RBCC

Full text data of F2

F2 [Confidence: low (only semi-automatic identification from reviews)]
Prothrombin; 3.4.21.5 (Coagulation factor II; Activation peptide fragment 1; Activation peptide fragment 2; Thrombin light chain; Thrombin heavy chain; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P00734
ID THRB_HUMAN Reviewed; 622 AA.
AC P00734; B2R7F7; B4E1A7; Q4QZ40; Q53H04; Q53H06; Q7Z7P3; Q9UCA1;
read moreDT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1990, sequence version 2.
DT 22-JAN-2014, entry version 194.
DE RecName: Full=Prothrombin;
DE EC=3.4.21.5;
DE AltName: Full=Coagulation factor II;
DE Contains:
DE RecName: Full=Activation peptide fragment 1;
DE Contains:
DE RecName: Full=Activation peptide fragment 2;
DE Contains:
DE RecName: Full=Thrombin light chain;
DE Contains:
DE RecName: Full=Thrombin heavy chain;
DE Flags: Precursor;
GN Name=F2;
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=2825773; DOI=10.1021/bi00393a033;
RA Degen S.J.F., Davie E.W.;
RT "Nucleotide sequence of the gene for human prothrombin.";
RL Biochemistry 26:6165-6177(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT FA2D GLY-72.
RC TISSUE=Blood;
RX PubMed=14962227; DOI=10.1046/j.1365-2516.2003.00838.x;
RA Wang W., Fu Q., Zhou R., Wu W., Ding Q., Hu Y., Wang X., Wang H.,
RA Wang Z.;
RT "Prothrombin Shanghai: hypoprothrombinaemia caused by substitution of
RT Gla29 by Gly.";
RL Haemophilia 10:94-97(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-165.
RC TISSUE=Liver, and Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MET-165.
RG SeattleSNPs variation discovery resource;
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-622.
RX PubMed=6305407; DOI=10.1021/bi00278a008;
RA Degen S.J.F., McGillivray R.T.A., Davie E.W.;
RT "Characterization of the complementary deoxyribonucleic acid and gene
RT coding for human prothrombin.";
RL Biochemistry 22:2087-2097(1983).
RN [8]
RP PROTEIN SEQUENCE OF 44-64.
RC TISSUE=Urine;
RX PubMed=8073540; DOI=10.1007/BF00431548;
RA Suzuki K., Moriyama M., Nakajima C., Kawamura K., Miyazawa K.,
RA Tsugawa R., Kikuchi N., Nagata K.;
RT "Isolation and partial characterization of crystal matrix protein as a
RT potent inhibitor of calcium oxalate crystal aggregation: evidence of
RT activation peptide of human prothrombin.";
RL Urol. Res. 22:45-50(1994).
RN [9]
RP PROTEIN SEQUENCE OF 44-314.
RX PubMed=266717; DOI=10.1073/pnas.74.5.1969;
RA Walz D.A., Hewett-Emmett D., Seegers W.H.;
RT "Amino acid sequence of human prothrombin fragments 1 and 2.";
RL Proc. Natl. Acad. Sci. U.S.A. 74:1969-1972(1977).
RN [10]
RP PROTEIN SEQUENCE OF 315-622, AND VARIANT GLN-532.
RX PubMed=873923;
RA Butkowski R.J., Elion J., Downing M.R., Mann K.G.;
RT "Primary structure of human prethrombin 2 and alpha-thrombin.";
RL J. Biol. Chem. 252:4942-4957(1977).
RN [11]
RP ENZYME REGULATION, AND HETERODIMER WITH SERPINA5.
RX PubMed=6323392;
RA Suzuki K., Nishioka J., Kusumoto H., Hashimoto S.;
RT "Mechanism of inhibition of activated protein C by protein C
RT inhibitor.";
RL J. Biochem. 95:187-195(1984).
RN [12]
RP PROTEOLYTIC PROCESSING.
RX PubMed=3759958;
RA Rabiet M.J., Blashill A., Furie B., Furie B.C.;
RT "Prothrombin fragment 1 X 2 X 3, a major product of prothrombin
RT activation in human plasma.";
RL J. Biol. Chem. 261:13210-13215(1986).
RN [13]
RP FUNCTION, AND CHARACTERIZATION.
RX PubMed=2856554;
RA Glenn K.C., Frost G.H., Bergmann J.S., Carney D.H.;
RT "Synthetic peptides bind to high-affinity thrombin receptors and
RT modulate thrombin mitogenesis.";
RL Pept. Res. 1:65-73(1988).
RN [14]
RP INVOLVEMENT IN RPRGL2 SUSCEPTIBILITY.
RX PubMed=11506076; DOI=10.1111/j.8755-8920.2001.460202.x;
RA Pihusch R., Buchholz T., Lohse P., Rubsamen H., Rogenhofer N.,
RA Hasbargen U., Hiller E., Thaler C.J.;
RT "Thrombophilic gene mutations and recurrent spontaneous abortion:
RT prothrombin mutation increases the risk in the first trimester.";
RL Am. J. Reprod. Immunol. 46:124-131(2001).
RN [15]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ISCHSTR.
RX PubMed=15534175; DOI=10.1001/archneur.61.11.1652;
RA Casas J.P., Hingorani A.D., Bautista L.E., Sharma P.;
RT "Meta-analysis of genetic studies in ischemic stroke: thirty-two genes
RT involving approximately 18,000 cases and 58,000 controls.";
RL Arch. Neurol. 61:1652-1661(2004).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-121 AND ASN-143, 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 [17]
RP CHARACTERIZATION OF THE TP508 PEPTIDE.
RX PubMed=15885491; DOI=10.1016/j.orthres.2004.12.005;
RA Li G., Cui Y., McIlmurray L., Allen W.E., Wang H.;
RT "rhBMP-2, rhVEGF(165), rhPTN and thrombin-related peptide, TP508
RT induce chemotaxis of human osteoblasts and microvascular endothelial
RT cells.";
RL J. Orthop. Res. 23:680-685(2005).
RN [18]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-121; ASN-143 AND ASN-416,
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 [19]
RP THERAPEUTIC USAGE OF THE TP508 PEPTIDE.
RX PubMed=17244316; DOI=10.1111/j.1524-475X.2006.00181.x;
RA Fife C., Mader J.T., Stone J., Brill L., Satterfield K., Norfleet A.,
RA Zwernemann A., Ryaby J.T., Carney D.H.;
RT "Thrombin peptide Chrysalin stimulates healing of diabetic foot ulcers
RT in a placebo-controlled phase I/II study.";
RL Wound Repair Regen. 15:23-34(2007).
RN [20]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-416, 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 [21]
RP GLYCOSYLATION AT ASN-416.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-416, STRUCTURE OF
RP CARBOHYDRATE, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [23]
RP GLYCOSYLATION AT ASN-121 AND ASN-143, STRUCTURE OF CARBOHYDRATES, AND
RP MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.M111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of
RT N-and O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
RX PubMed=2583108;
RA Bode W., Mayr I., Baumann U., Huber R., Stone S.R., Hofsteenge J.;
RT "The refined 1.9 A crystal structure of human alpha-thrombin:
RT interaction with D-Phe-Pro-Arg chloromethylketone and significance of
RT the Tyr-Pro-Pro-Trp insertion segment.";
RL EMBO J. 8:3467-3475(1989).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) IN COMPLEX WITH HIRUDIN.
RX PubMed=2369893;
RA Gruetter M.G., Priestle J.P., Rahuel J., Grossenbacher H., Bode W.,
RA Hofsteenge J., Stone S.R.;
RT "Crystal structure of the thrombin-hirudin complex: a novel mode of
RT serine protease inhibition.";
RL EMBO J. 9:2361-2365(1990).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEX WITH HIRUDIN.
RX PubMed=2374926; DOI=10.1126/science.2374926;
RA Rydel T.J., Ravichandran K.G., Tulinsky A., Bode W., Huber R.,
RA Roitsch C., Fenton J.W. II;
RT "The structure of a complex of recombinant hirudin and human alpha-
RT thrombin.";
RL Science 249:277-280(1990).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 328-622 IN COMPLEXES WITH
RP HIRUDIN AND SYNTHETIC INHIBITOR.
RX PubMed=8251938;
RA Priestle J.P., Rahuel J., Rink H., Tones M., Gruetter M.G.;
RT "Changes in interactions in complexes of hirudin derivatives and human
RT alpha-thrombin due to different crystal forms.";
RL Protein Sci. 2:1630-1642(1993).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RX PubMed=8071320;
RA Rydel T.J., Yin M., Padmanabhan K.P., Blankenship D.T., Cardin A.D.,
RA Correa P.E., Fenton J.W. II, Tulinsky A.;
RT "Crystallographic structure of human gamma-thrombin.";
RL J. Biol. Chem. 269:22000-22006(1994).
RN [29]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=9214615; DOI=10.1093/emboj/16.11.2977;
RA van de Locht A., Bode W., Huber R., le Bonniec B.F., Stone S.R.,
RA Esmon C.T., Stubbs M.T.;
RT "The thrombin E192Q-BPTI complex reveals gross structural
RT rearrangements: implications for the interaction with antithrombin and
RT thrombomodulin.";
RL EMBO J. 16:2977-2984(1997).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 328-601.
RX PubMed=10051558; DOI=10.1073/pnas.96.5.1852;
RA Guinto E.R., Caccia S., Rose T., Fuetterer K., Waksman G., di Cera E.;
RT "Unexpected crucial role of residue 225 in serine proteases.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:1852-1857(1999).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 333-621 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR.
RX PubMed=11493008; DOI=10.1006/jmbi.2001.4872;
RA Skordalakes E., Dodson G.G., Green D.S., Goodwin C.A., Scully M.F.,
RA Hudson H.R., Kakkar V.V., Deadman J.J.;
RT "Inhibition of human alpha-thrombin by a phosphonate tripeptide
RT proceeds via a metastable pentacoordinated phosphorus intermediate.";
RL J. Mol. Biol. 311:549-555(2001).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF 334-620 IN COMPLEX WITH
RP HIRUDIN AND SYNTHETIC INHIBITOR.
RX PubMed=16763681; DOI=10.1039/b602585d;
RA Schweizer E., Hoffmann-Roeder A., Olsen J.A., Seiler P.,
RA Obst-Sander U., Wagner B., Kansy M., Banner D.W., Diederich F.;
RT "Multipolar interactions in the D pocket of thrombin: large
RT differences between tricyclic imide and lactam inhibitors.";
