RBCC

Full text data of SERPINC1

SERPINC1 (AT3) [Confidence: low (only semi-automatic identification from reviews)]
Antithrombin-III; ATIII (Serpin C1; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P01008
ID ANT3_HUMAN Reviewed; 464 AA.
AC P01008; B2R6P0; P78439; P78447; Q13815; Q5TC78; Q7KZ43; Q7KZ97;
read moreAC Q9UC78;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 22-JAN-2014, entry version 186.
DE RecName: Full=Antithrombin-III;
DE Short=ATIII;
DE AltName: Full=Serpin C1;
DE Flags: Precursor;
GN Name=SERPINC1; Synonyms=AT3; ORFNames=PRO0309;
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 [GENOMIC DNA].
RX PubMed=6298709; DOI=10.1093/nar/10.24.8113;
RA Bock S.C., Wion K.L., Vehar G.A., Lawn R.M.;
RT "Cloning and expression of the cDNA for human antithrombin III.";
RL Nucleic Acids Res. 10:8113-8125(1982).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6572945; DOI=10.1073/pnas.80.7.1845;
RA Chandra T., Stackhouse R., Kidd V.J., Woo S.L.C.;
RT "Isolation and sequence characterization of a cDNA clone of human
RT antithrombin III.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:1845-1848(1983).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT AT3D MET-438.
RA Tsuji H., Takada O., Nakagawa M., Tanaka S., Hashimoto-Gotoh T.;
RT "Hereditary antithrombin III deficiency: identification of an
RT arginine-406 to methionine point mutation near protease reactive
RT site.";
RL (In) Yoshida T.O., Wilson J.M. (eds.);
RL Molecular approaches to the study and treatment of Human diseases,
RL pp.51-55, Elsevier, Amsterdam (1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8476848; DOI=10.1021/bi00067a008;
RA Olds R.J., Lane D.A., Chowdhury V., de Stefano V., Leone G.,
RA Thein S.L.;
RT "Complete nucleotide sequence of the antithrombin gene: evidence for
RT homologous recombination causing thrombophilia.";
RL Biochemistry 32:4216-4224(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Fetal liver;
RA Zhang C., Yu Y., Zhang S., Wei H., Bi J., Zhou G., Dong C., Zai Y.,
RA Xu W., Gao F., Liu M., He F.;
RT "Functional prediction of the coding sequences of 75 new genes deduced
RT by analysis of cDNA clones from human fetal liver.";
RL Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLU-30 AND ALA-147.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [9]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP PROTEIN SEQUENCE OF 33-464, GLYCOSYLATION AT ASN-128; ASN-167; ASN-187
RP AND ASN-224, AND DISULFIDE BONDS.
RA Petersen T.E., Dudek-Wojciechowska G., Sottrup-Jensen L.,
RA Magnusson S.;
RT "Primary structure of antithrombin-III (heparin cofactor). Partial
RT homology between alpha-1-antitrypsin and antithrombin-III.";
RL (In) Collen D., Wiman B., Verstraete M. (eds.);
RL The physiological inhibitors of blood coagulation and fibrinolysis,
RL pp.43-54, Elsevier, Amsterdam (1979).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 42-464.
RX PubMed=6305982;
RA Prochownik E.V., Markham A.F., Orkin S.H.;
RT "Isolation of a cDNA clone for human antithrombin III.";
RL J. Biol. Chem. 258:8389-8394(1983).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 137-208, AND VARIANT AT3D
RP LEU-439.
RX PubMed=3191114; DOI=10.1021/bi00416a052;
RA Bock S.C., Marrinan J.A., Radziejewska E.;
RT "Antithrombin III Utah: proline-407 to leucine mutation in a highly
RT conserved region near the inhibitor reactive site.";
RL Biochemistry 27:6171-6178(1988).
RN [13]
RP PROTEIN SEQUENCE OF 371-425, MASS SPECTROMETRY, AND VARIANT AT3D
RP THR-414.
RC TISSUE=Plasma;
RX PubMed=7734359; DOI=10.1111/j.1365-2141.1995.tb08368.x;
RA Lindo V.S., Kakkar V.V., Learmonth M., Melissari E., Zappacosta F.,
RA Panico M., Morris H.R.;
RT "Antithrombin-TRI (Ala382 to Thr) causing severe thromboembolic
RT tendency undergoes the S-to-R transition and is associated with a
RT plasma-inactive high-molecular-weight complex of aggregated
RT antithrombin.";
RL Br. J. Haematol. 89:589-601(1995).
RN [14]
RP REACTIVE SITE.
RX PubMed=7238875; DOI=10.1016/0014-5793(81)80255-4;
RA Bjoerk I., Danielsson A., Fenton J.W. II, Joernvall H.;
RT "The site in human antithrombin for functional proteolytic cleavage by
RT human thrombin.";
RL FEBS Lett. 126:257-260(1981).
RN [15]
RP HEPARIN-BINDING SITE.
RX PubMed=6693405;
RA Blackburn M.N., Smith R.L., Carson J., Sibley C.C.;
RT "The heparin-binding site of antithrombin III. Identification of a
RT critical tryptophan in the amino acid sequence.";
RL J. Biol. Chem. 259:939-941(1984).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-187, AND MASS
RP SPECTROMETRY.
RC TISSUE=Bile;
RX PubMed=15084671; DOI=10.1074/mcp.M400015-MCP200;
RA Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H.,
RA Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A.;
RT "A proteomic analysis of human bile.";
RL Mol. Cell. Proteomics 3:715-728(2004).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-128 AND ASN-187, 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 [18]
RP FUNCTION IN MEMBRANE-ANCHORED SERINE PROTEASE TMPRSS7 INHIBITION, AND
RP HETERODIMER WITH TMPRSS7.
RX PubMed=15853774; DOI=10.1042/BJ20050299;
RA Szabo R., Netzel-Arnett S., Hobson J.P., Antalis T.M., Bugge T.H.;
RT "Matriptase-3 is a novel phylogenetically preserved membrane-anchored
RT serine protease with broad serpin reactivity.";
RL Biochem. J. 390:231-242(2005).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-128; ASN-187 AND ASN-224,
RP 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 [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-224, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-128 AND ASN-187, 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 [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-187, STRUCTURE OF
RP 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 [23]
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 [24]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
RX PubMed=8087553; DOI=10.1016/S0969-2126(00)00028-9;
RA Carrell R.W., Stein P.E., Fermi G., Wardell M.R.;
RT "Biological implications of a 3 A structure of dimeric antithrombin.";
RL Structure 2:257-270(1994).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS).
RX PubMed=7656006; DOI=10.1038/nsb0194-48;
RA Schreuder H.A., de Boer B., Dijkema R., Mulders J., Theunissen H.J.M.,
RA Grootenhuis P.D.J., Hol W.G.J.;
RT "The intact and cleaved human antithrombin III complex as a model for
RT serpin-proteinase interactions.";
RL Nat. Struct. Biol. 1:48-54(1994).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=9067613; DOI=10.1006/jmbi.1996.0798;
RA Skinner R., Abrahams J.P., Whisstock J.C., Lesk A.M., Carrel R.W.,
RA Wardell M.R.;
RT "The 2.6 A structure of antithrombin indicates a conformational change
RT at the heparin binding site.";
RL J. Mol. Biol. 266:601-609(1997).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
RX PubMed=9761669; DOI=10.1006/jmbi.1998.2083;
RA Skinner R., Chang W.-S.W., Jin L., Pei X.Y., Huntington J.A.,
RA Abrahams J.P., Carrell R.W., Lomas D.A.;
RT "Implications for function and therapy of a 2.9 A structure of binary-
RT complexed antithrombin.";
RL J. Mol. Biol. 283:9-14(1998).
RN [28]
RP REVIEW.
RX PubMed=2126464; DOI=10.1016/0300-9084(90)90123-X;
RA Mourey L., Samama J.-P., Delarue M., Choay J., Lormeau J.C.,
RA Petitou M., Moras D.;
RT "Antithrombin III: structural and functional aspects.";
RL Biochimie 72:599-608(1990).
RN [29]
RP REVIEW ON VARIANTS.
RX PubMed=8236149;
RA Lane D.A., Olds R.J., Boisclair M., Chowdhury V., Thein S.L.,
RA Cooper D.N., Blajchman M., Perry D., Emmerich J., Aiach M.;
RT "Antithrombin III mutation database: first update. For the Thrombin
RT and its Inhibitors Subcommittee of the Scientific and Standardization
RT Committee of the International Society on Thrombosis and
RT Haemostasis.";
RL Thromb. Haemost. 70:361-369(1993).
RN [30]
RP REVIEW ON VARIANTS.
RX PubMed=7749926; DOI=10.1038/nsb0295-96;
RA Stein P.E., Carrell R.W.;
RT "What do dysfunctional serpins tell us about molecular mobility and
RT disease?";
RL Nat. Struct. Biol. 2:96-113(1995).
RN [31]
RP REVIEW ON VARIANTS.
RX PubMed=8664906;
RX DOI=10.1002/(SICI)1098-1004(1996)7:1<7::AID-HUMU2>3.3.CO;2-A;
RA Perry D.J., Carrell R.W.;
RT "Molecular genetics of human antithrombin deficiency.";
RL Hum. Mutat. 7:7-22(1996).
RN [32]
RP VARIANTS AT3D SER-17; PRO-23; ASN-39; CYS-56; LEU-73; CYS-79; HIS-79;
RP SER-79; ASN-87 DEL; CYS-89; LEU-90; CYS-95; SER-95; PRO-98; THR-112;
RP PHE-131; VAL-131; LYS-133; PHE-138-139-LYS DEL; PRO-148; PRO-150;
RP PRO-158; TYR-160; GLN-161; CYS-198; HIS-198; ILE-218 DEL; ASP-219;
RP LYS-219; ARG-257; LYS-269; ILE-283; ASN-316; LYS-334; ARG-412;
RP THR-414; PRO-416; SER-416; VAL-419; ASP-424; CYS-425; HIS-425;
RP PRO-425; LEU-426; CYS-434; LEU-434; SER-434; THR-436; LYS-437;
RP GLY-438; MET-438; LEU-439; THR-439; THR-453; ARG-456; THR-457;
RP ASP-459; LEU-461 AND PHE-462, AND VARIANTS GLU-30; THR-52 AND CYS-190.
RX PubMed=9031473;
RG The plasma coagulation inhibitors subcommittee of the scientific and standardization committee of the international society on thrombosis and haemostasis;
RA Lane D.A., Bayston T., Olds R.J., Fitches A.C., Cooper D.N.,
RA Millar D.S., Jochmans K., Perry D.J., Okajima K., Thein S.L.,
RA Emmerich J.;
RT "Antithrombin mutation database: 2nd (1997) update.";
RL Thromb. Haemost. 77:197-211(1997).
RN [33]
RP VARIANT AT3D CYS-79.
RX PubMed=6582486; DOI=10.1073/pnas.81.2.289;
RA Koide T., Odani S., Takahashi K., Ono T., Sakuragawa N.;
RT "Antithrombin III Toyama: replacement of arginine-47 by cysteine in
RT hereditary abnormal antithrombin III that lacks heparin-binding
RT ability.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:289-293(1984).
RN [34]
RP VARIANT AT3D LEU-73.
RX PubMed=3080419;
RA Chang J.Y., Tran T.H.;
RT "Antithrombin III Basel. Identification of a Pro-Leu substitution in a
RT hereditary abnormal antithrombin with impaired heparin cofactor
RT activity.";
RL J. Biol. Chem. 261:1174-1176(1986).
RN [35]
RP VARIANT AT3D LEU-426.
RX PubMed=3805013;
RA Stephens A.W., Thalley B.S., Hirs C.H.W.;
RT "Antithrombin-III Denver, a reactive site variant.";
RL J. Biol. Chem. 262:1044-1048(1987).
RN [36]
RP VARIANT AT3D THR-414.
RX PubMed=3179438;
RA Devrak-Kizuk R., Chui D.H.K., Prochownik E.V., Carter C.J.,
RA Ofosu F.A., Blajchman M.A.;
RT "Antithrombin-III-Hamilton: a gene with a point mutation (guanine to
RT adenine) in codon 382 causing impaired serine protease reactivity.";
RL Blood 72:1518-1523(1988).
RN [37]
RP VARIANTS AT3D CYS-425 AND HIS-425.
RX PubMed=3162733;
RA Erdjument H., Laned D.A., Panico M., di Marzo V., Morris H.R.;
RT "Single amino acid substitutions in the reactive site of antithrombin
RT leading to thrombosis. Congenital substitution of arginine 393 to
RT cysteine in antithrombin Northwick Park and to histidine in
RT antithrombin Glasgow.";
RL J. Biol. Chem. 263:5589-5593(1988).
RN [38]
RP VARIANT AT3D HIS-425.
RX PubMed=2781509; DOI=10.1016/0049-3848(89)90127-8;
RA Erdjument H., Lane D.A., Panico M., di Marzo V., Morris H.R.,
RA Bauer K., Rosenberg R.D.;
RT "Antithrombin Chicago, amino acid substitution of arginine 393 to
RT histidine.";
RL Thromb. Res. 54:613-619(1989).
RN [39]
RP VARIANT AT3D CYS-56.
RX PubMed=2365065; DOI=10.1016/0014-5793(90)81530-2;
RA Borg J.Y., Brennan S.O., Carrell R.W., George P., Perry D.J., Shaw J.;
RT "Antithrombin Rouen-IV 24 Arg-->Cys. The amino-terminal contribution
RT to heparin binding.";
RL FEBS Lett. 266:163-166(1990).
RN [40]
RP VARIANT GLU-30.
RX PubMed=1977621; DOI=10.1016/0014-5793(90)81057-U;
RA Daly M., Bruce D., Perry D.J., Price J., Harper P.L., O'Meara A.,
RA Carrell R.W.;
RT "Antithrombin Dublin (-3 Val-->Glu): an N-terminal variant which has
RT an aberrant signal peptidase cleavage site.";
RL FEBS Lett. 273:87-90(1990).
RN [41]
RP VARIANT AT3D GLN-161.
RX PubMed=2229057;
RA Gandrille S., Aiach M., Lane D.A., Vidaud D., Molho-Sabatier P.,
RA Caso R., de Moerloose P., Fiessinger J.-N., Clauser E.;
RT "Important role of arginine 129 in heparin-binding site of
RT antithrombin III. Identification of a novel mutation arginine 129 to
RT glutamine.";
RL J. Biol. Chem. 265:18997-19001(1990).
RN [42]
RP CHARACTERIZATION OF VARIANT AT3D THR-414, AND MUTAGENESIS OF ALA-414.
RX PubMed=2013320; DOI=10.1016/0014-5793(91)80305-M;
RA Austin R.C., Rachubinski R.A., Blachjman M.A.;
RT "Site-directed mutagenesis of alanine-382 of human antithrombin III.";
RL FEBS Lett. 280:254-258(1991).
