RBCC Red Blood Cell Collection

HP [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Haptoglobin (Zonulin; Haptoglobin alpha chain; Haptoglobin beta chain; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P00738
ID HPT_HUMAN Reviewed; 406 AA.
AC P00738; B0AZL5; P00737; Q0VAC4; Q0VAC5; Q2PP15; Q3B7J0; Q6LBY9;
read moreAC Q9UC67;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Haptoglobin;
DE AltName: Full=Zonulin;
DE Contains:
DE RecName: Full=Haptoglobin alpha chain;
DE Contains:
DE RecName: Full=Haptoglobin beta chain;
DE Flags: Precursor;
GN Name=HP;
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=6688992;
RA van der Straten A., Herzog A., Jacobs P., Cabezon T., Bollen A.;
RT "Molecular cloning of human haptoglobin cDNA: evidence for a single
RT mRNA coding for alpha 2 and beta chains.";
RL EMBO J. 2:1003-1007(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6310599; DOI=10.1073/pnas.80.19.5875;
RA Yang F., Brune J.L., Baldwin W.D., Barnett D.R., Bowman B.H.;
RT "Identification and characterization of human haptoglobin cDNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:5875-5879(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS 29-ALA--GLU-87 DEL; ASP-129
RP AND LYS-130.
RC TISSUE=Liver;
RX PubMed=6546723; DOI=10.1016/0014-5793(84)80215-X;
RA van der Straten A., Herzog A., Cabezon T., Bollen A.;
RT "Characterization of human haptoglobin cDNAs coding for alpha 2FS beta
RT and alpha 1S beta variants.";
RL FEBS Lett. 168:103-107(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT 29-ALA--GLU-87 DEL.
RX PubMed=6330675; DOI=10.1093/nar/12.11.4531;
RA Brune J.L., Yang F., Barnett D.R., Bowman B.H.;
RT "Evolution of haptoglobin: comparison of complementary DNA encoding Hp
RT alpha 1S and Hp alpha 2FS.";
RL Nucleic Acids Res. 12:4531-4538(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASP-129.
RX PubMed=4018023;
RA Bensi G., Raugei G., Klefenz H., Cortese R.;
RT "Structure and expression of the human haptoglobin locus.";
RL EMBO J. 4:119-126(1985).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2987228;
RA Maeda N.;
RT "Nucleotide sequence of the haptoglobin and haptoglobin-related gene
RT pair. The haptoglobin-related gene contains a retrovirus-like
RT element.";
RL J. Biol. Chem. 260:6698-6709(1985).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1478675; DOI=10.1016/S0888-7543(05)80116-8;
RA Erickson L.M., Kim H.S., Maeda N.;
RT "Junctions between genes in the haptoglobin gene cluster of
RT primates.";
RL Genomics 14:948-958(1992).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
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 [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ALLELES HP*1F AND HP*1S).
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-19.
RX PubMed=3519135;
RA van der Straten A., Falque J.-C., Loriau R., Bollen A., Cabezon T.;
RT "Expression of cloned human haptoglobin and alpha 1-antitrypsin
RT complementary DNAs in Saccharomyces cerevisiae.";
RL DNA 5:129-136(1986).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-406.
RX PubMed=6310515; DOI=10.1093/nar/11.17.5811;
RA Raugei G., Bensi G., Colantuoni V., Romano V., Santoro C.,
RA Costanzo F., Cortese R.;
RT "Sequence of human haptoglobin cDNA: evidence that the alpha and beta
RT subunits are coded by the same mRNA.";
RL Nucleic Acids Res. 11:5811-5819(1983).
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] OF 3-406.
RX PubMed=10493829; DOI=10.1006/geno.1999.5927;
RA Loftus B.J., Kim U.-J., Sneddon V.P., Kalush F., Brandon R.,
RA Fuhrmann J., Mason T., Crosby M.L., Barnstead M., Cronin L.,
RA Mays A.D., Cao Y., Xu R.X., Kang H.-L., Mitchell S., Eichler E.E.,
RA Harris P.C., Venter J.C., Adams M.D.;
RT "Genome duplications and other features in 12 Mb of DNA sequence from
RT human chromosome 16p and 16q.";
RL Genomics 60:295-308(1999).
RN [15]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 3-375.
RX PubMed=6325933; DOI=10.1038/309131a0;
RA Maeda N., Yang F., Barnett D.R., Bowman B.H., Smithies O.;
RT "Duplication within the haptoglobin Hp2 gene.";
RL Nature 309:131-135(1984).
RN [16]
RP PROTEIN SEQUENCE OF 19-28; 88-160 AND 162-406, AND DISULFIDE BONDS.
RX PubMed=6997877; DOI=10.1073/pnas.77.6.3388;
RA Kurosky A., Barnett D.R., Lee T.-H., Touchstone B., Hay R.E.,
RA Arnott M.S., Bowman B.H., Fitch W.M.;
RT "Covalent structure of human haptoglobin: a serine protease homolog.";
RL Proc. Natl. Acad. Sci. U.S.A. 77:3388-3392(1980).
RN [17]
RP PROTEIN SEQUENCE OF 162-176.
RC TISSUE=Eye;
RX PubMed=7637327;
RA Kliffen M., de Jong P.T.V.M., Luider T.M.;
RT "Protein analysis of human maculae in relation to age-related
RT maculopathy.";
RL Lab. Invest. 73:267-272(1995).
RN [18]
RP DISULFIDE BONDS.
RX PubMed=4573324;
RA Malchy B., Dixon G.H.;
RT "Studies on the interchain disulfides of human haptoglobins.";
RL Can. J. Biochem. 51:249-264(1973).
RN [19]
RP GLYCOSYLATION AT ASN-207 AND ASN-241.
RC TISSUE=Plasma, and Serum;
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-184; ASN-207; ASN-211 AND
RP ASN-241, 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 [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-184; ASN-207; ASN-211 AND
RP ASN-241, 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 [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-207 AND ASN-211, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [23]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-184; ASN-207; ASN-211 AND
RP ASN-241, 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 [24]
RP GLYCOSYLATION AT ASN-184 AND ASN-241.
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 [25]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-241, STRUCTURE OF
RP CARBOHYDRATE, 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 [26]
RP IDENTIFICATION AS ZONULIN.
RX PubMed=19805376; DOI=10.1073/pnas.0906773106;
RA Tripathi A., Lammers K.M., Goldblum S., Shea-Donohue T.,
RA Netzel-Arnett S., Buzza M.S., Antalis T.M., Vogel S.N., Zhao A.,
RA Yang S., Arrietta M.C., Meddings J.B., Fasano A.;
RT "Identification of human zonulin, a physiological modulator of tight
RT junctions, as prehaptoglobin-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:16799-16804(2009).
RN [27]
RP REVIEW.
RX PubMed=19659435; DOI=10.1089/ars.2009.2793;
RA Levy A.P., Asleh R., Blum S., Levy N.S., Miller-Lotan R.,
RA Kalet-Litman S., Anbinder Y., Lache O., Nakhoul F.M., Asaf R.,
RA Farbstein D., Pollak M., Soloveichik Y.Z., Strauss M., Alshiek J.,
RA Livshits A., Schwartz A., Awad H., Jad K., Goldenstein H.;
RT "Haptoglobin: basic and clinical aspects.";
RL Antioxid. Redox Signal. 12:293-304(2010).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [29]
RP FUNCTION OF ZONULIN.
RX PubMed=21248165; DOI=10.1152/physrev.00003.2008;
RA Fasano A.;
RT "Zonulin and its regulation of intestinal barrier function: the
RT biological door to inflammation, autoimmunity, and cancer.";
RL Physiol. Rev. 91:151-175(2011).
RN [30]
RP VARIANT AHP THR-247, AND CHARACTERIZATION OF VARIANT AHP THR-247.
RX PubMed=14999562; DOI=10.1007/s00439-004-1098-6;
RA Teye K., Quaye I.K., Koda Y., Soejima M., Pang H., Tsuneoka M.,
RA Amoah A.G., Adjei A., Kimura H.;
RT "A novel I247T missense mutation in the haptoglobin 2 beta-chain
RT decreases the expression of the protein and is associated with
RT ahaptoglobinemia.";
RL Hum. Genet. 114:499-502(2004).
CC -!- FUNCTION: As a result of hemolysis, hemoglobin is found to
CC accumulate in the kidney and is secreted in the urine. Haptoglobin
CC captures, and combines with free plasma hemoglobin to allow
CC hepatic recycling of heme iron and to prevent kidney damage.
CC Haptoglobin also acts as an Antimicrobial; Antioxidant, has
CC antibacterial activity and plays a role in modulating many aspects
CC of the acute phase response. Hemoglobin/haptoglobin complexes are
CC rapidely cleared by the macrophage CD163 scavenger receptor
CC expressed on the surface of liver Kupfer cells through an
CC endocytic lysosomal degradation pathway.
CC -!- FUNCTION: Uncleaved haptoglogin, also known as zonulin, plays a
