Full text data of AHSG
AHSG
(FETUA)
[Confidence: low (only semi-automatic identification from reviews)]
Alpha-2-HS-glycoprotein (Alpha-2-Z-globulin; Ba-alpha-2-glycoprotein; Fetuin-A; Alpha-2-HS-glycoprotein chain A; Alpha-2-HS-glycoprotein chain B; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Alpha-2-HS-glycoprotein (Alpha-2-Z-globulin; Ba-alpha-2-glycoprotein; Fetuin-A; Alpha-2-HS-glycoprotein chain A; Alpha-2-HS-glycoprotein chain B; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P02765
ID FETUA_HUMAN Reviewed; 367 AA.
AC P02765; A8K9N6; B2R7G1; O14961; O14962; Q9P152;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 159.
DE RecName: Full=Alpha-2-HS-glycoprotein;
DE AltName: Full=Alpha-2-Z-globulin;
DE AltName: Full=Ba-alpha-2-glycoprotein;
DE AltName: Full=Fetuin-A;
DE Contains:
DE RecName: Full=Alpha-2-HS-glycoprotein chain A;
DE Contains:
DE RecName: Full=Alpha-2-HS-glycoprotein chain B;
DE Flags: Precursor;
GN Name=AHSG; Synonyms=FETUA; ORFNames=PRO2743;
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=3474608; DOI=10.1073/pnas.84.13.4403;
RA Lee C.-C., Bowman B.H., Yang F.;
RT "Human alpha 2-HS-glycoprotein: the A and B chains with a connecting
RT sequence are encoded by a single mRNA transcript.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:4403-4407(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=9322749; DOI=10.1016/S0378-1119(97)00216-3;
RA Osawa M., Umetsu K., Sato M., Ohki T., Yukawa N., Suzuki T.,
RA Takeichi S.;
RT "Structure of the gene encoding human alpha 2-HS glycoprotein
RT (AHSG).";
RL Gene 196:121-125(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS AHSG*5 ASN-276 AND
RP AHSG*3 CYS-317.
RX PubMed=11415520; DOI=10.1046/j.1469-1809.2001.6510027.x;
RA Osawa M., Yuasa I., Kitano T., Henke J., Kaneko M., Udono T.,
RA Saitou N., Umetsu K.;
RT "Haplotype analysis of the human alpha2-HS glycoprotein (fetuin)
RT gene.";
RL Ann. Hum. Genet. 65:27-34(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-256.
RC TISSUE=Liver, and 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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP PROTEIN SEQUENCE OF 19-300.
RX PubMed=3944104;
RA Yoshioka Y., Gejyo F., Marti T., Rickli E.E., Burgi W., Offner G.D.,
RA Troxler R.F., Schmid K.;
RT "The complete amino acid sequence of the A-chain of human plasma alpha
RT 2HS-glycoprotein.";
RL J. Biol. Chem. 261:1665-1676(1986).
RN [9]
RP PROTEIN SEQUENCE OF 19-28.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 34-367, AND VARIANTS ALLELE AHSG*2
RP MET-248 AND SER-256.
RC TISSUE=Liver;
RX PubMed=9003486; DOI=10.1007/s004390050302;
RA Osawa M., Umetsu K., Ohki T., Nagasawa T., Suzuki T., Takeichi S.;
RT "Molecular evidence for human alpha 2-HS glycoprotein (AHSG)
RT polymorphism.";
RL Hum. Genet. 99:18-21(1997).
RN [11]
RP PROTEIN SEQUENCE OF 107-120, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 150-367.
RC TISSUE=Fetal liver;
RA Zhang C., Yu Y., Zhang S., Wei H., Zhang Y., Zhou G., Bi J., Liu M.,
RA He F.;
RT "Functional prediction of the coding sequences of 79 new genes deduced
RT by analysis of cDNA clones from human fetal liver.";
RL Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP PROTEIN SEQUENCE OF 341-367.
RX PubMed=6833285;
RA Gejyo F., Chang J.-L., Burgi W., Schmid K., Offner G.D., Troxler R.F.,
RA van Halbeek H., Dorland L., Gerwig G.J., Vliegenthart J.F.G.;
RT "Characterization of the B-chain of human plasma alpha 2HS-
RT glycoprotein. The complete amino acid sequence and primary structure
RT of its heteroglycan.";
RL J. Biol. Chem. 258:4966-4971(1983).
RN [14]
RP DISULFIDE BONDS.
RX PubMed=2645941; DOI=10.1016/0167-4838(89)90293-8;
RA Araki T., Yoshioka Y., Schmid K.;
RT "The position of the disulfide bonds in human plasma alpha 2 HS-
RT glycoprotein and the repeating double disulfide bonds in the domain
RT structure.";
RL Biochim. Biophys. Acta 994:195-199(1989).
RN [15]
RP DISULFIDE BONDS.
RX PubMed=2760061;
RA Kellerman J., Haupt H., Auerswald E.-A., Mueller-Esterl W.;
RT "The arrangement of disulfide loops in human alpha 2-HS glycoprotein.
RT Similarity to the disulfide bridge structures of cystatins and
RT kininogens.";
RL J. Biol. Chem. 264:14121-14128(1989).
RN [16]
RP PARTIAL PROTEIN SEQUENCE, AND PHOSPHORYLATION AT SER-138 AND SER-330.
RC TISSUE=Plasma;
RX PubMed=11439093; DOI=10.1042/0264-6021:3570437;
RA Haglund A.C., Ek B., Ek P.;
RT "Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein
RT (human fetuin) in vivo.";
RL Biochem. J. 357:437-445(2001).
RN [17]
RP GLYCOSYLATION AT ASN-176.
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 [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156, AND MASS
RP 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 [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156 AND ASN-176, 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 [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156 AND ASN-176, 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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [24]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156, 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 [25]
RP GLYCOSYLATION AT ASN-156.
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 [26]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156 AND ASN-176, STRUCTURE
RP OF CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [27]
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 [28]
RP GLYCOSYLATION AT ASN-156; ASN-176 AND SER-346, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.M111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of
RT N-and O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 0:0-0(2011).
CC -!- FUNCTION: Promotes endocytosis, possesses opsonic properties and
CC influences the mineral phase of bone. Shows affinity for calcium
CC and barium ions.
CC -!- SUBUNIT: Alpha-2-HS glycoprotein derives from this precursor, when
CC the connecting peptide is cleaved off. The two chains A and B are
CC held together by a single disulfide bond.
CC -!- INTERACTION:
CC P00519:ABL1; NbExp=1; IntAct=EBI-1223374, EBI-375543;
CC O88736:Hsd17b7 (xeno); NbExp=1; IntAct=EBI-1223374, EBI-2552537;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Synthesized in liver and selectively
CC concentrated in bone matrix. Secreted in plasma. It is also found
CC in dentin in much higher quantities than other plasma proteins.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- PTM: O- and N-glycosylated. O-glycosylated with core 1 or possibly
CC core 8 glycans. N-glycan at Asn-156: Hex5HexNAc4; N-glycan
CC heterogeneity at Asn-176: Hex5HexNAc4 (major) and Hex6HexNAc5
CC (minor).
CC -!- POLYMORPHISM: There are two common alleles, AHSG*1 and AHSG*2.
CC AHSG*1 has Thr-248/Thr-256; AHSG*2 has Met-248/Ser-256.
CC -!- SIMILARITY: Belongs to the fetuin family.
CC -!- SIMILARITY: Contains 2 cystatin fetuin-A-type domains.
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DR EMBL; M16961; AAA51683.1; -; mRNA.
DR EMBL; D67013; BAA22652.1; -; Genomic_DNA.
DR EMBL; AB038689; BAA92189.1; -; Genomic_DNA.
DR EMBL; AK292751; BAF85440.1; -; mRNA.
DR EMBL; AK312969; BAG35808.1; -; mRNA.
DR EMBL; AC068631; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78189.1; -; Genomic_DNA.
DR EMBL; BC048198; AAH48198.1; -; mRNA.
DR EMBL; BC052590; AAH52590.1; -; mRNA.