RN [43]
RP VARIANT AT3D SER-416.
RX PubMed=1906811; DOI=10.1016/0014-5793(91)80809-H;
RA Perry D.J., Daly M., Harper P.L., Tait R.C., Price J., Walker I.D.,
RA Carrell R.W.;
RT "Antithrombin Cambridge II, 384 Ala to Ser. Further evidence of the
RT role of the reactive centre loop in the inhibitory function of the
RT serpins.";
RL FEBS Lett. 285:248-250(1991).
RN [44]
RP VARIANT AT3D PHE-131.
RX PubMed=1555650; DOI=10.1016/0014-5793(92)80854-A;
RA Olds R.J., Lane D.A., Boisclair M., Sas G., Bock S.C., Thein S.L.;
RT "Antithrombin Budapest 3. An antithrombin variant with reduced heparin
RT affinity resulting from the substitution L99F.";
RL FEBS Lett. 300:241-246(1992).
RN [45]
RP VARIANT AT3D ASP-424.
RX PubMed=1547341;
RA Blajchman M.A., Fernandez-Rachubinski F., Sheffield W.P., Austin R.C.,
RA Schulman S.;
RT "Antithrombin-III Stockholm: a codon 392 (Gly-->Asp) mutation with
RT normal heparin binding and impaired serine protease reactivity.";
RL Blood 79:1428-1434(1992).
RN [46]
RP VARIANT AT3D PRO-148.
RX PubMed=8443391;
RA Okajima K., Abe H., Maeda S., Motomura M., Tsujihata M., Nagataki S.,
RA Okabe H., Takatsuki K.;
RT "Antithrombin III Nagasaki (Ser116-Pro): a heterozygous variant with
RT defective heparin binding associated with thrombosis.";
RL Blood 81:1300-1305(1993).
RN [47]
RP VARIANT AT3D 138-PHE-LYS-139 DEL.
RX PubMed=8486379; DOI=10.1006/geno.1993.1184;
RA Olds R.J., Lane D.A., Beresford C.H., Abildgaard U., Hughes P.M.,
RA Thein S.L.;
RT "A recurrent deletion in the antithrombin gene, AT106-108(-6 bp),
RT identified by DNA heteroduplex detection.";
RL Genomics 16:298-299(1993).
RN [48]
RP VARIANTS AT3D HIS-79 AND TYR-160.
RX PubMed=7981186;
RA Emmerich J., Vidaud D., Alhenc-Gelas M., Chadeuf G.,
RA Gouault-Heilmann M., Aillaud M.-F., Aiach M.;
RT "Three novel mutations of antithrombin inducing high-molecular-mass
RT compounds.";
RL Arterioscler. Thromb. 14:1958-1965(1994).
RN [49]
RP VARIANTS AT3D THR-112; TYR-152 AND ILE-283, AND VARIANT CYS-190.
RX PubMed=7959685; DOI=10.1007/BF00211016;
RA Millar D.S., Wacey A.I., Ribando J., Melissari E., Laursen B.,
RA Woods P., Kakkar V.V., Cooper D.N.;
RT "Three novel missense mutations in the antithrombin III (AT3) gene
RT causing recurrent venous thrombosis.";
RL Hum. Genet. 94:509-512(1994).
RN [50]
RP VARIANT AT3D ARG-456.
RX PubMed=8274732;
RA Jochmans K., Lissens W., Vervoort R., Peeters S., de Waelwe M.,
RA Liebaers I.;
RT "Antithrombin-Gly 424 Arg: a novel point mutation responsible for type
RT 1 antithrombin deficiency and neonatal thrombosis.";
RL Blood 83:146-151(1994).
RN [51]
RP VARIANTS AT3D SER-95; THR-453 AND PHE-462.
RX PubMed=7994035;
RA van Boven H.H., Olds R.J., Thein S.L., Reitsma P.H., Lane D.A.,
RA Briet E., Vandenbroucke J.P., Rosendaal F.R.;
RT "Hereditary antithrombin deficiency: heterogeneity of the molecular
RT basis and mortality in Dutch families.";
RL Blood 84:4209-4213(1994).
RN [52]
RP VARIANT AT3D ASP-219.
RX PubMed=7989582; DOI=10.1172/JCI117589;
RA Bruce D., Perry D.J., Borg J.-Y., Carrell R.W., Wardell M.R.;
RT "Thromboembolic disease due to thermolabile conformational changes of
RT antithrombin Rouen-VI (187 Asn-->Asp).";
RL J. Clin. Invest. 94:2265-2274(1994).
RN [53]
RP VARIANTS AT3D VAL-131 AND PRO-150.
RA Chowdhury V., Olds R.J., Lane D.A., Mille B., Pabinger I., Thein S.L.;
RT "Two novel antithrombin variants (L99V and Q118P) which alter the
RT heparin binding domain.";
RL Nouv. Rev. Fr. Hematol. 86:268-268(1994).
RN [54]
RP VARIANT AT3D 273-LYS--LYS-307 DEL.
RX PubMed=7878627;
RA Emmerich J., Chadeuf G., Alhenc-Gelas M., Gouault-Heilman M.,
RA Toulon P., Fiessinger J.-N., Aiach M.;
RT "Molecular basis of antithrombin type I deficiency: the first large
RT in-frame deletion and two novel mutations in exon 6.";
RL Thromb. Haemost. 72:534-539(1994).
RN [55]
RP VARIANT AT3D HIS-425.
RX PubMed=7832187; DOI=10.1002/ajh.2830480104;
RA Okajima K., Abe H., Wagatsuma M., Okabe H., Takatsuki K.;
RT "Antithrombin III Kumamoto II; a single mutation at Arg393-His
RT increased the affinity of antithrombin III for heparin.";
RL Am. J. Hematol. 48:12-18(1995).
RN [56]
RP VARIANT AT3D ARG-127.
RX PubMed=9157604;
RA Ozawa T., Takikawa Y., Niiya K., Fujiwara T., Suzuki K., Sato S.,
RA Sakuragawa N.;
RT "Antithrombin Morioka (Cys 95-Arg): a novel missense mutation causing
RT type I antithrombin deficiency.";
RL Thromb. Haemost. 77:403-403(1997).
RN [57]
RP VARIANT AT3D PRO-23.
RX PubMed=9845533;
RA Fitches A.C., Appleby R., Lane D.A., De Stefano V., Leone G.,
RA Olds R.J.;
RT "Impaired cotranslational processing as a mechanism for type I
RT antithrombin deficiency.";
RL Blood 92:4671-4676(1998).
RN [58]
RP VARIANTS AT3D ARG-32; LEU-73; CYS-79; HIS-198; ARG-257 AND ARG-412.
RX PubMed=9759613;
RA Jochmans K., Lissens W., Seneca S., Capel P., Chatelain B., Meeus P.,
RA Osselaer J.C., Peerlinck K., Seghers J., Slacmeulder M., Stibbe J.,
RA van de Loo J., Vermylen J., Liebaers I., De Waele M.;
RT "The molecular basis of antithrombin deficiency in Belgian and Dutch
RT families.";
RL Thromb. Haemost. 80:376-381(1998).
RN [59]
RP VARIANT THR-167.
RX PubMed=10361121;
RA Bayston T.A., Tripodi A., Mannucci P.M., Thompson E., Ireland H.,
RA Fitches A.C., Hananeia L., Olds R.J., Lane D.A.;
RT "Familial overexpression of beta-antithrombin caused by an Asn135-to-
RT Thr substitution.";
RL Blood 93:4242-4247(1999).
RN [60]
RP VARIANTS AT3D PHE-214; PRO-223; ILE-243; THR-251; VAL-283 AND PRO-397.
RX PubMed=10997988; DOI=10.1046/j.1365-2141.2000.02245.x;
RA Picard V., Bura A., Emmerich J., Alhenc-Gelas M., Biron C.,
RA Houbouyan-Reveillard L.L., Molho P., Labatide-Alanore A., Sie P.,
RA Toulon P., Verdy E., Aiach M.;
RT "Molecular bases of antithrombin deficiency in French families:
RT identification of seven novel mutations in the antithrombin gene.";
RL Br. J. Haematol. 110:731-734(2000).
RN [61]
RP VARIANT AT3D 152-HIS--PHE-154 DEL.
RX PubMed=11794707; DOI=10.1007/BF02982095;
RA Niiya K., Kiguchi T., Dansako H., Fujimura K., Fujimoto T., Iijima K.,
RA Tanimoto M., Harada M.;
RT "Two novel gene mutations in type I antithrombin deficiency.";
RL Int. J. Hematol. 74:469-472(2001).
RN [62]
RP VARIANT AT3D PRO-223.
RX PubMed=11713457; DOI=10.1067/mpd.2001.118191;
RA Baud O., Picard V., Durand P., Duchemin J., Proulle V.,
RA Alhenc-Gelas M., Devictor D., Dreyfus M.;
RT "Intracerebral hemorrhage associated with a novel antithrombin gene
RT mutation in a neonate.";
RL J. Pediatr. 139:741-743(2001).
RN [63]
RP VARIANT AT3D GLU-146.
RX PubMed=12353073; DOI=10.1267/THRO88030436;
RA Mushunje A., Zhou A., Huntington J.A., Conard J., Carrell R.W.;
RT "Antithrombin 'DREUX' (Lys 114Glu): a variant with complete loss of
RT heparin affinity.";
RL Thromb. Haemost. 88:436-443(2002).
RN [64]
RP VARIANT AT3D LEU-261.
RX PubMed=12595305; DOI=10.1182/blood-2002-11-3391;
RA Picard V., Dautzenberg M.-D., Villoutreix B.O., Orliaguet G.,
RA Alhenc-Gelas M., Aiach M.;
RT "Antithrombin Phe229Leu: a new homozygous variant leading to
RT spontaneous antithrombin polymerization in vivo associated with severe
RT childhood thrombosis.";
RL Blood 102:919-925(2003).
RN [65]
RP VARIANTS AT3D LYS-121; HIS-178; CYS-425; HIS-425 AND PRO-441.
RX PubMed=12894857; DOI=10.1007/BF02983246;
RA Nagaizumi K., Inaba H., Amano K., Suzuki M., Arai M., Fukutake K.;
RT "Five novel and four recurrent point mutations in the antithrombin
RT gene causing venous thrombosis.";
RL Int. J. Hematol. 78:79-83(2003).
RN [66]
RP VARIANTS AT3D LEU-179; CYS-425 AND LEU-426.
RX PubMed=15164384; DOI=10.1002/ajh.20067;
RA David D., Ribeiro S., Ferrao L., Gago T., Crespo F.;
RT "Molecular basis of inherited antithrombin deficiency in Portuguese
RT families: identification of genetic alterations and screening for
RT additional thrombotic risk factors.";
RL Am. J. Hematol. 76:163-171(2004).
RN [67]
RP VARIANT AT3D HIS-398.
RX PubMed=16908819; DOI=10.1001/archopht.124.8.1165;
RA Kuhli C., Jochmans K., Scharrer I., Luechtenberg M., Hattenbach L.-O.;
RT "Retinal vein occlusion associated with antithrombin deficiency
RT secondary to a novel G9840C missense mutation.";
RL Arch. Ophthalmol. 124:1165-1169(2006).
CC -!- FUNCTION: Most important serine protease inhibitor in plasma that
CC regulates the blood coagulation cascade. AT-III inhibits thrombin,
CC matriptase-3/TMPRSS7, as well as factors IXa, Xa and XIa. Its
CC inhibitory activity is greatly enhanced in the presence of
CC heparin.
CC -!- SUBUNIT: Forms protease inhibiting heterodimer with TMPRSS7.
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space.
CC -!- TISSUE SPECIFICITY: Found in plasma.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- MASS SPECTROMETRY: Mass=57863; Method=Electrospray; Range=33-464;
CC Source=PubMed:7734359;
CC -!- MASS SPECTROMETRY: Mass=57911; Method=Electrospray; Range=33-464;
CC Note=Variant Thr-414; Source=PubMed:7734359;
CC -!- DISEASE: Antithrombin III deficiency (AT3D) [MIM:613118]: An
CC important risk factor for hereditary thrombophilia, a hemostatic
CC disorder characterized by a tendency to recurrent thrombosis.
CC Antithrombin-III deficiency is classified into 4 types. Type I:
CC characterized by a 50% decrease in antigenic and functional
CC levels. Type II: has defects affecting the thrombin-binding
CC domain. Type III: alteration of the heparin-binding domain. Plasma
CC AT-III antigen levels are normal in type II and III. Type IV:
CC consists of miscellaneous group of unclassifiable mutations.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the serpin family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Antithrombin entry;
CC URL="http://en.wikipedia.org/wiki/Antithrombin";
CC -!- WEB RESOURCE: Name=Antithrombin mutation database;
CC URL="http://www1.imperial.ac.uk/medicine/about/divisions/is/haemo/coag/antithrombin/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SERPINC1";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/serpinc1/";
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;=SERPINC1";
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; L00185; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L00186; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; L00190; AAB40025.1; -; Genomic_DNA.
DR EMBL; D29832; BAA06212.1; -; mRNA.
DR EMBL; X68793; CAA48690.1; -; Genomic_DNA.
DR EMBL; AF130100; AAG35525.1; -; mRNA.
DR EMBL; AK312654; BAG35537.1; -; mRNA.
DR EMBL; AF386078; AAK60337.1; -; Genomic_DNA.
DR EMBL; AL136170; CAI19423.1; -; Genomic_DNA.
DR EMBL; CH471067; EAW90969.1; -; Genomic_DNA.
DR EMBL; M21643; AAA51793.1; -; Genomic_DNA.
DR EMBL; M21644; AAA51794.1; -; Genomic_DNA.
DR EMBL; M21643; AAA51794.1; JOINED; Genomic_DNA.
DR EMBL; M21642; AAA51796.1; -; Genomic_DNA.
DR EMBL; M21636; AAA51796.1; JOINED; Genomic_DNA.
DR EMBL; M21637; AAA51796.1; JOINED; Genomic_DNA.
DR EMBL; M21638; AAA51796.1; JOINED; Genomic_DNA.
DR EMBL; M21640; AAA51796.1; JOINED; Genomic_DNA.
DR EMBL; M21641; AAA51796.1; JOINED; Genomic_DNA.
DR PIR; A49494; XHHU3.
DR RefSeq; NP_000479.1; NM_000488.3.
DR UniGene; Hs.75599; -.
DR PDB; 1ANT; X-ray; 3.00 A; I/L=33-464.
DR PDB; 1ATH; X-ray; 3.20 A; A/B=33-464.
DR PDB; 1AZX; X-ray; 2.90 A; I/L=33-464.
DR PDB; 1BR8; X-ray; 2.90 A; I/L=33-464.
DR PDB; 1DZG; X-ray; 2.80 A; I/L=33-464.
DR PDB; 1DZH; X-ray; 2.85 A; I/L=33-464.
DR PDB; 1E03; X-ray; 2.90 A; I/L=33-464.
DR PDB; 1E04; X-ray; 2.60 A; I/L=33-464.
DR PDB; 1E05; X-ray; 2.62 A; I/L=33-464.
DR PDB; 1JVQ; X-ray; 2.60 A; I/L=33-464.
DR PDB; 1LK6; X-ray; 2.80 A; I/L=33-464.
DR PDB; 1NQ9; X-ray; 2.60 A; I/L=33-464.
DR PDB; 1OYH; X-ray; 2.62 A; I/L=33-464.
DR PDB; 1R1L; X-ray; 2.70 A; I/L=33-464.
DR PDB; 1SR5; X-ray; 3.10 A; A=33-464.
DR PDB; 1T1F; X-ray; 2.75 A; A/B/C=33-464.
DR PDB; 1TB6; X-ray; 2.50 A; I=33-464.
DR PDB; 2ANT; X-ray; 2.60 A; I/L=33-464.
DR PDB; 2B4X; X-ray; 2.80 A; I/L=37-463.
DR PDB; 2B5T; X-ray; 2.10 A; I=33-464.
DR PDB; 2BEH; X-ray; 2.70 A; I/L=33-464.
DR PDB; 2GD4; X-ray; 3.30 A; C/I=22-464.
DR PDB; 2HIJ; X-ray; 2.90 A; I/L=33-464.
DR PDB; 2ZNH; X-ray; 2.80 A; A/B=33-464.
DR PDB; 3EVJ; X-ray; 3.00 A; I/L=33-464.
DR PDB; 3KCG; X-ray; 1.70 A; I=33-464.
DR PDB; 4EB1; X-ray; 2.80 A; I/L=33-464.
DR PDBsum; 1ANT; -.
DR PDBsum; 1ATH; -.
DR PDBsum; 1AZX; -.
DR PDBsum; 1BR8; -.
DR PDBsum; 1DZG; -.
DR PDBsum; 1DZH; -.
DR PDBsum; 1E03; -.
DR PDBsum; 1E04; -.
DR PDBsum; 1E05; -.
DR PDBsum; 1JVQ; -.
DR PDBsum; 1LK6; -.
DR PDBsum; 1NQ9; -.
DR PDBsum; 1OYH; -.
DR PDBsum; 1R1L; -.
DR PDBsum; 1SR5; -.