CC role in intestinal permeability, allowing intercellular tight
CC junction disassembly, and controlling the equilibrium between
CC tolerance and immunity to non-self antigens.
CC -!- SUBUNIT: Tetramer of two alpha and two beta chains; disufide-
CC linked. The Hemoglobin/haptoglobin complex is composed of a
CC haptoglobin dimer bound to two hemoglobin alpha-beta dimers.
CC Interacts with CD163.
CC -!- INTERACTION:
CC P02647:APOA1; NbExp=3; IntAct=EBI-1220767, EBI-701692;
CC P02649:APOE; NbExp=7; IntAct=EBI-1220767, EBI-1222467;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- POLYMORPHISM: In the human populations there are two major allelic
CC forms, alpha-1 (1-1) with 83 residues and alpha-2 (2-2) with 142
CC residues. These alleles determine 3 possible genotypes, homozygous
CC (1-1 or 2-2) and heterozygous (2-1), and 3 major phenotypes
CC HP*1F/HP*1S and HP*2FS. The two main alleles of HP*1 are called
CC HP*1F (fast) and HP*1S (slow). The alleles exhibit different
CC oligomerization properties. In healthy males, but not in females,
CC the Hp 2-2 phenotype is associated with higher serum iron,
CC decreased Antimicrobial; Antioxidant capability, and less
CC efficient clearance from the circulation, than Hp 1-1 and 2-1.
CC -!- DISEASE: Anhaptoglobinemia (AHP) [MIM:614081]: A condition
CC characterized by the absence of the serum glycoprotein
CC haptoglobin. Serum levels of haptoglobin vary among normal
CC persons: levels are low in the neonatal period and in the elderly,
CC differ by population, and can be influenced by environmental
CC factors, such as infection. Secondary hypohaptoglobinemia can
CC occur as a consequence of hemolysis, during which haptoglobin
CC binds to free hemoglobin. Congenital haptoglobin deficiency is a
CC risk factor for anaphylactic non-hemolytic transfusion reactions.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- SIMILARITY: Contains 2 Sushi (CCP/SCR) domains.
CC -!- CAUTION: Although homologous to serine proteases, it has lost all
CC essential catalytic residues and has no enzymatic activity.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HP";
CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and
CC polymorphism database;
CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename;=HP";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Haptoglobin entry;
CC URL="http://en.wikipedia.org/wiki/Haptoglobin";
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DR EMBL; K00422; AAA52687.1; -; mRNA.
DR EMBL; K01763; AAA52684.1; -; mRNA.
DR EMBL; L29394; AAA52685.1; -; mRNA.
DR EMBL; X00637; CAA25267.1; -; mRNA.
DR EMBL; X01793; CAA25926.1; -; Genomic_DNA.
DR EMBL; X01786; CAA25926.1; JOINED; Genomic_DNA.
DR EMBL; X02206; CAA25926.1; JOINED; Genomic_DNA.
DR EMBL; X01789; CAA25926.1; JOINED; Genomic_DNA.
DR EMBL; X01791; CAA25926.1; JOINED; Genomic_DNA.
DR EMBL; M10935; AAA88080.1; -; Genomic_DNA.
DR EMBL; M69197; AAA88078.1; -; Genomic_DNA.
DR EMBL; AK314700; BAF98793.1; -; mRNA.
DR EMBL; DQ314870; ABC40729.1; -; Genomic_DNA.
DR EMBL; AC004682; AAC27432.1; -; Genomic_DNA.
DR EMBL; AC009087; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC107587; AAI07588.1; -; mRNA.
DR EMBL; BC121124; AAI21125.1; -; mRNA.
DR EMBL; BC121125; AAI21126.1; -; mRNA.
DR EMBL; M13192; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X00606; CAA25248.1; -; Genomic_DNA.
DR PIR; A92532; HPHU2.
DR PIR; A93521; HPHU1.
DR RefSeq; NP_001119574.1; NM_001126102.1.
DR RefSeq; NP_005134.1; NM_005143.3.
DR UniGene; Hs.513711; -.
DR UniGene; Hs.702099; -.
DR ProteinModelPortal; P00738; -.
DR SMR; P00738; 33-405.
DR IntAct; P00738; 16.
DR STRING; 9606.ENSP00000348170; -.
DR MEROPS; S01.972; -.
DR PhosphoSite; P00738; -.
DR DMDM; 123508; -.
DR DOSAC-COBS-2DPAGE; P00738; -.
DR SWISS-2DPAGE; P00738; -.
DR PaxDb; P00738; -.
DR PRIDE; P00738; -.
DR DNASU; 3240; -.
DR Ensembl; ENST00000355906; ENSP00000348170; ENSG00000257017.
DR Ensembl; ENST00000398131; ENSP00000381199; ENSG00000257017.
DR Ensembl; ENST00000565574; ENSP00000454966; ENSG00000257017.
DR Ensembl; ENST00000570083; ENSP00000457629; ENSG00000257017.
DR GeneID; 3240; -.
DR KEGG; hsa:3240; -.
DR UCSC; uc002fbr.4; human.
DR CTD; 3240; -.
DR GeneCards; GC16P072089; -.
DR HGNC; HGNC:5141; HP.
DR HPA; CAB003787; -.
DR HPA; HPA047750; -.
DR MIM; 140100; gene.
DR MIM; 614081; phenotype.
DR neXtProt; NX_P00738; -.
DR PharmGKB; PA29415; -.
DR eggNOG; NOG246387; -.
DR HOVERGEN; HBG005989; -.
DR InParanoid; P00738; -.
DR KO; K16142; -.
DR OMA; DDTWYAA; -.
DR OrthoDB; EOG722J8R; -.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR GeneWiki; Haptoglobin; -.
DR GenomeRNAi; 3240; -.
DR NextBio; 12895; -.
DR PRO; PR:P00738; -.
DR ArrayExpress; P00738; -.
DR Bgee; P00738; -.
DR CleanEx; HS_HP; -.
DR Genevestigator; P00738; -.
DR GO; GO:0071682; C:endocytic vesicle lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0031838; C:haptoglobin-hemoglobin complex; IDA:BHF-UCL.
DR GO; GO:0016209; F:antioxidant activity; IEA:UniProtKB-KW.
DR GO; GO:0003824; F:catalytic activity; IEA:InterPro.
DR GO; GO:0030492; F:hemoglobin binding; IDA:BHF-UCL.
DR GO; GO:0006953; P:acute-phase response; IEA:UniProtKB-KW.
DR GO; GO:0006879; P:cellular iron ion homeostasis; NAS:UniProtKB.
DR GO; GO:0006952; P:defense response; TAS:ProtInc.
DR GO; GO:0042742; P:defense response to bacterium; IEA:UniProtKB-KW.
DR GO; GO:0008152; P:metabolic process; IEA:GOC.
DR GO; GO:2000296; P:negative regulation of hydrogen peroxide catabolic process; IDA:BHF-UCL.
DR GO; GO:0051354; P:negative regulation of oxidoreductase activity; IDA:BHF-UCL.
DR GO; GO:0010942; P:positive regulation of cell death; IDA:BHF-UCL.
DR GO; GO:0042542; P:response to hydrogen peroxide; IDA:BHF-UCL.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR000436; Sushi_SCR_CCP.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00032; CCP; 2.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57535; SSF57535; 2.
DR PROSITE; PS50923; SUSHI; 2.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
PE 1: Evidence at protein level;
KW Acute phase; Antibiotic; Antimicrobial; Antioxidant;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Glycoprotein; Hemoglobin-binding; Immunity;
KW Polymorphism; Reference proteome; Repeat; Secreted;
KW Serine protease homolog; Signal; Sushi.
FT SIGNAL 1 18
FT CHAIN 19 406 Haptoglobin.
FT /FTId=PRO_0000028456.
FT CHAIN 19 160 Haptoglobin alpha chain.
FT /FTId=PRO_0000028457.
FT CHAIN 162 406 Haptoglobin beta chain.
FT /FTId=PRO_0000028458.
FT DOMAIN 31 88 Sushi 1.
FT DOMAIN 90 147 Sushi 2.
FT DOMAIN 162 404 Peptidase S1.
FT REGION 318 323 Interaction with CD163 (By similarity).
FT CARBOHYD 184 184 N-linked (GlcNAc...) (complex).
FT CARBOHYD 207 207 N-linked (GlcNAc...).
FT CARBOHYD 211 211 N-linked (GlcNAc...).
FT CARBOHYD 241 241 N-linked (GlcNAc...) (complex).
FT DISULFID 33 33 Interchain.
FT DISULFID 52 86
FT DISULFID 92 92 Interchain.
FT DISULFID 111 145
FT DISULFID 149 266 Interchain (between alpha and beta
FT chains).
FT DISULFID 309 340
FT DISULFID 351 381
FT VARIANT 29 87 Missing (in allele HP*1F and allele
FT HP*1S).
FT /FTId=VAR_017112.
FT VARIANT 129 129 N -> D (in allele HP*1F).
FT /FTId=VAR_005294.
FT VARIANT 130 130 E -> K (in allele HP*1F).
FT /FTId=VAR_017113.
FT VARIANT 247 247 I -> T (in AHP; causes reduced expression
FT of the protein; dbSNP:rs104894517).
FT /FTId=VAR_066214.
FT VARIANT 397 397 D -> H (in dbSNP:rs12646).
FT /FTId=VAR_017114.
FT CONFLICT 70 70 D -> N (in Ref. 2; AAA52687).
FT CONFLICT 130 130 E -> G (in Ref. 11; AAI07588).
SQ SEQUENCE 406 AA; 45205 MW; A98B56B2B1BE891E CRC64;
MSALGAVIAL LLWGQLFAVD SGNDVTDIAD DGCPKPPEIA HGYVEHSVRY QCKNYYKLRT
EGDGVYTLND KKQWINKAVG DKLPECEADD GCPKPPEIAH GYVEHSVRYQ CKNYYKLRTE
GDGVYTLNNE KQWINKAVGD KLPECEAVCG KPKNPANPVQ RILGGHLDAK GSFPWQAKMV
SHHNLTTGAT LINEQWLLTT AKNLFLNHSE NATAKDIAPT LTLYVGKKQL VEIEKVVLHP
NYSQVDIGLI KLKQKVSVNE RVMPICLPSK DYAEVGRVGY VSGWGRNANF KFTDHLKYVM
LPVADQDQCI RHYEGSTVPE KKTPKSPVGV QPILNEHTFC AGMSKYQEDT CYGDAGSAFA
VHDLEEDTWY ATGILSFDKS CAVAEYGVYV KVTSIQDWVQ KTIAEN
//