RL Org. Biomol. Chem. 4:2364-2375(2006).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS) OF 334-621 IN COMPLEX WITH
RP HIRUDIN.
RX PubMed=17685615; DOI=10.1021/ja0735002;
RA Liu C.C., Brustad E., Liu W., Schultz P.G.;
RT "Crystal structure of a biosynthetic sulfo-hirudin complexed to
RT thrombin.";
RL J. Am. Chem. Soc. 129:10648-10649(2007).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS) OF 335-621 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR.
RX PubMed=18291642; DOI=10.1016/j.bmcl.2008.01.098;
RA Isaacs R.C.A., Solinsky M.G., Cutrona K.J., Newton C.L.,
RA Naylor-Olsen A.M., McMasters D.R., Krueger J.A., Lewis S.D.,
RA Lucas B.J., Kuo L.C., Yan Y., Lynch J.J., Lyle E.A.;
RT "Structure-based design of novel groups for use in the P1 position of
RT thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles.";
RL Bioorg. Med. Chem. Lett. 18:2062-2066(2008).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 315-622 IN COMPLEX WITH
RP SERPINA5 AND HEPARIN.
RX PubMed=18362344; DOI=10.1073/pnas.0711055105;
RA Li W., Adams T.E., Nangalia J., Esmon C.T., Huntington J.A.;
RT "Molecular basis of thrombin recognition by protein C inhibitor
RT revealed by the 1.6-A structure of the heparin-bridged complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:4661-4666(2008).
RN [36]
RP VARIANT FA2D LYS-200, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=6405779; DOI=10.1111/j.1365-2141.1983.tb02092.x;
RA Board P.G., Shaw D.C.;
RT "Determination of the amino acid substitution in human prothrombin
RT type 3 (157 Glu leads to Lys) and the localization of a third thrombin
RT cleavage site.";
RL Br. J. Haematol. 54:245-254(1983).
RN [37]
RP VARIANT FA2D CYS-314, AND PROTEIN SEQUENCE OF 310-327.
RX PubMed=3771562;
RA Rabiet M.-J., Furie B.C., Furie B.;
RT "Molecular defect of prothrombin Barcelona. Substitution of cysteine
RT for arginine at residue 273.";
RL J. Biol. Chem. 261:15045-15048(1986).
RN [38]
RP VARIANT FA2D TRP-461, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3567158; DOI=10.1021/bi00378a020;
RA Miyata T., Morita T., Inomoto T., Kawauchi S., Shirakami A.,
RA Iwanaga S.;
RT "Prothrombin Tokushima, a replacement of arginine-418 by tryptophan
RT that impairs the fibrinogen clotting activity of derived thrombin
RT Tokushima.";
RL Biochemistry 26:1117-1122(1987).
RN [39]
RP VARIANT FA2D TRP-461.
RX PubMed=3801671;
RA Inomoto T., Shirakami A., Kawauchi S., Shigekiyo T., Saito S.,
RA Miyoshi K., Morita T., Iwanaga S.;
RT "Prothrombin Tokushima: characterization of dysfunctional thrombin
RT derived from a variant of human prothrombin.";
RL Blood 69:565-569(1987).
RN [40]
RP VARIANT FA2D CYS-425, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3242619; DOI=10.1021/bi00426a013;
RA Henriksen R.A., Mann K.G.;
RT "Identification of the primary structural defect in the dysthrombin
RT thrombin Quick I: substitution of cysteine for arginine-382.";
RL Biochemistry 27:9160-9165(1988).
RN [41]
RP VARIANT FA2D VAL-601, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2719946; DOI=10.1021/bi00431a017;
RA Henriksen R.A., Mann K.G.;
RT "Substitution of valine for glycine-558 in the congenital dysthrombin
RT thrombin Quick II alters primary substrate specificity.";
RL Biochemistry 28:2078-2082(1989).
RN [42]
RP VARIANT FA2D ALA-509, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=1354985; DOI=10.1021/bi00148a005;
RA Miyata T., Aruga R., Umeyama H., Bezeaud A., Guillin M.-C.,
RA Iwanaga S.;
RT "Prothrombin Salakta: substitution of glutamic acid-466 by alanine
RT reduces the fibrinogen clotting activity and the esterase activity.";
RL Biochemistry 31:7457-7462(1992).
RN [43]
RP VARIANTS FA2D THR-380 AND HIS-431.
RX PubMed=1421398;
RA Morishita E., Saito M., Kumabashiri I., Asakura H., Matsuda T.,
RA Yamaguchi K.;
RT "Prothrombin Himi: a compound heterozygote for two dysfunctional
RT prothrombin molecules (Met-337-->Thr and Arg-388-->His).";
RL Blood 80:2275-2280(1992).
RN [44]
RP VARIANT FA2D TRP-461.
RX PubMed=1349838;
RA Iwahana H., Yoshimoto K., Shigekiyo T., Shirakami A., Saito S.,
RA Itakura M.;
RT "Detection of a single base substitution of the gene for prothrombin
RT Tokushima. The application of PCR-SSCP for the genetic and molecular
RT analysis of dysprothrombinemia.";
RL Int. J. Hematol. 55:93-100(1992).
RN [45]
RP VARIANT FA2D HIS-314.
RX PubMed=7865694;
RA James H.L., Kim D.J., Zheng D.-Q., Girolami A.;
RT "Prothrombin Padua I: incomplete activation due to an amino acid
RT substitution at a factor Xa cleavage site.";
RL Blood Coagul. Fibrinolysis 5:841-844(1994).
RN [46]
RP VARIANT FA2D ALA-509.
RX PubMed=7792730;
RA Degen S.J.F., McDowell S.A., Sparks L.M., Scharrer I.;
RT "Prothrombin Frankfurt: a dysfunctional prothrombin characterized by
RT substitution of Glu-466 by Ala.";
RL Thromb. Haemost. 73:203-209(1995).
RN [47]
RP VARIANTS MET-165 AND THR-386.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [48]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [49]
RP VARIANTS MET-165; LYS-200; THR-386 AND GLN-532, AND MASS SPECTROMETRY.
RX PubMed=22028381; DOI=10.1093/jmcb/mjr024;
RA Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H.,
RA Lin X., Zeng R., Wu J.R.;
RT "Quantitative detection of single amino acid polymorphisms by targeted
RT proteomics.";
RL J. Mol. Cell Biol. 3:309-315(2011).
CC -!- FUNCTION: Thrombin, which cleaves bonds after Arg and Lys,
CC converts fibrinogen to fibrin and activates factors V, VII, VIII,
CC XIII, and, in complex with thrombomodulin, protein C. Functions in
CC blood homeostasis, inflammation and wound healing.
CC -!- CATALYTIC ACTIVITY: Selective cleavage of Arg-|-Gly bonds in
CC fibrinogen to form fibrin and release fibrinopeptides A and B.
CC -!- ENZYME REGULATION: Inhibited by SERPINA5.
CC -!- SUBUNIT: Heterodimer (named alpha-thrombin) of a light and a heavy
CC chain; disulfide-linked. Forms a heterodimer with SERPINA5.
CC -!- INTERACTION:
CC Q846V4:- (xeno); NbExp=5; IntAct=EBI-297094, EBI-989571;
CC P07204:THBD; NbExp=4; IntAct=EBI-297094, EBI-941422;
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space.
CC -!- TISSUE SPECIFICITY: Expressed by the liver and secreted in plasma.
CC -!- PTM: The gamma-carboxyglutamyl residues, which bind calcium ions,
CC result from the carboxylation of glutamyl residues by a microsomal
CC enzyme, the vitamin K-dependent carboxylase. The modified residues
CC are necessary for the calcium-dependent interaction with a
CC negatively charged phospholipid surface, which is essential for
CC the conversion of prothrombin to thrombin.
CC -!- PTM: N-glycosylated. N-glycan heterogeneity at Asn-121:
CC Hex3HexNAc3 (minor), Hex4HexNAc3 (minor) and Hex5HexNAc4 (major).
CC At Asn-143: Hex4HexNAc3 (minor) and Hex5HexNAc4 (major).
CC -!- DISEASE: Factor II deficiency (FA2D) [MIM:613679]: A very rare
CC blood coagulation disorder characterized by mucocutaneous bleeding
CC symptoms. The severity of the bleeding manifestations correlates
CC with blood factor II levels. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an
CC acute neurologic event leading to death of neural tissue of the
CC brain and resulting in loss of motor, sensory and/or cognitive
CC function. Ischemic strokes, resulting from vascular occlusion, is
CC considered to be a highly complex disease consisting of a group of
CC heterogeneous disorders with multiple genetic and environmental
CC risk factors. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry.
CC -!- DISEASE: Thrombophilia due to thrombin defect (THPH1)
CC [MIM:188050]: A multifactorial disorder of hemostasis
CC characterized by abnormal platelet aggregation in response to
CC various agents and recurrent thrombi formation. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry. A common genetic variation in the 3-prime untranslated
CC region of the prothrombin gene is associated with elevated plasma
CC prothrombin levels and an increased risk of venous thrombosis.
CC -!- DISEASE: Pregnancy loss, recurrent, 2 (RPRGL2) [MIM:614390]: A
CC common complication of pregnancy, resulting in spontaneous
CC abortion before the fetus has reached viability. The term includes
CC all miscarriages from the time of conception until 24 weeks of
CC gestation. Recurrent pregnancy loss is defined as 3 or more
CC consecutive spontaneous abortions. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- PHARMACEUTICAL: The peptide TP508 also known as Chrysalin
CC (Orthologic) could be used to accelerate repair of both soft and
CC hard tissues.
CC -!- MISCELLANEOUS: Prothrombin is activated on the surface of a
CC phospholipid membrane that binds the amino end of prothrombin and
CC factors Va and Xa in Ca-dependent interactions; factor Xa removes
CC the activation peptide and cleaves the remaining part into light
CC and heavy chains. The activation process starts slowly because
CC factor V itself has to be activated by the initial, small amounts
CC of thrombin.
CC -!- MISCELLANEOUS: It is not known whether 1 or 2 smaller activation
CC peptides, with additional cleavage after Arg-314, are released in
CC natural blood clotting.
