RBCC Red Blood Cell Collection

SERPIND1 (HCF2) [Confidence: low (only semi-automatic identification from reviews)]
Heparin cofactor 2 (Heparin cofactor II; HC-II; Protease inhibitor leuserpin-2; HLS2; Serpin D1; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P05546
ID HEP2_HUMAN Reviewed; 499 AA.
AC P05546; B2RAI1; D3DX34; Q6IBZ5;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1991, sequence version 3.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Heparin cofactor 2;
DE AltName: Full=Heparin cofactor II;
DE Short=HC-II;
DE AltName: Full=Protease inhibitor leuserpin-2;
DE Short=HLS2;
DE AltName: Full=Serpin D1;
DE Flags: Precursor;
GN Name=SERPIND1; Synonyms=HCF2;
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=2894851; DOI=10.1021/bi00402a039;
RA Blinder M.A., Marasa J.C., Reynolds C.H., Deaven L.L., Tollefsen D.M.;
RT "Heparin cofactor II: cDNA sequence, chromosome localization,
RT restriction fragment length polymorphism, and expression in
RT Escherichia coli.";
RL Biochemistry 27:752-759(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1671335; DOI=10.1021/bi00219a027;
RA Herzog R., Lutz S., Blin N., Marasa J.C., Blinder M.A.,
RA Tollefsen D.M.;
RT "Complete nucleotide sequence of the gene for human heparin cofactor
RT II and mapping to chromosomal band 22q11.";
RL Biochemistry 30:1350-1357(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 19-499.
RX PubMed=3003690; DOI=10.1093/nar/14.2.1073;
RA Ragg H.;
RT "A new member of the plasma protease inhibitor gene family.";
RL Nucleic Acids Res. 14:1073-1088(1986).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 333-499.
RX PubMed=3755044; DOI=10.1016/0006-291X(86)91228-3;
RA Inhorn R.C., Tollefsen D.M.;
RT "Isolation and characterization of a partial cDNA clone for heparin
RT cofactor II1.";
RL Biochem. Biophys. Res. Commun. 137:431-436(1986).
RN [8]
RP PROTEIN SEQUENCE OF 20-52 AND 464-499.
RX PubMed=3907702; DOI=10.1021/bi00345a008;
RA Griffith M.J., Noyes C.M., Tyndall J.A., Church F.C.;
RT "Structural evidence for leucine at the reactive site of heparin
RT cofactor II.";
RL Biochemistry 24:6777-6782(1985).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-119.
RX PubMed=2841345;
RA Ragg H., Preibisch G.;
RT "Structure and expression of the gene coding for the human serpin
RT hLS2.";
RL J. Biol. Chem. 263:12129-12134(1988).
RN [10]
RP PROTEIN SEQUENCE OF 58-85.
RX PubMed=1985958;
RA Church F.C., Pratt C.W., Hoffman M.;
RT "Leukocyte chemoattractant peptides from the serpin heparin cofactor
RT II.";
RL J. Biol. Chem. 266:704-709(1991).
RN [11]
RP FUNCTION OF N-TERMINAL ACIDIC DOMAIN.
RX PubMed=1939083;
RA van Deerlin V.M.D., Tollefsen D.M.;
RT "The N-terminal acidic domain of heparin cofactor II mediates the
RT inhibition of alpha-thrombin in the presence of glycosaminoglycans.";
RL J. Biol. Chem. 266:20223-20231(1991).
RN [12]
RP MUTAGENESIS OF ARG-122 AND LYS-204.
RX PubMed=2104620;
RA Blinder M.A., Tollefsen D.M.;