MIM 140100
*RECORD*
*FIELD* NO
140100
*FIELD* TI
*140100 HAPTOGLOBIN; HP
HAPTOGLOBIN, ALPHA POLYPEPTIDE, INCLUDED;;
HAPTOGLOBIN, BETA POLYPEPTIDE, INCLUDED;;
read moreBp, INCLUDED
*FIELD* TX

DESCRIPTION

Haptoglobin (HP), a plasma glycoprotein that binds free hemoglobin (see
141800), has a tetrameric structure of 2 alpha and 2 beta polypeptides
that are covalently associated by disulfide bonds. In human populations,
there are 3 common genetic haptoglobin types, Hp1 (140100.0001), Hp2
(140100.0002), and the heterozygous phenotype Hp2-1, reflecting
inherited variations in the HP polypeptides (summary by Yang et al.,
1983).

CLONING

Two loci had been thought to be involved in haptoglobin synthesis, 1 for
alpha chains and 1 for beta chains. The findings of Haugen et al. (1981)
indicated that the alpha and beta chains are encoded by a single gene.
They studied de novo biosynthesis of haptoglobin in a rabbit
reticulocyte cell-free translation system using mRNA preparations from
the livers of turpentine-treated rats. Analysis of the translation
mixtures with antiserum specific for the alpha subunit, the beta
subunit, or the native heterotetramer always resulted in recovery of a
single protein with molecular mass about 38.0 kD, which on cyanogen
bromide or trypsin digestion broke down into small peptic fragments that
reacted specifically with either anti-alpha or anti-beta antibodies. The
authors concluded that the primary translation product of haptoglobin
mRNA is a single polypeptide that contains the elements of both the
alpha and the beta subunits. Haptoglobin is synthesized as a single
precursor protein that is proteolytically processed after translation to
form the dissimilar alpha and beta subunits.

Black and Dixon (1968) reported the amino acid sequences of the alpha
chains of haptoglobin. There are similarities between the primary
structures of the alpha chain and of light chains of gamma globulins;
there are also functional homologies since both form complexes with
specific proteins. A common evolutionary origin was postulated. Amino
acid sequence data were summarized by Dayhoff (1972).

According to amino acid sequence data, haptoglobin is homologous to
serine proteases of the chymotrypsinogen family (Kurosky et al., 1980).

Yang et al. (1983) isolated recombinant plasmids containing cDNA coding
for haptoglobin by screening an adult human liver library with a mixed
oligonucleotide probe. A hitherto unknown arginine residue was deduced
between the alpha and beta sequences, which was the probable site of the
limited proteolysis that leads to the formation of the separate alpha
and beta polypeptides of mature haptoglobin. Comparison of the
haptoglobin alpha-beta junction region with the heavy-light-chain
junction of tissue-type plasminogen activator strengthens the
evolutionary homology of haptoglobin and serine proteases.

GENE FUNCTION

The alpha-2 chain is not found in any species but man. Black and Dixon
(1968) suggested that alpha-2 chains give a selective advantage because
their increased size reduces loss of the haptoglobin-hemoglobin complex
by the kidney and at the same time hemoglobin binding is unimpaired and
heme degradation enhanced.

Haptoglobin protects against the potentiation of bacterial growth by
hemoglobin (Eaton et al., 1982); herein might lie a basis for
polymorphism.

A major function of haptoglobin is to bind hemoglobin (Hb) to form a
stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue
damage. Clearance of the Hp-Hb complex can be mediated by the
monocyte/macrophage scavenger receptor CD163 (605545). Asleh et al.
(2003) assessed the scavenging function of Hp using radiolabeled Hp in
cell lines stably transfected with CD163 and in macrophages expressing
endogenous CD163. They found that the rate of clearance of Hp1-1-Hb by
CD163 was markedly greater than that of Hp2-2-Hb. Because diabetes is
associated with an increase in the nonenzymatic glycosylation of serum
proteins, including Hb, Asleh et al. (2003) also assessed the
antioxidant function of Hp with glycosylated and nonglycosylated Hb.
They identified a severe impairment in the ability of Hp to prevent
oxidation mediated by glycosylated Hb, and proposed that the specific
interaction between diabetes, cardiovascular disease, and Hp genotype is
the result of the heightened urgency of rapidly clearing glycosylated
Hb-Hp complexes from the subendothelial space before they can
oxidatively modify low density lipoprotein to atherogenic oxidized low
density lipoprotein.