CC -!- MISCELLANEOUS: Thrombin can itself cleave the N-terminal fragment
CC (fragment 1) of the prothrombin, prior to its activation by factor
CC Xa.
CC -!- MISCELLANEOUS: The cleavage after Arg-198, observed in vitro, does
CC not occur in plasma.
CC -!- SIMILARITY: Belongs to the peptidase S1 family.
CC -!- SIMILARITY: Contains 1 Gla (gamma-carboxy-glutamate) domain.
CC -!- SIMILARITY: Contains 2 kringle domains.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Thrombin entry;
CC URL="http://en.wikipedia.org/wiki/Thrombin";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/F2";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/f2/";
CC -----------------------------------------------------------------------
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DR EMBL; M17262; AAC63054.1; -; Genomic_DNA.
DR EMBL; AJ972449; CAJ01369.1; -; mRNA.
DR EMBL; AK303747; BAG64719.1; -; mRNA.
DR EMBL; AK312965; BAG35804.1; -; mRNA.
DR EMBL; AK222775; BAD96495.1; -; mRNA.
DR EMBL; AK222777; BAD96497.1; -; mRNA.
DR EMBL; AF478696; AAL77436.1; -; Genomic_DNA.
DR EMBL; BC051332; AAH51332.1; -; mRNA.
DR EMBL; V00595; CAA23842.1; -; mRNA.
DR PIR; A29351; TBHU.
DR RefSeq; NP_000497.1; NM_000506.3.
DR UniGene; Hs.655207; -.
DR PDB; 1A2C; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 1A3B; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 1A3E; X-ray; 1.85 A; H=364-622, L=328-363.
DR PDB; 1A46; X-ray; 2.12 A; H=364-622, L=328-363.
DR PDB; 1A4W; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 1A5G; X-ray; 2.06 A; H=364-622, L=328-363.
DR PDB; 1A61; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 1ABI; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1ABJ; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 1AD8; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1AE8; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1AFE; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1AHT; X-ray; 1.60 A; H=364-622, L=328-363.
DR PDB; 1AI8; X-ray; 1.85 A; H=364-622, L=328-363.
DR PDB; 1AIX; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 1AWF; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 1AWH; X-ray; 3.00 A; A/C=328-363, B/D=364-622.
DR PDB; 1AY6; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 1B5G; X-ray; 2.07 A; H=364-622, L=328-363.
DR PDB; 1B7X; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 1BA8; X-ray; 1.80 A; A=328-363, B=364-622.
DR PDB; 1BB0; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 1BCU; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1BHX; X-ray; 2.30 A; A=331-360, B=364-510, F=518-622.
DR PDB; 1BMM; X-ray; 2.60 A; H=364-622, L=328-363.
DR PDB; 1BMN; X-ray; 2.80 A; H=364-622, L=328-363.
DR PDB; 1BTH; X-ray; 2.30 A; H/K=364-622, J/L=328-363.
DR PDB; 1C1U; X-ray; 1.75 A; H=364-616, L=328-363.
DR PDB; 1C1V; X-ray; 1.98 A; H=364-616, L=328-363.
DR PDB; 1C1W; X-ray; 1.90 A; H=364-616, L=328-363.
DR PDB; 1C4U; X-ray; 2.10 A; 1=328-363, 2=364-622.
DR PDB; 1C4V; X-ray; 2.10 A; 1=328-363, 2=364-622.
DR PDB; 1C4Y; X-ray; 2.70 A; 1=328-363, 2=364-622.
DR PDB; 1C5L; X-ray; 1.47 A; H=364-622, L=328-363.
DR PDB; 1C5N; X-ray; 1.50 A; H=364-622, L=328-363.
DR PDB; 1C5O; X-ray; 1.90 A; H=364-622, L=328-363.
DR PDB; 1CA8; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 1D3D; X-ray; 2.04 A; A=333-360, B=364-620.
DR PDB; 1D3P; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 1D3Q; X-ray; 2.90 A; A=328-363, B=364-622.
DR PDB; 1D3T; X-ray; 3.00 A; A=328-363, B=364-622.
DR PDB; 1D4P; X-ray; 2.07 A; A=328-363, B=364-622.
DR PDB; 1D6W; X-ray; 2.00 A; A=334-620.
DR PDB; 1D9I; X-ray; 2.30 A; A=334-621.
DR PDB; 1DE7; X-ray; 2.00 A; H/K=364-619, J/L=328-363.
DR PDB; 1DIT; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1DM4; X-ray; 2.50 A; A=328-362, B=363-622.
DR PDB; 1DOJ; X-ray; 1.70 A; A=328-622.
DR PDB; 1DWB; X-ray; 3.16 A; H=364-622, L=328-363.
DR PDB; 1DWC; X-ray; 3.00 A; H=364-622, L=328-363.
DR PDB; 1DWD; X-ray; 3.00 A; H=364-622, L=328-363.
DR PDB; 1DWE; X-ray; 3.00 A; H=364-622, L=328-363.
DR PDB; 1DX5; X-ray; 2.30 A; A/B/C/D=328-363, M/N/O/P=364-622.
DR PDB; 1E0F; X-ray; 3.10 A; A/B/C=328-363, D/E/F=364-622.
DR PDB; 1EB1; X-ray; 1.80 A; H=364-620, L=334-360.
DR PDB; 1EOJ; X-ray; 2.10 A; A=334-620.
DR PDB; 1EOL; X-ray; 2.10 A; A=334-620.
DR PDB; 1FPC; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1FPH; X-ray; 2.50 A; H=364-622, L=328-363.
DR PDB; 1G30; X-ray; 2.00 A; A=328-363, B=364-622.
DR PDB; 1G32; X-ray; 1.90 A; A=328-363, B=364-622.
DR PDB; 1G37; X-ray; 2.00 A; A=334-620.
DR PDB; 1GHV; X-ray; 1.85 A; H=364-620, L=328-363.
DR PDB; 1GHW; X-ray; 1.75 A; H=364-620, L=328-363.
DR PDB; 1GHX; X-ray; 1.65 A; H=364-620, L=328-363.
DR PDB; 1GHY; X-ray; 1.85 A; H=364-620, L=328-363.
DR PDB; 1GJ4; X-ray; 1.81 A; H=364-621, L=328-363.
DR PDB; 1GJ5; X-ray; 1.73 A; H=364-621, L=328-363.
DR PDB; 1H8D; X-ray; 1.40 A; H=364-621, L=333-360.
DR PDB; 1H8I; X-ray; 1.75 A; H=364-622, L=334-360.
DR PDB; 1HAG; X-ray; 2.00 A; E=336-622.
DR PDB; 1HAH; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1HAI; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 1HAO; X-ray; 2.80 A; H=364-622, L=328-363.
DR PDB; 1HAP; X-ray; 2.80 A; H=364-622, L=328-363.
DR PDB; 1HBT; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1HDT; X-ray; 2.60 A; H=364-622, L=331-363.
DR PDB; 1HGT; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 1HLT; X-ray; 3.00 A; H/K=364-622, J/L=334-360.
DR PDB; 1HUT; X-ray; 2.90 A; H=364-622, L=328-363.
DR PDB; 1HXE; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 1HXF; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 1IHS; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1IHT; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 1JMO; X-ray; 2.20 A; H=363-622, L=315-362.
DR PDB; 1JOU; X-ray; 1.80 A; A/C/E=315-363, B/D/F=364-622.
DR PDB; 1JWT; X-ray; 2.50 A; A=328-622.
DR PDB; 1K21; X-ray; 1.86 A; H=364-622, L=328-363.
DR PDB; 1K22; X-ray; 1.93 A; H=364-622, L=328-363.
DR PDB; 1KTS; X-ray; 2.40 A; A=328-363, B=364-622.
DR PDB; 1KTT; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 1LHC; X-ray; 1.95 A; H=364-622, L=328-363.
DR PDB; 1LHD; X-ray; 2.35 A; H=364-622, L=328-363.
DR PDB; 1LHE; X-ray; 2.25 A; H=364-622, L=328-363.
DR PDB; 1LHF; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 1LHG; X-ray; 2.25 A; H=364-622, L=328-363.
DR PDB; 1MH0; X-ray; 2.80 A; A/B=334-620.
DR PDB; 1MU6; X-ray; 1.99 A; A=328-363, B=364-622.
DR PDB; 1MU8; X-ray; 2.00 A; A=328-363, B=364-622.
DR PDB; 1MUE; X-ray; 2.00 A; A=328-363, B=364-622.
DR PDB; 1NM6; X-ray; 1.80 A; A=335-621.
DR PDB; 1NO9; X-ray; 1.90 A; H=364-622, L=328-363.
DR PDB; 1NRN; X-ray; 3.10 A; H=364-622, L=328-363.
DR PDB; 1NRO; X-ray; 3.10 A; H=364-622, L=328-363.
DR PDB; 1NRP; X-ray; 3.00 A; H=364-622, L=328-363.
DR PDB; 1NRQ; X-ray; 3.50 A; H=364-622, L=328-363.
DR PDB; 1NRR; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 1NRS; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 1NT1; X-ray; 2.00 A; A=335-621.
DR PDB; 1NU7; X-ray; 2.20 A; A/E=332-359, B/F=364-622.
DR PDB; 1NU9; X-ray; 2.20 A; A/D=332-622.
DR PDB; 1NY2; X-ray; 2.30 A; 1=328-363, 2=364-622.
DR PDB; 1NZQ; X-ray; 2.18 A; H=364-620, L=328-363.
DR PDB; 1O0D; X-ray; 2.44 A; H=364-622, L=328-363.
DR PDB; 1O2G; X-ray; 1.58 A; H=364-622, L=328-363.
DR PDB; 1O5G; X-ray; 1.75 A; H=364-622, L=328-363.
DR PDB; 1OOK; X-ray; 2.30 A; A=328-363, B=364-622.
DR PDB; 1OYT; X-ray; 1.67 A; H=364-622, L=328-363.
DR PDB; 1P8V; X-ray; 2.60 A; B=333-361, C=364-621.
DR PDB; 1PPB; X-ray; 1.92 A; H=364-622, L=328-363.
DR PDB; 1QBV; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 1QHR; X-ray; 2.20 A; A=328-363, B=364-622.
DR PDB; 1QJ1; X-ray; 2.00 A; A=328-363, B=364-622.
DR PDB; 1QJ6; X-ray; 2.20 A; A=328-363, B=364-622.
DR PDB; 1QJ7; X-ray; 2.20 A; A=328-363, B=364-622.
DR PDB; 1QUR; X-ray; 2.00 A; H=364-620, L=334-360.
DR PDB; 1RD3; X-ray; 2.50 A; A/C=328-363, B/D=364-622.
DR PDB; 1RIW; X-ray; 2.04 A; A=328-363, B=364-510, C=518-622.
DR PDB; 1SB1; X-ray; 1.90 A; H=364-621, L=333-361.
DR PDB; 1SFQ; X-ray; 1.91 A; A/D=328-363, B/E=364-622.
DR PDB; 1SG8; X-ray; 2.30 A; A/D=328-363, B/E=364-622.
DR PDB; 1SGI; X-ray; 2.30 A; A/D=328-363, B/E=364-622.
DR PDB; 1SHH; X-ray; 1.55 A; A/D=328-363, B/E=364-622.
DR PDB; 1SL3; X-ray; 1.81 A; A=335-621.
DR PDB; 1SR5; X-ray; 3.10 A; B=328-363, C=364-622.
DR PDB; 1T4U; X-ray; 2.00 A; H=364-622, L=334-359.
DR PDB; 1T4V; X-ray; 2.00 A; H=364-622, L=334-359.
DR PDB; 1TA2; X-ray; 2.30 A; A=335-621.
DR PDB; 1TA6; X-ray; 1.90 A; A=335-621.
DR PDB; 1TB6; X-ray; 2.50 A; H=364-622, L=315-363.
DR PDB; 1TBZ; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1THP; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 1THR; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1THS; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 1TMB; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 1TMT; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 1TMU; X-ray; 2.50 A; H=364-622, L=333-360.
DR PDB; 1TOM; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 1TQ0; X-ray; 2.80 A; A/C=333-363, B/D=364-620.