RT "Site-directed mutagenesis of arginine 103 and lysine 185 in the
RT proposed glycosaminoglycan-binding site of heparin cofactor II.";
RL J. Biol. Chem. 265:286-291(1990).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-49 AND ASN-188, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [15]
RP GLYCOSYLATION AT ASN-49.
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 [16]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 20-499, GLYCOSYLATION AT
RP ASN-188 AND ASN-387, AND SULFATION AT TYR-79 AND TYR-92.
RX PubMed=12169660; DOI=10.1073/pnas.162232399;
RA Baglin T.P., Carrell R.W., Church F.C., Esmon C.T., Huntington J.A.;
RT "Crystal structures of native and thrombin-complexed heparin cofactor
RT II reveal a multistep allosteric mechanism.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:11079-11084(2002).
RN [17]
RP VARIANT THPH10 HIS-208.
RX PubMed=2647747;
RA Blinder M.A., Andersson T.R., Abildgaard U., Tollefsen D.M.;
RT "Heparin cofactor IIOslo. Mutation of Arg-189 to His decreases the
RT affinity for dermatan sulfate.";
RL J. Biol. Chem. 264:5128-5133(1989).
RN [18]
RP VARIANT THPH10 HIS-208, AND VARIANTS THR-7 AND MET-442.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [19]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [20]
RP VARIANT THPH10 LEU-462, AND CHARACTERIZATION OF VARIANT THPH10
RP LEU-462.
RX PubMed=11204559;
RA Kanagawa Y., Shigekiyo T., Aihara K., Akaike M., Azuma H.,
RA Matsumoto T.;
RT "Molecular mechanism of type I congenital heparin cofactor (HC) II
RT deficiency caused by a missense mutation at reactive P2 site: HC II
RT Tokushima.";
RL Thromb. Haemost. 85:101-107(2001).
RN [21]
RP VARIANT THPH10 LYS-447.
RX PubMed=15337701; DOI=10.1161/01.CIR.0000140763.51679.D9;
RA Corral J., Aznar J., Gonzalez-Conejero R., Villa P., Minano A.,
RA Vaya A., Carrell R.W., Huntington J.A., Vicente V.;
RT "Homozygous deficiency of heparin cofactor II: relevance of P17
RT glutamate residue in serpins, relationship with conformational
RT diseases, and role in thrombosis.";
RL Circulation 110:1303-1307(2004).
CC -!- FUNCTION: Thrombin inhibitor activated by the glycosaminoglycans,
CC heparin or dermatan sulfate. In the presence of the latter, HC-II
CC becomes the predominant thrombin inhibitor in place of
CC antithrombin III (AT-III). Also inhibits chymotrypsin, but in a
CC glycosaminoglycan-independent manner.
CC -!- FUNCTION: Peptides at the N-terminal of HC-II have chemotactic
CC activity for both monocytes and neutrophils.
CC -!- TISSUE SPECIFICITY: Expressed predominantly in liver. Also present
CC in plasma.
CC -!- DOMAIN: The N-terminal acidic repeat region mediates, in part, the
CC glycosaminoglycan-accelerated thrombin inhibition.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- DISEASE: Thrombophilia due to heparin cofactor 2 deficiency
CC (THPH10) [MIM:612356]: A hemostatic disorder characterized by a
CC tendency to recurrent thrombosis. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the serpin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAG30459.1; Type=Erroneous initiation;