Haptoglobin is an unusual secretory protein in that it is
proteolytically processed in the endoplasmic reticulum and not in the
Golgi. Wicher and Fries (2004) found that C1RL (608974) mediates this
cleavage. Coexpression of the proform of HP (proHP) and C1RL in COS-1
cells resulted in the cleavage of proHP in the endoplasmic reticulum.
C1RL showed specificity for proHP, in that it did not cleave the proform
of complement C1s, a protein similar to HP, particularly around the
cleavage site. Suppression of C1RL expression by RNA interference
reduced the cleavage of proHP by up to 45%.

MAPPING

Robson et al. (1969) presented evidence that the alpha haptoglobin locus
is on the long arm of chromosome 16. In a family with 46t(2G-;16G+) and
one with 46t(1-;16+), haptoglobin type was linked with the translocation
chromosome.

Gerner-Smidt et al. (1978) found evidence in a family with a balanced
translocation consistent with the view that the alpha-haptoglobin locus
is in the proximity of band 16q22. Povey et al. (1980) presented new
data suggesting that the male recombination fraction for 16qh (the
paracentromeric heterochromatin heteromorphism) and alpha-Hp is about
0.2.

By in situ hybridization, Simmers et al. (1985, 1986) showed that the
haptoglobin gene is distal to the fragile site that is precisely
localized at the proximal end of band 16q22.1. The fragile site with
which haptoglobin was found to be linked (Magenis et al., 1970) is
referred to as fra(16)(q22) or FRA16B.

BIOCHEMICAL FEATURES

- Crystal Structure

Andersen et al. (2012) presented the crystal structure of the dimeric
porcine haptoglobin-hemoglobin (see 141800) complex determined at
2.9-angstrom resolution. This structure revealed that haptoglobin
molecules dimerize through an unexpected beta-strand swap between 2
complement control protein (CCP) domains, defining a new fusion CCP
domain structure. The haptoglobin serine protease domain forms extensive
interactions with both the alpha- and beta-subunits of hemoglobin,
explaining the tight binding between haptoglobin and hemoglobin. The
hemoglobin-interacting region in the alpha-beta dimer is highly
overlapping with the interface between the 2 alpha-beta dimers that
constitute the native hemoglobin tetramer. Several hemoglobin residues
prone to oxidative modification after exposure to heme-induced reactive
oxygen species are buried in the haptoglobin-hemoglobin interface, thus
showing a direct protective role of haptoglobin. The haptoglobin loop
previously shown to be essential for binding of haptoglobin-hemoglobin
to the macrophage scavenger receptor CD163 (605545) protrudes from the
surface of the distal end of the complex, adjacent to the associated
hemoglobin alpha-subunit. Small-angle x-ray scattering measurements of
human haptoglobin-hemoglobin bound to the ligand-binding fragment of
CD163 confirmed receptor binding in this area, and showed that the rigid
dimeric complex can bind 2 receptors.

EVOLUTION

See review of the evolution of the haptoglobin gene by Maeda and
Smithies (1986).

In the chimpanzee, there are 3 genes in the haptoglobin family
(haptoglobin, HP; haptoglobin-related, HPR; and haptoglobin-primate,
HPP), whereas only 2 genes exist in humans (HP and HPR). The 2-gene
cluster of the human was formed after the separation of the human and
chimpanzee lineages by an unequal homologous crossover that deleted most
of the third gene. The 3-gene haptoglobin cluster in chimpanzees shows
evidence of many recombinations, insertions, and deletions during its
evolution. In the rhesus monkey, Erickson and Maeda (1994) found 6
different haplotypes among 11 individuals from 2 rhesus monkey families.
The 6 haplotypes included 2 types of haptoglobin gene clusters: one type
with a single gene and the other with 2 genes. DNA sequence analysis
indicated that the 1-gene and the 2-gene clusters were both formed by
unequal homologous crossovers between 2 genes of an ancestral 3-gene
cluster, near exon 5, the longest exon of the gene. This exon is also
the location of a separate unequal homologous crossover that occurred in
the human lineage to form the human 2-gene haptoglobin gene cluster from
an ancestral 3-gene cluster. The occurrence of independent homologous
unequal crossovers in rhesus monkey and human within the same region of
DNA suggests that the evolutionary history of the haptoglobin gene
cluster in primates is a consequence of frequent homologous pairings
facilitated by the longest and most conserved exon of the gene. Exon 5
contains more than 700 nucleotides.

MOLECULAR GENETICS

The haptoglobins, alpha-2-globulins whose name comes from their ability
to bind protein, were found to be polymorphic when studied by starch gel
electrophoresis by Smithies (1955). Several haptoglobin variants have
been identified in addition to the main types (Hp1, 140100.0001; Hp2,
140100.0002), and evidence of genic evolution through duplication (by
unequal crossingover) and subsequent independent mutation has been
provided.

A haptoglobin 2-1 modified (Hp2-1mod) phenotype results when the amount
of Hp2 polypeptide synthesized in Hp2 (140100.0002)/Hp1 heterozygotes is
less than that of Hp1 polypeptide. Maeda (1991) showed that the Hp2 DNA
from an individual with the modified phenotype had a C in place of the
normal A at nucleotide position -61 in one of the interleukin-6 (IL6)
responsive elements of the haptoglobin promoter region. Direct
sequencing of the haptoglobin promoter region, amplified by PCR, in DNA
from unrelated American blacks showed a C at -61 in all of 10 persons
with the modified phenotype, in 2 of 4 with a possible modified
phenotype, and in none of 15 with the standard Hp2-1 phenotype. The 2-1
modified phenotype was first described by Connell and Smithies (1959).
Giblett (1959) found it to be relatively common in blacks but, as found
by Harris et al. (1960), it occurs in other races. In the population
studied, Maeda (1991) found 3 other promoter sequences. This may explain
the variability of the modified phenotype. There may be variation in the
response of Hp2 alleles to the IL6-dependent factor during an
acute-phase response.

Haptoglobin variants with change in electrophoretic mobility of the
alpha polypeptide have been found (Giblett et al., 1966), whereas
others, e.g., the 'Marburg' phenotypes, have been found to have
alterations in the beta polypeptide chain (Cleve and Deicher, 1965).
Javid (1967) described a genetic variant of the haptoglobin beta
polypeptide chain and suggested that the locus be called Bp (for
'binding peptide,' since the beta chain binds hemoglobin), the
longer-known locus for the alpha chain being called Hp. Cleve et al.
(1969) concluded that haptoglobin Marburg is the result of a mutational
event other than a single base substitution. Haptoglobin P is another
beta variant.

Chapelle et al. (1982) found an association between Hp 2-2 and severity
of myocardial infarction.