DR PDBsum; 1T1F; -.
DR PDBsum; 1TB6; -.
DR PDBsum; 2ANT; -.
DR PDBsum; 2B4X; -.
DR PDBsum; 2B5T; -.
DR PDBsum; 2BEH; -.
DR PDBsum; 2GD4; -.
DR PDBsum; 2HIJ; -.
DR PDBsum; 2ZNH; -.
DR PDBsum; 3EVJ; -.
DR PDBsum; 3KCG; -.
DR PDBsum; 4EB1; -.
DR ProteinModelPortal; P01008; -.
DR SMR; P01008; 37-463.
DR DIP; DIP-38009N; -.
DR IntAct; P01008; 3.
DR BindingDB; P01008; -.
DR ChEMBL; CHEMBL1950; -.
DR DrugBank; DB01225; Enoxaparin.
DR DrugBank; DB00569; Fondaparinux sodium.
DR DrugBank; DB01109; Heparin.
DR MEROPS; I04.018; -.
DR PhosphoSite; P01008; -.
DR DMDM; 113936; -.
DR DOSAC-COBS-2DPAGE; P01008; -.
DR REPRODUCTION-2DPAGE; P01008; -.
DR SWISS-2DPAGE; P01008; -.
DR PaxDb; P01008; -.
DR PRIDE; P01008; -.
DR Ensembl; ENST00000367698; ENSP00000356671; ENSG00000117601.
DR GeneID; 462; -.
DR KEGG; hsa:462; -.
DR UCSC; uc001gjt.3; human.
DR CTD; 462; -.
DR GeneCards; GC01M173872; -.
DR HGNC; HGNC:775; SERPINC1.
DR HPA; CAB016790; -.
DR HPA; HPA001816; -.
DR HPA; HPA024007; -.
DR MIM; 107300; gene.
DR MIM; 613118; phenotype.
DR neXtProt; NX_P01008; -.
DR Orphanet; 82; Hereditary thrombophilia due to congenital antithrombin deficiency.
DR PharmGKB; PA35026; -.
DR eggNOG; COG4826; -.
DR HOVERGEN; HBG005957; -.
DR InParanoid; P01008; -.
DR KO; K03911; -.
DR OMA; KADGESC; -.
DR OrthoDB; EOG7327PB; -.
DR PhylomeDB; P01008; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; SERPINC1; human.
DR EvolutionaryTrace; P01008; -.
DR GeneWiki; Antithrombin; -.
DR GenomeRNAi; 462; -.
DR NextBio; 1911; -.
DR PMAP-CutDB; P01008; -.
DR PRO; PR:P01008; -.
DR ArrayExpress; P01008; -.
DR Bgee; P01008; -.
DR CleanEx; HS_SERPINC1; -.
DR Genevestigator; P01008; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; NAS:UniProtKB.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:2000266; P:regulation of blood coagulation, intrinsic pathway; IEA:InterPro.
DR GO; GO:0030162; P:regulation of proteolysis; IBA:RefGenome.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR InterPro; IPR015555; AT-III.
DR InterPro; IPR023795; Serpin_CS.
DR InterPro; IPR023796; Serpin_dom.
DR InterPro; IPR000215; Serpin_fam.
DR PANTHER; PTHR11461; PTHR11461; 1.
DR PANTHER; PTHR11461:SF53; PTHR11461:SF53; 1.
DR Pfam; PF00079; Serpin; 1.
DR SMART; SM00093; SERPIN; 1.
DR SUPFAM; SSF56574; SSF56574; 1.
DR PROSITE; PS00284; SERPIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hemostasis; Heparin-binding; Phosphoprotein;
KW Polymorphism; Protease inhibitor; Reference proteome; Secreted;
KW Serine protease inhibitor; Signal; Thrombophilia.
FT SIGNAL 1 32
FT CHAIN 33 464 Antithrombin-III.
FT /FTId=PRO_0000032489.
FT BINDING 81 81 Heparin.
FT BINDING 161 161 Heparin.
FT BINDING 177 177 Heparin.
FT SITE 425 426 Reactive bond.
FT CARBOHYD 128 128 N-linked (GlcNAc...).
FT CARBOHYD 167 167 N-linked (GlcNAc...).
FT CARBOHYD 187 187 N-linked (GlcNAc...) (complex).
FT CARBOHYD 224 224 N-linked (GlcNAc...).
FT DISULFID 40 160
FT DISULFID 53 127
FT DISULFID 279 462
FT VARIANT 17 17 Y -> S (in AT3D; type-I).
FT /FTId=VAR_027450.
FT VARIANT 23 23 L -> P (in AT3D; type-I; impairs
FT cotranslational processing).
FT /FTId=VAR_012748.
FT VARIANT 30 30 V -> E (in Dublin; dbSNP:rs2227624).
FT /FTId=VAR_007032.
FT VARIANT 32 32 C -> R (in AT3D; type-I).
FT /FTId=VAR_027451.
FT VARIANT 39 39 I -> N (in AT3D; type-II; Rouen-3; lack
FT of heparin-binding properties;
FT dbSNP:rs28929468).
FT /FTId=VAR_007033.
FT VARIANT 52 52 M -> T (previously Whitechapel).
FT /FTId=VAR_007034.
FT VARIANT 56 56 R -> C (in AT3D; type-II; Rouen-4; lack
FT of heparin-binding properties;
FT dbSNP:rs28929469).
FT /FTId=VAR_007035.
FT VARIANT 73 73 P -> L (in AT3D; type-II; Basel/
FT Franconville/Clichy-1/Clichy-2/Dublin-2;
FT lacks heparin-binding ability;
FT dbSNP:rs121909551).
FT /FTId=VAR_007036.
FT VARIANT 79 79 R -> C (in AT3D; Tours/Alger/Amiens/
FT Toyama/Paris-1/Paris-2/Padua-2/Barcelona-
FT 2/Kumamoto/Omura/Sasebo; lacks heparin-
FT binding ability).
FT /FTId=VAR_007037.
FT VARIANT 79 79 R -> H (in AT3D; type-II; Rouen-1/Padua-
FT 1/Bligny/Budapest-2; lack of heparin-
FT binding properties; dbSNP:rs121909552).
FT /FTId=VAR_007038.
FT VARIANT 79 79 R -> S (in AT3D; type-II; Rouen-2; lack
FT of heparin-binding properties).
FT /FTId=VAR_007039.
FT VARIANT 87 87 Missing (in AT3D; type-I).
FT /FTId=VAR_007040.
FT VARIANT 89 89 R -> C (in AT3D; type-I;
FT dbSNP:rs147266200).
FT /FTId=VAR_007041.
FT VARIANT 90 90 F -> L (in AT3D; type-I; Budapest-6).
FT /FTId=VAR_007042.
FT VARIANT 95 95 Y -> C (in AT3D; type-I).
FT /FTId=VAR_027452.
FT VARIANT 95 95 Y -> S (in AT3D; type-I).
FT /FTId=VAR_012316.
FT VARIANT 98 98 L -> P (in AT3D; type-I).
FT /FTId=VAR_027453.
FT VARIANT 108 109 Missing (in AT3D; type-I).
FT /FTId=VAR_007043.
FT VARIANT 112 112 P -> T (in AT3D; type-I).
FT /FTId=VAR_007044.
FT VARIANT 121 121 M -> K (in AT3D; type-I).
FT /FTId=VAR_027454.
FT VARIANT 127 127 C -> R (in AT3D; type-I).
FT /FTId=VAR_027455.
FT VARIANT 131 131 L -> F (in AT3D; type-II; Budapest-3/
FT Budapest-7).
FT /FTId=VAR_007045.
FT VARIANT 131 131 L -> V (in AT3D; type-II; Southport).
FT /FTId=VAR_007046.
FT VARIANT 133 133 Q -> K (in AT3D; type I).
FT /FTId=VAR_007047.
FT VARIANT 138 139 Missing (in AT3D; type-I).
FT /FTId=VAR_007048.
FT VARIANT 146 146 K -> E (in AT3D; Dreux; complete loss af
FT heparin binding).
FT /FTId=VAR_027456.
FT VARIANT 147 147 T -> A (in dbSNP:rs2227606).
FT /FTId=VAR_013085.
FT VARIANT 148 148 S -> P (in AT3D; type-II; Nagasaki;
FT defective heparin binding associated with
FT thrombosis).
FT /FTId=VAR_007049.
FT VARIANT 150 150 Q -> P (in AT3D; type-II; Vienna).
FT /FTId=VAR_007050.
FT VARIANT 152 154 Missing (in AT3D; type-I).
FT /FTId=VAR_012749.
FT VARIANT 152 152 H -> Y (in AT3D; type-I).
FT /FTId=VAR_007051.
FT VARIANT 153 153 Missing (in AT3D; type-I).
FT /FTId=VAR_007052.
FT VARIANT 158 158 L -> P (in AT3D; type-I).
FT /FTId=VAR_007053.
FT VARIANT 160 160 C -> Y (in AT3D; type-I).
FT /FTId=VAR_027457.
FT VARIANT 161 161 R -> Q (in AT3D; type-II; Geneva).
FT /FTId=VAR_007054.
FT VARIANT 167 167 N -> T.
FT /FTId=VAR_012750.
FT VARIANT 178 178 L -> H (in AT3D; type-I).
FT /FTId=VAR_027458.
FT VARIANT 179 179 F -> L (in AT3D; type-I).
FT /FTId=VAR_027459.
FT VARIANT 190 190 Y -> C (polymorphism in population of
FT Scandinavian origin).
FT /FTId=VAR_007055.
FT VARIANT 198 198 Y -> C (in AT3D; type-I and -II;
FT Whitechapel).
FT /FTId=VAR_007056.
FT VARIANT 198 198 Y -> H (in AT3D; type-I).
FT /FTId=VAR_027460.
FT VARIANT 214 214 S -> F (in AT3D; type-I).
FT /FTId=VAR_027461.
FT VARIANT 214 214 S -> Y (in AT3D; type-I).
FT /FTId=VAR_007057.
FT VARIANT 218 218 Missing (in AT3D; type-I).
FT /FTId=VAR_027462.
FT VARIANT 219 219 N -> D (in AT3D; type-II; Rouen-6;
FT increases affinity for heparin).
FT /FTId=VAR_007059.
FT VARIANT 219 219 N -> K (in AT3D; type-II; Glasgow-3).
FT /FTId=VAR_007058.
FT VARIANT 223 223 S -> P (in AT3D; type-I).
FT /FTId=VAR_027463.
FT VARIANT 243 243 T -> I (in AT3D; type-I).
FT /FTId=VAR_027464.
FT VARIANT 251 251 I -> T (in AT3D; type-I).
FT /FTId=VAR_027465.
FT VARIANT 257 257 W -> R (in AT3D; type-I).
FT /FTId=VAR_027466.
FT VARIANT 261 261 F -> L (in AT3D).
FT /FTId=VAR_027467.
FT VARIANT 269 269 E -> K (in AT3D; type-II; Truro,
FT increases affinity for heparin).
FT /FTId=VAR_007060.
FT VARIANT 273 307 Missing (in AT3D; type-I).
FT /FTId=VAR_007061.
FT VARIANT 283 283 M -> I (in AT3D; type-II).
FT /FTId=VAR_007062.
FT VARIANT 283 283 M -> V (in AT3D; type-II).
FT /FTId=VAR_027468.
FT VARIANT 302 302 L -> P (in AT3D; type-I).
FT /FTId=VAR_007063.
FT VARIANT 316 316 I -> N (in AT3D; type-II; Haslar/
FT Whitechapel).
FT /FTId=VAR_007064.
FT VARIANT 323 323 S -> P (in AT3D).
FT /FTId=VAR_027469.
FT VARIANT 334 334 E -> K (in AT3D; type-II).
FT /FTId=VAR_007065.
FT VARIANT 344 344 Missing (in AT3D; type-I).
FT /FTId=VAR_007066.
FT VARIANT 381 381 S -> P (in AT3D; type-I).
FT /FTId=VAR_007067.
FT VARIANT 391 391 R -> Q.
FT /FTId=VAR_007068.
FT VARIANT 397 397 S -> P (in AT3D; type-I).
FT /FTId=VAR_027470.
FT VARIANT 398 398 D -> H (in AT3D; type-I).
FT /FTId=VAR_027471.
FT VARIANT 412 412 S -> R (in AT3D; type-I).
FT /FTId=VAR_027472.
FT VARIANT 414 414 A -> T (in AT3D; type-II; Hamilton/
FT Glasgow-2; reduces interaction with
FT thrombin by 90%).
FT /FTId=VAR_007069.
FT VARIANT 416 416 A -> P (in AT3D; type-II; Charleville/
FT Sudbury/Vicenza/Cambridge-1;
FT dbSNP:rs28930978).
FT /FTId=VAR_007070.
FT VARIANT 416 416 A -> S (in AT3D; type-II; Cambridge-2;
FT dbSNP:rs121909548).
FT /FTId=VAR_007071.
FT VARIANT 419 419 A -> V (in AT3D; type-I).
FT /FTId=VAR_007072.
FT VARIANT 424 424 G -> D (in AT3D; type-II; Stockholm).
FT /FTId=VAR_007073.
FT VARIANT 425 425 R -> C (in AT3D; type-II; Northwick-Park/
FT Milano-1/Frankfurt-1; deprived of
FT inhibitory activity; dbSNP:rs121909554).
FT /FTId=VAR_007075.
FT VARIANT 425 425 R -> H (in AT3D; type-II; Glasgow/
FT Sheffield/Chicago/Avranches/Kumamoto-2;
FT increases affinity for heparin; deprived
FT of inhibitory activity).
FT /FTId=VAR_007074.
FT VARIANT 425 425 R -> P (in AT3D; type-II; Pescara;
FT deprived of inhibitory of activity).
FT /FTId=VAR_007076.
FT VARIANT 426 426 S -> L (in AT3D; type-II; Denver/Milano-
FT 2; deprived of inhibitory activity).
FT /FTId=VAR_007077.
FT VARIANT 434 434 F -> C (in AT3D; type-II; Rosny).
FT /FTId=VAR_007078.
FT VARIANT 434 434 F -> L (in AT3D; type-II; Maisons-
FT Laffite).
FT /FTId=VAR_007080.
FT VARIANT 434 434 F -> S (in AT3D; type-II; Torino).
FT /FTId=VAR_007079.
FT VARIANT 436 436 A -> T (in AT3D; type-II; Oslo/Paris-3).
FT /FTId=VAR_007081.
FT VARIANT 437 437 N -> K (in AT3D; type-II; La Rochelle).
FT /FTId=VAR_007082.
FT VARIANT 438 438 R -> G (in AT3D; type-II).
FT /FTId=VAR_009258.
FT VARIANT 438 438 R -> M (in AT3D; type-II; Kyoto).
FT /FTId=VAR_007083.
FT VARIANT 439 439 P -> L (in AT3D; type-II; Utah; deprived
FT of inhibitory activity).
FT /FTId=VAR_007084.
FT VARIANT 439 439 P -> T (in AT3D; type-II; Budapest-5).
FT /FTId=VAR_007085.
FT VARIANT 441 441 L -> P (in AT3D; type-II).
FT /FTId=VAR_027473.
FT VARIANT 453 453 I -> T (in AT3D; type-I).
FT /FTId=VAR_007086.
FT VARIANT 456 456 G -> R (in AT3D; type-I).
FT /FTId=VAR_007087.
FT VARIANT 457 457 R -> T (in AT3D; type-II).
FT /FTId=VAR_007088.
FT VARIANT 459 461 Missing (in AT3D; type-I).
FT /FTId=VAR_007089.
FT VARIANT 459 459 A -> D (in AT3D; type-I).
FT /FTId=VAR_007090.
FT VARIANT 461 461 P -> L (in AT3D; type-II; Budapest).
FT /FTId=VAR_007091.
FT VARIANT 462 462 C -> F (in AT3D; type-I).
FT /FTId=VAR_007092.
FT MUTAGEN 414 414 A->K: Reduces interaction with thrombin
FT by 99%.
FT MUTAGEN 414 414 A->Q: Reduces interaction with thrombin
FT by 80%.
FT CONFLICT 69 70 EQ -> QE (in Ref. 10; AA sequence).
FT CONFLICT 77 77 N -> NN (in Ref. 3; BAA06212).
FT CONFLICT 97 97 H -> R (in Ref. 5; AAG35525).
FT CONFLICT 120 120 A -> T (in Ref. 6; BAG35537).
FT CONFLICT 226 226 T -> A (in Ref. 6; BAG35537).
FT CONFLICT 247 249 Missing (in Ref. 10; AA sequence).
FT CONFLICT 388 388 Missing (in Ref. 13; AA sequence).
FT CONFLICT 395 395 Y -> YA (in Ref. 13; AA sequence).
FT HELIX 39 41
FT TURN 44 46
FT STRAND 51 53
FT HELIX 78 101
FT STRAND 104 106
FT STRAND 108 110
FT HELIX 112 123
FT HELIX 128 137
FT HELIX 140 142
FT HELIX 145 149
FT HELIX 151 166
FT TURN 167 169
FT STRAND 170 181
FT STRAND 184 186
FT HELIX 188 198
FT STRAND 203 205
FT HELIX 207 225
FT TURN 226 228
FT STRAND 236 239
FT STRAND 240 242
FT STRAND 245 255
FT STRAND 257 259
FT HELIX 263 265
FT STRAND 267 272
FT STRAND 274 276
FT STRAND 278 294
FT HELIX 296 298
FT STRAND 300 306
FT STRAND 309 317
FT STRAND 320 322
FT HELIX 324 329
FT HELIX 333 342
FT STRAND 344 353
FT STRAND 355 362
FT HELIX 364 369
FT HELIX 374 376
FT TURN 378 380
FT TURN 384 386
FT STRAND 389 392
FT STRAND 398 407
FT STRAND 409 413
FT STRAND 419 422
FT STRAND 423 426
FT STRAND 432 435
FT STRAND 440 446
FT TURN 447 450
FT STRAND 451 459
SQ SEQUENCE 464 AA; 52602 MW; 9A4E324F00683D9D CRC64;
MYSNVIGTVT SGKRKVYLLS LLLIGFWDCV TCHGSPVDIC TAKPRDIPMN PMCIYRSPEK
KATEDEGSEQ KIPEATNRRV WELSKANSRF ATTFYQHLAD SKNDNDNIFL SPLSISTAFA
MTKLGACNDT LQQLMEVFKF DTISEKTSDQ IHFFFAKLNC RLYRKANKSS KLVSANRLFG
DKSLTFNETY QDISELVYGA KLQPLDFKEN AEQSRAAINK WVSNKTEGRI TDVIPSEAIN
ELTVLVLVNT IYFKGLWKSK FSPENTRKEL FYKADGESCS ASMMYQEGKF RYRRVAEGTQ
VLELPFKGDD ITMVLILPKP EKSLAKVEKE LTPEVLQEWL DELEEMMLVV HMPRFRIEDG
FSLKEQLQDM GLVDLFSPEK SKLPGIVAEG RDDLYVSDAF HKAFLEVNEE GSEAAASTAV
VIAGRSLNPN RVTFKANRPF LVFIREVPLN TIIFMGRVAN PCVK
//