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DR EMBL; M12849; AAA52642.1; -; mRNA.
DR EMBL; M58600; AAA52641.1; -; Genomic_DNA.
DR EMBL; CR456573; CAG30459.1; ALT_INIT; mRNA.
DR EMBL; AK314200; BAG36878.1; -; mRNA.
DR EMBL; CH471176; EAX02941.1; -; Genomic_DNA.
DR EMBL; CH471176; EAX02942.1; -; Genomic_DNA.
DR EMBL; X03498; CAA27218.1; -; mRNA.
DR EMBL; M33660; AAA36185.1; -; Genomic_DNA.
DR PIR; A37924; A37924.
DR RefSeq; NP_000176.2; NM_000185.3.
DR RefSeq; XP_005261654.1; XM_005261597.1.
DR UniGene; Hs.474270; -.
DR PDB; 1JMJ; X-ray; 2.35 A; A/B=20-499.
DR PDB; 1JMO; X-ray; 2.20 A; A=20-499.
DR PDBsum; 1JMJ; -.
DR PDBsum; 1JMO; -.
DR ProteinModelPortal; P05546; -.
DR SMR; P05546; 73-499.
DR IntAct; P05546; 5.
DR STRING; 9606.ENSP00000215727; -.
DR DrugBank; DB00407; Ardeparin.
DR MEROPS; I04.019; -.
DR PhosphoSite; P05546; -.
DR DMDM; 123055; -.
DR PaxDb; P05546; -.
DR PRIDE; P05546; -.
DR DNASU; 3053; -.
DR Ensembl; ENST00000215727; ENSP00000215727; ENSG00000099937.
DR Ensembl; ENST00000406799; ENSP00000384050; ENSG00000099937.
DR GeneID; 3053; -.
DR KEGG; hsa:3053; -.
DR UCSC; uc002ztb.1; human.
DR CTD; 3053; -.
DR GeneCards; GC22P021139; -.
DR HGNC; HGNC:4838; SERPIND1.
DR HPA; CAB008639; -.
DR MIM; 142360; gene.
DR MIM; 612356; phenotype.
DR neXtProt; NX_P05546; -.
DR PharmGKB; PA35053; -.
DR eggNOG; COG4826; -.
DR HOGENOM; HOG000294159; -.
DR HOVERGEN; HBG101242; -.
DR InParanoid; P05546; -.
DR KO; K03912; -.
DR OMA; HIMKLTK; -.
DR OrthoDB; EOG7327PB; -.
DR PhylomeDB; P05546; -.
DR EvolutionaryTrace; P05546; -.
DR GeneWiki; Heparin_cofactor_II; -.
DR GenomeRNAi; 3053; -.
DR NextBio; 12085; -.
DR PMAP-CutDB; P05546; -.
DR PRO; PR:P05546; -.
DR Bgee; P05546; -.
DR CleanEx; HS_SERPIND1; -.
DR Genevestigator; P05546; -.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IBA:RefGenome.
DR GO; GO:0007596; P:blood coagulation; IEA:UniProtKB-KW.
DR GO; GO:0006935; P:chemotaxis; IEA:UniProtKB-KW.
DR GO; GO:0030162; P:regulation of proteolysis; IBA:RefGenome.
DR InterPro; IPR023795; Serpin_CS.
DR InterPro; IPR023796; Serpin_dom.
DR InterPro; IPR000215; Serpin_fam.
DR PANTHER; PTHR11461; PTHR11461; 1.
DR Pfam; PF00079; Serpin; 1.
DR SMART; SM00093; SERPIN; 1.
DR SUPFAM; SSF56574; SSF56574; 1.
DR PROSITE; PS00284; SERPIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Chemotaxis; Complete proteome;
KW Direct protein sequencing; Disease mutation; Glycoprotein; Hemostasis;
KW Heparin-binding; Phosphoprotein; Polymorphism; Protease inhibitor;
KW Reference proteome; Repeat; Serine protease inhibitor; Signal;
KW Sulfation; Thrombophilia.
FT SIGNAL 1 19
FT CHAIN 20 499 Heparin cofactor 2.
FT /FTId=PRO_0000032494.
FT REPEAT 73 83 1.
FT REPEAT 87 97 2.
FT REGION 68 79 Chemotactic activity.
FT REGION 73 97 2 X 11 AA approximate repeats, Asp/Glu-
FT rich (acidic) (hirudin-like).
FT REGION 192 212 Glycosaminoglycan-binding site.
FT SITE 463 464 Reactive bond (By similarity).