DR PDB; 1TQ7; X-ray; 2.40 A; A=320-363, B=364-620.
DR PDB; 1TWX; X-ray; 2.40 A; A=334-361, B=364-622.
DR PDB; 1UMA; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 1UVS; X-ray; 2.80 A; H=364-622, L=328-363.
DR PDB; 1VR1; X-ray; 1.90 A; H=364-620, L=334-360.
DR PDB; 1VZQ; X-ray; 1.54 A; H=364-620, L=334-360.
DR PDB; 1W7G; X-ray; 1.65 A; H=364-622, L=328-363.
DR PDB; 1WAY; X-ray; 2.02 A; A=328-363, B=364-622.
DR PDB; 1WBG; X-ray; 2.20 A; A=328-363, B=364-622.
DR PDB; 1XM1; X-ray; 2.30 A; A=328-622.
DR PDB; 1XMN; X-ray; 1.85 A; A/C/E/G=328-363, B/D/F/H=364-622.
DR PDB; 1YPE; X-ray; 1.81 A; H=364-620, L=334-360.
DR PDB; 1YPG; X-ray; 1.80 A; H=364-620, L=334-360.
DR PDB; 1YPJ; X-ray; 1.78 A; H=364-620, L=334-360.
DR PDB; 1YPK; X-ray; 1.78 A; H=364-620, L=334-360.
DR PDB; 1YPL; X-ray; 1.85 A; H=364-620, L=334-360.
DR PDB; 1YPM; X-ray; 1.85 A; H=364-620, L=334-360.
DR PDB; 1Z71; X-ray; 1.80 A; A=336-621.
DR PDB; 1Z8I; X-ray; 2.00 A; A=324-361, B=364-622.
DR PDB; 1Z8J; X-ray; 2.00 A; A=322-361, B=364-622.
DR PDB; 1ZGI; X-ray; 2.20 A; A=335-621.
DR PDB; 1ZGV; X-ray; 2.20 A; A=335-621.
DR PDB; 1ZRB; X-ray; 1.90 A; A=335-621.
DR PDB; 2A0Q; X-ray; 1.90 A; A/C=334-363, B/D=364-620.
DR PDB; 2A2X; X-ray; 2.44 A; H=364-622, L=330-363.
DR PDB; 2A45; X-ray; 3.65 A; A/D=328-363, B/E=364-622.
DR PDB; 2AFQ; X-ray; 1.93 A; A/C=332-360, B/D=364-622.
DR PDB; 2ANK; X-ray; 2.46 A; H=364-622, L=330-363.
DR PDB; 2ANM; X-ray; 2.40 A; H=364-620, L=328-363.
DR PDB; 2B5T; X-ray; 2.10 A; A/C=315-363, B/D=364-622.
DR PDB; 2BDY; X-ray; 1.61 A; A=334-622.
DR PDB; 2BVR; X-ray; 1.25 A; H=364-622, L=328-363.
DR PDB; 2BVS; X-ray; 1.40 A; H=364-622, L=328-363.
DR PDB; 2BVX; X-ray; 3.20 A; H=364-622, L=328-363.
DR PDB; 2BXT; X-ray; 1.83 A; H=364-622, L=328-363.
DR PDB; 2BXU; X-ray; 2.80 A; H=364-622, L=328-363.
DR PDB; 2C8W; X-ray; 1.96 A; A=328-363, B=364-622.
DR PDB; 2C8X; X-ray; 2.17 A; A=328-363, B=364-622.
DR PDB; 2C8Y; X-ray; 2.20 A; A=328-363, B=364-622.
DR PDB; 2C8Z; X-ray; 2.14 A; A=328-363, B=364-622.
DR PDB; 2C90; X-ray; 2.25 A; A=328-363, B=364-622.
DR PDB; 2C93; X-ray; 2.20 A; A=328-363, B=364-622.
DR PDB; 2CF8; X-ray; 1.30 A; H=364-620, L=334-361.
DR PDB; 2CF9; X-ray; 1.79 A; H=364-620, L=334-361.
DR PDB; 2CN0; X-ray; 1.30 A; H=364-620, L=334-361.
DR PDB; 2FEQ; X-ray; 2.44 A; H=364-622, L=328-363.
DR PDB; 2FES; X-ray; 2.42 A; H=364-622, L=328-363.
DR PDB; 2GDE; X-ray; 2.00 A; H=364-622, L=328-363.
DR PDB; 2GP9; X-ray; 1.87 A; A=328-363, B=364-622.
DR PDB; 2H9T; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 2HGT; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 2HNT; X-ray; 2.50 A; C=364-433, E=437-517, F=518-622, L=328-363.
DR PDB; 2HPP; X-ray; 3.30 A; H=364-622, L=328-363.
DR PDB; 2HPQ; X-ray; 3.30 A; H=364-622, L=328-363, P=213-291.
DR PDB; 2HWL; X-ray; 2.40 A; A/C=328-363, B/D=364-622.
DR PDB; 2JH0; X-ray; 1.70 A; C=328-363, D=364-622.
DR PDB; 2JH5; X-ray; 2.50 A; C=328-363, D=364-622.
DR PDB; 2JH6; X-ray; 2.21 A; C=328-363, D=364-622.
DR PDB; 2OD3; X-ray; 1.75 A; A=328-363, B=364-622.
DR PDB; 2PGB; X-ray; 1.54 A; A=328-363, B=364-622.
DR PDB; 2PGQ; X-ray; 1.80 A; A=319-363, B=364-622.
DR PDB; 2PKS; X-ray; 2.50 A; A=334-360, B=364-510, C=518-619.
DR PDB; 2PW8; X-ray; 1.84 A; H=364-621, L=334-360.
DR PDB; 2R2M; X-ray; 2.10 A; A=334-359, B=364-622.
DR PDB; 2THF; X-ray; 2.10 A; A=328-363, B=364-622.
DR PDB; 2UUF; X-ray; 1.26 A; A=328-363, B=364-622.
DR PDB; 2UUJ; X-ray; 1.32 A; A=328-363, B=364-622.
DR PDB; 2UUK; X-ray; 1.39 A; A=328-363, B=364-622.
DR PDB; 2V3H; X-ray; 1.79 A; H=364-620, L=334-361.
DR PDB; 2V3O; X-ray; 1.79 A; H=364-620, L=334-361.
DR PDB; 2ZC9; X-ray; 1.58 A; H=364-622, L=328-363.
DR PDB; 2ZDA; X-ray; 1.73 A; H=364-622, L=328-363.
DR PDB; 2ZDV; X-ray; 1.72 A; H=364-622, L=328-363.
DR PDB; 2ZF0; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 2ZFF; X-ray; 1.47 A; H=364-622, L=328-363.
DR PDB; 2ZFP; X-ray; 2.25 A; H=364-622, L=328-363.
DR PDB; 2ZFQ; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 2ZFR; X-ray; 1.85 A; H=364-622, L=328-363.
DR PDB; 2ZG0; X-ray; 1.75 A; H=364-622, L=328-363.
DR PDB; 2ZGB; X-ray; 1.60 A; H=364-622, L=328-363.
DR PDB; 2ZGX; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 2ZHE; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 2ZHF; X-ray; 1.98 A; H=364-622, L=328-363.
DR PDB; 2ZHQ; X-ray; 1.96 A; H=364-622, L=328-363.
DR PDB; 2ZHW; X-ray; 2.02 A; H=364-622, L=328-363.
DR PDB; 2ZI2; X-ray; 1.65 A; H=364-622, L=328-363.
DR PDB; 2ZIQ; X-ray; 1.65 A; H=364-622, L=328-363.
DR PDB; 2ZNK; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 2ZO3; X-ray; 1.70 A; H=364-622, L=328-363.
DR PDB; 3B23; X-ray; 2.40 A; A=328-363, B=364-622.
DR PDB; 3B9F; X-ray; 1.60 A; H=364-622, L=315-363.
DR PDB; 3BEF; X-ray; 2.20 A; A/D=318-363, B/E=364-622.
DR PDB; 3BEI; X-ray; 1.55 A; A=320-363, B=364-622.
DR PDB; 3BF6; X-ray; 2.50 A; H=364-622, L=328-363.
DR PDB; 3BIU; X-ray; 2.30 A; H=364-620, L=333-361.
DR PDB; 3BIV; X-ray; 1.80 A; H=364-620, L=333-361.
DR PDB; 3BV9; X-ray; 1.80 A; B=364-622.
DR PDB; 3C1K; X-ray; 1.84 A; A=335-621.
DR PDB; 3C27; X-ray; 2.18 A; A=334-359, B=364-622.
DR PDB; 3D49; X-ray; 1.50 A; H=364-622, L=328-363.
DR PDB; 3DA9; X-ray; 1.80 A; A=328-363, B=364-622.
DR PDB; 3DD2; X-ray; 1.90 A; H=364-621, L=332-361.
DR PDB; 3DHK; X-ray; 1.73 A; H=364-622, L=328-363.
DR PDB; 3DT0; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 3DUX; X-ray; 1.60 A; H=364-622, L=328-363.
DR PDB; 3E6P; X-ray; 2.10 A; H=364-622, L=206-363.
DR PDB; 3EE0; X-ray; 2.75 A; A=328-363, B=364-622.
DR PDB; 3EGK; X-ray; 2.20 A; H=364-622, L=328-363.
DR PDB; 3EQ0; X-ray; 1.53 A; H=364-622, L=328-363.
DR PDB; 3F68; X-ray; 1.75 A; H=364-622, L=328-363.
DR PDB; 3GIC; X-ray; 1.55 A; A=328-363, B=364-622.
DR PDB; 3GIS; X-ray; 2.40 A; A/C/E=315-363, B/D/F=364-622.
DR PDB; 3HAT; X-ray; 2.50 A; H=364-622, L=328-363.
DR PDB; 3HKJ; X-ray; 2.60 A; A/D=333-363, B/E=364-622.
DR PDB; 3HTC; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 3JZ1; X-ray; 1.60 A; A=328-363, B=364-622.
DR PDB; 3JZ2; X-ray; 2.40 A; A=328-363, B=364-622.
DR PDB; 3K65; X-ray; 1.85 A; A=199-314, B=315-622.
DR PDB; 3LDX; X-ray; 2.25 A; H=364-622, L=328-363.
DR PDB; 3LU9; X-ray; 1.80 A; A/D=318-363, B/E=364-622.
DR PDB; 3NXP; X-ray; 2.20 A; A=199-622.
DR PDB; 3P17; X-ray; 1.43 A; H=364-622, L=328-363.
DR PDB; 3P6Z; X-ray; 1.70 A; A/G=328-363, B/H=364-622.
DR PDB; 3P70; X-ray; 2.55 A; A/C/E/G=328-363, B/D/F/H=364-622.
DR PDB; 3PMH; X-ray; 3.20 A; A=328-363, B=364-622.
DR PDB; 3PO1; X-ray; 1.65 A; A=334-360, B=364-510, C=518-619.
DR PDB; 3QDZ; X-ray; 2.80 A; A/C=333-363, B/D=364-622.
DR PDB; 3QGN; X-ray; 2.10 A; A=333-363, B=364-622.
DR PDB; 3QLP; X-ray; 2.14 A; H=364-622, L=328-363.
DR PDB; 3QTO; X-ray; 1.52 A; H=364-622, L=328-363.
DR PDB; 3QTV; X-ray; 1.63 A; H=364-622, L=328-363.
DR PDB; 3QWC; X-ray; 1.75 A; H=364-622, L=328-363.
DR PDB; 3QX5; X-ray; 1.35 A; H=364-622, L=328-363.
DR PDB; 3R3G; X-ray; 1.75 A; A=333-363, B=364-622.
DR PDB; 3RLW; X-ray; 1.69 A; H=364-622, L=328-363.
DR PDB; 3RLY; X-ray; 1.51 A; H=364-622, L=328-363.
DR PDB; 3RM0; X-ray; 1.34 A; H=364-622, L=328-363.
DR PDB; 3RM2; X-ray; 1.23 A; H=364-622, L=328-363.
DR PDB; 3RML; X-ray; 1.53 A; H=364-622, L=328-363.
DR PDB; 3RMM; X-ray; 1.58 A; H=364-622, L=328-363.
DR PDB; 3RMN; X-ray; 1.78 A; H=364-622, L=328-363.
DR PDB; 3RMO; X-ray; 1.40 A; H=364-622, L=328-363.
DR PDB; 3S7H; X-ray; 1.90 A; A=329-363, B=364-622.
DR PDB; 3S7K; X-ray; 1.90 A; A/C=329-363, B/D=364-622.
DR PDB; 3SHA; X-ray; 1.52 A; H=364-622, L=328-363.
DR PDB; 3SHC; X-ray; 1.90 A; H=364-622, L=328-363.
DR PDB; 3SI3; X-ray; 1.55 A; H=364-622, L=328-363.
DR PDB; 3SI4; X-ray; 1.27 A; H=364-622, L=328-363.
DR PDB; 3SQE; X-ray; 1.90 A; E=333-622.
DR PDB; 3SQH; X-ray; 2.20 A; E=333-622.
DR PDB; 3SV2; X-ray; 1.30 A; H=364-622, L=328-363.
DR PDB; 3T5F; X-ray; 1.45 A; H=364-622, L=328-363.
DR PDB; 3TU7; X-ray; 2.49 A; H=364-622, L=328-363.
DR PDB; 3U69; X-ray; 1.55 A; H=364-622, L=334-363.
DR PDB; 3U8O; X-ray; 1.28 A; H=364-622, L=334-363.
DR PDB; 3U8R; X-ray; 1.47 A; H=364-622, L=334-363.
DR PDB; 3U8T; X-ray; 1.86 A; H=364-622, L=334-360.
DR PDB; 3U98; X-ray; 1.45 A; H=364-622, L=328-363.
DR PDB; 3U9A; X-ray; 1.58 A; H=364-622, L=328-363.
DR PDB; 3UTU; X-ray; 1.55 A; H=364-622, L=328-363.
DR PDB; 3UWJ; X-ray; 1.50 A; H=364-622, L=328-363.
DR PDB; 3VXE; X-ray; 1.25 A; H=364-622, L=328-363.
DR PDB; 3VXF; Other; 1.60 A; H=364-622, L=328-363.
DR PDB; 4AX9; X-ray; 1.90 A; H=364-620, L=334-361.
DR PDB; 4AYV; X-ray; 2.80 A; A=332-361, B=364-620.
DR PDB; 4AYY; X-ray; 2.60 A; A=332-361, B=364-620.
DR PDB; 4AZ2; X-ray; 2.60 A; A=332-361, B=364-620.
DR PDB; 4BAH; X-ray; 1.94 A; A=328-363, B=364-622.
DR PDB; 4BAK; X-ray; 1.94 A; A=328-363, B=364-622.
DR PDB; 4BAM; X-ray; 1.88 A; A=328-363, B=364-622.
DR PDB; 4BAN; X-ray; 1.87 A; A=328-363, B=364-622.
DR PDB; 4BAO; X-ray; 1.87 A; A=328-363, B=364-622.
DR PDB; 4BAQ; X-ray; 1.89 A; A=328-363, B=364-622.
DR PDB; 4BOH; X-ray; 2.60 A; A/H=364-622, B/L=328-363.
DR PDB; 4DIH; X-ray; 1.80 A; H=364-622, L=328-363.
