmin in determining the rate of iron
efflux from cells with mobilizable iron stores.
Mechanisms of brain and retinal iron homeostasis became subjects of
increased interest after the discovery of elevated iron levels in brains
of patients with Alzheimer disease (104300) and retinas of patients with
age-related macular degeneration (603075). To determine whether Cp and
its homolog hephestin (HEPH; 300167) are important for retinal iron
homeostasis, Hahn et al. (2004) studied retinas from mice deficient in
ceruloplasmin and/or hephestin. In normal mice, Cp and Heph localized to
Muller glia and retinal pigment epithelium, a blood-brain barrier. Mice
deficient in both Cp and Heph, but not each individually, had a
striking, age-dependent increase in iron of the retinal pigment
epithelium and retina. The iron storage protein ferritin (see 134790)
was also increased in the doubly null retinas. After retinal iron levels
had increased, mice null for both Cp and Heph had age-dependent retinal
pigment epithelium hypertrophy, hypoplasia, and death, photoreceptor
degeneration, and subretinal neovascularization, providing a model of
some features of the human retinal diseases aceruloplasminemia and
age-related macular degeneration. These pathologic changes indicated
that ceruloplasmin and hephestin are critical for central nervous system
iron homeostasis and that loss of both in the mouse leads to
age-dependent retinal neurodegeneration, providing a model that can be
used to test therapeutic efficacy of iron chelators and antiangiogenic
agents.
Stasi et al. (2007) found that Cp mRNA and Cp protein were upregulated
in the retinas of glaucomatous DBA/2 mice. Upregulation of Cp occurred
at approximately the time of extensive retinal ganglion cell (RGC) death
and increased with increasing age in the retinas but not in the brains
of the animals. No age-related Cp upregulation was detected in the
reference normal mouse strain (C57BL/6), which could develop significant
nonglaucomatous RGC loss toward the end of the same time frame. Cp
upregulation was also detected in most eyes from patients with glaucoma.
Cp upregulation was localized to the Muller cells within the retinas and
in the area of the inner limiting membrane. Stasi et al. (2007)
concluded that the timing of this upregulation suggested that it may
represent a reactive change of the retina in response to a noxious
stimulus or to RGC death. Stasi et al. (2007) hypothesized that such Cp
upregulation might represent a protective mechanism within the retina.
*FIELD* AV
.0001
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
CP, IVSAS, G-A, -1
In a family with hypo- or aceruloplasminemia (604290) reported by Morita
et al. (1992), Yoshida et al. (1995) demonstrated a G-to-A transition at
the splice acceptor site, converting the canonical AG to AA immediately
before the exon beginning with nucleotide 3019 of the cDNA. The parents
were first cousins, thus indicating autosomal recessive inheritance,
which was supported by the demonstration of homozygosity in the affected
sibs. In this disorder, there is no copper overload. One of the 4
aceruloplasmic sibs was free of neurologic symptoms although he showed
iron deposition. The proband from whom information on the distribution
of iron deposits in the brain, liver, pancreas, heart, kidney, spleen,
and thyroid gland was obtained had died at the age of 60 years, having
shown dementia in the advanced stages of his disorder.
.0002
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
CP, 5-BP INS
After the cloning of the Wilson disease gene, ATP7B (606882), Harris et
al. (1995) investigated a number of patients referred for molecular
diagnosis with neurologic degeneration and low serum ceruloplasmin. In
the course of this analysis, they recognized several patients who did
not have Wilson disease. One such patient identified in Japan and
reported as a case of familial apoceruloplasmin deficiency (604290)
(Miyajima et al., 1987) was found to have a mutation in the CP gene. The
patient was a Japanese woman, 61 years old at the time of study, who had
had retinal degeneration and blepharospasm for the previous 10 years.
She had also developed cogwheel rigidity and dysarthria. Her younger
sister, who was asymptomatic at the time of the original presentation
despite undetectable CP, was 51 years old and had recent onset of
retinal degeneration and basal ganglia symptoms. In each case, the
absence of serum CP was associated with mild anemia, low serum iron, and
elevated serum ferritin. Magnetic resonance imaging studies demonstrated
changes in the basal ganglia suggestive of elevated iron content in the
brain. The patient's daughter was entirely asymptomatic but had a serum
CP concentration that was 50% of normal, consistent with an obligate
heterozygote. There was no consanguinity in the family. Liver biopsy
confirmed the presence of excess iron. Although Southern blot analysis
of the patient's DNA was normal, PCR amplification of 18 of the 19 exons
composing the CP gene revealed a size difference in exon 7. Sequencing
of this exon uncovered a 5-bp insertion at amino acid 410, resulting in
a frameshift mutation and a truncated open reading frame after 445 amino
acids. The patient's daughter was heterozygous for the 5-bp insertion.
The study by Harris et al. (1995) demonstrated the essential role of
ceruloplasmin in human biology and identified aceruloplasminemia as an
autosomal recessive disorder of iron metabolism. The findings supported
previous studies that identified ceruloplasmin as a ferroxidase (Osaki
et al., 1966) with a role in the ferric iron uptake by transferrin.