FT MOD_RES 79 79 Sulfotyrosine.
FT MOD_RES 92 92 Sulfotyrosine.
FT CARBOHYD 49 49 N-linked (GlcNAc...) (complex).
FT CARBOHYD 188 188 N-linked (GlcNAc...).
FT CARBOHYD 387 387 N-linked (GlcNAc...).
FT VARIANT 7 7 A -> T (in dbSNP:rs5905).
FT /FTId=VAR_011746.
FT VARIANT 60 60 H -> P (in dbSNP:rs165867).
FT /FTId=VAR_011747.
FT VARIANT 87 87 S -> N (in dbSNP:rs34324685).
FT /FTId=VAR_051953.
FT VARIANT 129 129 L -> V (in dbSNP:rs11542069).
FT /FTId=VAR_051954.
FT VARIANT 208 208 R -> H (in THPH10; Oslo; decreased
FT affinity for dermatan sulfate;
FT dbSNP:rs5907).
FT /FTId=VAR_007112.
FT VARIANT 237 237 K -> R (in dbSNP:rs1042435).
FT /FTId=VAR_011748.
FT VARIANT 442 442 T -> M (in dbSNP:rs5904).
FT /FTId=VAR_011749.
FT VARIANT 447 447 E -> K (in THPH10).
FT /FTId=VAR_054977.
FT VARIANT 462 462 P -> L (in THPH10; Tokushima; impaired
FT secretion of the mutant molecules).
FT /FTId=VAR_054978.
FT MUTAGEN 122 122 R->L: Normal thrombin inhibition and
FT glycosaminoglycan affinity.
FT MUTAGEN 122 122 R->Q: Greatly reduced thrombin
FT inhibition. Normal glycosaminoglycan
FT affinity.
FT MUTAGEN 122 122 R->W: Greatly reduced thrombin
FT inhibition. Normal glycosaminoglycan
FT affinity.
FT MUTAGEN 204 204 K->M: Reduced heparin- and no dermatan
FT sulfate-activated inhibition.
FT MUTAGEN 204 204 K->N: Reduced heparin- and no dermatan
FT sulfate-activated inhibition.
FT MUTAGEN 204 204 K->T: Reduced heparin- and no dermatan
FT sulfate-activated inhibition.
FT CONFLICT 49 49 Missing (in Ref. 8; AA sequence).
FT CONFLICT 483 483 R -> P (in Ref. 8; AA sequence).
FT CONFLICT 486 486 C -> T (in Ref. 8; AA sequence).
FT CONFLICT 499 499 S -> Q (in Ref. 8; AA sequence).
FT HELIX 82 87
FT HELIX 90 92
FT HELIX 122 142
FT STRAND 151 153
FT HELIX 155 165
FT HELIX 166 168
FT HELIX 171 180
FT HELIX 183 189
FT HELIX 195 210
FT STRAND 214 227
FT HELIX 234 244
FT STRAND 248 251
FT HELIX 256 269
FT TURN 270 272
FT TURN 277 280
FT STRAND 287 296
FT STRAND 299 301
FT HELIX 305 307
FT STRAND 309 314
FT STRAND 316 318
FT STRAND 320 337
FT TURN 338 341
FT STRAND 342 349
FT TURN 350 352
FT STRAND 353 362
FT HELIX 363 365
FT HELIX 366 372
FT HELIX 375 384
FT STRAND 386 395
FT STRAND 397 400
FT HELIX 406 412
FT HELIX 416 418
FT TURN 425 427
FT STRAND 434 445
FT STRAND 447 451
FT STRAND 459 462
FT STRAND 468 470
FT STRAND 475 481
FT TURN 482 485
FT STRAND 486 494
SQ SEQUENCE 499 AA; 57071 MW; 3B0E353FE1F6DF05 CRC64;
MKHSLNALLI FLIITSAWGG SKGPLDQLEK GGETAQSADP QWEQLNNKNL SMPLLPADFH
KENTVTNDWI PEGEEDDDYL DLEKIFSEDD DYIDIVDSLS VSPTDSDVSA GNILQLFHGK
SRIQRLNILN AKFAFNLYRV LKDQVNTFDN IFIAPVGIST AMGMISLGLK GETHEQVHSI
LHFKDFVNAS SKYEITTIHN LFRKLTHRLF RRNFGYTLRS VNDLYIQKQF PILLDFKTKV
REYYFAEAQI ADFSDPAFIS KTNNHIMKLT KGLIKDALEN IDPATQMMIL NCIYFKGSWV
NKFPVEMTHN HNFRLNEREV VKVSMMQTKG NFLAANDQEL DCDILQLEYV GGISMLIVVP
HKMSGMKTLE AQLTPRVVER WQKSMTNRTR EVLLPKFKLE KNYNLVESLK LMGIRMLFDK
NGNMAGISDQ RIAIDLFKHQ GTITVNEEGT QATTVTTVGF MPLSTQVRFT VDRPFLFLIY
EHRTSCLLFM GRVANPSRS
//