DR PDB; 4DII; X-ray; 2.05 A; H=364-622, L=328-363.
DR PDB; 4DT7; X-ray; 1.90 A; A/C=332-363, B/D=364-622.
DR PDB; 4DY7; X-ray; 2.80 A; A/D=315-363, B/E=364-622.
DR PDB; 4E05; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 4E06; X-ray; 3.20 A; H=364-622, L=328-363.
DR PDB; 4E7R; X-ray; 2.25 A; G/H=364-622, L/M=328-363.
DR PDB; 4H6S; X-ray; 2.19 A; A=333-363, B=364-622.
DR PDB; 4H6T; X-ray; 2.40 A; A=317-622.
DR PDB; 4HFP; X-ray; 2.40 A; A/C=333-363, B/D=364-622.
DR PDB; 4HFY; X-ray; 3.00 A; A/B=333-622.
DR PDB; 4HTC; X-ray; 2.30 A; H=364-622, L=328-363.
DR PDB; 4HZH; X-ray; 3.30 A; A/B=90-622.
DR PDB; 4I7Y; X-ray; 2.40 A; H=364-622, L=328-363.
DR PDB; 4MLF; X-ray; 2.20 A; A=331-363, B=364-622.
DR PDB; 4N3L; X-ray; 1.94 A; H=364-622, L=328-363.
DR PDB; 4THN; X-ray; 2.50 A; H=364-622, L=328-363.
DR PDB; 5GDS; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 7KME; X-ray; 2.10 A; H=364-622, L=328-363.
DR PDB; 8KME; X-ray; 2.10 A; 1=328-363, 2=364-620.
DR PDBsum; 1A2C; -.
DR PDBsum; 1A3B; -.
DR PDBsum; 1A3E; -.
DR PDBsum; 1A46; -.
DR PDBsum; 1A4W; -.
DR PDBsum; 1A5G; -.
DR PDBsum; 1A61; -.
DR PDBsum; 1ABI; -.
DR PDBsum; 1ABJ; -.
DR PDBsum; 1AD8; -.
DR PDBsum; 1AE8; -.
DR PDBsum; 1AFE; -.
DR PDBsum; 1AHT; -.
DR PDBsum; 1AI8; -.
DR PDBsum; 1AIX; -.
DR PDBsum; 1AWF; -.
DR PDBsum; 1AWH; -.
DR PDBsum; 1AY6; -.
DR PDBsum; 1B5G; -.
DR PDBsum; 1B7X; -.
DR PDBsum; 1BA8; -.
DR PDBsum; 1BB0; -.
DR PDBsum; 1BCU; -.
DR PDBsum; 1BHX; -.
DR PDBsum; 1BMM; -.
DR PDBsum; 1BMN; -.
DR PDBsum; 1BTH; -.
DR PDBsum; 1C1U; -.
DR PDBsum; 1C1V; -.
DR PDBsum; 1C1W; -.
DR PDBsum; 1C4U; -.
DR PDBsum; 1C4V; -.
DR PDBsum; 1C4Y; -.
DR PDBsum; 1C5L; -.
DR PDBsum; 1C5N; -.
DR PDBsum; 1C5O; -.
DR PDBsum; 1CA8; -.
DR PDBsum; 1D3D; -.
DR PDBsum; 1D3P; -.
DR PDBsum; 1D3Q; -.
DR PDBsum; 1D3T; -.
DR PDBsum; 1D4P; -.
DR PDBsum; 1D6W; -.
DR PDBsum; 1D9I; -.
DR PDBsum; 1DE7; -.
DR PDBsum; 1DIT; -.
DR PDBsum; 1DM4; -.
DR PDBsum; 1DOJ; -.
DR PDBsum; 1DWB; -.
DR PDBsum; 1DWC; -.
DR PDBsum; 1DWD; -.
DR PDBsum; 1DWE; -.
DR PDBsum; 1DX5; -.
DR PDBsum; 1E0F; -.
DR PDBsum; 1EB1; -.
DR PDBsum; 1EOJ; -.
DR PDBsum; 1EOL; -.
DR PDBsum; 1FPC; -.
DR PDBsum; 1FPH; -.
DR PDBsum; 1G30; -.
DR PDBsum; 1G32; -.
DR PDBsum; 1G37; -.
DR PDBsum; 1GHV; -.
DR PDBsum; 1GHW; -.
DR PDBsum; 1GHX; -.
DR PDBsum; 1GHY; -.
DR PDBsum; 1GJ4; -.
DR PDBsum; 1GJ5; -.
DR PDBsum; 1H8D; -.
DR PDBsum; 1H8I; -.
DR PDBsum; 1HAG; -.
DR PDBsum; 1HAH; -.
DR PDBsum; 1HAI; -.
DR PDBsum; 1HAO; -.
DR PDBsum; 1HAP; -.
DR PDBsum; 1HBT; -.
DR PDBsum; 1HDT; -.
DR PDBsum; 1HGT; -.
DR PDBsum; 1HLT; -.
DR PDBsum; 1HUT; -.
DR PDBsum; 1HXE; -.
DR PDBsum; 1HXF; -.
DR PDBsum; 1IHS; -.
DR PDBsum; 1IHT; -.
DR PDBsum; 1JMO; -.
DR PDBsum; 1JOU; -.
DR PDBsum; 1JWT; -.
DR PDBsum; 1K21; -.
DR PDBsum; 1K22; -.
DR PDBsum; 1KTS; -.
DR PDBsum; 1KTT; -.
DR PDBsum; 1LHC; -.
DR PDBsum; 1LHD; -.
DR PDBsum; 1LHE; -.
DR PDBsum; 1LHF; -.
DR PDBsum; 1LHG; -.
DR PDBsum; 1MH0; -.
DR PDBsum; 1MU6; -.
DR PDBsum; 1MU8; -.
DR PDBsum; 1MUE; -.
DR PDBsum; 1NM6; -.
DR PDBsum; 1NO9; -.
DR PDBsum; 1NRN; -.
DR PDBsum; 1NRO; -.
DR PDBsum; 1NRP; -.
DR PDBsum; 1NRQ; -.
DR PDBsum; 1NRR; -.
DR PDBsum; 1NRS; -.
DR PDBsum; 1NT1; -.
DR PDBsum; 1NU7; -.
DR PDBsum; 1NU9; -.
DR PDBsum; 1NY2; -.
DR PDBsum; 1NZQ; -.
DR PDBsum; 1O0D; -.
DR PDBsum; 1O2G; -.
DR PDBsum; 1O5G; -.
DR PDBsum; 1OOK; -.
DR PDBsum; 1OYT; -.
DR PDBsum; 1P8V; -.
DR PDBsum; 1PPB; -.
DR PDBsum; 1QBV; -.
DR PDBsum; 1QHR; -.
DR PDBsum; 1QJ1; -.
DR PDBsum; 1QJ6; -.
DR PDBsum; 1QJ7; -.
DR PDBsum; 1QUR; -.
DR PDBsum; 1RD3; -.
DR PDBsum; 1RIW; -.
DR PDBsum; 1SB1; -.
DR PDBsum; 1SFQ; -.
DR PDBsum; 1SG8; -.
DR PDBsum; 1SGI; -.
DR PDBsum; 1SHH; -.
DR PDBsum; 1SL3; -.
DR PDBsum; 1SR5; -.
DR PDBsum; 1T4U; -.
DR PDBsum; 1T4V; -.
DR PDBsum; 1TA2; -.
DR PDBsum; 1TA6; -.
DR PDBsum; 1TB6; -.
DR PDBsum; 1TBZ; -.
DR PDBsum; 1THP; -.
DR PDBsum; 1THR; -.
DR PDBsum; 1THS; -.
DR PDBsum; 1TMB; -.
DR PDBsum; 1TMT; -.
DR PDBsum; 1TMU; -.
DR PDBsum; 1TOM; -.
DR PDBsum; 1TQ0; -.
DR PDBsum; 1TQ7; -.
DR PDBsum; 1TWX; -.
DR PDBsum; 1UMA; -.
DR PDBsum; 1UVS; -.
DR PDBsum; 1VR1; -.
DR PDBsum; 1VZQ; -.
DR PDBsum; 1W7G; -.
DR PDBsum; 1WAY; -.
DR PDBsum; 1WBG; -.
DR PDBsum; 1XM1; -.
DR PDBsum; 1XMN; -.
DR PDBsum; 1YPE; -.
DR PDBsum; 1YPG; -.
DR PDBsum; 1YPJ; -.
DR PDBsum; 1YPK; -.
DR PDBsum; 1YPL; -.
DR PDBsum; 1YPM; -.
DR PDBsum; 1Z71; -.
DR PDBsum; 1Z8I; -.
DR PDBsum; 1Z8J; -.
DR PDBsum; 1ZGI; -.
DR PDBsum; 1ZGV; -.
DR PDBsum; 1ZRB; -.
DR PDBsum; 2A0Q; -.
DR PDBsum; 2A2X; -.
DR PDBsum; 2A45; -.
DR PDBsum; 2AFQ; -.
DR PDBsum; 2ANK; -.
DR PDBsum; 2ANM; -.
DR PDBsum; 2B5T; -.
DR PDBsum; 2BDY; -.
DR PDBsum; 2BVR; -.
DR PDBsum; 2BVS; -.
DR PDBsum; 2BVX; -.
DR PDBsum; 2BXT; -.
DR PDBsum; 2BXU; -.
DR PDBsum; 2C8W; -.
DR PDBsum; 2C8X; -.
DR PDBsum; 2C8Y; -.
DR PDBsum; 2C8Z; -.
DR PDBsum; 2C90; -.
DR PDBsum; 2C93; -.
DR PDBsum; 2CF8; -.
DR PDBsum; 2CF9; -.
DR PDBsum; 2CN0; -.
DR PDBsum; 2FEQ; -.
DR PDBsum; 2FES; -.
DR PDBsum; 2GDE; -.
DR PDBsum; 2GP9; -.
DR PDBsum; 2H9T; -.
DR PDBsum; 2HGT; -.
DR PDBsum; 2HNT; -.
DR PDBsum; 2HPP; -.
DR PDBsum; 2HPQ; -.
DR PDBsum; 2HWL; -.
DR PDBsum; 2JH0; -.
DR PDBsum; 2JH5; -.
DR PDBsum; 2JH6; -.
DR PDBsum; 2OD3; -.
DR PDBsum; 2PGB; -.
DR PDBsum; 2PGQ; -.
DR PDBsum; 2PKS; -.
DR PDBsum; 2PW8; -.
DR PDBsum; 2R2M; -.
DR PDBsum; 2THF; -.
DR PDBsum; 2UUF; -.
DR PDBsum; 2UUJ; -.
DR PDBsum; 2UUK; -.
DR PDBsum; 2V3H; -.
DR PDBsum; 2V3O; -.
DR PDBsum; 2ZC9; -.
DR PDBsum; 2ZDA; -.
DR PDBsum; 2ZDV; -.
DR PDBsum; 2ZF0; -.
DR PDBsum; 2ZFF; -.
DR PDBsum; 2ZFP; -.
DR PDBsum; 2ZFQ; -.
DR PDBsum; 2ZFR; -.
DR PDBsum; 2ZG0; -.
DR PDBsum; 2ZGB; -.
DR PDBsum; 2ZGX; -.
DR PDBsum; 2ZHE; -.
DR PDBsum; 2ZHF; -.
DR PDBsum; 2ZHQ; -.
DR PDBsum; 2ZHW; -.
DR PDBsum; 2ZI2; -.
DR PDBsum; 2ZIQ; -.
DR PDBsum; 2ZNK; -.
DR PDBsum; 2ZO3; -.
DR PDBsum; 3B23; -.
DR PDBsum; 3B9F; -.
DR PDBsum; 3BEF; -.
DR PDBsum; 3BEI; -.
DR PDBsum; 3BF6; -.
DR PDBsum; 3BIU; -.
DR PDBsum; 3BIV; -.
DR PDBsum; 3BV9; -.
DR PDBsum; 3C1K; -.
DR PDBsum; 3C27; -.
DR PDBsum; 3D49; -.
DR PDBsum; 3DA9; -.
DR PDBsum; 3DD2; -.
DR PDBsum; 3DHK; -.
DR PDBsum; 3DT0; -.
DR PDBsum; 3DUX; -.
DR PDBsum; 3E6P; -.
DR PDBsum; 3EE0; -.
DR PDBsum; 3EGK; -.
DR PDBsum; 3EQ0; -.
DR PDBsum; 3F68; -.
DR PDBsum; 3GIC; -.
DR PDBsum; 3GIS; -.
DR PDBsum; 3HAT; -.
DR PDBsum; 3HKJ; -.
DR PDBsum; 3HTC; -.
DR PDBsum; 3JZ1; -.
DR PDBsum; 3JZ2; -.
DR PDBsum; 3K65; -.
DR PDBsum; 3LDX; -.
DR PDBsum; 3LU9; -.
DR PDBsum; 3NXP; -.
DR PDBsum; 3P17; -.
DR PDBsum; 3P6Z; -.
DR PDBsum; 3P70; -.
DR PDBsum; 3PMH; -.
DR PDBsum; 3PO1; -.
DR PDBsum; 3QDZ; -.
DR PDBsum; 3QGN; -.
DR PDBsum; 3QLP; -.
DR PDBsum; 3QTO; -.
DR PDBsum; 3QTV; -.
DR PDBsum; 3QWC; -.
DR PDBsum; 3QX5; -.
DR PDBsum; 3R3G; -.
DR PDBsum; 3RLW; -.
DR PDBsum; 3RLY; -.
DR PDBsum; 3RM0; -.
DR PDBsum; 3RM2; -.
DR PDBsum; 3RML; -.
DR PDBsum; 3RMM; -.
DR PDBsum; 3RMN; -.
DR PDBsum; 3RMO; -.
DR PDBsum; 3S7H; -.
DR PDBsum; 3S7K; -.
DR PDBsum; 3SHA; -.
DR PDBsum; 3SHC; -.
DR PDBsum; 3SI3; -.
DR PDBsum; 3SI4; -.
DR PDBsum; 3SQE; -.
DR PDBsum; 3SQH; -.
DR PDBsum; 3SV2; -.
DR PDBsum; 3T5F; -.
DR PDBsum; 3TU7; -.
DR PDBsum; 3U69; -.
DR PDBsum; 3U8O; -.
DR PDBsum; 3U8R; -.
DR PDBsum; 3U8T; -.
DR PDBsum; 3U98; -.
DR PDBsum; 3U9A; -.
DR PDBsum; 3UTU; -.
DR PDBsum; 3UWJ; -.
DR PDBsum; 3VXE; -.
DR PDBsum; 3VXF; -.
DR PDBsum; 4AX9; -.
DR PDBsum; 4AYV; -.
DR PDBsum; 4AYY; -.
DR PDBsum; 4AZ2; -.
DR PDBsum; 4BAH; -.
DR PDBsum; 4BAK; -.
DR PDBsum; 4BAM; -.
DR PDBsum; 4BAN; -.
DR PDBsum; 4BAO; -.
DR PDBsum; 4BAQ; -.
DR PDBsum; 4BOH; -.
DR PDBsum; 4DIH; -.
DR PDBsum; 4DII; -.
DR PDBsum; 4DT7; -.
DR PDBsum; 4DY7; -.
DR PDBsum; 4E05; -.
DR PDBsum; 4E06; -.
DR PDBsum; 4E7R; -.
DR PDBsum; 4H6S; -.
DR PDBsum; 4H6T; -.
DR PDBsum; 4HFP; -.
DR PDBsum; 4HFY; -.
DR PDBsum; 4HTC; -.
DR PDBsum; 4HZH; -.
DR PDBsum; 4I7Y; -.
DR PDBsum; 4MLF; -.
DR PDBsum; 4N3L; -.
DR PDBsum; 4THN; -.
DR PDBsum; 5GDS; -.
DR PDBsum; 7KME; -.
DR PDBsum; 8KME; -.
DR ProteinModelPortal; P00734; -.
DR SMR; P00734; 51-622.
DR DIP; DIP-6115N; -.
DR IntAct; P00734; 7.
DR MINT; MINT-147273; -.
DR STRING; 9606.ENSP00000308541; -.
DR BindingDB; P00734; -.
DR ChEMBL; CHEMBL2096988; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR DrugBank; DB00278; Argatroban.
DR DrugBank; DB00006; Bivalirudin.
DR DrugBank; DB00100; Coagulation Factor IX.
DR DrugBank; DB00055; Drotrecogin alfa.
DR DrugBank; DB01225; Enoxaparin.
DR DrugBank; DB01109; Heparin.
DR DrugBank; DB00001; Lepirudin.
DR DrugBank; DB00170; Menadione.
DR DrugBank; DB01123; Proflavine.
DR DrugBank; DB00641; Simvastatin.
DR DrugBank; DB04786; Suramin.
DR DrugBank; DB00682; Warfarin.
DR DrugBank; DB04898; Ximelagatran.
DR GuidetoPHARMACOLOGY; 2362; -.
DR MEROPS; S01.217; -.
DR PhosphoSite; P00734; -.
DR UniCarbKB; P00734; -.
DR DMDM; 135807; -.
DR SWISS-2DPAGE; P00734; -.
DR PaxDb; P00734; -.
DR PeptideAtlas; P00734; -.
DR PRIDE; P00734; -.
DR DNASU; 2147; -.
DR Ensembl; ENST00000311907; ENSP00000308541; ENSG00000180210.
DR GeneID; 2147; -.
DR KEGG; hsa:2147; -.
DR UCSC; uc001ndf.4; human.
DR CTD; 2147; -.
DR GeneCards; GC11P046740; -.
DR H-InvDB; HIX0026188; -.
DR HGNC; HGNC:3535; F2.
DR HPA; CAB016780; -.
DR HPA; CAB018650; -.
DR MIM; 176930; gene.