Consistent with this concept, the anemia that develops in
copper-deficient animals is unresponsive to iron but is correctable by
ceruloplasmin administration (Lee et al., 1968). It is also consistent
with the essential role of a homologous copper oxidase in iron
metabolism in yeast.
.0003
ACERULOPLASMINEMIA
HYPOCERULOPLASMINEMIA, INCLUDED
CP, TRP858TER
Takahashi et al. (1996) reported a ceruloplasmin mutation in a kindred
with aceruloplasminemia (604290) and expanded the information on the
clinical implications of the disorder. Their patient was a 45-year-old
woman who came to attention after a several-month history of difficulty
in walking and slurring of speech. She had previously been in excellent
health with the exception of insulin-dependent diabetes mellitus
beginning at age 31 years. Physical examination revealed ataxic gait,
scanning speech, and retinal degeneration. MRI of the brain was
consistent with increased basal ganglia iron content, and laboratory
studies revealed a low serum iron concentration and no detectable serum
ceruloplasmin. A homozygous G-to-A substitution in exon 15 resulted in a
nonsense mutation at amino acid 858 (trp858 to ter). The patient's
younger, neurologically asymptomatic brother was also found to be
homozygous for this mutation. Thus, the authors found that
aceruloplasminemia appears to be a genetic cause of both diabetes and
neurologic disease.
Miyajima et al. (2001) characterized 3 Japanese patients from 2 families
who had cerebellar ataxia with hypoceruloplasminemia. Onset was in the
fourth decade of life. Signs of cerebellar dysfunction included
relatively nondisabling gait ataxia and dysarthria, as well as
hyperreflexia. Brain and abdominal MRI showed cerebellar atrophy and no
low-signal intensities in the basal ganglia, thalamus, and liver. Direct
mutation analysis excluded 8 previously characterized forms of
cerebellar ataxia. The deficiency in serum ceruloplasmin was partial;
protein concentrations and ferroxidase activities ranged from 36 to 41%
of control values. The patients were heterozygous for the trp858-to-ter
mutation of the CP gene. Serum iron concentration and transferrin
saturation were normal. At autopsy, pathologic and biochemical
examinations showed marked loss of Purkinje cells, a large iron
deposition in the cerebellum, and small depositions in the basal
ganglia, thalamus, and liver. Cerebellar ataxia reflected the site of
iron deposition. The authors concluded that heterozygosity for mutation
of the CP gene can result in cerebellar ataxia.
.0004
ACERULOPLASMINEMIA
CERULOPLASMIN BELFAST
CP, 1-BP DEL, 2389G
In 2 brothers with aceruloplasminemia (604290) reported by Logan et al.
(1994), Harris et al. (1996) found homozygosity for a single basepair
deletion (2389G) in exon 13 of the CP gene. The nucleotide sequence
surrounded this deletion site (TGGAGA) corresponded to a consensus
sequence 'hotspot' for nucleotide deletions (Krawczak and Cooper, 1991).
The proband had been admitted to hospital at the age of 49 years with a
6-week history of thirst and polyuria and a 2-week history of
progressive confusion. Neurologic examination was normal. He was started
on a diabetic diet and oral sulfonylurea. At the age of 52, he suddenly
left his work one day and was found at home the next day sitting in a
chair with the appearance of not having been to bed. When asked why he
was not at work he replied, 'What work?' Dementia progressed thereafter,
confusion occurring episodically. The younger brother, who worked as a
railway laborer, developed diabetes and mental slowing at the age of 47
years. The symptoms seemed to have developed over a period of days and
were progressive thereafter. The abnormal ceruloplasmin in this case was
referred to as ceruloplasmin Belfast. The nucleotide deletion resulted
in a frameshift with change of 11 amino acids and a premature stop codon
at codon 789.
.0005
ACERULOPLASMINEMIA
HEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
CP, 1-BP INS, 184A
In a patient with hereditary ceruloplasmin deficiency characterized by
systemic hemosiderosis, diabetes mellitus, pigment degeneration of the
retina, and neurologic abnormalities, Okamoto et al. (1996) reported a
novel homozygous mutation, a base insertion of adenine at position 184,
that produced a premature stop codon.