The human haptoglobin HP*2 allele contains a 1.7-kb intragenic
duplication that arose after a unique nonhomologous recombination
between the prototype HP*1 alleles. During a genetic screening of 13,000
children of survivors exposed to atomic-bomb radiation and 10,000
children of unexposed persons, Asakawa et al. (1999) identified 2
children suspected of carrying de novo mutations at the HP locus (1 in
each group). DNA analysis of single-cell-derived colonies of
Epstein-Barr virus-transformed B cells revealed that the 2 children were
mosaics comprising HP*2/HP*2 and HP*2/HP*1 cells at a ratio of
approximately 3 to 1. It was inferred that the latter cells were caused
by reversion of 1 HP*2 allele to HP*1 through an intramolecular
homologous recombination between the duplicated segments of the HP*2
allele that excised 1 of the segments. Because the mosaicism was
substantial (approximately 25%), this recombination must have occurred
in early embryogenesis. The frequency of finding these children and the
extent of their mosaicism corresponded to an HP*2-to-HP*1 reversion rate
of 8 x 10(-6) per cell during development. This led to the prediction
that the HP*1 allele also will be represented, although usually at a
very low frequency, in any HP2-2 person. Asakawa et al. (1999) tested
this prediction by using PCR for a single individual and found the HP*1
allele at frequencies of 4 x 10(-6) and 3 x 10(-6) in somatic and sperm
cells, respectively. The HP*1 allele was detected by PCR in all 4 other
HP2-2 individuals, which supported the regular but rare occurrence
somatically of homologous recombination within duplicated regions in
humans, as well as previous observations in mouse and Drosophila.

Levy et al. (2002) determined the haptoglobin phenotype in 206
individuals with cardiovascular disease and 206 matched controls. In
multivariate analyses controlling for conventional cardiovascular
disease risk factors, Levy et al. (2002) found that for individuals with
diabetes mellitus, the odds ratio of having cardiovascular disease was
5.0 times greater with the Hp2-2 phenotype than with the Hp1-1 phenotype
(p = 0.002). An intermediate risk of cardiovascular disease was
associated with the Hp2-1 phenotype, and there were no significant
differences in risk by haptoglobin type for individuals without
diabetes.

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

- Anhaptoglobinemia and Hypohaptoglobinemia

In a Japanese individual with anhaptoglobinemia (also termed
ahaptoglobinemia) (614081) found by ELISA analysis of 9,711 unrelated
blood samples, Koda et al. (1998) identified a homozygous 28-kb deletion
allele on chromosome 16q22 (140100.0003) extending from the promoter
region of the HP gene to exon 5 of the haptoglobin-related gene (HPR;
140210), resulting in a null allele, HP0. Seven Japanese persons from 3
families with hypohaptoglobinemia (see 614081) carried the HP0 deletion
allele in compound heterozygosity with 1 of the codominant HP
polymorphisms. Six individuals with genotype HP2/HP0 had an extremely
low level of haptoglobin compared to controls with the HP2/HP2 genotype,
whereas 1 individual with the HP1/HP0 genotype had a serum level that
was approximately half the level of controls with the HP1/HP1 genotype.
This demonstrated a gene-dosage effect.

Teye et al. (2003) found that 17 (13.8%) of 123 Ghanaian individuals
with undetectable malaria infection had decreased serum haptoglobin as
assessed by double immunodiffusion followed by Western blotting. Nine
(7.3%) were ahaptoglobinemic and 8 (6.5%) were hypohaptoglobinemic.
There was a strong association between a -61A-C polymorphism in the HP
gene (140100.0004) and ahaptoglobinemia (p = 0.0125).

Teye et al. (2004) identified a heterozygous mutation in the HP gene
(I247T; 140100.0005) in a Ghanaian individual who was ahaptoglobinemic
as assessed by several assays. The I247T mutation caused reduced
expression of the HP protein when transfected into COS-7 cells. This
individual was also homozygous for the hypomorphic -61A-C allele
(140100.0004).

HISTORY

From study of cases of ring chromosome 13 and their families, Bloom et
al. (1967) concluded that the haptoglobin alpha locus was located near
one or the other end of chromosome 13. This later proved to be
incorrect.

Castiglione et al. (1985) found no evidence of linkage between HP and
APRT within 12 map units, despite the fact that both loci had previously
been mapped within band 16q22. The apparent inconsistency was explained
by the finding of Fratini et al. (1986) that APRT is located at 16q24
and that the gene order is cen--FRA16B--HP--FRA16D--APRT--qter.

*FIELD* AV
.0001
HAPTOGLOBIN, ALPHA-1, FAST-SLOW POLYMORPHISM
HP, LYS53GLU

The fast and slow forms of alpha-1, so-called from their electrophoretic
mobilities, differ in the amino acid at position 54, lysine (F) or
glutamic acid (S) (Black and Dixon, 1968).

Yang et al. (1983) stated that the lys-to-glu change occurs at codon 53.

Maeda (1991) stated that the HP1F and HP1S polypeptides differ by 2
amino acids at positions 52 and 53: aspartic acid and lysine in HB1F and
asparagine and glutamic acid in HP1S.

.0002
HAPTOGLOBIN, ALPHA-2
HP, 1.7-KB DUP

The alpha-2 chain originated through a chromosomal aberration (unequal
crossingover) in a person who was heterozygous alpha-1F/alpha-1S. The
alpha-2 chain is nearly twice as long as the alpha-1 chain and consists
of portions of alpha-1F and alpha-1S (Black and Dixon, 1968). The HP*2
allele has an internal duplication of 1.7 kb that includes 2 of the
alpha-chain exons. The HP2-alpha polypeptide consists of 142 amino
acids, while the HP1-alpha polypeptide has 83 amino acids (Maeda, 1991).
Marles et al. (1993) showed that homologous crossingover between HP*2
and either an HP*1F or HP*1S allele in HP*2/HP*1 heterozygotes can
change the usual type of HP*2 to 3 other forms: HP*2SS, HP*2FF, or
HP*2SF. Marles et al. (1993) described a nuclear family in which the
uncommon genotype HP*2SS in one parent caused initial confusion in
assigning genotypes to the rest of the nuclear family.

.0003
ANHAPTOGLOBINEMIA
HYPOHAPTOGLOBINEMIA, INCLUDED
HP, DEL

In a Japanese person with anhaptoglobinemia (614081), Koda et al. (1998)
found homozygosity for deletion of a segment of chromosome 16 extending
from at least the promoter region of HP to HPR-alpha but not to
HPR-beta. In addition, they found 7 persons with hypohaptoglobinemia
(see 614081) in 3 families, and the genotype of 6 of the 7 individuals
was found to be HP2/HP-del. The HP2/HP-del individuals with
hypohaptoglobinemia had an extremely low level of haptoglobin, compared
with the level obtained in 52 healthy volunteers with phenotype HP2,
whereas the serum haptoglobin level of an individual with HP1/HP-del was
0.50 mg/ml, which was approximately half the level of haptoglobin in
control sera from the HP1 phenotype, showing a gene-dosage effect. By
DNA sequencing of all exons, the other allele (HP2) of individuals with
HP2/HP-del was found to have no mutations. Hypohaptoglobinemia and
anhaptoglobinemia have no clear pathologic consequences.

Anhaptoglobinemia due to homozygous deletion of a segment measuring
approximately 28 kb on chromosome 16 and extending from the promoter
region of the HP gene to exon 5 of the haptoglobin-related gene (HPR;
140210) had been found in Japan, Korea, and China but not elsewhere. In
these countries, anhaptoglobinemia has important clinical consequences;
it is responsible for anaphylactic reactions in blood transfusions (Koda
et al., 2000; Morishita et al., 2000). Teye et al. (2003) found that the
so-called Hp0 anhaptoglobinemia phenotype in Ghana (West Africa) (see
140100.0004) has a different genetic basis than that seen in Asia.

.0004
ANHAPTOGLOBINEMIA, SUSCEPTIBILITY TO
HP, -61A-C

In Ghana, West Africa, Teye et al. (2003) found that a -61A-C base
substitution in the promoter region of the HP gene was associated with
anhaptoglobinemia (614081) and was strongly associated with the HP*2
allele (140100.0002). This base substitution was found to decrease
transcriptional activity significantly.