DR MIM; 188050; phenotype.
DR MIM; 601367; phenotype.
DR MIM; 613679; phenotype.
DR MIM; 614390; phenotype.
DR neXtProt; NX_P00734; -.
DR Orphanet; 325; Congenital factor II deficiency.
DR Orphanet; 64738; Non rare thrombophilia.
DR PharmGKB; PA157; -.
DR eggNOG; COG5640; -.
DR HOVERGEN; HBG108381; -.
DR InParanoid; P00734; -.
DR KO; K01313; -.
DR OMA; GIECQLW; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR SABIO-RK; P00734; -.
DR EvolutionaryTrace; P00734; -.
DR GeneWiki; Thrombin; -.
DR GenomeRNAi; 2147; -.
DR NextBio; 8681; -.
DR PMAP-CutDB; P00734; -.
DR PRO; PR:P00734; -.
DR ArrayExpress; P00734; -.
DR Bgee; P00734; -.
DR CleanEx; HS_F2; -.
DR Genevestigator; P00734; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0008083; F:growth factor activity; TAS:BHF-UCL.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0070053; F:thrombospondin receptor activity; IDA:BHF-UCL.
DR GO; GO:0006953; P:acute-phase response; IEA:UniProtKB-KW.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0051480; P:cytosolic calcium ion homeostasis; IDA:BHF-UCL.
DR GO; GO:0042730; P:fibrinolysis; IDA:UniProtKB.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0048712; P:negative regulation of astrocyte differentiation; IDA:BHF-UCL.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; TAS:BHF-UCL.
DR GO; GO:0010544; P:negative regulation of platelet activation; TAS:BHF-UCL.
DR GO; GO:0045861; P:negative regulation of proteolysis; IDA:BHF-UCL.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; IDA:BHF-UCL.
DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IEA:Ensembl.
DR GO; GO:1900738; P:positive regulation of phospholipase C-activating G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:BHF-UCL.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IDA:UniProtKB.
DR GO; GO:0051281; P:positive regulation of release of sequestered calcium ion into cytosol; IDA:BHF-UCL.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; TAS:Reactome.
DR GO; GO:0008360; P:regulation of cell shape; IEA:Ensembl.
DR GO; GO:0010468; P:regulation of gene expression; IEA:Ensembl.
DR Gene3D; 2.40.20.10; -; 2.
DR Gene3D; 4.10.140.10; -; 1.
DR Gene3D; 4.10.740.10; -; 1.
DR InterPro; IPR017857; Coagulation_fac_subgr_Gla_dom.
DR InterPro; IPR000294; GLA_domain.
DR InterPro; IPR000001; Kringle.
DR InterPro; IPR013806; Kringle-like.
DR InterPro; IPR018056; Kringle_CS.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR003966; Prothrombin/thrombin.
DR InterPro; IPR018992; Thrombin_light_chain.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00594; Gla; 1.
DR Pfam; PF00051; Kringle; 2.
DR Pfam; PF09396; Thrombin_light; 1.
DR Pfam; PF00089; Trypsin; 1.
DR PIRSF; PIRSF001149; Thrombin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR PRINTS; PR00001; GLABLOOD.
DR PRINTS; PR01505; PROTHROMBIN.
DR SMART; SM00069; GLA; 1.
DR SMART; SM00130; KR; 2.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57440; SSF57440; 2.
DR SUPFAM; SSF57630; SSF57630; 1.
DR PROSITE; PS00011; GLA_1; 1.
DR PROSITE; PS50998; GLA_2; 1.
DR PROSITE; PS00021; KRINGLE_1; 2.
DR PROSITE; PS50070; KRINGLE_2; 2.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acute phase; Blood coagulation; Calcium;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Gamma-carboxyglutamic acid; Glycoprotein; Hemostasis; Hydrolase;
KW Kringle; Pharmaceutical; Polymorphism; Protease; Reference proteome;
KW Repeat; Secreted; Serine protease; Signal; Thrombophilia; Zymogen.
FT SIGNAL 1 24 Potential.
FT PROPEP 25 43
FT /FTId=PRO_0000028159.
FT CHAIN 44 622 Prothrombin.
FT /FTId=PRO_0000028160.
FT PEPTIDE 44 198 Activation peptide fragment 1.
FT /FTId=PRO_0000028161.
FT PEPTIDE 199 327 Activation peptide fragment 2.
FT /FTId=PRO_0000028162.
FT CHAIN 328 363 Thrombin light chain.
FT /FTId=PRO_0000028163.
FT CHAIN 364 622 Thrombin heavy chain.
FT /FTId=PRO_0000028164.
FT DOMAIN 44 89 Gla.
FT DOMAIN 108 186 Kringle 1.
FT DOMAIN 213 291 Kringle 2.
FT DOMAIN 364 618 Peptidase S1.
FT REGION 551 573 High affinity receptor-binding region
FT which is also known as the TP508 peptide.
FT ACT_SITE 406 406 Charge relay system.
FT ACT_SITE 462 462 Charge relay system.
FT ACT_SITE 568 568 Charge relay system.
FT SITE 198 199 Cleavage; by thrombin.
FT SITE 327 328 Cleavage; by factor Xa.
FT SITE 363 364 Cleavage; by factor Xa.
FT MOD_RES 49 49 4-carboxyglutamate.
FT MOD_RES 50 50 4-carboxyglutamate.
FT MOD_RES 57 57 4-carboxyglutamate.
FT MOD_RES 59 59 4-carboxyglutamate.
FT MOD_RES 62 62 4-carboxyglutamate.
FT MOD_RES 63 63 4-carboxyglutamate.
FT MOD_RES 68 68 4-carboxyglutamate.
FT MOD_RES 69 69 4-carboxyglutamate.
FT MOD_RES 72 72 4-carboxyglutamate.
FT MOD_RES 75 75 4-carboxyglutamate.
FT CARBOHYD 121 121 N-linked (GlcNAc...) (complex).
FT CARBOHYD 143 143 N-linked (GlcNAc...) (complex).
FT CARBOHYD 416 416 N-linked (GlcNAc...) (complex).
FT DISULFID 60 65
FT DISULFID 90 103
FT DISULFID 108 186
FT DISULFID 129 169
FT DISULFID 157 181
FT DISULFID 213 291
FT DISULFID 234 274
FT DISULFID 262 286
FT DISULFID 336 482 Interchain (between light and heavy
FT chains).
FT DISULFID 391 407
FT DISULFID 536 550 By similarity.
FT DISULFID 564 594 By similarity.
FT VARIANT 72 72 E -> G (in FA2D; Shanghai).
FT /FTId=VAR_055232.
FT VARIANT 165 165 T -> M (polymorphism confirmed at protein
FT level; dbSNP:rs5896).
FT /FTId=VAR_011781.
FT VARIANT 200 200 E -> K (in FA2D; prothrombin type 3;
FT variant confirmed at protein level;
FT dbSNP:rs62623459).
FT /FTId=VAR_006711.
FT VARIANT 314 314 R -> C (in FA2D; Barcelona/Madrid).
FT /FTId=VAR_006712.
FT VARIANT 314 314 R -> H (in FA2D; Padua-1).
FT /FTId=VAR_006713.
FT VARIANT 380 380 M -> T (in FA2D; Himi-1).
FT /FTId=VAR_006714.
FT VARIANT 386 386 P -> T (polymorphism confirmed at protein
FT level; dbSNP:rs5897).
FT /FTId=VAR_011782.
FT VARIANT 425 425 R -> C (in FA2D; Quick-1).
FT /FTId=VAR_006715.
FT VARIANT 431 431 R -> H (in FA2D; Himi-2).
FT /FTId=VAR_006716.
FT VARIANT 461 461 R -> W (in FA2D; Tokushima).
FT /FTId=VAR_006717.
FT VARIANT 509 509 E -> A (in FA2D; Salakta/Frankfurt).
FT /FTId=VAR_006718.
FT VARIANT 532 532 E -> Q (polymorphism confirmed at protein
FT level).
FT /FTId=VAR_068913.
FT VARIANT 601 601 G -> V (in FA2D; Quick-2).
FT /FTId=VAR_006719.
FT CONFLICT 9 25 Missing (in Ref. 3; BAG64719).
FT CONFLICT 66 66 S -> N (in Ref. 4; BAD96497).
FT CONFLICT 119 119 H -> N (in Ref. 9; AA sequence).
FT CONFLICT 121 121 N -> S (in Ref. 9; AA sequence).
FT CONFLICT 164 164 T -> I (in Ref. 9; AA sequence).
FT CONFLICT 164 164 T -> N (in Ref. 7; CAA23842).
FT CONFLICT 176 176 V -> A (in Ref. 9; AA sequence).
FT CONFLICT 183 183 I -> T (in Ref. 9; AA sequence).
FT CONFLICT 194 195 AM -> MV (in Ref. 9; AA sequence).
FT CONFLICT 308 308 D -> DEE (in Ref. 9; AA sequence).
FT CONFLICT 335 335 D -> N (in Ref. 10; AA sequence).
FT CONFLICT 337 337 G -> R (in Ref. 4; BAD96495).
FT CONFLICT 349 349 D -> N (in Ref. 10; AA sequence).
FT CONFLICT 369 369 D -> N (in Ref. 10; AA sequence).
FT CONFLICT 398 398 D -> N (in Ref. 10; AA sequence).
FT CONFLICT 414 414 D -> N (in Ref. 10; AA sequence).
FT CONFLICT 485 485 D -> N (in Ref. 10; AA sequence).
FT CONFLICT 494 494 Q -> G (in Ref. 10; AA sequence).
FT CONFLICT 504 504 W -> Y (in Ref. 10; AA sequence).
FT CONFLICT 509 509 E -> S (in Ref. 10; AA sequence).
FT CONFLICT 511 511 W -> V (in Ref. 10; AA sequence).
FT CONFLICT 514 514 N -> D (in Ref. 10; AA sequence).
FT CONFLICT 529 530 PI -> AL (in Ref. 10; AA sequence).
FT HELIX 216 218
FT STRAND 229 231
FT STRAND 233 235
FT HELIX 240 246
FT STRAND 273 275
FT STRAND 277 279
FT STRAND 283 285
FT STRAND 322 324
FT HELIX 326 329
FT STRAND 330 332
FT TURN 334 337
FT TURN 340 342
FT HELIX 343 345
FT HELIX 352 358
FT TURN 360 362
FT STRAND 367 369
FT STRAND 372 375
FT STRAND 378 383
FT TURN 384 387
FT STRAND 388 395
FT STRAND 397 403
FT HELIX 405 407
FT STRAND 408 410
FT HELIX 411 413
FT HELIX 419 421
FT STRAND 422 427
FT STRAND 430 433
FT TURN 436 438
FT STRAND 440 449
FT TURN 455 458
FT STRAND 464 470
FT HELIX 486 492
FT STRAND 498 504
FT STRAND 507 509
FT TURN 510 513
FT HELIX 515 518
FT STRAND 524 530
FT HELIX 533 538
FT STRAND 540 542
FT STRAND 548 551
FT HELIX 555 557
FT TURN 565 569
FT STRAND 571 575
FT TURN 577 579
FT STRAND 582 590
FT STRAND 592 595
FT STRAND 596 598
FT STRAND 601 605
FT HELIX 607 609
FT HELIX 610 620
SQ SEQUENCE 622 AA; 70037 MW; 8A25E1DA88208FCF CRC64;
MAHVRGLQLP GCLALAALCS LVHSQHVFLA PQQARSLLQR VRRANTFLEE VRKGNLEREC
VEETCSYEEA FEALESSTAT DVFWAKYTAC ETARTPRDKL AACLEGNCAE GLGTNYRGHV
NITRSGIECQ LWRSRYPHKP EINSTTHPGA DLQENFCRNP DSSTTGPWCY TTDPTVRRQE
CSIPVCGQDQ VTVAMTPRSE GSSVNLSPPL EQCVPDRGQQ YQGRLAVTTH GLPCLAWASA
QAKALSKHQD FNSAVQLVEN FCRNPDGDEE GVWCYVAGKP GDFGYCDLNY CEEAVEEETG
DGLDEDSDRA IEGRTATSEY QTFFNPRTFG SGEADCGLRP LFEKKSLEDK TERELLESYI
DGRIVEGSDA EIGMSPWQVM LFRKSPQELL CGASLISDRW VLTAAHCLLY PPWDKNFTEN
DLLVRIGKHS RTRYERNIEK ISMLEKIYIH PRYNWRENLD RDIALMKLKK PVAFSDYIHP
VCLPDRETAA SLLQAGYKGR VTGWGNLKET WTANVGKGQP SVLQVVNLPI VERPVCKDST
RIRITDNMFC AGYKPDEGKR GDACEGDSGG PFVMKSPFNN RWYQMGIVSW GEGCDRDGKY
GFYTHVFRLK KWIQKVIDQF GE
//