MIM 107300
*RECORD*
*FIELD* NO
107300
*FIELD* TI
*107300 SERPIN PEPTIDASE INHIBITOR, CLADE C (ANTITHROMBIN), MEMBER 1; SERPINC1
;;ANTITHROMBIN III; AT3;;
read moreANTITHROMBIN;;
HEPARIN COFACTOR I
*FIELD* TX

DESCRIPTION

Antithrombin III is the most important inhibitor of thrombin (176930)
and other coagulation proteinases. It belongs to the serine proteinase
inhibitor (serpin) superfamily of inhibitors and structurally related
proteins, which contain reactive centers that have evolved to attract
and entrap certain proteinases. Inherited antithrombin III deficiency
(AT3D; 613118) is a risk factor for the early development of venous
thromboembolism (THPH7) (summary by Lane et al., 1994).

Antithrombin III regulates clot formation both by inhibiting thrombin
activity directly and by interfering with earlier stages of the clotting
cascade. Rosenberg and Bauer (1987) gave an excellent review of defects
in the anticoagulant systems. They wrote as follows: 'The coagulation
cascade can be pictured as a series of reactions in which a zymogen, a
cofactor, and a converting enzyme interact to form a multimolecular
complex on a natural surface. In each case, the 4 reactants must be
present if the conversion of a zymogen to the corresponding serine
protease is to take place at any significant rate. The principal natural
anticoagulant systems that are able to exert damping effects on the
various steps of the cascade are the heparin-antithrombin and protein
C-thrombomodulin mechanisms that regulate the serine proteases and the
cofactors or activated cofactors, respectively.'

CLONING

Bock et al. (1982) cloned an AT3 cDNA from a human liver cDNA library.
Bjork et al. (1981, 1982) also cloned and characterized the AT3 gene,
which encodes a deduced mature secreted peptide of 432 amino acids, 6 of
which are cysteines forming 3 disulfide bonds. The protein has 4
glycosylation sites. It is synthesized with a 32-residue leader sequence
cleaved prior to its secretion from the hepatocyte into the blood. The
protein contains 2 important functional domains, the reactive center and
the glycosaminoglycan-binding site. The reactive center is located near
the C terminus, with the proteinase target cleavage site on the
inhibitor at arg393-ser394. The glycosaminoglycan-binding region is
located in the N terminus and is involved in the interaction with
heparin and certain endothelial cell surface heparan sulfate
proteoglycans. The reactive center and the heparin-binding site are
conformationally linked; induced perturbations of one may influence the
function of the other (summary by Lane et al., 1994).

GENE STRUCTURE

The AT3 gene has 7 exons. It contains 9 complete and 1 partial
repetitive ALU sequence elements, which occur in the introns of the gene
at a higher frequency (about 22% of the intron sequence) than in the
genome as a whole (about 5%) (Chandra et al., 1983; Olds et al., 1993).

MAPPING

Using a purified cDNA probe of the AT3 gene and a series of
human/Chinese hamster cell hybrids, Kao et al. (1984) assigned the gene
to chromosome 1 by Southern blot analysis. Kao et al. (1984) assigned
the AT3 gene to 1p31.3-qter.

By in situ hybridization and quantitative analysis of DNA dosage in
carriers of chromosome 1 deletions, Bock et al. (1985) assigned AT3 to
1q23-q25. Pakstis et al. (1989) reported linkage data between AT3 and
the anonymous DNA fragment D1S75 (maximum lod score = 4.67 at theta =
11.4). In a linkage map of chromosome 1 prepared by Rouleau et al.
(1990), it was concluded that AT3 lies about 17 cM distal to FY
(110700).

MOLECULAR GENETICS

Prochownik et al. (1983) found deletion of the AT3 gene in affected
members of a family with AT-III deficiency (613118) but no deletion in
affected members of another family. A common DNA polymorphism was found
in the gene at codons 304 and 305, which code for leucine and glutamine,
respectively, and are either CTGCAA or CTGCAG. Although these are
synonymous in amino acid code, they differ with respect to Pst1
restriction, the former not being cleaved.

In 1 of 16 kindreds with AT-III deficiency, Bock and Prochownik (1987)
identified hemizygosity of the AT3 locus. In the remaining 15 kindreds,
2 copies of the AT3 gene were present and appeared to be grossly normal
at the level of whole genome Southern blotting. This suggested to the
authors that small deletions, insertions or limited nucleotide
substitutions in the AT3 gene, or 'trans-acting' defects involving the
processing, modification, or secretion of biologically active AT3 were
responsible for the great majority of the abnormalities.

Using DNA probes, Sacks et al. (1988) found no evidence of gene deletion
in 2 families with inherited antithrombin III deficiency. However,
linkage analysis showed close linkage (no recombination) between the AT3
gene, as marked by a common polymorphism, and the disorder.

Borg et al. (1988) identified a novel AT-III variant that showed
defective heparin binding (107300.0016). This and other mutant forms of
AT-III that showed a heparin-binding defect suggested that arginine-47
is a prime heparin-binding site in antithrombin. Borg et al. (1990)
studied the basis of reduced heparin affinity.

Leone et al. (1988) used crossed immunoelectrofocusing (CIEF) to
investigate molecular heterogeneity in 16 families with congenital
defects of AT-III. Of these, 8 families had quantitative deficiency of
AT-III and showed a normal CIEF pattern. Of the 8 AT-III molecular
variants studied, 6 had 1 of 2 abnormal patterns, depending on whether
they were variants with defective binding to heparin or variants with
defective binding to serine proteases. Two variants that were deficient
in the inactivation of serine proteases showed a normal CIEF pattern.

Wu et al. (1989) used PCR to demonstrate a DNA length polymorphism
5-prime to the AT3 gene due to the presence of 32- or 108-bp
nonhomologous DNA segments (Bock and Levitan, 1983). Mutations at
residues pro41 and arg47 lead to loss of heparin binding, whereas
mutations at residues arg393 and ser394 of the reactive site results in
a loss of thrombin inhibitory activity.

Grundy et al. (1991) pointed out that although AT-III deficiency usually
follows an autosomal dominant pattern of inheritance, a few patients
with defective heparin binding have been shown to be homozygous for a
lesion in the arg47 residue (see 107300.0003, 107300.0015).