.0005
ANHAPTOGLOBINEMIA, SUSCEPTIBILITY TO
HP, ILE247THR

In a Ghanaian patient with anhaptoglobinemia (614081) previously found
to be homozygous for a -61A-C transversion in the promoter region of the
HP gene (140100.0004) (Teye et al., 2003), Teye et al. (2004) identified
a heterozygous 6802T-C transition in exon 7, resulting in an
ile247-to-thr (I247T) mutation. The I247T mutation caused reduced
expression of the HP protein when transfected into COS-7 cells, compared
with the wildtype.

*FIELD* SA
Bensi et al. (1985); Bias and Migeon (1967); Chow et al. (1983); Cook
et al. (1969); Ferguson-Smith and Aitken (1978); Gerald et al. (1967);
Giblett et al. (1964); Javid and Yingling (1968); Kirk (1968); Lefranc
et al. (1981); Lush (1966); Maeda et al. (1984); McGill et al. (1984);
Mulley et al. (1989); Oliviero et al. (1985); Oliviero et al. (1985);
Smithies (1959); Smithies et al. (1962); Smithies et al. (1962);
Smithies and Walker (1955); Sutton (1970); van der Straten et al.
(1984); Weerts et al. (1965)
*FIELD* RF
1. Andersen, C. B. F.; Torvund-Jensen, M.; Nielsen, M. J.; de Oliveira,
C. L. P.; Hersleth, H.-P.; Andersen, N. H.; Pedersen, J. S.; Andersen,
G. R.; Moestrup, S. K.: Structure of the haptoglobin-haemoglobin
complex. Nature 489: 456-459, 2012.

2. Asakawa, J.; Kodaira, M.; Nakamura, N.; Satoh, C.; Fujita, M.:
Chimerism in humans after intragenic recombination at the haptoglobin
locus during early embryogenesis. Proc. Nat. Acad. Sci. 96: 10314-10319,
1999.

3. Asleh, R.; Marsh, S.; Shilkrut, M.; Binah, O.; Guetta, J.; Lejbkowicz,
F.; Enav, B.; Shehadeh, N.; Kanter, Y.; Lache, O.; Cohen, O.; Levy,
N. S.; Levy, A. P.: Genetically determined heterogeneity in hemoglobin
scavenging and susceptibility to diabetic cardiovascular disease. Circ.
Res. 92: 1193-1200, 2003.

4. Bensi, G.; Raugei, G.; Klefenz, H.; Cortese, R.: Structure and
expression of the human haptoglobin locus. EMBO J. 4: 119-126, 1985.

5. Bias, W. B.; Migeon, B. R.: Haptoglobin: a locus on the D(1) chromosome? Am.
J. Hum. Genet. 19: 393-398, 1967.

6. Black, J. A.; Dixon, G. H.: Amino-acid sequence of alpha chains
of human haptoglobins. Nature 218: 736-741, 1968.

7. Bloom, G. E.; Gerald, P. S.; Reisman, L. E.: Ring D chromosome:
a second case associated with anomalous haptoglobin inheritance. Science 156:
1746-1748, 1967.

8. Castiglione, C. M.; Kidd, J. R.; Tischfield, J. A.; Stambrook,
P. J.; Murphy, P. D.; Sparkes, R. A.; Kidd, K. K.: Polymorphism and
linkage of APRT. (Abstract) Cytogenet. Cell Genet. 40: 601 only,
1985.

9. Chapelle, J.-P.; Albert, A.; Smeets, J.-P.; Heusghem, C.; Kulbertus,
H. E.: Effect of the haptoglobin phenotype on the size of a myocardial
infarct. New Eng. J. Med. 307: 457-463, 1982.

10. Chow, V.; Murray, R. K.; Dixon, J. D.; Kurosky, A.: Biosynthesis
of rabbit haptoglobin: chemical evidence for a single chain precursor. FEBS
Lett. 153: 275-279, 1983.

11. Cleve, H.; Bowman, B. H.; Gordon, S.: Biochemical characterization
of the beta-chain variant haptoglobin Marburg. Humangenetik 7: 337-343,
1969.

12. Cleve, H.; Deicher, H.: Haptoglobin 'Marburg': Untersuchungen
ueber eine seltene erbliche Haptoglobin-variante mit zwei verschiedenen
Phaenotypen inerhalb einer Familie. Humangenetik 1: 537-550, 1965.

13. Connell, G. E.; Smithies, O.: Human haptoglobins: estimation
and purification. Biochem. J. 72: 115-121, 1959.

14. Cook, P. J. L.; Gray, J. E.; Brack, R. A.; Robson, E. B.; Howlett,
R. M.: Data on haptoglobin and the D group chromosomes. Ann. Hum.
Genet. 33: 125-138, 1969.

15. Dayhoff, M. O.: Miscellaneous proteins. Atlas of Protein Sequence
and Structure. Vol. 5 Washington: National Biomedical Research Foundation
(pub.) 1972. Pp. D309, and D314-D315.

16. Eaton, J. W.; Brandt, P.; Mahoney, J. R.; Lee, J. T., Jr.: Haptoglobin:
a natural bacteriostat. Science 215: 691-693, 1982.

17. Erickson, L. M.; Maeda, N.: Parallel evolutionary events in the
haptoglobin gene clusters of rhesus monkey and human. Genomics 22:
579-589, 1994.

18. Ferguson-Smith, M. A.; Aitken, D. A.: Heterozygosity at the alpha-haptoglobin
locus associated with a deletion, 16q22-16qter. (Abstract) Cytogenet.
Cell Genet. 22: 513 only, 1978.

19. Fratini, A.; Simmers, R. N.; Callen, D. F.; Hyland, V. J.; Tischfield,
J. A.; Stambrook, P. J.; Sutherland, G. R.: A new location for the
human adenine phosphoribosyltransferase gene (APRT) distal to the
haptoglobin (HP) and fra(16)(q23) (FRA16D) loci. Cytogenet. Cell
Genet. 43: 10-13, 1986.

20. Gerald, P. S.; Warner, S.; Singer, J. D.; Corcoran, P. A.; Umansky,
I.: A ring D chromosome and anomalous inheritance of haptoglobin
type. J. Pediat. 70: 172-179, 1967.

21. Gerner-Smidt, P.; Friedrich, U.; Petersen, G. B.; Tischfield,
J. A.: A balanced translocation t(11;16) (q13;p11), a cytogenetic
study and an attempt at gene localization. Hum. Genet. 42: 61-66,
1978.

22. Giblett, E. R.: Haptoglobin types in American Negroes. Nature 183:
192-193, 1959.

23. Giblett, E. R.; Hickman, G. C.; Smithies, O.: Variant haptoglobin
phenotypes. Cold Spring Harbor Symp. Quant. Biol. 29: 321-326, 1964.

24. Giblett, E. R.; Uchida, I. A.; Brooks, L. E.: Two rare haptoglobin
phenotypes, 1-B and 2-B, containing a previously undescribed alpha
polypeptide chain. Am. J. Hum. Genet. 18: 448-453, 1966.

25. Harris, H.; Lawler, S. D.; Robson, E. B.; Smithies, O.: The occurrence
of two unusual serum protein phenotypes in a single pedigree. Ann.
Hum. Genet. 24: 63-69, 1960.

26. Haugen, T. H.; Hanley, J. M.; Heath, E. C.: Haptoglobin: a novel
mode of biosynthesis of a liver secretory glycoprotein. J. Biol.
Chem. 256: 1055-1057, 1981.

27. Javid, J.: Haptoglobin 2-1 Bellevue, a haptoglobin beta-chain
mutant. Proc. Nat. Acad. Sci. 57: 920-924, 1967.

28. Javid, J.; Yingling, W.: Immunogenetics of human haptoglobins.
I. The antigenic structure of normal Hp phenotypes. J. Clin. Invest. 47:
2290-2296, 1968.

29. Kirk, R. L.: The haptoglobin groups in man.In: Monographs in
Human Genetics. Basel and New York: S. Karger (pub.) 4: 1968.