*FIELD* SA
Decker and Mohrenweiser (1978); Kellermann and Walter (1972); McCombs
and Bowman (1969); McCombs et al. (1970); Poulik (1968); Schwartzman
et al. (1980); Shokeir and Shreffler (1970); Shokeir et al. (1967);
Stolc (1984)
*FIELD* RF
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*FIELD* CN
Jane Kelly - updated: 10/18/2007
Victor A. McKusick - updated: 11/24/2004
Cassandra L. Kniffin - reorganized: 7/3/2002
Victor A. McKusick - updated: 5/21/2002
Victor A. McKusick - updated: 11/10/1999
Victor A. McKusick - updated: 10/29/1999
Victor A. McKusick - updated: 1/26/1998
Victor A. McKusick - updated: 5/13/1997
Moyra Smith - updated: 1/28/1997
Moyra Smith - updated: 5/12/1996
Alan F. Scott - updated: 6/26/1995
*FIELD* CD
Victor A. McKusick: 6/24/1986
*FIELD* ED
carol: 04/07/2011
carol: 10/8/2008
carol: 10/18/2007
alopez: 12/6/2004
terry: 11/24/2004
carol: 7/3/2002
ckniffin: 7/3/2002
ckniffin: 6/12/2002
mgross: 6/4/2002
terry: 5/21/2002
carol: 4/29/2002
mgross: 11/11/1999
mgross: 11/10/1999
terry: 10/29/1999
carol: 1/13/1999
terry: 1/26/1998
terry: 7/7/1997
jenny: 5/13/1997
terry: 5/13/1997
terry: 5/7/1997
terry: 1/28/1997
mark: 1/27/1997
mark: 10/3/1996
terry: 9/9/1996
carol: 5/22/1996
carol: 5/12/1996
terry: 4/17/1996
mark: 3/7/1996
mark: 2/15/1996
terry: 2/8/1996
terry: 10/30/1995
mark: 3/17/1995
carol: 1/17/1995
mimadm: 6/25/1994
supermim: 3/16/1992
MIM
604290
*RECORD*
*FIELD* NO
604290
*FIELD* TI
#604290 ACERULOPLASMINEMIA
HYPOCERULOPLASMINEMIA, INCLUDED;;
CERULOPLASMIN DEFICIENCY, INCLUDED;;
read moreHEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because aceruloplasminemia is
caused by mutation in the gene encoding ceruloplasmin (CP; 117700).
CLINICAL FEATURES
- Aceruloplasminemia
Logan et al. (1994) reported 2 brothers with complete ceruloplasmin
deficiency who presented in their late forties with dementia and
diabetes mellitus. The proband had been admitted to hospital at the age
of 49 years with a 6-week history of thirst and polyuria and a 2-week
history of progressive confusion. Neurologic examination was normal. He
was started on a diabetic diet and oral sulfonylurea. At the age of 52,
he suddenly left his work one day and was found at home the next day
sitting in a chair with the appearance of not having been to bed. When
asked why he was not at work he replied, 'What work?' Dementia
progressed thereafter, confusion occurring episodically. The younger
brother, who worked as a railway laborer, developed diabetes and mental
slowing at the age of 47 years. The symptoms seemed to have developed
over a period of days and were progressive thereafter. Twelve relatives
had partial ceruloplasmin deficiency. Both brothers had low serum iron
and increased liver iron, and there was no copper overload. Transmission
of the abnormality was autosomal recessive. The abnormal ceruloplasmin
in this case was referred to as ceruloplasmin Belfast.
Morita et al. (1992) described a 55-year-old patient with complete
ceruloplasmin deficiency who presented with dementia, diabetes,
torticollis, chorea, and ataxia. A postmortem study of this proband
demonstrated excessive iron deposition, mainly in the brain, liver, and
pancreas. Morita et al. (1995) reported a clinical pathologic study of
the family reported by Morita et al. (1992), which contained 3 affected
sibs of consanguineous parents. Clinical symptoms were progressive
dementia, extrapyramidal disorders, cerebellar ataxia, and diabetes
mellitus, all of which appeared when they were between 30 and 50 years
old. All had almost completely absent levels of serum ceruloplasmin and
increased serum ferritin (see 134790) concentrations. The dentate
nucleus, thalamus, putamen, caudate nucleus, and liver of each patient
showed low signal intensities on T1- and T2-weighted MRIs. Autopsy
revealed severe destruction of the basal ganglia and dentate nucleus
with considerable iron deposition in neuronal and glial cells, whereas
the cerebral cortex showed mild iron deposition in glial cells without
neuronal involvement. Iron deposition in hepatocytes and in neural and
glial cells of the brain was demonstrated by electron microscopy with
energy-dispersive x-ray analysis.
Harris et al. (1995) reported a 61-year-old Japanese woman who had had
retinal degeneration and blepharospasm for the previous 10 years. She
had also developed cogwheel rigidity and dysarthria. Her 51-year-old
sister, who was asymptomatic at the time of the original presentation
despite undetectable CP, had recent onset of retinal degeneration and
basal ganglia symptoms. In each case, the absence of serum CP was
associated with mild anemia, low serum iron, and elevated serum
ferritin. Magnetic resonance imaging studies demonstrated changes in the
basal ganglia suggestive of elevated iron content in the brain. The
patient's daughter was entirely asymptomatic but had a serum CP
concentration that was 50% of normal, consistent with an obligate
heterozygote. There was no consanguinity in the family. Liver biopsy
confirmed the presence of excess iron.
Takahashi et al. (1996) reported a kindred with aceruloplasminemia.
Their patient was a 45-year-old woman who came to attention after a
several-month history of difficulty in walking and slurring of speech.
She had previously been in excellent health with the exception of
insulin-dependent diabetes mellitus beginning at age 31 years. Physical
examination revealed ataxic gait, scanning speech, and retinal
degeneration. MRI of the brain was consistent with increased basal
ganglia iron content, and laboratory studies revealed a low serum iron
concentration and no detectable serum ceruloplasmin.