- Classification of Antithrombin Variants

Sas (1988) and De Stefano and Leone (1989) addressed the question of
classification of mutant forms of antithrombin III leading to
deficiency. Sas (1988) commented on the confused state of the
classification of AT-III variants and used the term 'toponym' for the
geographic names assigned to variants.

Manson et al. (1989) classified mutations in the AT3 gene as
CRM-negative (also referred to as 'classic' or type I) and CRM-positive
(also referred to as 'mutant' or type II) cases; in type II, immunologic
methods demonstrate in the plasma protein product from the mutant
allele. Manson et al. (1989) further classified the AT-III mutants into
those involving 1 of the 2 heparin-binding sites in the N terminus
(mutations at pro41 or arg47) and those involving the thrombin-binding
region toward the C terminus (mutations in ala382, arg393, ser394, or
pro407).

Emmerich et al. (1994) noted that Lane et al. (1993) had proposed a new
classification of AT3 genetic abnormalities. Type I (quantitative)
deficiencies are predominantly due to nonsense mutations, frameshift
mutations, and large deletions, preventing the expression of the mutated
allele. Type II (qualitative) deficiencies are due to missense mutations
resulting in normal circulating levels of AT3 with either an abnormal
reactive site (RS) or an abnormal heparin-binding site (HBS). Amino acid
substitutions affecting a domain highly conserved in serpins, i.e., C
terminal to P1-prime, result in decreased AT3 circulating levels and
prevent both coagulation protease inhibition and heparin-binding
affinity; this mutations have been described as having a pleiotropic
effect (PE).

- Reviews

Blajchman et al. (1992) provided a review of molecular defects
underlying inherited antithrombin deficiency.

Lane et al. (1996) gave an extensive review of the molecular genetics of
antithrombin deficiency.

Lane et al. (1994) described a database of mutations in the AT3 gene. A
recent update was said to list 184 entries: 68 reports of type I
'classical' and 116 reports of type II 'variant' deficiencies.

Perry and Carrell (1996) also provided a catalog of AT3 mutations
responsible for types I and II deficiency.

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

ANIMAL MODEL

Cleavage of the carboxyl-terminal loop of antithrombin induces a
conformational change in the molecule. O'Reilly et al. (1999)
demonstrated that the cleaved conformation of antithrombin had potent
antiangiogenic and antitumor activity in mouse models. The latent form
of intact antithrombin, which is similar in conformation to the cleaved
molecule, also inhibited angiogenesis and tumor growth. O'Reilly et al.
(1999) concluded that these data provide further evidence that the
clotting and fibrinolytic pathways are directly involved in the
regulation of angiogenesis. O'Reilly et al. (1999) found that the
cleaved antithrombin potently inhibited endothelial cell proliferation
induced by bovine fibroblast growth factor or by vascular endothelial
growth factor in a dose-dependent fashion with a half-maximal inhibition
seen at 50 to 100 ng/ml. O'Reilly et al. (1999) suggested that cleaved
antithrombin and other angiogenesis inhibitors offer the potential for
improved efficacy and diminished toxicity in the treatment of cancer and
other angiogenesis-dependent diseases.

Green et al. (2003) showed that Drosophila 'necrotic' (nec) mutations
can mimic alpha-1-antitrypsin deficiency. They identified 2 nec
mutations homologous to an antithrombin point mutation that is
responsible for neonatal thrombosis. Transgenic flies carrying an amino
acid substitution equivalent to that found in Siiyama variant
antitrypsin (107400.0039) failed to complement nec-null mutations and
demonstrated a dominant temperature-dependent inactivation of the
wildtype nec allele. Green et al. (2003) concluded that the Drosophila
nec system can be used as a powerful system to study serpin
polymerization in vivo.

*FIELD* AV
.0001
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ALA404THR

This variant, designated AT-III Oslo, was found in the family first
described as an example of thrombophilia due to deficiency of AT-III
(613118) by Egeberg (1965). Hultin et al. (1988) provided further
information. AT-III Oslo is a type I form of deficiency. AT-III protein
is decreased in both the immunologic and the functional assay.

.0002
MOVED TO 107300.0007
.0003
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG47CYS

AT-III Toyama was described by Sakuragawa et al. (1983). In a patient
with recurrent thrombophlebitis and deficiency of AT-III (613118), Koide
et al. (1984) identified homozygosity for AT-III Toyama, an arg47-to-cys
substitution. Members of the family who were heterozygous for the
mutation were asymptomatic.

This mutation has also been described as AT-III Paris (Wolf et al.,
1982), AT-III Padua-2 (Girolami et al., 1983), AT-III Tours (Duchange et
al., 1986), AT-III Barcelona-2 (Fontcuberta et al., 1988), AT-III Alger
(Fischer et al., 1986), AT-III Amiens, and AT-III Paris-2.

Chasse et al. (1984) identified the abnormality in heterozygous state in
9 members of a French family, all without thrombotic complications.
Duchange et al. (1986) confirmed that the mutation (AT-III Tours) in
this family was a C-to-T transition leading to an arg47-to-cys
substitution. The deficiency in AT-III Tours shows retention of normal
activity in the absence of heparin and diminished activity in the
presence of heparin, with a decrease or complete loss of heparin-binding
ability. Most type 3 deficiencies are silent in the heterozygous state
and associated with severe thrombotic disorders only in homozygotes
(Boyer et al., 1986; Sakuragawa et al., 1983; Duchange et al., 1987).

This variant, described in homozygous form by Fischer et al. (1986), was
shown by Brunel et al. (1987) also to have substitution of cysteine for
arginine-47. The same mutation was identified by Perry and Carrell
(1989).

.0004
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1

AT-III Roma was studied by Leone et al. (1983) and De Stefano et al.
(1987).

.0005
REMOVED FROM DATABASE
.0006
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1

In a family with AT-III Trento described by Girolami et al. (1984), only
1 of 5 individuals with the variant showed thrombotic phenomena despite
the finding that the variant resulted in an overall decrease in
antithrombin III activities (613118). Further study by Girolami et al.
(1986) showed that a von Willebrand defect segregated independently in
this family. Only the symptomatic proposita and a niece showed the
isolated AT III abnormality. The authors noted that the proposita's
niece was very young and suggested that there was a strong possibility
of her developing thrombosis.

.0007
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ALA384PRO

AT-III Vicenza was described by Barbui et al. (1983).

The same variant was described by Aiach et al. (1985) as AT-III
Charleville. Molho-Sabatier et al. (1989) demonstrated that the AT-III
Charleville mutation represents a substitution of proline for alanine at
residue 384.

Perry and Carrell (1989) and Caso et al. (1991) also demonstrated this
change, which resulted from a GCA-to-CCA transition in exon 6. This is a
reactive site mutation. Pewarchuk et al. (1990) used PCR to identify the
same abnormality in a family with an extensive history of deep venous
thrombosis (613118).

This variant has also been referred to as AT-III Cambridge I and AT-III
Sudbury (Pewarchuk et al., 1990).

.0008
MOVED TO 107300.0003
.0009
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1

In 4 members of a large Tunisian family, Boyer et al. (1986) identified
a qualitative defect of antithrombin III, designated AT-III
Fontainebleu. The propositus was a 3-year-year old girl who died from
massive intracardiac thrombosis despite oral anticoagulant therapy.
Heparin cofactor activity was undetectable in plasma and anti-factor Xa
activity was absent. Her parents, first cousins, and her sister had
levels of heparin cofactor activity close to 50% of normal. Boyer et al.
(1986) concluded that the abnormal protein was present in homozygous
state in the propositus and in heterozygous state in her parents and
sister. Only the propositus had thrombotic episodes (613118).

.0010
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG393PRO

AT-III Pescara, described by Leone et al. (1987) in a family with a high
incidence of thrombosis (613118), was shown by Lane et al. (1989) to
have a CGT-to-CCT change in the AT3 gene, resulting in substitution of
proline for arginine-393. The defect concerned binding to serine
proteases.

.0011
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, SER394LEU

Sambrano et al. (1986) identified a qualitative defect in AT-III,
designated AT-III Denver, in a 16-year-old girl who presented with an
acute lower extremity deep vein thrombosis (613118) occurring
spontaneously 2 months after initiation of oral contraceptives. A
qualitative defect was documented in 3 of 7 family members in 2
generations. The structural abnormality was a replacement of serine-394
by leucine. AT-III Denver was studied further by Stephens et al. (1987,
1988).

In AT-III Milano-2, Olds et al. (1989) found a TCG-to-TTG change in
codon 394 predicting the same ser394-to-leu substitution. This mutation
is defective in serpin activity but binds heparin normally.

.0012
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, PRO41LEU

AT-III Clichy, a substitution of leucine for proline-41, was described
by Chang and Tran (1986), Aiach et al. (1987), and Molho-Sabatier et al.
(1989). The variant has also been called AT-III Clichy-2, AT-III Basel,
AT-III Franconville.

Aiach et al. (1987) found the mutation in heterozygous state in a
24-year-old woman presenting with a thoracic outlet syndrome.

Perry and Carrell (1989) described the same substitution in this
heparin-binding mutation, which was caused by a CGT-to-CAT change in
exon 2.

Olds et al. (1990) noted that this mutation occurs within a CG
dinucleotide, a recognized hotspot for single base mutations.

In a woman referred for routine prepregnancy testing and in several
members of her family, de Roux et al. (1990) found heterozygosity for
the pro41-to-leu mutation. None had had thrombotic complications.
Testing of the properties of the mutant AT-III suggested that proline-41
is more involved in the molecular changes induced by heparin than in the
primary binding of the activator.

.0013
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, VAL-3GLU

AT-III Dublin was described by Daly et al. (1987) in heterozygous state
in 3 Irish individuals with no evidence of hypercoagulation-related
problems. In the course of sequencing the AT3 gene in an AT-III Dublin
heterozygote, Daly et al. (1990) identified a valine-to-glutamic acid
substitution at position -3 in the signal peptide. A second, unrelated
individual being investigated for recurrent thromboses was found to be
heterozygous for same mutation. N-terminal sequencing of the
antithrombin protein from both heterozygotes showed a truncated
antithrombin in which the N-terminal dipeptide is absent. Daly et al.
(1990) proposed that the prepeptide mutation redirects signal peptidase
cleavage to a site 2 amino acids downstream into the mature protein.

Durr et al. (1992) found this mutation in southwest Germans and
Portuguese, with frequencies of 0.007 and 0.00024, respectively.

.0014
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1

Grau et al. (1988) described a quantitative and qualitative defect of
AT-III in 4 members of a Spanish family with a thrombotic tendency
(613118). The authors referred to the variant as AT-III Barcelona.

.0015
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG47HIS

Owen et al. (1987) described this heparin-binding defect (AT-III Rouen
I), a substitution of histidine at arginine-47 (R47H). Perry and Carrell
(1989) found the same substitution, caused by a CCG-to-CTG change in
exon 2.

Caso et al. (1990) identified the same mutation, which they called
antithrombin Padua I, in several members of a family. No pathologic
consequence (i.e., thrombosis) appeared to be associated with the
mutation in this family. Caso et al. (1990) stated that the substitution
resulted from a change of CGT to CAT in exon 2.

Emmerich et al. (1994) reported 2 brothers with AT-III deficiency and
thromboembolic events who were compound heterozygous for 2 mutations in
the AT3 gene: R47H, inherited from the mother, and a 9-bp deletion
(107300.0050), probably inherited from the father, who had died from a
pulmonary embolism at age 68. The 9-bp deletion results in a
substitution of val426 by ala, a deletion of the tripeptide
ala427-asn428-pro429, and a shift of the cys430 to position 427, which
probably impairs the formation of the last disulfide bond.

.0016
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG47SER

Borg et al. (1988) identified heterozygosity for an arg47-to-ser (R47S)
substitution in the AT3 gene in a 40-year-old man who was admitted to
hospital with a sudden myocardial infarction that lacked extensive
coronary artery disease. His 13-year-old daughter displayed the same
antithrombin abnormality. The variant, designated AT-III Rouen II,
showed defective heparin and heparan sulfate activities. There was no
definite family history of thrombosis.

.0017
MOVED TO 107300.0003
.0018
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG393CYS

In a 47-year-old patient presenting with recurrent venous
thromboembolism (613118), Aiach et al. (1988) identified a reactive site
variant, AT-III Avranches, in the AT3 gene that changed arginine-393 to
cysteine. They identified the same abnormality with defective
serine-protease inhibition in 2 of the patient's relatives.

.0019
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, PRO407LEU

In affected members of a family from Utah with antithrombin III
deficiency and thrombosis (613118) (Bock et al., 1985), Bock et al.
(1988) identified heterozygosity for a substitution of leucine for
proline-407 in the AT3 gene. AT-III Utah results in type I deficiency;
antithrombin III shows a 50% decrease in both the immunologic and the
functional assay.

.0020
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG393CYS

AT-III Northwick Park, described by Lane et al. (1987), was shown by
Erdjument et al. (1988) to have substitution of cysteine for
arginine-393. The same substitution was found by Erdjument et al. (1988)
in AT-III Milano-1. The mutation leads to thrombosis (613118).

.0021
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG393HIS

AT-III Glasgow, described by Lane et al. (1987), was shown by Erdjument
et al. (1988) and by Owen et al. (1988) to have substitution of
histidine for arginine-393 and to lead to thrombosis (613118).

Lane et al. (1989) showed that AT-III Sheffield has the same
substitution. Owen et al. (1988) also demonstrated replacement of
arginine by histidine at residue 393 in a 41-year-old male with a
history of thrombotic events. Arginine-393 is located in the site
involved in interaction with thrombin; the susceptibility to thrombosis
with this mutation is thus explained. Molho-Sabatier et al. (1989) also
found the arg393-to-his mutation in a variant form of AT-III.

AT-III Chicago, a functionally inactive antithrombin III associated with
thrombotic disease, was found by Erdjument et al. (1989) to have the
same substitution.