30. Koda, Y.; Soejima, M.; Yoshioka, N.; Kimura, H.: The haptoglobin-gene
deletion responsible for anhaptoglobinemia. Am. J. Hum. Genet. 62:
245-252, 1998.

31. Koda, Y.; Watanabe, Y.; Soejima, M.; Shimada, E.; Nishimura, M.;
Morishita, K.; Moriya, S.; Mitsunaga, S.; Tadokoro, K.; Kimura, H.
: Simple PCR detection of haptoglobin gene deletion in anhaptoglobinemic
patients with antihaptoglobin antibody that causes anaphylactic transfusion
reactions. Blood 95: 1138-1143, 2000.

32. Kurosky, A.; Barnett, D. R.; Lee, T.-H.; Touchstone, B.; Hay,
R. E.; Arnott, M. S.; Bowman, B. H.; Fitch, W. M.: Covalent structure
of human haptoglobin: a serine protease homology. Proc. Nat. Acad.
Sci. 77: 3388-3392, 1980.

33. Lefranc, G.; Lefranc, M.-P.; Seger, J.; Salier, J.-P.; Chakhachiro,
L.; Loiselet, J.: Sex limited ahaptoglobinaemia. Hum. Genet. 58:
294-297, 1981.

34. Levy, A. P.; Hochberg, I.; Jablonski, K.; Resnick, H. E.; Lee,
E. T.; Best, L.; Howard, B. V.: Haptoglobin phenotype is an independent
risk factor for cardiovascular disease in individuals with diabetes:
the strong heart study. J. Am. Coll. Cardiol. 40: 1984-1990, 2002.

35. Lush, I. E.: The Biochemical Genetics of Vertebrates Except Man.
Philadelphia: W. B. Saunders (pub.) 1966.

36. Maeda, N.: DNA polymorphisms in the controlling region of the
human haptoglobin genes: a molecular explanation for the haptoglobin
2-1 modified phenotype. Am. J. Hum. Genet. 49: 158-166, 1991.

37. Maeda, N.; Smithies, O.: The evolution of multigene families:
human haptoglobin genes. Annu. Rev. Genet. 20: 81-108, 1986.

38. Maeda, N.; Yang, F.; Barnett, D. R.; Bowman, B. H.; Smithies,
O.: Duplication within the haptoglobin Hp-2 gene. Nature 309: 131-135,
1984.

39. Magenis, R. E.; Hecht, F.; Lovrien, E. W.: Heritable fragile
site on chromosome 16: probable localization of haptoglobin locus
in man. Science 170: 85-87, 1970.

40. Marles, S. L.; McAlpine, P. J.; Zelinski, T.; Phillips, S.; Maeda,
N.; Greenberg, C. R.: Identification of an uncommon haptoglobin type
using DNA and protein analysis. Hum. Genet. 92: 364-366, 1993.

41. McGill, J. R.; Yang, F.; Baldwin, W. D.; Brune, J. L.; Barnett,
D. R.; Bowman, B. H.; Moore, C. M.: Localization of the haptoglobin
alpha and beta genes (HPA and HPB) to human chromosome 16q22 by in
situ hybridization. Cytogenet. Cell Genet. 38: 155-157, 1984.

42. Morishita, K.; Shimada, E.; Watanabe, Y.; Kimura, H.: Anaphylactic
transfusion reactions associated with anti-haptoglobin in a patient
with ahaptoglobinemia. (Letter) Transfusion 40: 120-121, 2000.

43. Mulley, J. C.; Hyland, V. J.; Fratini, A.; Bates, L. J.; Gedeon,
A. K.; Sutherland, G. R.: A linkage group with FRA16B (the fragile
site at 16q22.2). Hum. Genet. 82: 131-133, 1989.

44. Oliviero, S.; DeMarchi, M.; Bensi, G.; Raugei, G.; Carbonara,
A. O.: A new restriction fragment length polymorphism in the haptoglobin
gene region. Hum. Genet. 70: 66-70, 1985.

45. Oliviero, S.; DeMarchi, M.; Carbonara, A. O.; Bernini, L. F.;
Bensi, G.; Raugei, G.: Molecular evidence of triplication in the
haptoglobin Johnson variant gene. Hum. Genet. 71: 49-52, 1985.

46. Povey, S.; Jeremiah, S. J.; Barker, R. F.; Hopkinson, D. A.; Robson,
E. B.; Cook, P. J. L.; Solomon, E.; Bobrow, M.; Marritt, B.; Buckton,
K. E.: Assignment of the human locus determining phosphoglycolate
phosphatase (PGP) to chromosome 16. Ann. Hum. Genet. 43: 241-248,
1980.

47. Robson, E. B.; Polani, P. E.; Dart, S. J.; Jacobs, P. A.; Renwick,
J. H.: Probable assignment of the alpha locus of haptoglobin to chromosome
16 in man. Nature 223: 1163-1165, 1969.

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

49. Simmers, R. N.; Stupans, I.; Sutherland, G. R.: Localization
of the human haptoglobin genes distal to the fragile site at 16q22
using in situ hybridization. Cytogenet. Cell Genet. 41: 38-41, 1986.

50. Simmers, R. N.; Stupans, I.; Sutherland, G. R.: The haptoglobin
gene is distal to the fragile site at 16q22. (Abstract) Cytogenet.
Cell Genet. 40: 745 only, 1985.

51. Smithies, O.: An improved procedure for starch-gel electrophoresis:
further variations in the serum proteins of normal individuals. Biochem.
J. 71: 585-587, 1959.

52. Smithies, O.: Zone electrophoresis in starch gels: group variations
in the serum proteins of normal human adults. Biochem. J. 61: 629-641,
1955.

53. Smithies, O.; Connell, G. E.; Dixon, G. H.: Inheritance of haptoglobin
subtypes. Am. J. Hum. Genet. 14: 14-21, 1962.

54. Smithies, O.; Connell, G. E.; Dixon, G. H.: Chromosomal rearrangements
and the evolution of haptoglobin genes. Nature 196: 232-236, 1962.

55. Smithies, O.; Walker, N. F.: Genetic control of some serum proteins
in normal humans. Nature 176: 1265-1266, 1955.

56. Sutton, H. E.: The haptoglobins. Prog. Med. Genet. 7: 163-216,
1970.

57. Teye, K.; Quaye, I. K. E.; Koda, Y.; Soejima, M.; Pang, H.; Tsuneoka,
M.; Amoah, A. G. B.; Adjei, A.; Kimura, H.: A novel I247T missense
mutation in the haptoglobin 2 beta-chain decreases the expression
of the protein and is associated with ahaptoglobinemia. Hum. Genet. 114:
499-502, 2004.

58. Teye, K.; Quaye, I. K. E.; Koda, Y.; Soejima, M.; Tsuneoka, M.;
Pang, H.; Ekem, I.; Amoah, A. G. B.; Adjei, A.; Kimura, H.: A-61C
and C-101G Hp gene promoter polymorphisms are, respectively, associated
with ahaptoglobinaemia and hypohaptoglobinaemia in Ghana. Clin. Genet. 64:
439-443, 2003.

59. van der Straten, A.; Herzog, A.; Cabezon, T.; Bollen, A.: Characterization
of human haptoglobin cDNAs coding for alpha(2FS)beta and alpha(1S)beta
variants. FEBS Lett. 168: 103-107, 1984.

60. Weerts, G.; Nix, W.; Deicher, H.: Isolierung und naehere Charakterisierung
eines neuen Haptoglobins: HP-Marburg. Blut 12: 65-77, 1965.

61. Wicher, K.; Fries, E.: Prohaptoglobin is proteolytically cleaved
in the endoplasmic reticulum by the complement C1r-like protein. Proc.
Nat. Acad. Sci. 101: 14390-14395, 2004.