Okamoto et al. (1996) reviewed the findings in 4 pedigrees with
aceruloplasminemia. Clinical manifestations, which occurred after middle
age, included extrapyramidal signs, cerebellar ataxia, dementia, and
memory loss. Neuroimaging studies revealed iron deposition in the basal
ganglia and in the red and dentate nuclei. Diagnostic laboratory
findings included deficiency of ceruloplasmin, low serum iron, and high
serum ferritin. The hepatic iron content was high, but cirrhosis was not
usually present.
- Hypoceruloplasminemia
Edwards et al. (1979) studied a kindred in which 14 members had low
serum ceruloplasmin and low serum copper without the abnormalities of
Wilson disease (277900). The phenotype segregated in a pattern
suggesting heterozygosity for a mutant gene. One member of the family
with low levels had been followed for over 25 years and had remained
completely well.
Miyajima et al. (1987) described a 52-year-old woman with blepharospasm,
retinal degeneration, and high density areas in the basal ganglia and
liver by CT scan. Studies showed accumulation of iron, not copper, in
liver and brain. Serum ceruloplasmin was less than 0.6 mg/dl (normal,
17-37 mg/dl) and serum apoceruloplasmin was undetectable. A sister and a
brother demonstrated retinal degeneration and iron deposition in the
basal ganglia and liver, respectively. Serum ceruloplasmin was less than
0.8 mg/dl in both cases.
CLINICAL MANAGEMENT
Logan et al. (1994) treated their index patient with
ceruloplasmin-containing fresh-frozen plasma, resulting in an increase
in serum iron that was dose dependent. Miyajima et al. (1997) reported
favorable results with desferrioxamine in the treatment of
aceruloplasminemia.
INHERITANCE
The study by Harris et al. (1995) (see MOLECULAR GENETICS) demonstrated
the essential role of ceruloplasmin in human biology and identified
aceruloplasminemia as an autosomal recessive disorder of iron
metabolism. Okamoto et al. (1996) noted that consanguinity occurred in 3
of 4 affected pedigrees, suggesting autosomal recessive inheritance.
MAPPING
Logan et al. (1994) performed DNA analysis on 2 affected brothers and
showed genetic linkage between the ceruloplasmin deficiency and various
polymorphic markers flanking the ceruloplasmin gene on 3q25.
PATHOGENESIS
Ceruloplasmin catalyzes the oxidation of ferrous iron to ferric iron or
the peroxidation of Fe(II) transferrin to form Fe(III) transferrin
(Logan et al., 1994). The molecular findings by Harris et al. (1995)
supported previous studies that identified ceruloplasmin as a
ferroxidase (Osaki et al., 1966) with a role in the ferric iron uptake
by transferrin. Consistent with this concept, the anemia that develops
in copper-deficient animals is unresponsive to iron but is correctable
by ceruloplasmin administration (Lee et al., 1968). It is also
consistent with the essential role of a homologous copper oxidase in
iron metabolism in yeast.
Blepharospasm has been related to abnormality of the basal ganglia, as
in blepharospasm-oromandibular dystonia (Meige syndrome); see Casey
(1980) and Tanner et al. (1982).
MOLECULAR GENETICS
After the cloning of the Wilson disease gene, Harris et al. (1995)
investigated a number of patients referred for molecular diagnosis with
neurologic degeneration and low or absent serum ceruloplasmin. In the
course of this analysis, they recognized several patients who did not
have Wilson disease. One such patient identified in Japan and reported
as a case of familial apoceruloplasmin deficiency (Miyajima et al.,
1987) was found to have a mutation in the ceruloplasmin gene
(117700.0002). The patient's daughter was heterozygous for the 5-bp
insertion.
In the Japanese family reported by Morita et al. (1992), Yoshida et al.
(1995) demonstrated a homozygous mutation in the ceruloplasmin gene
(117700.0001) in 4 sibs with aceruloplasminemia, 3 of whom showed
extrapyramidal disorders, cerebellar ataxia, progressive dementia, and
diabetes mellitus.
Roy and Andrews (2001) reviewed disorders of iron metabolism, with
emphasis on aberrations in hemochromatosis (235200), Friedreich ataxia
(229300), aceruloplasminemia, and other inherited disorders.
ANIMAL MODEL
To determine whether aceruloplasmin and its homolog hephestin (HEPH;
300167) are important for retinal iron homeostasis, Hahn et al. (2004)
studied retinas from mice deficient in Cp and/or Heph. Mice deficient in
both, but not each individually, had a striking, age-dependent increase
in the iron content of retinal pigment epithelium and the retina. The
iron storage protein ferritin was also increased in the double-null
retinas. The pathology indicated that Cp and Heph are critical for
central nervous system iron homeostasis and that loss of both in the
mouse leads to age-dependent retinal neurodegeneration, thus explaining
the retinal degeneration of aceruloplasiminemia.
*FIELD* SA
Harris et al. (1996); Krawczak and Cooper (1991)
*FIELD* RF
1. Casey, D. E.: Pharmacology of blepharospasm-oromandibular dystonia
syndrome. Neurology 30: 690-695, 1980.