MIM 142360
*RECORD*
*FIELD* NO
142360
*FIELD* TI
*142360 HEPARIN COFACTOR II; HCF2
;;LEUSERPIN 2; LS2;;
SERPIND1
*FIELD* TX

DESCRIPTION
read more
Heparin cofactor II is a serine protease inhibitor in plasma that
rapidly inhibits thrombin in the presence of dermatan sulfate or heparin
(Kondo et al., 1996).

CLONING

From a human liver cDNA library, Ragg (1986) isolated a novel member of
the protease inhibitor family. The inhibitor, named leuserpin-2, has 48
amino acids and contains a leucine residue at its putative reactive
center. It shows about 25% to 28% homology to 3 human members of the
plasma protease inhibitor family: antithrombin III (AT3; 107300),
alpha-1-antitrypsin (PI; 107400), and alpha-1-antichymotrypsin (AACT;
107280). Comparison with published partial amino acid sequences
suggested that LS2 is closely related or identical to heparin cofactor
II.

Blinder et al. (1988) isolated an apparently full-length cDNA for HCF II
from a human liver cDNA library.

GENE STRUCTURE

Herzog et al. (1991) determined that the HCF2 gene contains 5 exons.

MAPPING

By blot hybridization of a probe to DNA isolated from sorted human
chromosomes, Blinder et al. (1988) mapped the HCF2 gene to chromosome
22. By use of rodent-human somatic cell hybrids carrying only parts of
human chromosome 22 and by study of a chronic myelogenous leukemia cell
line, Herzog et al. (1991) localized the HCF2 gene to chromosome 22q11,
proximal to the breakpoint cluster region (151410).

GENE FUNCTION

Aihara et al. (2004) measured plasma HCF II activity, HDL cholesterol
level, and carotid artery plaque thickness in 306 Japanese individuals
over 40 (mean age, 68.9 years) and observed that HCF II activity
decreased with age. Multiple regression analysis revealed that plasma
HCF II activity and HDL cholesterol level were independently associated
with decreased plaque thickness and that the antiatherogenic
contribution of HCF II activity was stronger than that of HDL
cholesterol.

MOLECULAR GENETICS

Using crossed immunolectrophoresis, Andersson et al. (1987) were the
first to demonstrate molecular heterogeneity of the HCF II molecule, the
so-called 'Oslo variant,' in affected members of 2 Norwegian families
with HCF II deficiency (612356). Their findings were consistent with an
autosomal dominant pattern of inheritance; affected individuals had half
the normal amount of normal HCF II and were presumed heterozygotes.

Using PCR, Blinder et al. (1989) amplified DNA fragments encoding the
N-terminal 220 amino acids of HCF II from a patient with the Oslo
variant. They identified a point mutation resulting in an arg189-to-his
(R189H; 142360.0001) substitution in 1 allele. Blinder et al. (1989)
created the same mutation in the cDNA of native HCF II by
oligonucleotide-directed mutagenesis and expressed it in E. coli. The
recombinant cofactor reacted with thrombin in the presence of heparin,
but not dermatan sulfate, confirming that the R189H mutation is
responsible for the functional abnormality in HCF II Oslo.

ANIMAL MODEL

Vicente et al. (2007) reported that Hcf2 -/- mice are born at the
expected mendelian frequency and that they appear normal and are
fertile. However, Vicente et al. (2007) found that Hcf2 -/- mice were
more sensitive than wildtype mice to neointima formation following
mechanical dilation of the common carotid artery. Dermatan sulfate
administered intravenously within 48 hours of injury inhibited neointima
formation in wildtype mice, but it had no effect in Hcf2 -/- mice. In
addition, Hcf2 deletion increased the size of diet-induced
atherosclerotic lesions that developed in the aortic arch of ApoE
(107741) -/- mice. Vicente et al. (2007) concluded that HCF2 deficiency
promotes atherogenesis and neointima formation and that treatment with
dermatan sulfate reduces neointima formation in an HCF2-dependent
manner.

*FIELD* AV
.0001
HEPARIN COFACTOR II DEFICIENCY
HCF2, ARG189HIS

By means of the polymerase chain reaction (PCR), Blinder et al. (1989)
amplified DNA fragments encoding the N-terminal 220 amino acid residues
of heparin cofactor II from a patient with HCF II deficiency (612356)
and the Oslo HCF II variant. A point mutation (G-to-A) resulting in
substitution of his for arg189 was found in 1 allele. The same mutation
was created in the cDNA of native heparin cofactor II by
oligonucleotide-directed mutagenesis and was expressed in E. coli. The
recombinant cofactor reacted with thrombin in the presence of heparin,
but not dermatan sulfate, confirming that this mutation is responsible
for the functional abnormality in HCF II Oslo.

.0002
HEPARIN COFACTOR II DEFICIENCY
HCF2, 1-BP INS, T, EXON 2

Kondo et al. (1996) studied the defect in a Japanese patient with type I
HCF II deficiency (612356) who suffered from angina pectoris and
coronary artery disease. PCR-based sequence analysis showed that the
patient's HCF2 gene had a 1-bp insertion, a T after the GAT codon for
asp88 in exon 2, resulting in a frameshift. The abnormal HCF II Awaji
protein was predicted to have an altered amino acid sequence from
position 89 and to terminate at residue 107, thus being composed of the
NH2-terminal one-fifth of normal HCF II and therefore dysfunctional for
thrombin inhibition. The sister appeared to have the same mutation.
Cellular studies suggested that the abnormal HCF II Awaji protein is
secreted normally but rapidly degraded in the circulating blood.