DR EMBL; D67012; BAA22651.1; -; mRNA.
DR EMBL; AF119895; AAF69649.1; -; mRNA.
DR PIR; A29081; WOHU.
DR RefSeq; NP_001613.2; NM_001622.2.
DR UniGene; Hs.324746; -.
DR ProteinModelPortal; P02765; -.
DR IntAct; P02765; 9.
DR MINT; MINT-5004009; -.
DR STRING; 9606.ENSP00000393887; -.
DR MEROPS; I25.020; -.
DR PhosphoSite; P02765; -.
DR UniCarbKB; P02765; -.
DR DMDM; 112910; -.
DR DOSAC-COBS-2DPAGE; P02765; -.
DR SWISS-2DPAGE; P02765; -.
DR PaxDb; P02765; -.
DR PRIDE; P02765; -.
DR DNASU; 197; -.
DR Ensembl; ENST00000411641; ENSP00000393887; ENSG00000145192.
DR GeneID; 197; -.
DR KEGG; hsa:197; -.
DR CTD; 197; -.
DR GeneCards; GC03P186330; -.
DR H-InvDB; HIX0024338; -.
DR HGNC; HGNC:349; AHSG.
DR HPA; CAB026209; -.
DR HPA; HPA001524; -.
DR HPA; HPA001525; -.
DR MIM; 138680; gene.
DR neXtProt; NX_P02765; -.
DR PharmGKB; PA24642; -.
DR eggNOG; NOG44208; -.
DR HOVERGEN; HBG051607; -.
DR InParanoid; P02765; -.
DR OrthoDB; EOG71K63R; -.
DR ChiTaRS; AHSG; human.
DR GeneWiki; Alpha-2-HS-glycoprotein; -.
DR GenomeRNAi; 197; -.
DR NextBio; 790; -.
DR PMAP-CutDB; P02765; -.
DR PRO; PR:P02765; -.
DR ArrayExpress; P02765; -.
DR Bgee; P02765; -.
DR CleanEx; HS_AHSG; -.
DR Genevestigator; P02765; -.
DR GO; GO:0005615; C:extracellular space; NAS:UniProtKB.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0019210; F:kinase inhibitor activity; NAS:UniProtKB.
DR GO; GO:0006953; P:acute-phase response; IDA:UniProtKB.
DR GO; GO:0030502; P:negative regulation of bone mineralization; ISS:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0001503; P:ossification; IEA:Ensembl.
DR GO; GO:0006907; P:pinocytosis; NAS:UniProtKB.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IDA:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; NAS:UniProtKB.
DR InterPro; IPR025760; Cystatin_Fetuin_A.
DR InterPro; IPR000010; Prot_inh_cystat.
DR InterPro; IPR001363; Prot_inh_fetuin_CS.
DR Pfam; PF00031; Cystatin; 1.
DR SMART; SM00043; CY; 2.
DR PROSITE; PS51529; CYSTATIN_FETUIN_A; 2.
DR PROSITE; PS01254; FETUIN_1; 1.
DR PROSITE; PS01255; FETUIN_2; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Direct protein sequencing; Disulfide bond;
KW Glycoprotein; Mineral balance; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1 18
FT CHAIN 19 300 Alpha-2-HS-glycoprotein chain A.
FT /FTId=PRO_0000008887.
FT PROPEP 301 340 Connecting peptide.
FT /FTId=PRO_0000008888.
FT CHAIN 341 367 Alpha-2-HS-glycoprotein chain B.
FT /FTId=PRO_0000008889.
FT DOMAIN 27 133 Cystatin fetuin-A-type 1.
FT DOMAIN 144 255 Cystatin fetuin-A-type 2.
FT MOD_RES 138 138 Phosphoserine.
FT MOD_RES 325 325 Phosphoserine (By similarity).
FT MOD_RES 328 328 Phosphoserine (By similarity).
FT MOD_RES 330 330 Phosphoserine.
FT CARBOHYD 156 156 N-linked (GlcNAc...) (complex).
FT /FTId=CAR_000064.
FT CARBOHYD 176 176 N-linked (GlcNAc...) (complex).
FT /FTId=CAR_000065.
FT CARBOHYD 256 256 O-linked (GalNAc...).
FT /FTId=CAR_000066.
FT CARBOHYD 270 270 O-linked (GalNAc...).
FT /FTId=CAR_000067.
FT CARBOHYD 346 346 O-linked (GalNAc...).
FT /FTId=CAR_000068.
FT DISULFID 32 358 Interchain (between A and B chains).
FT DISULFID 89 100
FT DISULFID 114 132
FT DISULFID 146 149
FT DISULFID 208 219
FT DISULFID 230 247
FT VARIANT 142 142 V -> L (in dbSNP:rs7633550).
FT /FTId=VAR_055802.
FT VARIANT 248 248 T -> M (in allele AHSG*2; dbSNP:rs4917).
FT /FTId=VAR_002388.
FT VARIANT 256 256 T -> S (in allele AHSG*2; dbSNP:rs4918).
FT /FTId=VAR_002389.
FT VARIANT 276 276 D -> N (in allele AHSG*5;
FT dbSNP:rs70961709).
FT /FTId=VAR_012474.
FT VARIANT 317 317 R -> C (in allele AHSG*3;
FT dbSNP:rs35457250).
FT /FTId=VAR_012475.
FT CONFLICT 16 16 C -> W (in Ref. 2; BAA22652).
FT CONFLICT 54 54 W -> K (in Ref. 8; AA sequence).
FT CONFLICT 125 125 F -> S (in Ref. 10; BAA22651).
FT CONFLICT 150 182 PLLAPLNDTRVVHAAKAALAAFNAQNNGSNFQL -> MVGW
FT QEGANHKNGAGRSQKQEMAEKMVPEVASG (in Ref.
FT 12; AAF69649).
FT CONFLICT 204 204 S -> C (in Ref. 2; BAA22652).
SQ SEQUENCE 367 AA; 39325 MW; 1AAF0C8D6B7E2789 CRC64;
MKSLVLLLCL AQLWGCHSAP HGPGLIYRQP NCDDPETEEA ALVAIDYINQ NLPWGYKHTL
NQIDEVKVWP QQPSGELFEI EIDTLETTCH VLDPTPVARC SVRQLKEHAV EGDCDFQLLK
LDGKFSVVYA KCDSSPDSAE DVRKVCQDCP LLAPLNDTRV VHAAKAALAA FNAQNNGSNF
QLEEISRAQL VPLPPSTYVE FTVSGTDCVA KEATEAAKCN LLAEKQYGFC KATLSEKLGG
AEVAVTCTVF QTQPVTSQPQ PEGANEAVPT PVVDPDAPPS PPLGAPGLPP AGSPPDSHVL
LAAPPGHQLH RAHYDLRHTF MGVVSLGSPS GEVSHPRKTR TVVQPSVGAA AGPVVPPCPG
RIRHFKV
//
ID FETUA_HUMAN Reviewed; 367 AA.
AC P02765; A8K9N6; B2R7G1; O14961; O14962; Q9P152;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 159.
DE RecName: Full=Alpha-2-HS-glycoprotein;
DE AltName: Full=Alpha-2-Z-globulin;
DE AltName: Full=Ba-alpha-2-glycoprotein;
DE AltName: Full=Fetuin-A;
DE Contains:
DE RecName: Full=Alpha-2-HS-glycoprotein chain A;
DE Contains:
DE RecName: Full=Alpha-2-HS-glycoprotein chain B;
DE Flags: Precursor;
GN Name=AHSG; Synonyms=FETUA; ORFNames=PRO2743;
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=3474608; DOI=10.1073/pnas.84.13.4403;
RA Lee C.-C., Bowman B.H., Yang F.;
RT "Human alpha 2-HS-glycoprotein: the A and B chains with a connecting
RT sequence are encoded by a single mRNA transcript.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:4403-4407(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=9322749; DOI=10.1016/S0378-1119(97)00216-3;
RA Osawa M., Umetsu K., Sato M., Ohki T., Yukawa N., Suzuki T.,
RA Takeichi S.;
RT "Structure of the gene encoding human alpha 2-HS glycoprotein
RT (AHSG).";
RL Gene 196:121-125(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS AHSG*5 ASN-276 AND
RP AHSG*3 CYS-317.