2. Edwards, C. Q.; Williams, D. M.; Cartwright, G. E.: Hereditary
hypoceruloplasminemia. Clin. Genet. 15: 311-316, 1979.
3. Hahn, P.; Qian, Y.; Dentchev, T.; Chen, L.; Beard, J.; Harris,
Z. L.; Dunaief, J. L.: Disruption of ceruloplasmin and hephaestin
in mice causes retinal iron overload and retinal degeneration with
features of age-related macular degeneration. Proc. Nat. Acad. Sci. 101:
13850-13855, 2004.
4. Harris, Z. L.; Migas, M. C.; Hughes, A. E.; Logan, J. I.; Gitlin,
J. D.: Familial dementia due to a frameshift mutation in the caeruloplasmin
gene. Quart. J. Med. 89: 355-359, 1996.
5. Harris, Z. L.; Takahashi, Y.; Miyajima, H.; Serizawa, M.; MacGillivray,
R. T. A.; Gitlin, J. D.: Aceruloplasminemia: molecular characterization
of this disorder of iron metabolism. Proc. Nat. Acad. Sci. 92: 2539-2543,
1995.
6. Krawczak, M.; Cooper, D. N.: Gene deletions causing human genetic
disease: mechanisms of mutagenesis and the role of the local DNA sequence
environment. Hum. Genet. 86: 425-441, 1991.
7. Lee, G. R.; Nacht, S.; Lukens, J. N.; Cartwright, G. E.: Iron
metabolism in copper-deficient swine. J. Clin. Invest. 47: 2058-2069,
1968.
8. Logan, J. I.; Harveyson, K. B.; Wisdom, G. B.; Hughes, A. E.; Archbold,
G. P. R.: Hereditary caeruloplasmin deficiency, dementia and diabetes
mellitus. Quart. J. Med. 87: 663-670, 1994.
9. Miyajima, H.; Nishimura, Y.; Mizoguchi, K.; Sakamoto, M.; Shimizu,
T.; Honda, N.: Familial apoceruloplasmin deficiency associated with
blepharospasm and retinal degeneration. Neurology 37: 761-767, 1987.
10. Miyajima, H.; Takahashi, Y.; Kamata, T.; Shimizu, H.; Sakai, N.;
Gitlin, J. D.: Use of desferrioxamine in the treatment of aceruloplasminemia. Ann.
Neurol. 41: 404-407, 1997.
11. Morita, H.; Ikeda, S.; Yamamoto, K.; Morita, S.; Yoshida, K.;
Nomoto, S.; Kato, M.; Yanagisawa, N.: Hereditary ceruloplasmin deficiency
with hemosiderosis: a clinicopathological study of a Japanese family. Ann.
Neurol. 37: 646-656, 1995.
12. Morita, H.; Inoue, A.; Yanagisawa, N.: A case with ceruloplasmin
deficiency which showed dementia, ataxia and iron deposition in the
brain. Rinsho Shinkeigaku 32: 483-487, 1992.
13. Okamoto, N.; Wada, S.; Oga, T.; Kawabata, Y.; Baba, Y.; Habu,
D.; Takeda, Z.; Wada, Y.: Hereditary ceruloplasmin deficiency with
hemosiderosis. Hum. Genet. 97: 755-758, 1996.
14. Osaki, S.; Johnson, D. A.; Frieden, E.: The possible significance
of the ferrous oxidase activity of ceruloplasmin in normal human serum. J.
Biol. Chem. 241: 2746-2751, 1966.
15. Roy, C. N.; Andrews, N. C.: Recent advances in disorders of iron
metabolism: mutations, mechanisms and modifiers. Hum. Molec. Genet. 10:
2181-2186, 2001.
16. Takahashi, Y.; Miyajima, H.; Shirabe, S.; Nagataki, S.; Suenaga,
A.; Gitlin, J. D.: Characterization of a nonsense mutation in the
ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum.
Molec. Genet. 5: 81-84, 1996.
17. Tanner, C. M.; Glantz, R. H.; Klawans, H. L.: Meige disease:
acute and chronic cholinergic effects. Neurology 32: 783-785, 1982.
18. Yoshida, K.; Furihata, K.; Takeda, S.; Nakamura, A.; Yamamoto,
K.; Morita, H.; Hiyamuta, S.; Ikeda, S.; Shimizu, N.; Yanagisawa,
N.: A mutation in the ceruloplasmin gene is associated with systemic
hemosiderosis in humans. Nature Genet. 9: 267-272, 1995.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm;
Retinal degeneration
NEUROLOGIC:
[Central nervous system];
Ataxia;
Chorea;
Torticollis;
Extrapyramidal symptoms;
Cogwheel rigidity;
Progressive dementia;
Dysarthria;
Scanning speech
ENDOCRINE FEATURES:
Diabetes mellitus
HEMATOLOGY:
Mild anemia
LABORATORY ABNORMALITIES:
Iron deposition in basal ganglia, liver, pancreas, visceral organs
detectable by CT and MRI;
Decreased or absent serum ceruloplasmin;
Decreased serum iron;
Increased serum ferritin
MISCELLANEOUS:
Onset between age 30-50 years
MOLECULAR BASIS:
Caused by mutations in the ceruloplasmin gene (CP, 117700.0001).