MIM 176930
*RECORD*
*FIELD* NO
176930
*FIELD* TI
*176930 COAGULATION FACTOR II; F2
;;THROMBIN;;
PROTHROMBIN;;
FACTOR II
*FIELD* TX

read moreDESCRIPTION

The F2 gene encodes coagulation factor II (EC 3.4.21.5), or prothrombin,
a vitamin K-dependent glycoprotein synthesized in the liver as an
inactive zymogen. Prothrombin is activated to the serine protease
thrombin by factor Xa (F10; 613872) in the presence of phospholipids,
calcium, and factor Va (F5; 612309). The activated thrombin enzyme plays
an important role in hemostasis and thrombosis: it converts fibrinogen
(134820) to fibrin for blood clot formation, stimulates platelet
aggregation, and activates coagulation factors V, VIII (F8; 300841), and
XIII (F13A1; 134570). Thrombin also inhibits coagulation by activating
protein C (PROC; 612283) (summary by Lancellotti and De Cristofaro,
2009).

CLONING

Degen and Davie (1987) determined the nucleotide sequence of the human
prothrombin gene, which encodes a 622-residue pre-propeptide with a
molecular mass of about 70 kD. The mature circulating protein has 579
residues. The prothrombin protein contains 5 domains: the propeptide
(residues -43 to -1), the Gla domain (residues 1 to 40), a kringle
domain (residues 41 to 155), a kringle-2 domain (residues 156 to 271),
and a serine protease domain (residues 272 to 579). The prothrombin
protein undergoes several cleavage events to generate the active enzyme
alpha-thrombin, which is composed of a light (alpha) and heavy (beta)
chain covalently linked by a disulfide bond (summary by Lancellotti and
De Cristofaro, 2009).

Degen et al. (1990) cloned cDNAs for mouse coagulation factor II and
compared the gene and predicted protein structure with that of human
prothrombin.

GENE STRUCTURE

Degen and Davie (1987) determined that the prothrombin gene contains 14
exons and spans about 21 kb. The gene contains 30 Alu repeats and 2 Kpn
repeats, which constitute about 40% of the gene.

MAPPING

Royle et al. (1987) assigned the gene for human prothrombin (F2) to
chromosome 11p11-q12 by analysis of a panel of somatic cell hybrid DNAs
and by in situ hybridization, using both cDNA and genomic probes.

Degen et al. (1990) mapped the mouse F2 gene to chromosome 2, about 1.8
map units proximal to the catalase locus.

BIOCHEMICAL FEATURES

- Crystal Structure

Celikel et al. (2003) determined that the structure of platelet GP1BA
(606672) bound to thrombin at 2.3 angstrom resolution and defined 2
sites that bind to exosite II and exosite I of 2 distinct alpha-thrombin
molecules, respectively. GP1BA occupancy may be sequential, as the site
binding to alpha-thrombin exosite I appears to be cryptic in the
unoccupied receptor but exposed when a first thrombin molecule is bound
through exosite II. Celikel et al. (2003) suggested that these
interactions may modulate alpha-thrombin function by mediating GP1BA
clustering and cleavage of protease-activator receptors, which promote
platelet activation, while limiting fibrinogen clotting through blockade
of exosite I.