62. Yang, F.; Brune, J. L.; Baldwin, W. D.; Barnett, D. R.; Bowman,
B. H.: Identification and characterization of human haptoglobin cDNA. Proc.
Nat. Acad. Sci. 80: 5875-5879, 1983.

*FIELD* CN
Ada Hamosh - updated: 11/1/2012
Cassandra L. Kniffin - updated: 7/8/2011
Patricia A. Hartz - updated: 10/15/2004
Victor A. McKusick - updated: 6/1/2004
Marla J. F. O'Neill - updated: 2/19/2004
Victor A. McKusick - updated: 12/4/2003
Victor A. McKusick - updated: 10/21/1999
Victor A. McKusick - updated: 4/18/1998
Victor A. McKusick - updated: 3/5/1997

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

*FIELD* ED
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warfield: 4/8/1994
pfoster: 2/18/1994
carol: 12/22/1993

MIM 614081
*RECORD*
*FIELD* NO
614081
*FIELD* TI
#614081 ANHAPTOGLOBINEMIA; AHP
;;AHAPTOGLOBINEMIA
HYPOHAPTOGLOBINEMIA, INCLUDED
*FIELD* TX
read moreA number sign (#) is used with this entry because anhaptoglobinemia and
hypohaptoglobinemia are caused by homozygous mutation in the gene
encoding haptoglobin (HP; 140100) on chromosome 16q22.

DESCRIPTION

Anhaptoglobinemia refers to absence of the serum glycoprotein
haptoglobin, a hemoglobin-binding acute-phase protein (summary by Teye
et al., 2004). Serum levels of haptoglobin vary among normal persons:
levels are low in the neonatal period and in the elderly, differ by
population, and can be influenced by environmental factors, such as
infection. Secondary hypohaptoglobinemia can occur as a consequence of
hemolysis, during which haptoglobin binds to free hemoglobin (summary by
Delanghe et al., 1998).

CLINICAL FEATURES

Koda et al. (2000) reported 2 Asian anhaptoglobinemic patients with
antihaptoglobin antibodies who developed anaphylactic transfusion
reactions.

Teye et al. (2004) stated that anhaptoglobinemia has important clinical
consequences, such as protecting against the cattle pathogen Trypanosoma
brucei and being associated with higher CD4 cell counts in patients with
HIV infection (Quaye et al., 2000).

- Acquired Hypo- or Anhaptoglobinemia

Teye et al. (2003) noted that serum levels of haptoglobin can decrease
secondarily following hemolysis, as haptoglobin is saturated by free
hemoglobin. This is often observed in sub-Saharan African regions where
malaria is endemic. In those with low haptoglobin levels at baseline,
hemolysis due to malaria can result in clinical anhaptoglobinemia.

OTHER FEATURES

Panter et al. (1985) found an association between familial idiopathic
epilepsy and low serum levels of haptoglobin. Artificially-induced
hypohaptoglobinemia in mice caused delayed clearance of free hemoglobin
from the central nervous system and engendered the peroxidation of brain
lipids. Panter et al. (1985) hypothesized that hypohaptoglobinemia,
either inherited or acquired via traumatic processes, may prevent
efficient clearance of interstitial hemoglobin from the central nervous
system, thereby predisposing these individuals to encephalic
inflammation and the appearance of seizure disorders.

MOLECULAR GENETICS

In a Japanese individual with anhaptoglobinemia found by ELISA analysis
of 9,711 unrelated blood samples, Koda et al. (1998) identified a
homozygous 28-kb deletion allele on chromosome 16q22 (140100.0003)
extending from the promoter region of the HP gene to exon 5 of the
haptoglobin-related gene (HPR; 140210), resulting in a null allele,
termed HP0.

Teye et al. (2003) found that 17 (13.8%) of 123 Ghanaian individuals
with undetectable malaria infection had decreased serum haptoglobin as
assessed by double immunodiffusion followed by Western blotting. Nine
(7.3%) were anhaptoglobinemic and 8 (6.5%) were hypohaptoglobinemic.
There was a strong association between a -61A-C polymorphism in the HP
gene (140100.0004) and anhaptoglobinemia (p = 0.0125).

Teye et al. (2004) identified a heterozygous mutation in the HP gene
(I247T; 140100.0005) in a Ghanaian individual who was anhaptoglobinemic
as assessed by several assays. The I247T mutation caused reduced
expression of the HP protein when transfected into COS-7 cells. This
individual was also homozygous for the hypomorphic -61A-C allele
(140100.0004).

- Hypohaptoglobinemia

Koda et al. (1998) found that 7 Japanese persons from 3 families with
hypohaptoglobinemia carried the deletion allele HP0 (140100.0003) in
compound heterozygosity with 1 of the codominant HP polymorphisms. Six
individuals with the HP2 (140100.0002)/HP0 genotype had an extremely low
level of haptoglobin compared to controls with the HP2/HP2 genotype,
whereas 1 individual with the HP1 (140100.0001)/HP0 genotype had a serum
level that was approximately half the level of controls with the HP1/HP1
genotype. This demonstrated a gene dosage effect.

POPULATION GENETICS

Koda et al. (2000) estimated that the frequency of individuals
homozygous for the Asian deletion HP0 allele (140100.0003) was 1 in
4,000 among Japanese, 1 in 1,500 among Koreans, and 1 in 1,000 among
Chinese. This allele had not been identified in non-Asian populations.

*FIELD* RF
1. Delanghe, J.; Langlois, M.; De Buyzere, M.: Congenital anhaptoglobinemia
versus acquired hypohaptoglobinemia. (Letter) Blood 91: 3524 only,
1998.

2. Koda, Y.; Soejima, M.; Yoshioka, N.; Kimura, H.: The haptoglobin-gene
deletion responsible for anhaptoglobinemia. Am. J. Hum. Genet. 62:
245-252, 1998.

3. Koda, Y.; Watanabe, Y.; Soejima, M.; Shimada, E.; Nishimura, M.;
Morishita, K.; Moriya, S.; Mitsunaga, S.; Tadokoro, K.; Kimura, H.
: Simple PCR detection of haptoglobin gene deletion in anhaptoglobinemic
patients with antihaptoglobin antibody that causes anaphylactic transfusion
reactions. Blood 95: 1138-1143, 2000.

4. Panter, S. S.; Sadrzadeh, S. M. H.; Hallaway, P. E.; Haines, J.
L.; Anderson, V. E.; Eaton, J. W.: Hypohaptoglobinemia associated
with familial epilepsy. J. Exp. Med. 161: 748-754, 1985.

5. Quaye, I. K. E.; Ekuban, F. A.; Brandful, J. A. M.; Gyan, B. A.;
Akanmori, B. D.; Ankrah, N. A.: Haptoglobin phenotypes in HIV-1-seropositive
patients in Ghana: decreased risk for Hp0 individuals. Hum. Hered. 50:
382-383, 2000.

6. Teye, K.; Quaye, I. K. E.; Koda, Y.; Soejima, M.; Pang, H.; Tsuneoka,
M.; Amoah, A. G. B.; Adjei, A.; Kimura, H.: A novel I247T missense
mutation in the haptoglobin 2 beta-chain decreases the expression
of the protein and is associated with ahaptoglobinemia. Hum. Genet. 114:
499-502, 2004.

7. Teye, K.; Quaye, I. K. E.; Koda, Y.; Soejima, M.; Tsuneoka, M.;
Pang, H.; Ekem, I.; Amoah, A. G. B.; Adjei, A.; Kimura, H.: A-61C
and C-101G Hp gene promoter polymorphisms are, respectively, associated
with ahaptoglobinaemia and hypohaptoglobinaemia in Ghana. Clin. Genet. 64:
439-443, 2003.

*FIELD* CD
Cassandra L. Kniffin: 7/8/2011

*FIELD* ED
carol: 02/26/2013
alopez: 10/3/2012
terry: 8/2/2011
carol: 7/8/2011
ckniffin: 7/8/2011