RX PubMed=11415520; DOI=10.1046/j.1469-1809.2001.6510027.x;
RA Osawa M., Yuasa I., Kitano T., Henke J., Kaneko M., Udono T.,
RA Saitou N., Umetsu K.;
RT "Haplotype analysis of the human alpha2-HS glycoprotein (fetuin)
RT gene.";
RL Ann. Hum. Genet. 65:27-34(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-256.
RC TISSUE=Liver, and 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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [8]
RP PROTEIN SEQUENCE OF 19-300.
RX PubMed=3944104;
RA Yoshioka Y., Gejyo F., Marti T., Rickli E.E., Burgi W., Offner G.D.,
RA Troxler R.F., Schmid K.;
RT "The complete amino acid sequence of the A-chain of human plasma alpha
RT 2HS-glycoprotein.";
RL J. Biol. Chem. 261:1665-1676(1986).
RN [9]
RP PROTEIN SEQUENCE OF 19-28.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 34-367, AND VARIANTS ALLELE AHSG*2
RP MET-248 AND SER-256.
RC TISSUE=Liver;
RX PubMed=9003486; DOI=10.1007/s004390050302;
RA Osawa M., Umetsu K., Ohki T., Nagasawa T., Suzuki T., Takeichi S.;
RT "Molecular evidence for human alpha 2-HS glycoprotein (AHSG)
RT polymorphism.";
RL Hum. Genet. 99:18-21(1997).
RN [11]
RP PROTEIN SEQUENCE OF 107-120, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 150-367.
RC TISSUE=Fetal liver;
RA Zhang C., Yu Y., Zhang S., Wei H., Zhang Y., Zhou G., Bi J., Liu M.,
RA He F.;
RT "Functional prediction of the coding sequences of 79 new genes deduced
RT by analysis of cDNA clones from human fetal liver.";
RL Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP PROTEIN SEQUENCE OF 341-367.
RX PubMed=6833285;
RA Gejyo F., Chang J.-L., Burgi W., Schmid K., Offner G.D., Troxler R.F.,
RA van Halbeek H., Dorland L., Gerwig G.J., Vliegenthart J.F.G.;
RT "Characterization of the B-chain of human plasma alpha 2HS-
RT glycoprotein. The complete amino acid sequence and primary structure
RT of its heteroglycan.";
RL J. Biol. Chem. 258:4966-4971(1983).
RN [14]
RP DISULFIDE BONDS.
RX PubMed=2645941; DOI=10.1016/0167-4838(89)90293-8;
RA Araki T., Yoshioka Y., Schmid K.;
RT "The position of the disulfide bonds in human plasma alpha 2 HS-
RT glycoprotein and the repeating double disulfide bonds in the domain
RT structure.";
RL Biochim. Biophys. Acta 994:195-199(1989).
RN [15]
RP DISULFIDE BONDS.
RX PubMed=2760061;
RA Kellerman J., Haupt H., Auerswald E.-A., Mueller-Esterl W.;
RT "The arrangement of disulfide loops in human alpha 2-HS glycoprotein.
RT Similarity to the disulfide bridge structures of cystatins and
RT kininogens.";
RL J. Biol. Chem. 264:14121-14128(1989).
RN [16]
RP PARTIAL PROTEIN SEQUENCE, AND PHOSPHORYLATION AT SER-138 AND SER-330.
RC TISSUE=Plasma;
RX PubMed=11439093; DOI=10.1042/0264-6021:3570437;
RA Haglund A.C., Ek B., Ek P.;
RT "Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein
RT (human fetuin) in vivo.";
RL Biochem. J. 357:437-445(2001).
RN [17]
RP GLYCOSYLATION AT ASN-176.
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 [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156, AND MASS
RP 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 [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156 AND ASN-176, 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 [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156 AND ASN-176, 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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-138, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=18318008; DOI=10.1002/pmic.200700884;
RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,
RA Zou H., Gu J.;
RT "Large-scale phosphoproteome analysis of human liver tissue by
RT enrichment and fractionation of phosphopeptides with strong anion
RT exchange chromatography.";
RL Proteomics 8:1346-1361(2008).
RN [24]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156, 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 [25]
RP GLYCOSYLATION AT ASN-156.
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 [26]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-156 AND ASN-176, STRUCTURE
RP OF CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [27]
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 [28]
RP GLYCOSYLATION AT ASN-156; ASN-176 AND SER-346, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.M111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of
RT N-and O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 0:0-0(2011).
CC -!- FUNCTION: Promotes endocytosis, possesses opsonic properties and
CC influences the mineral phase of bone. Shows affinity for calcium
CC and barium ions.
CC -!- SUBUNIT: Alpha-2-HS glycoprotein derives from this precursor, when
CC the connecting peptide is cleaved off. The two chains A and B are
CC held together by a single disulfide bond.
CC -!- INTERACTION:
CC P00519:ABL1; NbExp=1; IntAct=EBI-1223374, EBI-375543;
CC O88736:Hsd17b7 (xeno); NbExp=1; IntAct=EBI-1223374, EBI-2552537;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Synthesized in liver and selectively
CC concentrated in bone matrix. Secreted in plasma. It is also found
CC in dentin in much higher quantities than other plasma proteins.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- PTM: O- and N-glycosylated. O-glycosylated with core 1 or possibly
CC core 8 glycans. N-glycan at Asn-156: Hex5HexNAc4; N-glycan
CC heterogeneity at Asn-176: Hex5HexNAc4 (major) and Hex6HexNAc5
CC (minor).
CC -!- POLYMORPHISM: There are two common alleles, AHSG*1 and AHSG*2.
CC AHSG*1 has Thr-248/Thr-256; AHSG*2 has Met-248/Ser-256.
CC -!- SIMILARITY: Belongs to the fetuin family.
CC -!- SIMILARITY: Contains 2 cystatin fetuin-A-type domains.
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DR EMBL; M16961; AAA51683.1; -; mRNA.
DR EMBL; D67013; BAA22652.1; -; Genomic_DNA.
DR EMBL; AB038689; BAA92189.1; -; Genomic_DNA.
DR EMBL; AK292751; BAF85440.1; -; mRNA.
DR EMBL; AK312969; BAG35808.1; -; mRNA.
DR EMBL; AC068631; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78189.1; -; Genomic_DNA.
DR EMBL; BC048198; AAH48198.1; -; mRNA.
DR EMBL; BC052590; AAH52590.1; -; mRNA.
DR EMBL; D67012; BAA22651.1; -; mRNA.
DR EMBL; AF119895; AAF69649.1; -; mRNA.
DR PIR; A29081; WOHU.
DR RefSeq; NP_001613.2; NM_001622.2.
DR UniGene; Hs.324746; -.
DR ProteinModelPortal; P02765; -.
DR IntAct; P02765; 9.
DR MINT; MINT-5004009; -.
DR STRING; 9606.ENSP00000393887; -.
DR MEROPS; I25.020; -.
DR PhosphoSite; P02765; -.
DR UniCarbKB; P02765; -.
DR DMDM; 112910; -.
DR DOSAC-COBS-2DPAGE; P02765; -.
DR SWISS-2DPAGE; P02765; -.
DR PaxDb; P02765; -.
DR PRIDE; P02765; -.
DR DNASU; 197; -.
DR Ensembl; ENST00000411641; ENSP00000393887; ENSG00000145192.
DR GeneID; 197; -.
DR KEGG; hsa:197; -.
DR CTD; 197; -.
DR GeneCards; GC03P186330; -.
DR H-InvDB; HIX0024338; -.
DR HGNC; HGNC:349; AHSG.
DR HPA; CAB026209; -.
DR HPA; HPA001524; -.
DR HPA; HPA001525; -.
DR MIM; 138680; gene.
DR neXtProt; NX_P02765; -.
DR PharmGKB; PA24642; -.