.0022
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ALA382THR

In a French-Canadian family, Devraj-Kizuk et al. (1988) demonstrated a
structural mutant of AT-III with defective serine protease activity,
which they termed AT-III Hamilton. The propositus, a 54-year-old man
with a history of recurrent thromboembolic events (613118), and his 2
asymptomatic adult children were heterozygous. Exon 6 showed a G-to-A
point mutation in the first base of codon 382, leading to the
substitution of threonine for alanine. Alanine-382, 12 residues from the
reactive center of the enzyme, is a highly conserved amino acid in the
family of serine protease inhibitors known as the serpins. In this
reactive site mutation, Perry and Carrell (1989) found substitution of
threonine for alanine-382 as a consequence of a GCA-to-ACA change in
exon 6.

.0023
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ILE7ASN

Brennan et al. (1988) demonstrated a substitution of asparagine for
isoleucine at position 7 in a mutant antithrombin III, designated AT-III
Rouen III, isolated from the plasma of a patient with pulmonary embolism
(613118). The mutation introduced a new asn-cys-thr glycosylation
sequence. The new oligosaccharide attachment site occupied the base of
the presumed heparin-binding site, and the finding explained the
consequent decrease in heparin affinity. Perry and Carrell (1989) also
found this substitution, which was due to an ATC-to-AAC change, as the
basis of a molecule defective in heparin binding.

.0024
MOVED TO 107300.0012
.0025
MOVED TO 107300.0003
.0026
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG24CYS

In a 25-year-old man who unexpectedly developed coronary thrombosis
(613118), Borg et al. (1990) identified heterozygosity for a CGC-to-TGC
transition at nucleotide 166 in exon 2 of the AT3 gene, resulting in an
arg24-to-cys substitution. He inherited the mutation from his
asymptomatic father. He inherited a hypofibrinogenemia from his mother.
The AT3 mutation, designated AT-III Rouen IV, results in impaired
heparin binding.

.0027
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ALA384SER

Harper et al. (1991) identified AT-III Cambridge II, which has a
substitution of serine for alanine-384. This mutation occurs at the same
codon as AT-III Cambridge I (107300.0007). Perry et al. (1991)
identified 4 unrelated persons with an identical antithrombin variant,
associated in one of them with episodes of recurrent venous thromboses
(613118). In each case, the plasma antithrombin concentration was normal
and the only functional abnormality was a minor but consistent decrease
in the heparin-induced thrombin inhibition, suggesting a mutation at or
near the reactive center of the molecule. Amplification and direct
sequencing of exon 6 showed a G-to-T mutation at nucleotide 1246, which
corresponded to a substitution of serine for alanine at residue 384.

.0028
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 1-BP DEL, A

Grundy et al. (1991) identified 2 patients, each from unrelated families
segregating AT-III deficiency and a history of thrombosis (613118), who
were heterozygous for different frameshift mutations involving the same
GAG codon (glu245) in exon 4 of the AT3 gene. One patient had a
heterozygous deletion of the A nucleotide, whereas the second had a
heterozygous deletion of an A and a G (107300.0029). Grundy et al.
(1991) pointed out that the deletion-prone glu245 codon is located
within a GAGAG motif that is effectively a short overlapping direct
repeat. In addition, a short inverted repeat flanked the site of
deletion. They pointed to similar deletion hotspots in the F8, HPRT,
HBA2, and HBB genes and pointed out common characteristics of these
hotspots.

.0029
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 2-BP DEL, AG

See 107300.0028 and Grundy et al. (1991).

.0030
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 1-BP INS, 780A

In a woman who developed pulmonary embolism during the postpartum period
of her first delivery and has AT-III deficiency (613118), Vidaud et al.
(1991) identified heterozygosity for an insertion of an adenine at
position 780 of the AT3 gene, according to the cDNA numbering of Chandra
et al. (1983). The mutation generated a frameshift that modified the
amino acid sequence and introduced a premature stop codon at position
232 of the protein. The woman's mother, who also had AT-III deficiency
and reported a history of recurrent venous thrombosis, was heterozygous
for the mutation.

.0031
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, SER291PRO

In a woman with type I AT-III deficiency who experienced several deep
vein thromboses (613118), Vidaud et al. (1991) identified heterozygosity
for a 2-bp deletion at positions 965 and 966 or at 967 and 968. (Because
2 AG dinucleotides were located next to each other, it was impossible to
tell which of the 2 was deleted.) The deletion created a new reading
frame from lysine-290 on, converting ser291 to proline and introducing a
stop codon at position 309 in the protein sequence. Her 2 children were
also heterozygous for the mutation and had decreased AT-III levels.

.0032
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ASP309LYS

In a 48-year-old man with type I antithrombin III deficiency and a
history of thrombotic events (613118), Vidaud et al. (1991) found
heterozygosity for a 4-bp deletion in the AT3 gene, resulting in a new
reading frame beyond leu308, changing aspartic acid-309 to lysine and
resulting in a TGA stop codon at amino acid position 313. One of his
sons, who was then 35 years old, was heterozygous for the mutation and
had AT-III deficiency but was free of thrombotic events.

.0033
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG129TER

In 3 patients from 2 apparently unrelated families with thrombophilia
due to type Ia AT-III deficiency (613118), Gandrille et al. (1991)
identified a heterozygous C-to-T mutation at codon 129 of the AT3 gene,
resulting in change from arginine to stop. Olds et al. (1991) reported 4
further kindreds in which the same mutation was associated with type Ia
AT-III deficiency and thrombotic disease. They stated that this mutation
was present in about 10% of their families with type Ia. (Type Ia is
characterized by the presence of only half the normal AT-III
concentration in plasma, with no detectable variant protein.) The
mutation in AT-III Geneva (107300.0034) occurs at the same codon.

.0034
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ARG129GLN

In a patient with type Ia deficiency of antithrombin III who had 1
episode of pulmonary embolism (613118), Gandrille et al. (1990)
identified heterozygosity for a G-A transition in the AT3 gene,
resulting in substitution of glutamine for arginine-129. The finding of
mutations at arginine-129 indicates its importance to the
heparin-binding site of AT3. The mutation was designated AT-III Geneva.

.0035
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, PRO429LEU

AT-III Budapest was the first type 2a AT-III variant described (Sas et
al., 1974, 1975, 1978). The propositus and several members of the
kindred had had thromboembolic episodes (613118). The parents of the
propositus were consanguineous.

Olds et al. (1992) showed that the AT-III Budapest allele, for which the
propositus was homozygous, contained a single nucleotide substitution
leading to the replacement of proline by leucine at codon 429. Proline
at this position is highly conserved across the whole of the serpin
family of proteins.

.0036
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, SER349PRO

In affected members of an English family segregating recurrent venous
thrombosis (613118), Grundy et al. (1992) identified heterozygosity for
a point mutation in exon 4 of the AT3 gene, resulting in substitution of
proline for serine-349.

.0037
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, GLY392ASP

Antithrombin III Stockholm, found in a woman who developed a pulmonary
embolus (613118) while on oral contraceptives at age 19, was shown by
Blajchman et al. (1992) to have a substitution of aspartic acid for
glycine-392, resulting from a G-to-A change in the second base of codon
392.

.0038
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, LEU99PHE

Olds et al. (1992) described a CTC-to-TTC transition at codon 99 of the
AT3 gene, altering the normal leucine to phenylalanine. The proband had
a history of venous thrombotic disease (613118) and was found to be
homozygous for the mutation. The variant protein showed reduced heparin
affinity and reduced antiproteinase activity in the presence of either
unfractionated heparin or the AT-binding heparin pentasaccharide, when
compared to normal AT. The substitution is located near the proposed
heparin-binding site.

.0039
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 1-BP INS, T, CODON 48

In a patient with antithrombin III deficiency and a proven family
history of thromboembolic disease (613118), Daly et al. (1992)
identified heterozygosity for a 1-bp insertion (T) in exon 2 of the AT3
gene, causing a frameshift at codon 48 from a valine (GTC) to a cysteine
(TGT) and a premature stop codon at position 72. A truncated AT3 protein
could not be detected in plasma, suggesting that it failed to be
secreted or was rapidly degraded. The mutation was designated AT48(+T).

.0040
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 1-BP INS, A, CODON 208

Daly et al. (1992) studied a 37-year-old woman with antithrombin III
deficiency and a proven family history of thromboembolic disease
(613118). Using PCR and direct sequencing of amplified DNA, they
identified an insertion of an A in exon 3B of the AT3 gene, changing
codon 208 from AAT (asparagine) to AAA (lysine) and creating a
frameshift with a stop codon at position 209. No abnormal AT3 was
detected in the plasma. The mutation was designated AT208(+A).

.0041
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 1-BP DEL, A, CODON 370

Daly et al. (1992) studied a 24-year-old woman with antithrombin III
deficiency and a history of thromboembolic disease (613118). Using PCR
and direct sequencing of amplified DNA, they identified a deletion of an
A in codon 370 in exon 5 of the AT3 gene, changing AAG (lysine) to AGG
(arginine) and resulting in a frameshift with a stop codon at position
375. No abnormal antithrombin protein was detected in the plasma. The
mutation was designated AT370(-A).

.0042
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ALA387VAL

In a patient with recurrent venous thrombosis and an AT-III
activity/antigen level consistent with type I AT-III deficiency
(613118), White et al. (1992) identified heterozygosity for a C-T
transition in the AT3 gene, resulting in an ala387-to-val substitution
near the reactive site.

.0043
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, SER116PRO

In a 33-year-old man who had recurrent cerebral infarctions (613118),
Okajima et al. (1993) found a T-to-C transition in exon 3a which
resulted in the substitution of proline for serine at codon 116. The
patient was heterozygous for the mutation, which lacked affinity for
heparin. The variant was designated AT-III Nagasaki.

.0044
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, LEU-10PRO

Most secretory proteins, including antithrombin, are synthesized with a
signal peptide, which is cleaved before the mature protein is exported
from the cell. The signal peptide is important in the process whereby
nascent protein is recognized as requiring subsequent modification
within the endoplasmic reticulum (ER). Fitches et al. (1998) identified
a novel mutation, which affected the central hydrophobic domain of the
AT3 signal peptide, in a proband presenting with venous thrombotic
disease and type I AT3 deficiency (613118). The mutation was a 2436T-C
transition, resulting in a leucine to proline change at the -10 residue
of the signal peptide. Fitches et al. (1998) investigated the basis of
the phenotype by examining expression in mammalian cells of a range of
variant AT3 cDNAs with mutations affecting the -10 residue. Glycosylated
AT3 was secreted from COS-7 cells transfected with wildtype AT3, -10leu
deletion, -10val or -10met variants, but not variants with pro, thr,
arg, or gly at -10. Cell-free expression of wildtype and variant AT3
cDNAs was then performed in the presence of canine pancreatic
microsomes, as a substitute for the ER. Variant AT3 proteins with pro,
thr, arg, or gly at residue -10 did not undergo posttranslational
glycosylation, and their susceptibility to trypsin digestion suggested
that they had not been translocated into microsomes. The results
suggested that the ability of AT3 signal peptide to direct the protein
to the ER for cotranslational processing events is critically dependent
on maintaining the hydrophobic nature of the region including residue
-10. The investigations defined impaired cotranslational processing as a
hitherto unrecognized cause of hereditary AT3 deficiency.

.0045
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ASN135THR

In a 25-year-old Italian woman who had experienced no thrombosis and had
no family history of venous thrombosis, Bayston et al. (1999) found
antithrombin deficiency (613118) with borderline levels (approximately
70% antigen and activity) of antithrombin. Direct sequencing of
amplified DNA showed a mutation in codon 135, AAC to ACC, predicting a
heterozygous asn135-to-thr substitution. This substitution altered the
predicted consensus sequence for glycosylation, asn-X-ser, adjacent to
the heparin interaction site of antithrombin. Antithrombin isolated from
plasma of the patient by heparin-Sepharose chromatography contained
amounts of beta-antithrombin (the very high affinity fraction) greatly
increased (approximately 20 to 30% of total) above the trace levels
found in normals. Expression of the residue 135 variant in both a
cell-free system and COS-7 cells confirmed altered glycosylation arising
as a consequence of the mutation. Wildtype and variant protein were
translated and then exported from COS-7 cells with apparently equal
efficiency, in contrast to the reduced level of variant observed in
plasma of the affected individual. This case represented a novel cause
of antithrombin deficiency, removal of glycosylation consensus sequence,
and highlighted the potentially important role of beta-antithrombin in
regulating coagulation.

.0046
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, ASN187ASP

Bruce et al. (1994) described thromboembolic disease due to thermolabile
conformational changes of AT-III Rouen VI (613118), which carries an
asn187-to-asp missense mutation in the AT3 gene.

.0047
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, SER191PRO

Baud et al. (2001) reported a neonate who died from a fatal cerebral
hemorrhage involving the left thalamus following deep cerebral vein
thrombosis (613118). The child was heterozygous for a 6472T-C transition
in the AT3 gene, resulting in a serine-to-proline substitution at codon
191 (S191P). Antithrombin levels were in the low normal range. An
asymptomatic sister, mother, and maternal grandfather had the same
mutation. A maternal aunt had suffered an undiagnosed pulmonary embolism
presumably secondary to antithrombin III deficiency.

.0048
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, CYS95ARG

Ozawa et al. (1997) described antithrombin III deficiency (613118)
caused by a T-to-C transition in the AT3 gene, resulting in a
cys95-to-arg (C95R) substitution. Because this cysteine is responsible
for the forming of an intramolecular disulfide bond, the mutation
ostensibly affects the folding of AT3 molecules. Tanaka et al. (2002)
transfected Chinese hamster ovary cells with the cDNA of AT-III Morioka
and compared its intracellular fate to that of wildtype AT-III. They
found that the mutant AT-III is not transported to the Golgi apparatus
and accumulates without degradation in novel structures surrounded by a
single membrane derived from the endoplasmic reticulum.

.0049
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 3-BP DEL

In a proband with early-onset thrombosis and antithrombin III deficiency
(613118), Raja et al. (2003) identified a heterozygous 3-bp deletion
corresponding to the codon for the P1 arginine-393 residue (ARG393DEL).
The mutation abolished inhibitor activity toward thrombin and factor Xa,
but bound to either full-length or pentasaccharide heparins with
substantially higher affinity than that of the normal inhibitor. The
authors suggested that the unusually severe thrombosis associated with
this mutation may be explained by the ability of antithrombin London to
bind endogenous heparan sulfate or heparan molecules and to thereby
block activation of the normal inhibitor.

.0050
THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY
SERPINC1, 9-BP DEL, NT13395

See 107300.0015 and Emmerich et al., 1994.