.0003
THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY
HCF2, 2-BP DEL, 12896TT

In 2 unrelated patients from the Rimini province in northern Italy with
type I HCF II deficiency and thrombophilia (THPH10; 612356), Bernardi et
al. (1996) identified heterozygosity for a 2-bp deletion (12896delTT) in
exon 5 of the HCF2 gene, resulting in a frameshift at leu457 that
elongates the protein by 4 amino acids. The variant was designated HCF
II Rimini. In both probands, another hereditary thrombophilic alteration
was diagnosed: the factor V Leiden mutation (R506Q; 612309.0001) was
detected in 1 and type I protein C deficiency (176860) in the other. The
tracing of the single defects in several unaffected members of each
family indicated that the mutations clinically manifested only in the
doubly heterozygous condition; the asymptomatic son of the proband with
the HCF2 deletion and the factor V Leiden mutation was the only other
double heterozygote detected.

.0004
THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY
HCF2, PRO443LEU

In a 66-year-old Japanese woman with type I congenital HCF II deficiency
and widespread atherosclerotic lesions (612356), Kanagawa et al. (2001)
identified a heterozygous 12854C-T transition in exon 5 of the HCF2
gene, resulting in a pro443-to-leu (P443L) substitution. The variant,
which was designated HCF II Tokushima, was found in 6 other family
members with HCF II deficiency, but not in healthy unaffected
individuals. Transfected COS-1 cells exhibited perinuclear
immunohistochemical staining, indicating impaired secretion of the
mutant HCF II molecules due to intracellular degradation.

*FIELD* RF
1. Aihara, K.; Azuma, H.; Takamori, N.; Kanagawa, Y.; Akaike, M.;
Fujimura, M.; Yoshida, T.; Hashizume, S.; Kato, M.; Yamaguchi, H.;
Kato, S.; Ikeda, Y.; Arase, T.; Kondo, A.; Matsumoto, T.: Heparin
cofactor II is a novel protective factor against carotid atherosclerosis
in elderly individuals. Circulation 109: 2761-2765, 2004.

2. Andersson, T. R.; Larsen, M. L.; Abildgaard, U.: Low heparin cofactor
II associated with abnormal crossed immunoelectrophoresis pattern
in two Norwegian families. Thromb. Res. 47: 243-248, 1987.

3. Bernardi, F.; Legnani, C.; Micheletti, F.; Lunghi, B.; Ferraresi,
P.; Palareti, G.; Biagi, R.; Marchetti, G.: A heparin cofactor II
mutation (HCII Rimini) combined with factor V Leiden or type I protein
C deficiency in two unrelated thrombophilic subjects. Thromb. Haemost. 76:
505-509, 1996.

4. Blinder, M. A.; Andersson, T. R.; Abildgaard, U.; Tollefsen, D.
M.: Heparin cofactor II(Oslo): mutation of arg-189-to-his decreases
the affinity for dermatan sulfate. J. Biol. Chem. 264: 5128-5133,
1989.

5. Blinder, M. A.; Marasa, J. C.; Reynolds, C. H.; Deaven, L. L.;
Tollefsen, D. M.: Heparin cofactor II: cDNA sequence, chromosome
localization, restriction fragment length polymorphism, and expression
in Escherichia coli. Biochemistry 27: 752-759, 1988.

6. Herzog, R.; Lutz, S.; Blin, N.; Marasa, J. C.; Blinder, M. A.;
Tollefsen, D. M.: Complete nucleotide sequence of the gene for human
heparin cofactor II and mapping to chromosomal band 22q11. Biochemistry 30:
1350-1357, 1991.

7. Kanagawa, Y.; Shigekiyo, T.; Aihara, K.; Akaike, M.; Azuma, H.;
Matsumoto, T.: Molecular mechanism of type I congenital heparin cofactor
(HC) II deficiency caused by a missense mutation at reactive P2 site:
HC II Tokushima. Thromb. Haemost. 85: 101-107, 2001.