DR eggNOG; NOG44208; -.
DR HOVERGEN; HBG051607; -.
DR InParanoid; P02765; -.
DR OrthoDB; EOG71K63R; -.
DR ChiTaRS; AHSG; human.
DR GeneWiki; Alpha-2-HS-glycoprotein; -.
DR GenomeRNAi; 197; -.
DR NextBio; 790; -.
DR PMAP-CutDB; P02765; -.
DR PRO; PR:P02765; -.
DR ArrayExpress; P02765; -.
DR Bgee; P02765; -.
DR CleanEx; HS_AHSG; -.
DR Genevestigator; P02765; -.
DR GO; GO:0005615; C:extracellular space; NAS:UniProtKB.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0019210; F:kinase inhibitor activity; NAS:UniProtKB.
DR GO; GO:0006953; P:acute-phase response; IDA:UniProtKB.
DR GO; GO:0030502; P:negative regulation of bone mineralization; ISS:UniProtKB.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0001503; P:ossification; IEA:Ensembl.
DR GO; GO:0006907; P:pinocytosis; NAS:UniProtKB.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IDA:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; NAS:UniProtKB.
DR InterPro; IPR025760; Cystatin_Fetuin_A.
DR InterPro; IPR000010; Prot_inh_cystat.
DR InterPro; IPR001363; Prot_inh_fetuin_CS.
DR Pfam; PF00031; Cystatin; 1.
DR SMART; SM00043; CY; 2.
DR PROSITE; PS51529; CYSTATIN_FETUIN_A; 2.
DR PROSITE; PS01254; FETUIN_1; 1.
DR PROSITE; PS01255; FETUIN_2; 1.
PE 1: Evidence at protein level;
KW Complete proteome; Direct protein sequencing; Disulfide bond;
KW Glycoprotein; Mineral balance; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1 18
FT CHAIN 19 300 Alpha-2-HS-glycoprotein chain A.
FT /FTId=PRO_0000008887.
FT PROPEP 301 340 Connecting peptide.
FT /FTId=PRO_0000008888.
FT CHAIN 341 367 Alpha-2-HS-glycoprotein chain B.
FT /FTId=PRO_0000008889.
FT DOMAIN 27 133 Cystatin fetuin-A-type 1.
FT DOMAIN 144 255 Cystatin fetuin-A-type 2.
FT MOD_RES 138 138 Phosphoserine.
FT MOD_RES 325 325 Phosphoserine (By similarity).
FT MOD_RES 328 328 Phosphoserine (By similarity).
FT MOD_RES 330 330 Phosphoserine.
FT CARBOHYD 156 156 N-linked (GlcNAc...) (complex).
FT /FTId=CAR_000064.
FT CARBOHYD 176 176 N-linked (GlcNAc...) (complex).
FT /FTId=CAR_000065.
FT CARBOHYD 256 256 O-linked (GalNAc...).
FT /FTId=CAR_000066.
FT CARBOHYD 270 270 O-linked (GalNAc...).
FT /FTId=CAR_000067.
FT CARBOHYD 346 346 O-linked (GalNAc...).
FT /FTId=CAR_000068.
FT DISULFID 32 358 Interchain (between A and B chains).
FT DISULFID 89 100
FT DISULFID 114 132
FT DISULFID 146 149
FT DISULFID 208 219
FT DISULFID 230 247
FT VARIANT 142 142 V -> L (in dbSNP:rs7633550).
FT /FTId=VAR_055802.
FT VARIANT 248 248 T -> M (in allele AHSG*2; dbSNP:rs4917).
FT /FTId=VAR_002388.
FT VARIANT 256 256 T -> S (in allele AHSG*2; dbSNP:rs4918).
FT /FTId=VAR_002389.
FT VARIANT 276 276 D -> N (in allele AHSG*5;
FT dbSNP:rs70961709).
FT /FTId=VAR_012474.
FT VARIANT 317 317 R -> C (in allele AHSG*3;
FT dbSNP:rs35457250).
FT /FTId=VAR_012475.
FT CONFLICT 16 16 C -> W (in Ref. 2; BAA22652).
FT CONFLICT 54 54 W -> K (in Ref. 8; AA sequence).
FT CONFLICT 125 125 F -> S (in Ref. 10; BAA22651).
FT CONFLICT 150 182 PLLAPLNDTRVVHAAKAALAAFNAQNNGSNFQL -> MVGW
FT QEGANHKNGAGRSQKQEMAEKMVPEVASG (in Ref.
FT 12; AAF69649).
FT CONFLICT 204 204 S -> C (in Ref. 2; BAA22652).
SQ SEQUENCE 367 AA; 39325 MW; 1AAF0C8D6B7E2789 CRC64;
MKSLVLLLCL AQLWGCHSAP HGPGLIYRQP NCDDPETEEA ALVAIDYINQ NLPWGYKHTL
NQIDEVKVWP QQPSGELFEI EIDTLETTCH VLDPTPVARC SVRQLKEHAV EGDCDFQLLK
LDGKFSVVYA KCDSSPDSAE DVRKVCQDCP LLAPLNDTRV VHAAKAALAA FNAQNNGSNF
QLEEISRAQL VPLPPSTYVE FTVSGTDCVA KEATEAAKCN LLAEKQYGFC KATLSEKLGG
AEVAVTCTVF QTQPVTSQPQ PEGANEAVPT PVVDPDAPPS PPLGAPGLPP AGSPPDSHVL
LAAPPGHQLH RAHYDLRHTF MGVVSLGSPS GEVSHPRKTR TVVQPSVGAA AGPVVPPCPG
RIRHFKV
//
MIM
138680
*RECORD*
*FIELD* NO
138680
*FIELD* TI
*138680 ALPHA-2-HS-GLYCOPROTEIN; AHSG
;;A2HS; AHS; HSGA;;
FETUIN, MOUSE, HOMOLOG OF;;
read moreFETUIN A; FETUA
*FIELD* TX
CLONING
Anderson and Anderson (1977) applied the 2-D electrophoretic technique
of O'Farrell (O'Farrell, 1975) to the analysis of human plasma proteins.
Genetic variants involving charge or size 'should be routinely
detectable in at least 20 proteins at once.' About 30 polypeptides were
identified, including alpha-2HS-glycoprotein (alpha-2-Heremans-Schmid
glycoprotein). They recognized 3 phenotypes reflecting 2 autosomal,
about equally frequent, codominant alleles. Using polyacrylamide gel
isoelectric focusing with immunofixation, Umetsu et al. (1984) described
a polymorphism of alpha-2-HS-glycoproteins with 3 common phenotypes
designated AHS1-1, AHS2-1 and AHS2-2. Cox and Andrews (1983) used silver
stain immunofixation to demonstrate 3 codominant alleles.
A2HS is one of the few 'negative' acute-phase reactants of human plasma.
It promotes endocytosis, has opsonic properties, and, because of its
high affinity for calcium, probably plays some role in the metabolism of
bone where it is concentrated up to 300-fold relative to other plasma
proteins. The concentration of AHSG in bone falls progressively
throughout childhood to adult life. A2HS consists of 2 polypeptide
chains termed A and B. The amino acid sequence of the longer A chain was
determined by Yoshioka et al. (1986) and the amino acid sequence and
carbohydrate sequence of the shorter B chain were reported by Gejyo et
al. (1983).
In search of the human homolog for pp63, a phosphorylated rat hepatic
glycoprotein that inhibits insulin receptor tyrosine kinase, Srinivas et
al. (1993) isolated a DNA clone from a human liver gamma-gt11 cDNA
library. DNA sequence analysis revealed identity with the mRNA product
of the AHSG gene; the amino acid sequences of AHSG and pp63 showed 70%
identity, including complete conservation of the cysteine residues.