*FIELD* SA
Bauer et al. (1985); Beukes and Heyns (1980); Blajchman et al. (1992);
Brenner et al. (1988); Carvalho and Ellman (1976); Cosgriff et al.
(1983); Egeberg (1965); Erdjument et al. (1988); Filip et al. (1976);
Gallus (1984); Griffith et al. (1983); Gruenberg et al. (1975); Gyde
et al. (1978); Halal et al. (1983); Hofman et al. (1980); Knot et
al. (1986); Laharrague et al. (1980); Lane et al. (1989); Lane et
al. (1987); Leone et al. (1983); Leone et al. (1980); Magenis et al.
(1978); Mannucci et al. (1982); Manotti et al. (1982); Matsuo et al.
(1979); Mohanty et al. (1982); Odegard and Abildgaard (1977); Peterson
and Blackburn (1985); Pitney et al. (1980); Prochownik (1985); Scully
et al. (1981); Shapiro et al. (1981); Stathakis et al. (1977); Tengborn
et al. (1985); Towne et al. (1981); Vomberg et al. (1987); Williams
and Murano (1981); Winter et al. (1982)
*FIELD* RF
1. Aiach, M.; Francois, D.; Priollet, P.; Capron, L.; Roncato, M.;
Alhenc-Gelas, M.; Fiessinger, J.-N.: An abnormal antithrombin III
(AT III) with low heparin affinity: AT III Clichy. Brit. J. Haemat. 66:
515-522, 1987.

2. Aiach, M.; Nora, M.; Fiessinger, J. N.; Roncato, M.; Francois,
D.; Alhenc-Gelas, M.: A functional abnormal antithrombin III (ATIII)
deficiency: ATIII Charleville. Thromb. Haemost. 39: 559-570, 1985.

3. Aiach, M.; Roncato, M.; Chadeuf, G.; Dezellus, P.; Capron, L.;
Fiessinger, J. N.: Antithrombin III Avranches, a new variant with
defective serine-protease inhibition: comparison with antithrombin
III Charleville. Thromb. Haemost. 60: 94-96, 1988.

4. Barbui, T.; Finazzi, G.; Rodeghiero, F.; Dini, E.: Immunoelectrophoretic
evidence of a thrombin-induced abnormality in a new variant of hereditary
dysfunctional antithrombin III (AT III 'Vicenza'). Brit. J. Haemat. 54:
561-565, 1983.

5. Baud, O.; Picard, V.; Durand, P.; Duchemin, J.; Proulle, V.; Albenc-Gelas,
M.; Devictor, D.; Dreyfus, M.: Intracerebral hemorrhage associated
with a novel antithrombin gene mutation in a neonate. J. Pediat. 139:
741-743, 2001.

6. Bauer, K. A.; Goodman, T. L.; Kass, B. L.; Rosenberg, R. D.: Elevated
factor Xa activity in the blood of asymptomatic patients with congenital
antithrombin deficiency. J. Clin. Invest. 76: 826-836, 1985.

7. Bayston, T. A.; Tripodi, A.; Mannucci, P. M.; Thompson, E.; Ireland,
H.; Fitches, A. C.; Hananeia, L.; Olds, R. J.; Lane, D. A.: Familial
overexpression of beta-antithrombin caused by an asn135-to-thr substitution. Blood 93:
4242-4247, 1999.

8. Beukes, C. A.; Heyns, A. D.: A South African family with antithrombin
III deficiency. S. Afr. Med. J. 58: 528-530, 1980.

9. Bjork, I.; Danielsson, A.; Fenton, J. W.; Jornvall, H.: The site
in human antithrombin for functional proteolytic cleavage by human
thrombin. FEBS Lett. 126: 257-260, 1981.

10. Bjork, I.; Jackson, C. M.; Jornvall, H.; Lavine, K. K.; Nordling,
K.; Salsgiver, W. J.: The active site of antithrombin: release of
the same proteolytically cleaved form of the inhibitor from complexes
with factor IXa, factor Xa, and thrombin. J. Biol. Chem. 257: 2406-2411,
1982.

11. Blajchman, M. A.; Austin, R. C.; Fernandez-Rachubinski, F.; Sheffield,
W. P.: Molecular basis of inherited human antithrombin deficiency. Blood 80:
2159-2171, 1992.

12. Blajchman, M. A.; Fernandez-Rachubinski, F.; Sheffield, W. P.;
Austin, R. C.; Schulman, S.: Antithrombin-III-Stockholm: a codon
392 (gly-to-asp) mutation with normal heparin binding and impaired
serine protease reactivity. Blood 79: 1428-1434, 1992.

13. Bock, S. C.; Harris, J. F.; Balazs, I.; Trent, J. M.: Assignment
of the human antithrombin III structural gene to chromosome 1q23-25. Cytogenet.
Cell Genet. 39: 67-69, 1985.

14. Bock, S. C.; Harris, J. F.; Schwartz, C. E.; Ward, J. H.; Hershgold,
E. J.; Skolnick, M. H.: Hereditary thrombosis in a Utah kindred is
caused by a dysfunctional antithrombin III gene. Am. J. Hum. Genet. 37:
32-41, 1985.

15. Bock, S. C.; Levitan, D. J.: Characterization of an unusual DNA
length polymorphism 5-prime to the human antithrombin III gene. Nucleic
Acids Res. 11: 8569-8582, 1983.

16. Bock, S. C.; Marrinan, J. A.; Radziejewska, E.: Antithrombin
III Utah: proline-407 to leucine mutation in a highly conserved region
near the inhibitor reactive site. Biochemistry 27: 6171-6178, 1988.
Note: Erratum: Biochemistry 28: 3628 only, 1989.

17. Bock, S. C.; Prochownik, E. V.: Molecular genetic survey of 16
kindreds with hereditary antithrombin III deficiency. Blood 70:
1273-1278, 1987.

18. Bock, S. C.; Wion, K. L.; Vehar, G. A.; Lawn, R. M.: Cloning
and expression of the cDNA for human antithrombin III. Nucleic Acids
Res. 10: 8113-8126, 1982.

19. Borg, J.-Y.; Brennan, S. O.; Carrell, R. W.; George, P.; Perry,
D. J.; Shaw, J.: Antithrombin Rouen-IV 24 arg-to-cys: the amino-terminal
contribution to heparin binding. FEBS Lett. 266: 163-166, 1990.

20. Borg, J. Y.; Owen, M. C.; Soria, C.; Soria, J.; Caen, J.; Carrell,
R. W.: Proposed heparin binding site in antithrombin based on arginine
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thrombophilia. Thromb. Diath. Haemorrh. 32: 105-115, 1974.

124. Sas, G.; Koves, A.; Peto, I.; Domjan, G.: Thrombogenic effects
of some concentrates of coagulation factors: a possible role of contaminating
endotoxin. (Letter) Thromb. Haemost. 39: 530-532, 1978.

125. Sas, G.; Pepper, D. S.; Cash, J. D.: Further investigations
on antithrombin III in the plasma of patients with the abnormality
of 'antithrombin III Budapest'. Thromb. Diath. Haemorrh. 33: 564-572,
1975.

126. Scully, M. F.; De Haas, H.; Chan, P.; Kakkar, V. V.: Hereditary
antithrombin III deficiency in an English family. Brit. J. Haemat. 47:
235-240, 1981.

127. Shapiro, M. E.; Rodvien, R.; Bauer, K. A.; Salzman, E. W.: Acute
aortic thrombosis in antithrombin III deficiency. JAMA 245: 1759-1761,
1981.

128. Stathakis, N. E.; Papayannis, A. G.; Antonopoulos, M.; Gardikas,
C.: Familial thrombosis due to antithrombin III deficiency in a Greek
family. Acta Haemat. 57: 47-54, 1977.

129. Stephens, A. W.; Siddiqui, A.; Hirs, C. H. W.: Site-directed
mutagenesis of the reactive center (serine 394) of antithrombin III. J.
Biol. Chem. 263: 15849-15852, 1988.

130. Stephens, A. W.; Thalley, B. S.; Hirs, C. H. W.: Antithrombin-III
Denver, a reactive site variant. J. Biol. Chem. 262: 1044-1048,
1987.

131. Tanaka, Y.; Ueda, K.; Ozawa, T.; Sakuragawa, N.; Yokota, S.;
Sato, R.; Okamura, S.; Morita, M.; Imanaka, T.: Intracellular accumulation
of antithrombin Morioka (C95R), a novel mutation causing type I antithrombin
deficiency. J. Biol. Chem. 277: 51058-51067, 2002.

132. Tengborn, L.; Frohm, B.; Nilsson, L.-E.; Nilsson, I. M.: A Swedish
family with abnormal antithrombin III. Scand. J. Haemat. 34: 412-416,
1985.

133. Towne, J. B.; Bernhard, V. M.; Hussey, C.; Garancis, J. C.:
Antithrombin deficiency--a cause of unexplained thrombosis in vascular
surgery. Surgery 89: 735-742, 1981.

134. Vidaud, D.; Emmerich, J.; Sirieix, M. E.; Sie, P.; Alhenc-Gelas,
M.; Aiach, M.: Molecular basis for antithrombin III type I deficiency:
three novel mutations located in exon IV. Blood 78: 2305-2309, 1991.

135. Vomberg, P. P.; Breederveld, C.; Fleury, P.; Arts, W. F. M.:
Cerebral thromboembolism due to antithrombin III deficiency in two
children. Neuropediatrics 18: 42-44, 1987.

136. White, D.; Abraham, G.; Carter, C.; Kakkar, V. V.; Cooper, D.
N.: A novel missense mutation in the antithrombin III gene (ala387-to-val)
causing recurrent venous thrombosis. Hum. Genet. 90: 472-473, 1992.

137. Williams, L.; Murano, G.: Human antithrombin III heterogeneity. Blood 57:
229-232, 1981.

138. Winter, J. H.; Fenech, A.; Ridley, W.; Bennett, B.; Cumming,
A. M.; Mackie, M.; Douglas, A. S.: Familial antithrombin III deficiency. Quart.
J. Med. 51: 373-395, 1982.

139. Wolf, M.; Boyer, C.; Lavergne, J. M.; Larrieu, M. J.: A new
familial variant of antithrombin III: 'antithrombin III Paris.'. Brit.
J. Haemat. 51: 285-295, 1982.

140. Wu, S.; Seino, S.; Bell, G. I.: Human antithrombin II (AT3)
gene length polymorphism revealed by the polymerase chain reaction. Nucleic
Acids Res. 17: 6433, 1989.

*FIELD* CN
Carol A. Bocchini - updated: 11/17/2009
Ada Hamosh - updated: 4/15/2003
Ada Hamosh - updated: 1/25/2002
Victor A. McKusick - updated: 2/28/2001
Victor A. McKusick - updated: 1/19/2000
Ada Hamosh - updated: 9/15/1999
Victor A. McKusick - updated: 2/1/1999

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
terry: 11/29/2012
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terry: 4/15/2003
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terry: 12/22/1994
jason: 7/1/1994
mimadm: 3/28/1994
carol: 2/23/1994
carol: 7/9/1993
carol: 6/3/1993

MIM 613118
*RECORD*
*FIELD* NO
613118
*FIELD* TI
#613118 ANTITHROMBIN III DEFICIENCY; AT3D
;;THROMBOPHILIA DUE TO ANTITHROMBIN III DEFICIENCY; THPH7
read more*FIELD* TX
A number sign (#) is used with this entry because susceptibility to
thrombophilia can be conferred by variation in the SERPINC1 gene, which
encodes antithrombin III (AT3; 107300), on chromosome 1q23-q25.

DESCRIPTION

Deficiency of antithrombin III is a major risk factor for venous
thromboembolic disease. Two categories of AT-III deficiency have been
defined on the basis of AT-III antigen levels in the plasma of affected
individuals. The majority of AT-III deficiency families belong in the
type I (classic) deficiency group and have a quantitatively abnormal
phenotype in which antigen and heparin cofactor levels are both reduced
to about 50% of normal. The second category of AT-III deficiency has
been termed type II (functional) deficiency. Affected individuals from
these kindreds produce dysfunctional AT-III molecules; they have reduced
heparin cofactor activity levels (about 50% of normal) but levels of
AT-III antigen are often normal or nearly normal (summary by Bock and
Prochownik, 1987).

The 2 categories of antithrombmin III deficiency have been classified
further. Type I (low functional and immunologic antithrombin) has been
subdivided into subtype Ia (reduced levels of normal antithrombin), and
type Ib (reduced levels of antithrombin and the presence of low levels
of a variant). Type II (low functional but normal immunologic
antithrombin) has been subdivided into subtype IIa (functional
abnormalities affecting both the reactive site and the heparin-binding
site of AT3); subtype IIb (functional abnormalities limited to the
reactive site); and subtype IIc (functional abnormalities limited to the
heparin-binding site) (summary by Lane et al., 1992).

CLINICAL FEATURES

Egeberg (1965) described a pedigree in which persons in 3 generations
had florid thrombophlebitis and other thrombotic disease associated with
about half-normal levels of antithrombin III. He suggested that
antithrombin III may be the same as heparin cofactor. Antithrombin
deficiency in individual patients with severe venoocclusive disease and
an impressive family history was also reported by Penick (1969) and by
Nesje and Kordt (1970).

Marciniak et al. (1974) described a large kindred from eastern Kentucky
that had an extensive history of recurrent venous thrombosis and
pulmonary embolism. Nine persons in 3 generations showed low
antithrombin III levels (26 to 49% of normal). Five others were
suspected of having the biochemical defect. Male-to-male transmission
was noted. They concluded that antithrombin III is the sole blood
component through which heparin exerts its anticoagulant effect.

Tullis and Watanabe (1978) described the seventh reported family and
suggested that familial hypercoagulability may be due, in some instances
at least, to platelet antithrombin deficiency (with the serum deficiency
representing a secondary defect).

A CRM+ form of antithrombin III deficiency was described by Sas et al.
(1980). Not only does heparin require AT-III for its anticoagulant
effect, but it also increases the turnover rate of AT-III. Both normal
persons and persons with AT-III deficiency show a decrease in plasma
AT-III levels when given heparin intravenously. In persons with AT-III
deficiency the effect may lead to recurrent thrombosis despite heparin
therapy.

The many special problems of pregnancy in women with AT-III deficiency
were discussed by Nelson et al. (1985).