*FIELD* CN
Cassandra L. Kniffin - revised: 6/11/2002
*FIELD* CD
John F. Jackson: 1/1/1996
*FIELD* ED
joanna: 06/13/2002
ckniffin: 6/11/2002
*FIELD* CN
Victor A. McKusick - updated: 11/24/2004
Cassandra L. Kniffin - reorganized: 7/3/2002
George E. Tiller - updated: 2/12/2002
*FIELD* CD
Victor A. McKusick: 11/9/1999
*FIELD* ED
alopez: 12/06/2004
terry: 11/24/2004
carol: 7/7/2004
carol: 7/3/2002
ckniffin: 7/3/2002
ckniffin: 6/17/2002
cwells: 2/18/2002
cwells: 2/12/2002
mgross: 11/10/1999
*RECORD*
*FIELD* NO
604290
*FIELD* TI
#604290 ACERULOPLASMINEMIA
HYPOCERULOPLASMINEMIA, INCLUDED;;
CERULOPLASMIN DEFICIENCY, INCLUDED;;
read moreHEMOSIDEROSIS, SYSTEMIC, DUE TO ACERULOPLASMINEMIA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because aceruloplasminemia is
caused by mutation in the gene encoding ceruloplasmin (CP; 117700).
CLINICAL FEATURES
- Aceruloplasminemia
Logan et al. (1994) reported 2 brothers with complete ceruloplasmin
deficiency who presented in their late forties with dementia and
diabetes mellitus. The proband had been admitted to hospital at the age
of 49 years with a 6-week history of thirst and polyuria and a 2-week
history of progressive confusion. Neurologic examination was normal. He
was started on a diabetic diet and oral sulfonylurea. At the age of 52,
he suddenly left his work one day and was found at home the next day
sitting in a chair with the appearance of not having been to bed. When
asked why he was not at work he replied, 'What work?' Dementia
progressed thereafter, confusion occurring episodically. The younger
brother, who worked as a railway laborer, developed diabetes and mental
slowing at the age of 47 years. The symptoms seemed to have developed
over a period of days and were progressive thereafter. Twelve relatives
had partial ceruloplasmin deficiency. Both brothers had low serum iron
and increased liver iron, and there was no copper overload. Transmission
of the abnormality was autosomal recessive. The abnormal ceruloplasmin
in this case was referred to as ceruloplasmin Belfast.
Morita et al. (1992) described a 55-year-old patient with complete
ceruloplasmin deficiency who presented with dementia, diabetes,
torticollis, chorea, and ataxia. A postmortem study of this proband
demonstrated excessive iron deposition, mainly in the brain, liver, and
pancreas. Morita et al. (1995) reported a clinical pathologic study of
the family reported by Morita et al. (1992), which contained 3 affected
sibs of consanguineous parents. Clinical symptoms were progressive
dementia, extrapyramidal disorders, cerebellar ataxia, and diabetes
mellitus, all of which appeared when they were between 30 and 50 years
old. All had almost completely absent levels of serum ceruloplasmin and
increased serum ferritin (see 134790) concentrations. The dentate
nucleus, thalamus, putamen, caudate nucleus, and liver of each patient
showed low signal intensities on T1- and T2-weighted MRIs. Autopsy
revealed severe destruction of the basal ganglia and dentate nucleus
with considerable iron deposition in neuronal and glial cells, whereas
the cerebral cortex showed mild iron deposition in glial cells without
neuronal involvement. Iron deposition in hepatocytes and in neural and
glial cells of the brain was demonstrated by electron microscopy with
energy-dispersive x-ray analysis.
Harris et al. (1995) reported a 61-year-old Japanese woman who had had
retinal degeneration and blepharospasm for the previous 10 years. She
had also developed cogwheel rigidity and dysarthria. Her 51-year-old
sister, who was asymptomatic at the time of the original presentation
despite undetectable CP, had recent onset of retinal degeneration and
basal ganglia symptoms. In each case, the absence of serum CP was
associated with mild anemia, low serum iron, and elevated serum
ferritin. Magnetic resonance imaging studies demonstrated changes in the
basal ganglia suggestive of elevated iron content in the brain. The
patient's daughter was entirely asymptomatic but had a serum CP
concentration that was 50% of normal, consistent with an obligate
heterozygote. There was no consanguinity in the family. Liver biopsy
confirmed the presence of excess iron.
Takahashi et al. (1996) reported a kindred with aceruloplasminemia.
Their patient was a 45-year-old woman who came to attention after a
several-month history of difficulty in walking and slurring of speech.
She had previously been in excellent health with the exception of
insulin-dependent diabetes mellitus beginning at age 31 years. Physical
examination revealed ataxic gait, scanning speech, and retinal
degeneration. MRI of the brain was consistent with increased basal
ganglia iron content, and laboratory studies revealed a low serum iron
concentration and no detectable serum ceruloplasmin.