8. Kondo, S.; Tokunaga, F.; Kario, K.; Matsuo, T.; Koide, T.: Molecular
and cellular basis for type I heparin cofactor II deficiency (heparin
cofactor II Awaji). Blood 87: 1006-1012, 1996.

9. Ragg, H.: A new member of the plasma protease inhibitor gene family. Nucleic
Acids Res. 14: 1073-1088, 1986.

10. Vicente, C. P.; He, L.; Tollefsen, D. M.: Accelerated atherogenesis
and neointima formation in heparin cofactor II-deficient mice. Blood 110:
4261-4267, 2007.

*FIELD* CN
Patricia A. Hartz - updated: 10/23/2008
Marla J. F. O'Neill - updated: 1/31/2006
Marla J. F. O'Neill - updated: 5/16/2005
Victor A. McKusick - updated: 12/13/1999
Alan F. Scott - edited: 12/27/1996

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

*FIELD* ED
carol: 03/01/2012
carol: 2/28/2012
carol: 11/19/2009
mgross: 10/23/2008
carol: 10/8/2008
wwang: 2/3/2006
terry: 1/31/2006
wwang: 7/11/2005
wwang: 7/7/2005
terry: 5/16/2005
terry: 6/2/2004
joanna: 3/17/2004
terry: 3/13/2002
mcapotos: 12/17/1999
mcapotos: 12/16/1999
terry: 12/13/1999
mark: 12/27/1996
mark: 3/21/1996
terry: 3/13/1996
mimadm: 9/24/1994
carol: 10/9/1992
supermim: 3/16/1992
carol: 8/7/1991
supermim: 3/20/1990
ddp: 10/27/1989

MIM 612356
*RECORD*
*FIELD* NO
612356
*FIELD* TI
#612356 HEPARIN COFACTOR II DEFICIENCY
;;THROMBOPHILIA DUE TO HEPARIN COFACTOR II DEFICIENCY; THPH10;;
read moreHCF II DEFICIENCY;;
HCF2 DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because heparin cofactor II
deficiency, which is a risk factor for thrombophilia, results from
heterozygous mutation in the HCF2 gene (142360).

DESCRIPTION

Heparin cofactor II (HCF2; 142360) rapidly inhibits thrombin in plasma
in the presence of dermatan sulfate or heparin. Congenital HCF2
deficiency is associated with thromboembolism and is classified into
type I (quantitative) or type II (qualitative) deficiency (Kondo et al.,
1996).

CLINICAL FEATURES

In a 42-year-old woman with intracranial thrombosis, Tran et al. (1985)
found that HCF II was about 50% of normal. The same was true of the
mother and sister, both of whom had had thrombotic complications.

Sie et al. (1985) studied the family of a 36-year-old man with recurrent
deep vein thrombosis and HCF II deficiency. The mother, half brother,
and daughter likewise had low levels and some had an unusual frequency
of thrombosis.

Matsuo et al. (1992) reported a Japanese family with type I hereditary
HCF II deficiency. The propositus, a 61-year-old man, had coronary
artery disease requiring percutaneous transluminal coronary angioplasty
4 times in 1 year because of restenosis. Heparin was apparently
ineffective in preventing restenosis by thrombin generation. After the
fourth angioplasty, a specific thrombin inhibitor was used with success.

Villa et al. (1999) reported a 29-year-old woman who at the age of 22
suffered a first episode of deep venous thrombosis in the lower right
leg complicated by a pulmonary embolism 1 week after starting oral
contraceptives. She was found to have type I deficiency of antithrombin
III (613118) in heterozygous state and to be homozygous for HCF II
deficiency. Her sister was also homozygous for HCF II deficiency but had
normal levels of antithrombin III and had not suffered thrombotic events
despite thrombotic risk factors such as the use of oral contraceptives,
pregnancy, and surgery. Several other members of the family were
heterozygous for HCF II deficiency but had not had thrombotic episodes
despite circumstantial risk factors. This suggested that the thrombotic
risk in an individual with HCF II deficiency and normal AT levels is
low.

INHERITANCE

Using crossed immunoelectrophoresis, Andersson et al. (1987) were the
first to demonstrate molecular heterogeneity of the HCF II molecule, the
so-called 'Oslo variant,' in affected members of 2 Norwegian families
with HCF II deficiency. Their findings were consistent with an autosomal
dominant pattern of inheritance; affected individuals had half the
normal amount of normal HCF II and were presumed heterozygotes.