Northern blot analysis demonstrated a 1.8-kb mRNA in human liver and a
hepatoma cell line. AHSG purified from human serum specifically
inhibited insulin-stimulated autophosphorylation of the insulin receptor
(INSR; 147670) in vitro and in vivo; ASHG also inhibited insulin-induced
tyrosine phosphorylation of insulin receptor substrate-1 (IRS1; 147545)
and the association of IRS1 with the p85 subunit of
phosphatidylinositol-3 kinase (PIK3R1; 171833) in hepatoma cells. ASHG
did not compete with insulin for binding to INSR. Srinivas et al. (1993)
concluded that human AHSG functions to regulate insulin action at the
insulin receptor tyrosine kinase level.
The product of the AHSG gene is commonly referred to as fetuin in
species other than the human (Jahnen-Dechent, 1998). Terkelsen et al.
(1998) described the distribution of protein and mRNA in embryonic and
neonatal rat tissues. The first fetal plasma protein to be described was
fetuin, which was purified from fetal and newborn calf serum by Pedersen
(1944). Fetuin was subsequently shown to be a very abundant plasma
protein in fetal cattle, sheep, pig, and goat, and also to be present in
humans and rodents.
MAPPING
Eiberg et al. (1984) found linkage of A2HS with pseudocholinesterase-E1
(BCHE; 177400)--maximum male lod = 5.02 at theta = 0.10 and with
transferrin (TF; 190000). In their data, TF and BCHE showed peak male
lod = 2.21 at theta = 0.24. The only positive lod score with the
centromere of chromosome 3, which from evidence skimpy at that time was
thought to carry the TF-BCHE linkage group, was with TF--0.47 at theta
0.23. They proposed that the order is cen--TF--BCHE--A2HS. From studies
in a large Hutterite kindred, Zelinski et al. (1987) concluded that the
order of the 3 loci is AHSG-TF-BCHE. From study of a child with a
duplication of chromosome 3, Cox et al. (1984) concluded that the AHSG
locus is located in the 3cen-q13 segment.
Cox and Francke (1985) used hybrids of human fetal liver and rat
hepatoma cells to study the location of the genes for serum proteins. In
this way they gave direct assignment of the orosomucoid gene to
chromosome 9 and the alpha-2-HS-glycoprotein gene to chromosome 3, these
having been previously assigned by linkage to 'anchor' loci.
Boutin et al. (1985) estimated the frequency of the alleles HSGA1 and
HSGA2 (their symbology) to be 0.65 and 0.35, respectively. Lee et al.
(1987) showed that the A and B chains of AHSG are encoded by a single
gene. They used the AHSG cDNA to map the gene to 3q21-qter by analysis
of human-mouse somatic cell hybrids. By in situ hybridization, Magnuson
et al. (1988) narrowed the assignment to 3q27-q29.
While constructing a contig in the 3q27 region, Rizzu and Baldini (1995)
identified 2 YAC clones that were positive for the polymorphic marker
D3S1602. One was also positive for a sequence tagged site (STS) derived
from the cininogen (or kininogen) gene (KNG; 612358). Because of the
known evolutionary and structural relationship of KNG to other members
of the cystatin gene superfamily, they tested the physical linkage of
AHSG, KNG, and histidine-rich glycoprotein (HRG; 142640), all of which
were previously mapped to 3q. The results showed colocalization of the 3
genes to 2 independent, partially overlapping YAC clones within
approximately 1 Mb of DNA. Fluorescence in situ hybridization confirmed
the location of the 2 YAC clones to 3q27.
GENE STRUCTURE
Osawa et al. (1997) determined that the coding region of the AHSG gene
spans approximately 8.2 kb and contains 7 exons. The 5-prime promoter
region contains several characteristic sequences such as an A/T-rich
sequence, C/EBP-binding site, and hepatocyte nuclear factor-5 (HNF5) and
serum response factor (SRF; 600589) sites.
MOLECULAR GENETICS
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
Eiberg et al. (1984) studied the AHSG system by means of 1-dimensional
isoelectric focusing combined with immunofixation on cellulose acetate
strips. In the Danish population, 2 frequent alleles, S and F, with
frequencies of 0.357 and 0.635, respectively, and a rare allele, R, with
frequency 0.008, were recognized. Umetsu et al. (1988) reported the
polymorphism of AHSG in a population in the Philippines.
To identify the molecular basis of the 2 common AHSG alleles, AHSG*1 and
AHSG*2, Osawa et al. (1997) sequenced AHSG cDNA obtained by RT-PCR from
polyadenylated RNA of 7 liver tissue samples. Nucleotide substitutions
of C-to-T at amino acid position 230 (thr230met; 138680.0001) and C-to-G
at position 238 (thr238ser; 138680.0002) were common among samples
exhibiting phenotypes 2-1 or 2. Since these substitutions were expected
to give rise to an NlaIII site and a SacI site, respectively, for the
potential AHSG*2, Osawa et al. (1997) analyzed these substitutions by
PCR-RFLP using genomic DNA of 68 individuals. The results were
consistent with the IEF analysis of the corresponding serum, indicating
that AHSG*1 is characterized by ACG (thr) at position 230 in exon 6 and
ACC (thr) at position 238 in exon 7, and that AHSG*2 is characterized by
ATG (met) at position 230 and AGC (ser) at position 238.
In 176 unrelated Japanese individuals, Osawa et al. (2005) found
significant differences in AHSG protein levels between 3 major AHSG
genotypes, with the lowest levels in AHSG*2 homozygotes. There was no
association between AHSG levels and serum calcium values, but there was
a significant negative correlation with free phosphate levels. Osawa et
al. (2005) concluded that the AHSG polymorphism causes hereditary
variation in serum AHSG and phosphate levels.
Lavebratt et al. (2005) genotyped 356 overweight or obese (see 601665)
and 148 lean Swedish men for 4 SNPs in the AHSG gene and found that
homozygosity for the AHSG*2 haplotype (see 138680.0001) conferred an
increased risk for leanness (OR, 1.90; p = 0.027). Lavebratt et al.
(2005) concluded that AHSG modulates body mass.
Lehtinen et al. (2007) investigated whether polymorphisms in AHSG
contribute to the development of calcified atherosclerotic plaque in the
coronary and carotid arteries and to carotid artery intima-media
thickness. Four SNPs in AHSG were nominally associated with coronary
artery calcified plaque in European Americans with diabetes mellitus
type 2 (T2DM; 125853) (P less than 0.05). Two 3-SNP haplotypes in the
exon 6-7 region were associated with coronary calcification in European
Americans with T2DM (P less than 0.06). They concluded that sequence
variants in the AHSG gene affect the extent of coronary calcification in
T2DM-affected European Americans, consistent with the known biologic
role of AHSG in vascular calcification.
ANIMAL MODEL
Jahnen-Dechent et al. (1997) proposed that the fetuin family of serum
proteins inhibits unwanted mineralization. To test this hypothesis in
animals, they cloned the mouse fetuin gene and generated mice lacking
fetuin. Expression studies demonstrated that mice homozygous for the
gene deletion lacked fetuin protein and that mice heterozygous for the
null mutation produced roughly half the amount of fetuin protein
produced by wildtype mice. Fetuin-deficient mice were fertile and showed
no gross anatomic abnormalities. However, the serum inhibition of
apatite formation was compromised in these mice as well as in
heterozygotes. In addition, some homozygous fetuin-deficient female
ex-breeders developed ectopic microcalcifications in soft tissues. These
results corroborate a role for fetuin in serum calcium homeostasis. The
fact that generalized ectopic calcification did not occur in
fetuin-deficient mice proved that additional inhibitors of phase
separation exist in serum.
In Ahsg-null mice, Mathews et al. (2002) observed increased basal and
insulin (INS; 176730)-stimulated phosphorylation of the insulin receptor
(147670) and the downstream signaling molecules mitogen-activated
protein kinase (see 176948) and Akt (see 164730) in liver and skeletal
muscle. Glucose and insulin tolerance tests in Ahsg-null mice indicated
significantly enhanced glucose clearance and insulin sensitivity. When
fed a high-fat diet, Ahsg-null mice were resistant to weight gain,
demonstrated significantly decreased body fat, and remained insulin
sensitive. Mathews et al. (2002) suggested that AHSG may play a
significant role in regulating postprandial glucose disposal, insulin
sensitivity, weight gain, and fat accumulation.