Okamoto et al. (1996) reviewed the findings in 4 pedigrees with
aceruloplasminemia. Clinical manifestations, which occurred after middle
age, included extrapyramidal signs, cerebellar ataxia, dementia, and
memory loss. Neuroimaging studies revealed iron deposition in the basal
ganglia and in the red and dentate nuclei. Diagnostic laboratory
findings included deficiency of ceruloplasmin, low serum iron, and high
serum ferritin. The hepatic iron content was high, but cirrhosis was not
usually present.
- Hypoceruloplasminemia
Edwards et al. (1979) studied a kindred in which 14 members had low
serum ceruloplasmin and low serum copper without the abnormalities of
Wilson disease (277900). The phenotype segregated in a pattern
suggesting heterozygosity for a mutant gene. One member of the family
with low levels had been followed for over 25 years and had remained
completely well.
Miyajima et al. (1987) described a 52-year-old woman with blepharospasm,
retinal degeneration, and high density areas in the basal ganglia and
liver by CT scan. Studies showed accumulation of iron, not copper, in
liver and brain. Serum ceruloplasmin was less than 0.6 mg/dl (normal,
17-37 mg/dl) and serum apoceruloplasmin was undetectable. A sister and a
brother demonstrated retinal degeneration and iron deposition in the
basal ganglia and liver, respectively. Serum ceruloplasmin was less than
0.8 mg/dl in both cases.
CLINICAL MANAGEMENT
Logan et al. (1994) treated their index patient with
ceruloplasmin-containing fresh-frozen plasma, resulting in an increase
in serum iron that was dose dependent. Miyajima et al. (1997) reported
favorable results with desferrioxamine in the treatment of
aceruloplasminemia.
INHERITANCE
The study by Harris et al. (1995) (see MOLECULAR GENETICS) demonstrated
the essential role of ceruloplasmin in human biology and identified
aceruloplasminemia as an autosomal recessive disorder of iron
metabolism. Okamoto et al. (1996) noted that consanguinity occurred in 3
of 4 affected pedigrees, suggesting autosomal recessive inheritance.
MAPPING
Logan et al. (1994) performed DNA analysis on 2 affected brothers and
showed genetic linkage between the ceruloplasmin deficiency and various
polymorphic markers flanking the ceruloplasmin gene on 3q25.
PATHOGENESIS
Ceruloplasmin catalyzes the oxidation of ferrous iron to ferric iron or
the peroxidation of Fe(II) transferrin to form Fe(III) transferrin
(Logan et al., 1994). The molecular findings by Harris et al. (1995)
supported previous studies that identified ceruloplasmin as a
ferroxidase (Osaki et al., 1966) with a role in the ferric iron uptake
by transferrin. Consistent with this concept, the anemia that develops
in copper-deficient animals is unresponsive to iron but is correctable
by ceruloplasmin administration (Lee et al., 1968). It is also
consistent with the essential role of a homologous copper oxidase in
iron metabolism in yeast.
Blepharospasm has been related to abnormality of the basal ganglia, as
in blepharospasm-oromandibular dystonia (Meige syndrome); see Casey
(1980) and Tanner et al. (1982).
MOLECULAR GENETICS
After the cloning of the Wilson disease gene, Harris et al. (1995)
investigated a number of patients referred for molecular diagnosis with
neurologic degeneration and low or absent serum ceruloplasmin. In the
course of this analysis, they recognized several patients who did not
have Wilson disease. One such patient identified in Japan and reported
as a case of familial apoceruloplasmin deficiency (Miyajima et al.,
1987) was found to have a mutation in the ceruloplasmin gene
(117700.0002). The patient's daughter was heterozygous for the 5-bp
insertion.
In the Japanese family reported by Morita et al. (1992), Yoshida et al.
(1995) demonstrated a homozygous mutation in the ceruloplasmin gene
(117700.0001) in 4 sibs with aceruloplasminemia, 3 of whom showed
extrapyramidal disorders, cerebellar ataxia, progressive dementia, and
diabetes mellitus.
Roy and Andrews (2001) reviewed disorders of iron metabolism, with
emphasis on aberrations in hemochromatosis (235200), Friedreich ataxia
(229300), aceruloplasminemia, and other inherited disorders.
ANIMAL MODEL
To determine whether aceruloplasmin and its homolog hephestin (HEPH;
300167) are important for retinal iron homeostasis, Hahn et al. (2004)
studied retinas from mice deficient in Cp and/or Heph. Mice deficient in
both, but not each individually, had a striking, age-dependent increase
in the iron content of retinal pigment epithelium and the retina. The
iron storage protein ferritin was also increased in the double-null
retinas. The pathology indicated that Cp and Heph are critical for
central nervous system iron homeostasis and that loss of both in the
mouse leads to age-dependent retinal neurodegeneration, thus explaining
the retinal degeneration of aceruloplasiminemia.
*FIELD* SA
Harris et al. (1996); Krawczak and Cooper (1991)
*FIELD* RF
1. Casey, D. E.: Pharmacology of blepharospasm-oromandibular dystonia
syndrome. Neurology 30: 690-695, 1980.
2. Edwards, C. Q.; Williams, D. M.; Cartwright, G. E.: Hereditary
hypoceruloplasminemia. Clin. Genet. 15: 311-316, 1979.