MAPPING

HCF II deficiency results from mutation in the HCF2 gene, which maps to
chromosome 22q11 (Herzog et al., 1991).

MOLECULAR GENETICS

Using PCR, Blinder et al. (1989) amplified DNA fragments encoding the
N-terminal 220 amino acids of HCF II from a patient with the Oslo
variant. They identified a point mutation resulting in an arg189-to-his
(R189H; 142360.0001) substitution in 1 allele. Blinder et al. (1989)
created the same mutation in the cDNA of native HCF II by
oligonucleotide-directed mutagenesis and expressed it in E. coli. The
recombinant cofactor reacted with thrombin in the presence of heparin,
but not dermatan sulfate, confirming that the R189H mutation is
responsible for the functional abnormality in HCF II Oslo.

PATHOGENESIS

In COS-1 cells transfected with the Tokushima variant of HCF II (P443L;
142360.0004), Kanagawa et al. (2001) observed immunohistochemical
staining primarily in the perinuclear area. They concluded that impaired
secretion of mutant HCF II molecules due to intracellular degradation is
the molecular pathogenesis of type I congenital HCF II deficiency caused
by this mutation.

*FIELD* RF
1. Andersson, T. R.; Larsen, M. L.; Abildgaard, U.: Low heparin cofactor
II associated with abnormal crossed immunoelectrophoresis pattern
in two Norwegian families. Thromb. Res. 47: 243-248, 1987.

2. Blinder, M. A.; Andersson, T. R.; Abildgaard, U.; Tollefsen, D.
M.: Heparin cofactor II(Oslo): mutation of arg-189-to-his decreases
the affinity for dermatan sulfate. J. Biol. Chem. 264: 5128-5133,
1989.

3. Herzog, R.; Lutz, S.; Blin, N.; Marasa, J. C.; Blinder, M. A.;
Tollefsen, D. M.: Complete nucleotide sequence of the gene for human
heparin cofactor II and mapping to chromosomal band 22q11. Biochemistry 30:
1350-1357, 1991.

4. Kanagawa, Y.; Shigekiyo, T.; Aihara, K.; Akaike, M.; Azuma, H.;
Matsumoto, T.: Molecular mechanism of type I congenital heparin cofactor
(HC) II deficiency caused by a missense mutation at reactive P2 site:
HC II Tokushima. Thromb. Haemost. 85: 101-107, 2001.

5. Kondo, S.; Tokunaga, F.; Kario, K.; Matsuo, T.; Koide, T.: Molecular
and cellular basis for type I heparin cofactor II deficiency (heparin
cofactor II Awaji). Blood 87: 1006-1012, 1996.

6. Matsuo, T.; Kario, K.; Sakamoto, S.; Yamada, T.; Miki, T.; Hirase,
T.; Kobayashi, H.: Hereditary heparin cofactor II deficiency and
coronary artery disease. Thromb. Res. 65: 495-505, 1992.

7. Sie, P.; Dupouy, D.; Pichon, J.; Boneu, B.: Constitutional heparin
co-factor II deficiency associated with recurrent thrombosis. Lancet 326:
414-416, 1985. Note: Originally Volume II.

8. Tran, T. H.; Marbet, G. A.; Duckert, F.: Association of hereditary
heparin co-factor II deficiency with thrombosis. Lancet 326: 413-414,
1985. Note: Originally Volume II.

9. Villa, P.; Aznar, J.; Vaya, A.; Espana, F.; Ferrando, F.; Mira,
Y.; Estelles, A.: Hereditary homozygous heparin cofactor II deficiency
and the risk of developing venous thrombosis. Thromb. Haemost. 82:
1011-1014, 1999.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Vascular];
Post-angioplasty coronary artery restenosis;
Disseminated intravascular coagulation;
Intracranial thrombosis;
Recurrent deep vein thrombosis

LABORATORY ABNORMALITIES:
Heparin cofactor II deficiency

MOLECULAR BASIS:
Caused by mutation in the heparin cofactor II gene (HCF2, 142360.0001)

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

*FIELD* ED
joanna: 10/28/2008

*FIELD* CD
Matthew B. Gross: 10/23/2008

*FIELD* ED
carol: 03/01/2012
carol: 2/28/2012
ckniffin: 2/23/2012
carol: 11/19/2009
carol: 11/18/2009
terry: 4/8/2009
mgross: 10/23/2008