*FIELD* AV
.0001
LEANNESS, SUSCEPTIBILITY TO
AHSG, THR230MET
Osawa et al. (1997) demonstrated that there is a double difference in
the structure of the AHSG*1 and AHSG*2 alleles. AHSG*1 is characterized
by ACG (thr) at position 230 in exon 6 and ACC (thr) at position 238 in
exon 7 (138680.0002); AHSG*2 is characterized by ATG (met) at position
230 and AGC (ser) at position 238. Osawa et al. (2005) found association
between the AHSG*2 haplotype and lower AHSG protein levels.
Lavebratt et al. (2005) genotyped 356 overweight or obese (see 601665)
and 148 lean Swedish men for 1 intronic and 3 nonsynonymous SNPs in the
AHSG gene and found that homozygosity for a haplotype comprising the
dbSNP rs2593813 G allele and the AHSG*2 allele (dbSNP rs4917 met and
dbSNP rs4918 ser) conferred an increased risk for leanness (OR, 1.90; p
= 0.027). The authors designated the polymorphism THR248MET based on a
different numbering system. Lavebratt et al. (2005) suggested that a low
level of AHSG is protective against fatness.
.0002
LEANNESS, SUSCEPTIBILITY TO
AHSG, THR238SER
See 138680.0001 and Lavebratt et al. (2005).
Lavebratt et al. (2005) designated the polymorphism THR256SER based on a
different numbering system.
.0003
LEANNESS, SUSCEPTIBILITY TO
AHSG, 1639A-G
See 138680.0001 and Lavebratt et al. (2005).
*FIELD* SA
Cox et al. (1986); Umetsu et al. (1984); Umetsu et al. (1987); Umetsu
et al. (1986)
*FIELD* RF
1. Anderson, L.; Anderson, N. G.: High resolution two-dimensional
electrophoresis of human plasma proteins. Proc. Nat. Acad. Sci. 74:
5421-5425, 1977.
2. Boutin, B.; Feng, S. H.; Arnaud, P.: The genetic polymorphism
of alpha(2)-HS glycoprotein: study by ultrathin-layer isoelectric
focusing and immunoblot. Am. J. Hum. Genet. 37: 1098-1105, 1985.
3. Cox, D. W.; Andrews, B. J.: Silver stain immunofixation for alpha-2-HS-glycoprotein:
a new method for detection of protein heterogeneity.In: Stathakos,
D.: Electrophoresis '82. Berlin: Walter de Gruyter (pub.) 1983.
Pp. 243-247.
4. Cox, D. W.; Andrews, B. J.; Wills, D. E.: Genetic polymorphism
of alpha-2-HS-glycoprotein. Am. J. Hum. Genet. 38: 699-706, 1986.
5. Cox, D. W.; Francke, U.: Direct assignment of orosomucoid to human
chromosome 9 and alpha-2-HS-glycoprotein to chromosome 3 using human
fetal liver x rat hepatoma hybrids. Hum. Genet. 70: 109-115, 1985.
6. Cox, D. W.; Francke, U.; Allderdice, P. W.; McAlpine, P. J.: Gene
mapping of human serum proteins using hepatoma hybrids and human chromosome
deletions and duplications. Genetics 107 (suppl.): s22-s23, 1984.
7. Eiberg, H.; Mohr, J.; Nielsen, L. S.: A2HS: new methods of phenotyping
and analysis of linkage relations: assignment to chromosome 3. (Abstract) Cytogenet.
Cell Genet. 37: 461 only, 1984.
8. Gejyo, F.; Chang, J.-L.; Burgi, W.; Schmid, K.; Offner, G. D.;
Troxler, R. F.; Van Halbeek, H.; Dorland, L.; Gerwig, G. J.; Vliegenthart,
J. F. G.: Characterization of the B-chain of human plasma alpha(2)HS-glycoprotein:
the complete amino acid sequence and primary structure of its heteroglycan. J.
Biol. Chem. 258: 4966-4971, 1983.
9. Jahnen-Dechent, W.: Personal Communication. Meinz, Germany
7/22/1998.
10. Jahnen-Dechent, W.; Schinke, T.; Trindl, A.; Muller-Esterl, W.;
Sablitzky, F.; Kaiser, S.; Blessing, M.: Cloning and targeted deletion
of the mouse fetuin gene. J. Biol. Chem. 272: 31496-31503, 1997.
11. Lavebratt, C.; Wahlqvist, S.; Nordfors, L.; Hoffstedt, J.; Arner,
P.: AHSG gene variant is associated with leanness among Swedish men. Hum.
Genet. 117: 54-60, 2005.
12. Lee, C.-C.; Bowman, B. H.; Yang, F.: Human alpha-2-HS-glycoprotein:
the A and B chains with a connecting sequence are encoded by a single
mRNA transcript. Proc. Nat. Acad. Sci. 84: 4403-4407, 1987.
13. Lehtinen, A. B.; Burdon, K. P.; Lewis, J. P.; Langefeld, C. D.;
Ziegler, J. T.; Rich, S. S.; Register, T. C.; Carr, J. J.; Freedman,
B. I.; Bowden, D. W.: Association of alpha-2-Heremans-Schmid glycoprotein
polymorphisms with subclinical atherosclerosis. J. Clin. Endocr.
Metab. 92: 345-352, 2007.
14. Magnuson, V. L.; McCombs, J. L.; Lee, C.-C.; Yang, F.; Bowman,
B. H.; McGill, J. R.: Human alpha-2-HS-glycoprotein localized to
3q27-q29 by in situ hybridization. Cytogenet. Cell Genet. 47: 72-74,
1988.
15. Mathews, S. T.; Singh, G. P.; Ranalletta, M.; Cintron, V. J.;
Qiang, X.; Goustin, A. S.; Jen, K.-L. C.; Charron, M. J.; Jahnen-Dechent,
W.; Grunberger, G.: Improved insulin sensitivity and resistance to
weight gain in mice null for the Ahsg gene. Diabetes 51: 2450-2458,
2002.
16. O'Farrell, P. H.: High resolution two-dimensional electrophoresis
of proteins. J. Biol. Chem. 250: 4007-4021, 1975.
17. Osawa, M.; Tian, W.; Horiuchi, H.; Kaneko, M.; Umetsu, K.: Association
of alpha-2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG
and phosphate serum levels. Hum. Genet. 116: 146-151, 2005.
18. Osawa, M.; Umetsu, K.; Ohki, T.; Nagasawa, T.; Suzuki, T.; Takeichi,
S.: Molecular evidence for human alpha2-HS glycoprotein (AHSG) polymorphism. Hum.
Genet. 99: 18-21, 1997.
19. Osawa, M.; Umetsu, K.; Sato, M.; Ohki, T.; Yukawa, N.; Suzuki,
T.; Takeichi, S.: Structure of the gene encoding human alpha 2-HS
glycoprotein (AHSG). Gene 196: 121-125, 1997.
20. Pedersen, K. O.: Fetuin, a new globulin isolated from serum.
(Letter) Nature 154: 575, 1944.
21. Rizzu, P.; Baldini, A.: Three members of the human cystatin gene
superfamily, AHSG, HRG, and KNG, map within one megabase of genomic
DNA at 3q27. Cytogenet. Cell Genet. 70: 26-28, 1995.
22. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.
23. Srinivas, P. R.; Wagner, A. S.; Reddy, L. V.; Deutsch, D. D.;
Leon, M. A.; Goustin, A. S.; Grunberger, G.: Serum alpha(2)-HS-glycoprotein
is an inhibitor of the human insulin receptor at the tyrosine kinase
level. Molec. Endocr. 7: 1445-1455, 1993.
24. Terkelsen, O. B. F.; Jahnen-Dechent, W.; Nielsen, H.; Moos, T.;
Fink, E.; Nawratil, P.; Muller-Esterl, W.; Mollgard, K.: Rat fetuin:
distribution of protein and mRNA in embryonic and neonatal rat tissues. Anat.
Embryol. 197: 125-133, 1998.