3. Hahn, P.; Qian, Y.; Dentchev, T.; Chen, L.; Beard, J.; Harris,
Z. L.; Dunaief, J. L.: Disruption of ceruloplasmin and hephaestin
in mice causes retinal iron overload and retinal degeneration with
features of age-related macular degeneration. Proc. Nat. Acad. Sci. 101:
13850-13855, 2004.
4. Harris, Z. L.; Migas, M. C.; Hughes, A. E.; Logan, J. I.; Gitlin,
J. D.: Familial dementia due to a frameshift mutation in the caeruloplasmin
gene. Quart. J. Med. 89: 355-359, 1996.
5. Harris, Z. L.; Takahashi, Y.; Miyajima, H.; Serizawa, M.; MacGillivray,
R. T. A.; Gitlin, J. D.: Aceruloplasminemia: molecular characterization
of this disorder of iron metabolism. Proc. Nat. Acad. Sci. 92: 2539-2543,
1995.
6. Krawczak, M.; Cooper, D. N.: Gene deletions causing human genetic
disease: mechanisms of mutagenesis and the role of the local DNA sequence
environment. Hum. Genet. 86: 425-441, 1991.
7. Lee, G. R.; Nacht, S.; Lukens, J. N.; Cartwright, G. E.: Iron
metabolism in copper-deficient swine. J. Clin. Invest. 47: 2058-2069,
1968.
8. Logan, J. I.; Harveyson, K. B.; Wisdom, G. B.; Hughes, A. E.; Archbold,
G. P. R.: Hereditary caeruloplasmin deficiency, dementia and diabetes
mellitus. Quart. J. Med. 87: 663-670, 1994.
9. Miyajima, H.; Nishimura, Y.; Mizoguchi, K.; Sakamoto, M.; Shimizu,
T.; Honda, N.: Familial apoceruloplasmin deficiency associated with
blepharospasm and retinal degeneration. Neurology 37: 761-767, 1987.
10. Miyajima, H.; Takahashi, Y.; Kamata, T.; Shimizu, H.; Sakai, N.;
Gitlin, J. D.: Use of desferrioxamine in the treatment of aceruloplasminemia. Ann.
Neurol. 41: 404-407, 1997.
11. Morita, H.; Ikeda, S.; Yamamoto, K.; Morita, S.; Yoshida, K.;
Nomoto, S.; Kato, M.; Yanagisawa, N.: Hereditary ceruloplasmin deficiency
with hemosiderosis: a clinicopathological study of a Japanese family. Ann.
Neurol. 37: 646-656, 1995.
12. Morita, H.; Inoue, A.; Yanagisawa, N.: A case with ceruloplasmin
deficiency which showed dementia, ataxia and iron deposition in the
brain. Rinsho Shinkeigaku 32: 483-487, 1992.
13. Okamoto, N.; Wada, S.; Oga, T.; Kawabata, Y.; Baba, Y.; Habu,
D.; Takeda, Z.; Wada, Y.: Hereditary ceruloplasmin deficiency with
hemosiderosis. Hum. Genet. 97: 755-758, 1996.
14. Osaki, S.; Johnson, D. A.; Frieden, E.: The possible significance
of the ferrous oxidase activity of ceruloplasmin in normal human serum. J.
Biol. Chem. 241: 2746-2751, 1966.
15. Roy, C. N.; Andrews, N. C.: Recent advances in disorders of iron
metabolism: mutations, mechanisms and modifiers. Hum. Molec. Genet. 10:
2181-2186, 2001.
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*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Blepharospasm;
Retinal degeneration
NEUROLOGIC:
[Central nervous system];
Ataxia;
Chorea;
Torticollis;
Extrapyramidal symptoms;
Cogwheel rigidity;
Progressive dementia;
Dysarthria;
Scanning speech
ENDOCRINE FEATURES:
Diabetes mellitus
HEMATOLOGY:
Mild anemia
LABORATORY ABNORMALITIES:
Iron deposition in basal ganglia, liver, pancreas, visceral organs
detectable by CT and MRI;
Decreased or absent serum ceruloplasmin;
Decreased serum iron;
Increased serum ferritin
MISCELLANEOUS:
Onset between age 30-50 years
MOLECULAR BASIS:
Caused by mutations in the ceruloplasmin gene (CP, 117700.0001).
*FIELD* CN
Cassandra L. Kniffin - revised: 6/11/2002
*FIELD* CD
John F. Jackson: 1/1/1996
*FIELD* ED
joanna: 06/13/2002
ckniffin: 6/11/2002
*FIELD* CN
Victor A. McKusick - updated: 11/24/2004
Cassandra L. Kniffin - reorganized: 7/3/2002
George E. Tiller - updated: 2/12/2002
*FIELD* CD
Victor A. McKusick: 11/9/1999
*FIELD* ED
alopez: 12/06/2004
terry: 11/24/2004
carol: 7/7/2004
carol: 7/3/2002
ckniffin: 7/3/2002
ckniffin: 6/17/2002
cwells: 2/18/2002
cwells: 2/12/2002
mgross: 11/10/1999