Wilson et al. (1987) found that 16 of 123 patients with acute mesenteric
infarction (13%) had mesenteric venous thromboses. Of these, 6 patients
could be studied for antithrombin III deficiency; deficiency was found
in 3.

Aiach et al. (1987) described a family with a variant form of AT-III
(107300.0012) that was apparently not associated with an increased
incidence of venous thrombosis.

Johnson et al. (1990) described 2 sisters who at ages 27 and 40 had
serious peripheral and CNS arterial thrombotic disease. Cigarette
smoking was the only clear additional risk factor.

Rosendaal et al. (1991) found no evidence of excess mortality in 171
individuals from 10 families with either proven deficiency of AT-III or
a 50% probability of being affected. They suggested, therefore, that a
policy of prophylactic anticoagulation for patients with AT-III
deficiency cannot be recommended.

Mitchell et al. (1991) proposed that the lower risk of thromboembolic
complications in AT-III-deficient children may be due in part to a
protective effect of elevated levels of alpha-2-macroglobulin (A2M;
103950) during childhood.

Heijboer et al. (1990) investigated the prevalence of isolated
deficiencies of antithrombin III, protein C, protein S, and plasminogen
in 277 consecutive outpatients with venographically proved acute deep
vein thrombosis, as compared with 138 age-matched and sex-matched
controls without deep vein thrombosis. They found deficiencies of 1 of
these proteins in 23 (8.3%) of the patients as compared with 2.2% of
controls. The positive predictive values for the presence of an isolated
protein deficiency in patients with recurrent, familial, or juvenile
deep-vein thrombosis, defined as the proportion of patients with the
clinical finding who had a deficiency of 1 or more of the proteins, were
9%, 16%, and 12%, respectively. Heijboer et al. (1990) concluded that
acute venous thrombosis in most outpatients cannot be explained by
abnormalities of coagulation-inhibiting and fibrinolytic proteins and
that information from the medical history concerning recurrent or
familial venous thrombosis or the onset at an early age is not useful
for identifying patients with protein deficiencies.

Pabinger et al. (1994) found that the probability for thrombosis was
significantly higher in AT3-deficient females taking an oral
contraceptive compared to AT3-deficient females who were not. In
patients with protein C and protein S deficiency, there was no
significant difference between the contraceptive and noncontraceptive
groups. Pabinger et al. (1994) suggested that all contraceptives should
be strictly avoided in these females and that AT3 measurement should be
mandatory in female relatives of known AT3-deficient patients before
starting contraceptives.

MAPPING

Lovrien et al. (1978) found linkage of AT3 deficiency and Duffy blood
group (FY; 110700) on chromosome 1 (lod score of 1.2 at a recombination
fraction of 0.1 in males and 0.3 in females). Bishop et al. (1978)
presented corroborating data on linkage with Duffy. The provisional
assignment of antithrombin III deficiency to chromosome 1 by linkage to
the Duffy blood group locus was confirmed (Bishop et al., 1982; Winter
et al., 1982). For the linkage of AT3 deficiency and FY, Winter et al.
(1982) found a combined maximum lod score of 4.2 at recombination
fractions around 0.1. Two patients with deletions of 1q had half-normal
levels of antithrombin III, suggesting that the AT3 locus lies in bands
1q22-q25.

INHERITANCE

Grundy et al. (1991) pointed out that although AT-III deficiency usually
follows an autosomal dominant pattern of inheritance, a few patients
with defective heparin binding have been shown to be homozygous for a
lesion in the arg47 residue (see 107300.0003, 107300.0015).

MOLECULAR GENETICS

In the first family reported with thrombophilia due to AT-III deficiency
by Egeberg (1965), Hultin et al. (1988) identified a mutation in the AT3
gene (107300.0001). The AT-III protein in patients with AT-III Oslo is
decreased in both the immunologic and the functional assay.

Borg et al. (1988) identified a novel AT-III variant that showed
defective heparin binding (107300.0016). The mutation was not associated
with thrombophilia. This and other mutant forms of AT-III that showed a
heparin-binding defect (e.g., 107300.0003 and 107300.0015) suggested
that arginine-47 is a prime heparin-binding site in antithrombin. Borg
et al. (1990) studied the basis of reduced heparin affinity.

In a patient with recurrent thrombophlebitis and AT-III deficiency,
Koide et al. (1984) identified homozygosity for an arg47-to-cys mutation
in the AT3 gene (107300.0003). Members of the family who were
heterozygous for the mutation were asymptomatic.

In a patient presenting with recurrent venous thromboembolism, Aiach et
al. (1988) identified a reactive site variant (107300.0018) in the AT3
gene. The mutation resulted in defective serine protease inhibition.

POPULATION GENETICS

Rosenberg (1975) placed the prevalence of AT-III deficiency at 1 per
2,000 and the frequency among hospitalized patients with recurrent or
extensive thrombosis at 2 to 3%.

Harper et al. (1991) concluded that the frequency of antithrombin
deficiency is about 5% among patients who present with venous thrombosis
before the age of 40 years. About 2% of all such patients have a
dysfunctional variant of AT-III.

In a survey of over 4,000 Scottish blood donors with a sensitive heparin
cofactor assay, Tait et al. (1991) found an incidence of hereditary
AT-III deficiency of 1 in 350 donors, most of whom were clinically
asymptomatic.

Perry and Carrell (1996) estimated that AT-III deficiency has a
prevalence of 1:630 in the general population and is found in 3 to 5% of
patients with thrombotic disease.

*FIELD* RF
1. Aiach, M.; Francois, D.; Priollet, P.; Capron, L.; Roncato, M.;
Alhenc-Gelas, M.; Fiessinger, J.-N.: An abnormal antithrombin III
(AT III) with low heparin affinity: AT III Clichy. Brit. J. Haemat. 66:
515-522, 1987.

2. Aiach, M.; Roncato, M.; Chadeuf, G.; Dezellus, P.; Capron, L.;
Fiessinger, J. N.: Antithrombin III Avranches, a new variant with
defective serine-protease inhibition: comparison with antithrombin
III Charleville. Thromb. Haemost. 60: 94-96, 1988.

3. Bishop, D. T.; Martin, B.; Baty, B.; Cosgriff, T.; Hershgold, E.
J.; Skolnick, M.: Linkage of antithrombin III deficiency to Duffy
blood group. (Abstract) Am. J. Hum. Genet. 30: 48A, 1978.

4. Bishop, D. T.; Skolnick, M. H.; Baty, B.; Cosgriff, T.; Martin,
B.; Hershgold, E.: Linkage of familial antithrombin III deficiency
to Duffy (Fy). (Abstract) Cytogenet. Cell Genet. 32: 255, 1982.

5. Bock, S. C.; Prochownik, E. V.: Molecular genetic survey of 16
kindreds with hereditary antithrombin III deficiency. Blood 70:
1273-1278, 1987.

6. Borg, J.-Y.; Brennan, S. O.; Carrell, R. W.; George, P.; Perry,
D. J.; Shaw, J.: Antithrombin Rouen-IV 24 arg-to-cys: the amino-terminal
contribution to heparin binding. FEBS Lett. 266: 163-166, 1990.

7. Borg, J. Y.; Owen, M. C.; Soria, C.; Soria, J.; Caen, J.; Carrell,
R. W.: Proposed heparin binding site in antithrombin based on arginine
47: a new variant Rouen-II, arg-to-ser. J. Clin. Invest. 81: 1292-1296,
1988.

8. Egeberg, O.: Inherited antithrombin deficiency causing thrombophilia. Thromb.
Diath. Haemorrh. 13: 516-530, 1965.

9. Grundy, C. B.; Thomas, F.; Millar, D. S.; Krawczak, M.; Melissari,
E.; Lindo, V.; Moffat, E.; Kakkar, V. V.; Cooper, D. N.: Recurrent
deletion in the human antithrombin III gene. Blood 78: 1027-1032,
1991.

10. Harper, P. L.; Luddington, R. J.; Daly, M.; Bruce, D.; Williamson,
D.; Edgar, P. F.; Perry, D. J.; Carrell, R. W.: The incidence of
dysfunctional antithrombin variants: four cases in 210 patients with
thromboembolic disease. Brit. J. Haemat. 77: 360-364, 1991.

11. Heijboer, H.; Brandjes, D. P. M.; Buller, H. R.; Sturk, A.; ten
Cate, J. W.: Deficiencies of coagulation-inhibiting and fibrinolytic
proteins in outpatients with deep-vein thrombosis. New Eng. J. Med. 323:
1512-1516, 1990.

12. Hultin, M. B.; McKay, J.; Abildgaard, U.: Antithrombin Oslo:
type Ib classification of the first reported antithrombin-deficient
family, with a review of hereditary antithrombin variants. Thromb.
Haemost. 59: 468-473, 1988.

13. Johnson, E. J.; Prentice, C. R. M.; Parapia, L. A.: Premature
arterial disease associated with familial antithrombin III deficiency. Thromb.
Haemost. 63: 13-15, 1990.

14. Koide, T.; Odani, S.; Takahashi, K.; Ono, T.; Sakuragawa, N.:
Antithrombin III Toyama: replacement of arginine-47 by cysteine in
hereditary abnormal antithrombin III that lacks heparin-binding ability. Proc.
Nat. Acad. Sci. 81: 289-293, 1984.

15. Lane, D. A.; Olds, R. R.; Thein, S.-L.: Antithrombin and its
deficiency states. Blood Coagul. Fibrinolysis 3: 315-341, 1992.

16. Lovrien, E. W.; Magenis, R. E.; Rivas, M. L.; Goodnight, S.; Moreland,
R.; Rowe, S.: Linkage study of antithrombin III. Cytogenet. Cell
Genet. 22: 319-323, 1978.

17. Marciniak, E.; Farley, C. H.; DeSimone, P. A.: Familial thrombosis
due to antithrombin III deficiency. Blood 43: 219-231, 1974.

18. Mitchell, L.; Piovella, F.; Ofosu, F.; Andrew, M.: Alpha-2-macroglobulin
may provide protection from thromboembolic events in antithrombin
III-deficient children. Blood 78: 2299-2304, 1991.

19. Nelson, D. M.; Stempel, L. E.; Brandt, J. T.: Hereditary antithrombin
III deficiency and pregnancy: report of two cases and review of the
literature. Obstet. Gynec. 65: 848-853, 1985.

20. Nesje, O. A.; Kordt, K. F.: Hypoantithrombinemi som arsak til
mesenterialvenethrombose. Nord. Med. 83: 367-368, 1970.

21. Pabinger, I.; Schneider, B.; GTH Study Group on Natural Inhibitors
: Thrombotic risk of women with hereditary antithrombin III-, protein
C- and protein S-deficiency taking oral contraceptive medication. Thromb.
Haemost. 71: 548-552, 1994.

22. Penick, G. D.: Blood states that predispose to thrombosis.In:
Sherry, S.; Brinkhous, K. M.; Genton, E.; Stengle, J. M.: Thrombosis.
Washington, D. C.: National Academy of Sciences (pub.) 1969.

23. Perry, D. J.; Carrell, R. W.: Molecular genetics of human antithrombin
deficiency. Hum. Mutat. 7: 7-22, 1996.

24. Rosenberg, R. D.: Actions and interactions of antithrombin and
heparin. New Eng. J. Med. 292: 146-151, 1975.

25. Rosendaal, F. R.; Heijboer, H.; Briet, E.; Buller, H. R.; Brandjes,
D. P. M.; de Bruin, K.; Hommes, D. W.; Vandenbroucke, J. P.: Mortality
in hereditary antithrombin-III deficiency--1830 to 1989. Lancet 337:
260-262, 1991.

26. Sas, G.; Peto, I.; Banhegyi, D.; Blasko, G.; Domjan, G.: Heterogeneity
of the 'classical' antithrombin III deficiency. Thromb. Haemost. 43:
133-136, 1980.

27. Tait, R. C.; Walker, I. D.; Perry, D. J.; Carrell, R. W.; Islam,
S. I. A.; McCall, F.; Mitchell, R.; Davidson, J. F.: Prevalence of
antithrombin III deficiency subtypes in 4000 healthy blood donors.
(Abstract) Thromb. Haemost. 65: 839 only, 1991.

28. Tullis, J. L.; Watanabe, K.: Platelet antithrombin deficiency:
a new clinical entity. Am. J. Med. 65: 472-478, 1978.

29. Wilson, C.; Walker, I. D.; Davidson, J. F.; Imrie, C. W.: Mesenteric
venous thrombosis and antithrombin III deficiency. J. Clin. Path. 40:
906-908, 1987.

30. Winter, J. H.; Bennett, B.; Watt, J. L.; Brown, T.; San Roman,
C.; Schinzel, A.; King, J.; Cook, P. J. L.: Confirmation of linkage
between antithrombin III and Duffy blood group and assignment of AT3
to 1q22-1q25. Ann. Hum. Genet. 46: 29-34, 1982.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Autosomal recessive

CARDIOVASCULAR:
[Vascular];
Venoocclusive disease;
Deep vein thrombosis;
Recurrent thrombophlebitis (e.g. homozygous 107300.0008 AT-III TOYAMA);
Arterial occlusion rare

RESPIRATORY:
[Lung];
Pulmonary embolism

ABDOMEN:
[Gastrointestinal];
Mesenteric vein thrombosis

NEUROLOGIC:
[Central nervous system];
Cerebral vein thrombosis

LABORATORY ABNORMALITIES:
Antithrombin III deficiency;
Type I, classic, decreased antithrombin III levels;
Type II, normal antithrombin III level but decreased activity

MOLECULAR BASIS:
Caused by mutation in the antithrombin III gene (AT3, 107300.0001)

*FIELD* CN
Ada Hamosh - reviewed: 5/12/2000
Kelly A. Przylepa - revised: 3/16/2000

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

*FIELD* ED
joanna: 03/08/2012
joanna: 10/28/2008
joanna: 5/16/2000
joanna: 5/12/2000
kayiaros: 3/16/2000

*FIELD* CD
Carol A. Bocchini: 11/11/2009

*FIELD* ED
carol: 04/30/2012
terry: 3/27/2012
carol: 3/1/2012
carol: 2/28/2012
ckniffin: 2/23/2012
carol: 6/22/2011
carol: 4/22/2011
terry: 1/21/2010
carol: 11/19/2009
carol: 11/18/2009
terry: 11/16/2009
carol: 11/13/2009

RBCC Red Blood Cell Collection

Full text data of SERPINC1