25. Umetsu, K.; Kashimura, S.; Ikeda, N.; Suzuki, T.: A new alpha-2-HS-glycoprotein
typing by isoelectric focusing. Hum. Genet. 67: 70-71, 1984.
26. Umetsu, K.; Kashimura, S.; Ikeda, N.; Suzuki, T.: A new alpha-2-HS-glycoprotein
allele (AHS*5*) in two Japanese families. Hum. Genet. 68: 264-265,
1984.
27. Umetsu, K.; Yuasa, I.; Ikuta, M.; Suzuki, T.: Alpha-2-HS-glycoprotein
(A2HS) polymorphism in a Japanese population: existence of two new
variants. Jpn. J. Hum. Genet. 32: 263-266, 1987.
28. Umetsu, K.; Yuasa, I.; Nishimura, H.; Sasaki, H.; Suzuki, T.:
Genetic polymorphisms of orosomucoid and alpha-2-HS-glycoprotein in
a Philippine population. Hum. Hered. 38: 287-290, 1988.
29. Umetsu, K.; Yuasa, I.; Suzuki, T.: The polymorphism of desialyzed
alpha-2-HS-glycoprotein (AHS): isoelectric focusing in 2.5M urea as
a method for identification of genetic variants. Hum. Genet. 73:
372-373, 1986.
30. Yoshioka, Y.; Gejyo, F.; Marti, T.; Rickli, E. E.; Burgi, W.;
Offner, G. D.; Troxler, R. F.; Schmid, K.: The complete amino acid
sequence of the A-chain of human plasma alpha-2HS-glycoprotein. J.
Biol. Chem. 261: 1665-1676, 1986.
31. Zelinski, T.; Kaita, H.; Lewis, M.; Coghlan, G.; Craig, D.: The
sequence of chromosome 3 loci AHSG:TF:CHE1. Hum. Hered. 37: 1-6,
1987.
*FIELD* CN
Marla J. F. O'Neill - reorganized: 12/19/2007
Marla J. F. O'Neill - updated: 7/5/2005
Marla J. F. O'Neill - updated: 3/30/2005
Marla J. F. O'Neill - updated: 3/23/2005
Victor A. McKusick - updated: 9/4/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
mgross: 10/24/2008
carol: 12/19/2007
wwang: 7/13/2005
wwang: 7/11/2005
wwang: 7/8/2005
terry: 7/5/2005
carol: 3/30/2005
wwang: 3/30/2005
tkritzer: 3/28/2005
tkritzer: 3/23/2005
mgross: 5/22/2001
mgross: 4/8/1999
dkim: 9/9/1998
carol: 9/8/1998
terry: 9/4/1998
mark: 1/15/1997
jenny: 1/10/1997
terry: 12/30/1996
mark: 8/18/1995
pfoster: 2/18/1994
carol: 7/22/1993
supermim: 3/16/1992
carol: 2/8/1991
supermim: 3/20/1990
*RECORD*
*FIELD* NO
138680
*FIELD* TI
*138680 ALPHA-2-HS-GLYCOPROTEIN; AHSG
;;A2HS; AHS; HSGA;;
FETUIN, MOUSE, HOMOLOG OF;;
read moreFETUIN A; FETUA
*FIELD* TX
CLONING
Anderson and Anderson (1977) applied the 2-D electrophoretic technique
of O'Farrell (O'Farrell, 1975) to the analysis of human plasma proteins.
Genetic variants involving charge or size 'should be routinely
detectable in at least 20 proteins at once.' About 30 polypeptides were
identified, including alpha-2HS-glycoprotein (alpha-2-Heremans-Schmid
glycoprotein). They recognized 3 phenotypes reflecting 2 autosomal,
about equally frequent, codominant alleles. Using polyacrylamide gel
isoelectric focusing with immunofixation, Umetsu et al. (1984) described
a polymorphism of alpha-2-HS-glycoproteins with 3 common phenotypes
designated AHS1-1, AHS2-1 and AHS2-2. Cox and Andrews (1983) used silver
stain immunofixation to demonstrate 3 codominant alleles.
A2HS is one of the few 'negative' acute-phase reactants of human plasma.
It promotes endocytosis, has opsonic properties, and, because of its
high affinity for calcium, probably plays some role in the metabolism of
bone where it is concentrated up to 300-fold relative to other plasma
proteins. The concentration of AHSG in bone falls progressively
throughout childhood to adult life. A2HS consists of 2 polypeptide
chains termed A and B. The amino acid sequence of the longer A chain was
determined by Yoshioka et al. (1986) and the amino acid sequence and
carbohydrate sequence of the shorter B chain were reported by Gejyo et
al. (1983).
In search of the human homolog for pp63, a phosphorylated rat hepatic
glycoprotein that inhibits insulin receptor tyrosine kinase, Srinivas et
al. (1993) isolated a DNA clone from a human liver gamma-gt11 cDNA
library. DNA sequence analysis revealed identity with the mRNA product
of the AHSG gene; the amino acid sequences of AHSG and pp63 showed 70%
identity, including complete conservation of the cysteine residues.
Northern blot analysis demonstrated a 1.8-kb mRNA in human liver and a
hepatoma cell line. AHSG purified from human serum specifically
inhibited insulin-stimulated autophosphorylation of the insulin receptor
(INSR; 147670) in vitro and in vivo; ASHG also inhibited insulin-induced
tyrosine phosphorylation of insulin receptor substrate-1 (IRS1; 147545)
and the association of IRS1 with the p85 subunit of
phosphatidylinositol-3 kinase (PIK3R1; 171833) in hepatoma cells. ASHG
did not compete with insulin for binding to INSR. Srinivas et al. (1993)
concluded that human AHSG functions to regulate insulin action at the
insulin receptor tyrosine kinase level.
The product of the AHSG gene is commonly referred to as fetuin in
species other than the human (Jahnen-Dechent, 1998). Terkelsen et al.
(1998) described the distribution of protein and mRNA in embryonic and
neonatal rat tissues. The first fetal plasma protein to be described was
fetuin, which was purified from fetal and newborn calf serum by Pedersen
(1944). Fetuin was subsequently shown to be a very abundant plasma
protein in fetal cattle, sheep, pig, and goat, and also to be present in
humans and rodents.
MAPPING
Eiberg et al. (1984) found linkage of A2HS with pseudocholinesterase-E1
(BCHE; 177400)--maximum male lod = 5.02 at theta = 0.10 and with
transferrin (TF; 190000). In their data, TF and BCHE showed peak male
lod = 2.21 at theta = 0.24. The only positive lod score with the
centromere of chromosome 3, which from evidence skimpy at that time was
thought to carry the TF-BCHE linkage group, was with TF--0.47 at theta
0.23. They proposed that the order is cen--TF--BCHE--A2HS. From studies
in a large Hutterite kindred, Zelinski et al. (1987) concluded that the
order of the 3 loci is AHSG-TF-BCHE. From study of a child with a
duplication of chromosome 3, Cox et al. (1984) concluded that the AHSG
locus is located in the 3cen-q13 segment.
Cox and Francke (1985) used hybrids of human fetal liver and rat
hepatoma cells to study the location of the genes for serum proteins. In
this way they gave direct assignment of the orosomucoid gene to
chromosome 9 and the alpha-2-HS-glycoprotein gene to chromosome 3, these
having been previously assigned by linkage to 'anchor' loci.
Boutin et al. (1985) estimated the frequency of the alleles HSGA1 and
HSGA2 (their symbology) to be 0.65 and 0.35, respectively. Lee et al.
(1987) showed that the A and B chains of AHSG are encoded by a single
gene. They used the AHSG cDNA to map the gene to 3q21-qter by analysis
of human-mouse somatic cell hybrids. By in situ hybridization, Magnuson
et al. (1988) narrowed the assignment to 3q27-q29.
While constructing a contig in the 3q27 region, Rizzu and Baldini (1995)
identified 2 YAC clones that were positive for the polymorphic marker
D3S1602. One was also positive for a sequence tagged site (STS) derived
from the cininogen (or kininogen) gene (KNG; 612358). Because of the
known evolutionary and structural relationship of KNG to other members
of the cystatin gene superfamily, they tested the physical linkage of
AHSG, KNG, and histidine-rich glycoprotein (HRG; 142640), all of which
were previously mapped to 3q. The results showed colocalization of the 3
genes to 2 independent, partially overlapping YAC clones within
approximately 1 Mb of DNA. Fluorescence in situ hybridization confirmed
the location of the 2 YAC clones to 3q27.
GENE STRUCTURE
Osawa et al. (1997) determined that the coding region of the AHSG gene
spans approximately 8.2 kb and contains 7 exons. The 5-prime promoter
region contains several characteristic sequences such as an A/T-rich
sequence, C/EBP-binding site, and hepatocyte nuclear factor-5 (HNF5) and
serum response factor (SRF; 600589) sites.
MOLECULAR GENETICS
Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).
Eiberg et al. (1984) studied the AHSG system by means of 1-dimensional
isoelectric focusing combined with immunofixation on cellulose acetate
strips. In the Danish population, 2 frequent alleles, S and F, with
frequencies of 0.357 and 0.635, respectively, and a rare allele, R, with
frequency 0.008, were recognized. Umetsu et al. (1988) reported the
polymorphism of AHSG in a population in the Philippines.
To identify the molecular basis of the 2 common AHSG alleles, AHSG*1 and
AHSG*2, Osawa et al. (1997) sequenced AHSG cDNA obtained by RT-PCR from
polyadenylated RNA of 7 liver tissue samples. Nucleotide substitutions
of C-to-T at amino acid position 230 (thr230met; 138680.0001) and C-to-G
at position 238 (thr238ser; 138680.0002) were common among samples
exhibiting phenotypes 2-1 or 2. Since these substitutions were expected
to give rise to an NlaIII site and a SacI site, respectively, for the
potential AHSG*2, Osawa et al. (1997) analyzed these substitutions by
PCR-RFLP using genomic DNA of 68 individuals. The results were
consistent with the IEF analysis of the corresponding serum, indicating
that AHSG*1 is characterized by ACG (thr) at position 230 in exon 6 and
ACC (thr) at position 238 in exon 7, and that AHSG*2 is characterized by
ATG (met) at position 230 and AGC (ser) at position 238.
In 176 unrelated Japanese individuals, Osawa et al. (2005) found
significant differences in AHSG protein levels between 3 major AHSG
genotypes, with the lowest levels in AHSG*2 homozygotes. There was no
association between AHSG levels and serum calcium values, but there was
a significant negative correlation with free phosphate levels. Osawa et
al. (2005) concluded that the AHSG polymorphism causes hereditary
variation in serum AHSG and phosphate levels.
Lavebratt et al. (2005) genotyped 356 overweight or obese (see 601665)
and 148 lean Swedish men for 4 SNPs in the AHSG gene and found that
homozygosity for the AHSG*2 haplotype (see 138680.0001) conferred an
increased risk for leanness (OR, 1.90; p = 0.027). Lavebratt et al.
(2005) concluded that AHSG modulates body mass.
Lehtinen et al. (2007) investigated whether polymorphisms in AHSG
contribute to the development of calcified atherosclerotic plaque in the
coronary and carotid arteries and to carotid artery intima-media
thickness. Four SNPs in AHSG were nominally associated with coronary
artery calcified plaque in European Americans with diabetes mellitus
type 2 (T2DM; 125853) (P less than 0.05). Two 3-SNP haplotypes in the
exon 6-7 region were associated with coronary calcification in European
Americans with T2DM (P less than 0.06). They concluded that sequence
variants in the AHSG gene affect the extent of coronary calcification in
T2DM-affected European Americans, consistent with the known biologic
role of AHSG in vascular calcification.
ANIMAL MODEL
Jahnen-Dechent et al. (1997) proposed that the fetuin family of serum
proteins inhibits unwanted mineralization. To test this hypothesis in
animals, they cloned the mouse fetuin gene and generated mice lacking
fetuin. Expression studies demonstrated that mice homozygous for the
gene deletion lacked fetuin protein and that mice heterozygous for the
null mutation produced roughly half the amount of fetuin protein
produced by wildtype mice. Fetuin-deficient mice were fertile and showed
no gross anatomic abnormalities. However, the serum inhibition of
apatite formation was compromised in these mice as well as in
heterozygotes. In addition, some homozygous fetuin-deficient female
ex-breeders developed ectopic microcalcifications in soft tissues. These
results corroborate a role for fetuin in serum calcium homeostasis. The
fact that generalized ectopic calcification did not occur in
fetuin-deficient mice proved that additional inhibitors of phase
separation exist in serum.
In Ahsg-null mice, Mathews et al. (2002) observed increased basal and
insulin (INS; 176730)-stimulated phosphorylation of the insulin receptor
(147670) and the downstream signaling molecules mitogen-activated
protein kinase (see 176948) and Akt (see 164730) in liver and skeletal
muscle. Glucose and insulin tolerance tests in Ahsg-null mice indicated
significantly enhanced glucose clearance and insulin sensitivity. When
fed a high-fat diet, Ahsg-null mice were resistant to weight gain,
demonstrated significantly decreased body fat, and remained insulin
sensitive. Mathews et al. (2002) suggested that AHSG may play a
significant role in regulating postprandial glucose disposal, insulin
sensitivity, weight gain, and fat accumulation.
*FIELD* AV
.0001
LEANNESS, SUSCEPTIBILITY TO
AHSG, THR230MET
Osawa et al. (1997) demonstrated that there is a double difference in
the structure of the AHSG*1 and AHSG*2 alleles. AHSG*1 is characterized
by ACG (thr) at position 230 in exon 6 and ACC (thr) at position 238 in
exon 7 (138680.0002); AHSG*2 is characterized by ATG (met) at position
230 and AGC (ser) at position 238. Osawa et al. (2005) found association
between the AHSG*2 haplotype and lower AHSG protein levels.
Lavebratt et al. (2005) genotyped 356 overweight or obese (see 601665)
and 148 lean Swedish men for 1 intronic and 3 nonsynonymous SNPs in the
AHSG gene and found that homozygosity for a haplotype comprising the
dbSNP rs2593813 G allele and the AHSG*2 allele (dbSNP rs4917 met and
dbSNP rs4918 ser) conferred an increased risk for leanness (OR, 1.90; p
= 0.027). The authors designated the polymorphism THR248MET based on a
different numbering system. Lavebratt et al. (2005) suggested that a low
level of AHSG is protective against fatness.
.0002
LEANNESS, SUSCEPTIBILITY TO
AHSG, THR238SER
See 138680.0001 and Lavebratt et al. (2005).
Lavebratt et al. (2005) designated the polymorphism THR256SER based on a
different numbering system.
.0003
LEANNESS, SUSCEPTIBILITY TO
AHSG, 1639A-G
See 138680.0001 and Lavebratt et al. (2005).
*FIELD* SA
Cox et al. (1986); Umetsu et al. (1984); Umetsu et al. (1987); Umetsu
et al. (1986)
*FIELD* RF
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*FIELD* CN
Marla J. F. O'Neill - reorganized: 12/19/2007
Marla J. F. O'Neill - updated: 7/5/2005
Marla J. F. O'Neill - updated: 3/30/2005
Marla J. F. O'Neill - updated: 3/23/2005
Victor A. McKusick - updated: 9/4/1998
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
mgross: 10/24/2008
carol: 12/19/2007
wwang: 7/13/2005
wwang: 7/11/2005
wwang: 7/8/2005
terry: 7/5/2005
carol: 3/30/2005
wwang: 3/30/2005
tkritzer: 3/28/2005
tkritzer: 3/23/2005
mgross: 5/22/2001
mgross: 4/8/1999
dkim: 9/9/1998
carol: 9/8/1998
terry: 9/4/1998
mark: 1/15/1997
jenny: 1/10/1997
terry: 12/30/1996
mark: 8/18/1995
pfoster: 2/18/1994
carol: 7/22/1993
supermim: 3/16/1992
carol: 2/8/1991
supermim: 3/20/1990