Dumas et al. (2003) independently determined the crystal structure of
the GP1BA-thrombin complex at 2.6 angstrom resolution. They found that
in the crystal lattice, the periodic arrangement of GP1BA-thrombin
complexes mirrors a scaffold that could serve as a driving force for
tight platelet adhesion.

Kroh et al. (2009) found that von Willebrand factor-binding protein
(VWFBP), which is secreted by Staphyloccocus aureus, is a potent
nonenzymatic conformational activator of prothrombin. VWFBP was found to
share homology with staphylocoagulase, another protein secreted by
Staphylococcus aureus that can activate prothrombin. However, the
mechanism of VWFBP activation of prothrombin was different from that of
staphylocoagulase, with VWFBP showing weaker affinity for prothrombin
and resulting in a slow conformational change with a specific need for
binding of the substrate fibrinogen to complete the process. The
findings suggested a unique mechanism for fibrin deposition during S.
aureus endocarditis.

MOLECULAR GENETICS

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

- Congenital Prothrombin Deficiency and Dysprothrombinemia

Congenital prothrombin deficiency, also known as hypoprothrombinemia
(613679), is a rare autosomal recessive disorder characterized by severe
bleeding manifestations and decreased prothrombin antigen levels and
activity to below 10% of normal values. Dysprothrombinemia, which is
characterized by normal antigen levels but a dysfunctional prothrombin
molecule, shows a more variable level in bleeding tendency, and there is
often a good correlation between the levels of prothrombin activity and
clinical severity. Akhavan et al. (2002) stated that 32 molecular
defects in prothrombin had been identified. Complete prothrombin
deficiency, or aprothombinemia, is believed to be incompatible with life
(review by Meeks and Abshire, 2008).

The allelic variants causing dysprothrombinemia are usually indicated
according to the city or area where they were described for the first
time: see, e.g., prothrombin Barcelona (176930.0002) and prothrombin
Tokushima (176930.0003). The abnormalities are usually caused by a
defect in activation of the protease, such as prothrombin Barcelona, or
a defect in the protease itself, such as prothrombin Quick (176930.0004;
176930.0005) and prothrombin Tokushima (reviews by Girolami et al., 1998
and Lancellotti and De Cristofaro, 2009).

- Thrombophilia

Poort et al. (1996) described a common genetic variation in the 3-prime
untranslated region of the prothrombin gene that is associated with
elevated plasma prothrombin levels and an increased risk of venous
thrombosis (THPH1; 188050): a 20210G-A transition (176930.0009) (Degen
and Davie, 1987). They found this single base substitution in 18% of
probands of thrombophilic families, 6% of unselected consecutive
patients with deep vein thrombosis, and 2% of healthy controls.
Rosendaal et al. (1997) found that the mutation was associated with a
4-fold increased risk of myocardial infarction in women, while among men
the risk was increased 1.5-fold (Doggen et al., 1998).

Martinelli et al. (1998) found that the 20210G-A mutation in the
prothrombin gene (176930.0009) and the factor V Leiden mutation
(612309.0001) are associated with 'idiopathic' cerebral vein thrombosis.
The use of oral contraceptives was also strongly and independently
associated with the disorder. The presence of both the prothrombin gene
mutation and oral contraceptive use raised the risk of cerebral vein
thrombosis further. The F2 and F5 mutations had previously been known to
be common genetic determinants of deep vein thrombosis of the lower
extremities. Cerebral vein thrombosis is a frightening event because of
the severity of the clinical manifestations and the high mortality rate,
estimated to be 5 to 30%. Clinically, cerebral vein thrombosis presents
with a wide range of symptoms, including headache, focal deficits (motor
or sensory), dysphasia, seizures, and impaired consciousness. The
findings of Martinelli et al. (1998) represent a prime example of the
interaction of endogenous (genetic) and exogenous factors in causation
of disease (Bertina and Rosendaal, 1998).

De Stefano et al. (1999) examined the relative risk of recurrent deep
venous thrombosis using a proportional-hazards model. The authors found
that while patients who were heterozygous for factor V Leiden had a risk
of recurrent deep venous thrombosis that was similar to that among
patients who had no known mutations in either factor II or factor V,
patients who were heterozygous for both factor V Leiden and prothrombin
20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did
carriers of factor V Leiden alone.

The factor V Leiden mutation (612309.0001) and the 20210G-A mutation in
the prothrombin gene (176930.0009) are the most frequent abnormalities
associated with venous thromboembolism. Martinelli et al. (2000)
compared the prevalence and incidence rate of venous thromboembolism in
relatives with either of these 2 mutations or both. The study population
included 1,076 relatives of probands with the prothrombin gene mutation,
factor V Leiden, or both, who underwent screening for inherited
thrombophilia and were found to be carriers of single mutations or
double mutations or who were noncarriers. The prevalence of venous
thromboembolism was 5.7% in relatives with the prothrombin gene
mutation, 7.8% in those with factor V Leiden, 17.1% in those with both
mutations, and 2.5% in noncarriers. Annual incidences of thrombosis were
0.13%, 0.19%, 0.42%, and 0.066%, respectively. The relative risk of
thrombosis was 2 times higher in carriers of the prothrombin gene
mutation, 3 times higher in those with factor V Leiden, and 6 times
higher in double carriers than in noncarriers. The incidence of venous
thromboembolism in carriers of the prothrombin gene mutation was
slightly lower than that observed in carriers of factor V Leiden,
whereas in carriers of both mutations it was 2 or 3 times higher. From
these findings, Martinelli et al. (2000) concluded that lifelong primary
anticoagulant prophylaxis of venous thromboembolism is not needed in
asymptomatic carriers of single or double mutations. Anticoagulant
prophylaxis seems to be indicated only when transient risk factors for
thrombosis coexist with mutations.

In affected members of a Japanese family with recurrent thrombophilia,
Miyawaki et al. (2012) identified a heterozygous mutation in the F2 gene
(R596L; 176930.0015). The family had originally been reported by Sakai
et al. (2001). In vitro ELISA studies showed that the mutant prothrombin
did not form a complex with antithrombin (SERPINC1; 107300) even when
heparin was added. A thrombin generation assay showed that the mutant
prothrombin activity was lower than wildtype, but its inactivation in
reconstituted plasma was exceedingly slow. Miyawaki et al. (2012)
concluded that although the procoagulant activity of the R596L mutant
prothrombin was somewhat impaired, the antithrombin:thrombin complex was
considerably impaired, causing continued facilitation of coagulation.
The findings indicated that R596L was a gain-of-function mutation
resulting in the resistance to antithrombin, and conferring
susceptibility to thrombosis. The mutant variant was termed 'prothrombin
Yukuhashi.'

- Susceptibility to Recurrent Pregnancy Loss

Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or
more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128
women without miscarriage and found that heterozygosity for the 20210G-A
mutation of prothrombin (176930.0009) was more common in patients with
abortions in the first trimester (p = 0.027; odds ratio, 8.5). Noting
that in addition to fibrin generation, thrombin also activates tissue
components represented in the placenta and induces cellular responses,
Pihusch et al. (2001) suggested that increased prothrombin levels might
affect placental function by influencing pivotal mechanisms such as cell
adhesion, smooth muscle proliferation, and vasculogenesis.

ANIMAL MODEL

Several observations suggest that prothrombin may serve a broader
physiologic role than simply stemming blood loss, including the
identification of multiple G protein-coupled, thrombin-activated
receptors, and the well-documented mitogenic activity of thrombin in in
vitro test systems. To explore further the physiologic roles of
prothrombin in vivo, Sun et al. (1998) generated prothrombin-deficient
mice by knockout techniques. Inactivation of the F2 gene led to partial
embryonic lethality with more than half of the F2 -/- embryos dying
between embryonic days 9.5 and 11.5. Bleeding into the yolk sac cavity
and varying degrees of tissue necrosis were observed in many of the F2
-/- embryos within this gestational time frame. At least one-quarter of
the F2 -/- mice survived to term, but they ultimately developed fatal
hemorrhagic events and died within a few days of birth. The study
demonstrated that F2 is important in maintaining vascular integrity
during development as well as in postnatal life.

*FIELD* AV
.0001
PROTHROMBIN TYPE 3
F2, GLU157LYS

Board and Shaw (1983) showed that prothrombin type 3 is due to a
glu157-to-lys (E157K) substitution in the F2 gene. This was the first
identification of the specific change in a variant prothrombin, isolated
from individuals heterozygous for prothrombin type 3. This substitution
explained the relatively slow electrophoretic mobility of prothrombin
type 3 compared to wildtype at alkaline pH.

.0002
DYSPROTHROMBINEMIA
F2, ARG271CYS

This F2 variant is referred to as prothrombin Barcelona.

In a patient with normal prothrombin antigen levels, but low prothrombin
coagulant activity (see 613679) (Rabiet et al., 1979), Rabiet et al.
(1986) found that the defect was due to an arg271-to-cys (R271C)
substitution in the F2 gene. The peptide bond between arg271 and thr272
is one of 2 sites of cleavage by factor Xa, indicating that activation
of the variant Barcelona prothrombin protein to functional thrombin was
impaired.

.0003
DYSPROTHROMBINEMIA
F2, ARG418TRP

This F2 variant is referred to as prothrombin Tokushima.

In a 10-year-old Japanese girl who was compound heterozygous for
dysprothrombinemia (see 613679) and hypoprothrombinemia, Miyata et al.
(1987) identified a heterozygous 9490T-to-C transition in the F2 gene,
resulting in an arg418-to-trp (R418W) substitution on the maternal
allele. The patient had originally been reported by Inomoto et al.
(1987), who determined that the prothrombin variant showed about 22%
clotting activity and reduced platelet aggregating activity, suggesting
a defect in the catalytic region (Lancellotti and De Cristofaro, 2009).
Shirakami et al. (1983) and Shirakami and Kawauchi (1984) concluded from
study of this pedigree that the proband was a 'double heterozygote' for
a dysprothrombinemia variant (R418W), inherited from the mother, and a
hypoprothrombinemia (613679) variant, inherited from the father. Indeed,
Iwahana et al. (1992) determined that the hypoprothombinemia variant
inherited from the father was a 1-bp insertion (4177insT; 176930.0008).

.0004
DYSPROTHROMBINEMIA
F2, ARG382CYS

This F2 variant is referred to as prothrombin Quick I.

A patient with dysprothrombinemia (see 613679) originally studied by
Quick et al. (1955), Quick and Hussey (1962), and Owen et al. (1978) was
later found to be compound heterozygous for 2 defective alleles in the
F2 gene. Henriksen and Mann (1988) identified a heterozygous C-to-T
transition resulting in an arg382-to-cys (R382C) substitution, and
Henriksen and Mann (1989) identified a heterozygous G-to-T transversion
resulting in a gly558-to-val (G558V; 176930.0005) substitution. The
patient had less than 2% of normal prothrombin activity. Laboratory
studies by Henriksen and Mann (1988, 1989) showed that both variants
resulted in a structural change in the catalytic region causing
defective interaction with fibrinogen.

Banfield and MacGillivray (1992) found that the arginine residue at
codon 382 is conserved in 11 species ranging from the human to the gecko
(a lizard), the newt, and fish, including rainbow trout, sturgeon, and
the hagfish.

.0005
DYSPROTHROMBINEMIA
F2, GLY558VAL

This F2 variant is referred to as prothrombin Quick II.

See 176930.0004 and Henriksen and Mann (1989).

.0006
DYSPROTHROMBINEMIA
F2, MET337THR

This F2 variant is referred to as prothrombin Himi I.

In a girl with dysprothrombinemia (see 613679), Morishita et al. (1992)
found a congenitally dysfunctional form of prothrombin, called
prothrombin Himi, which was associated with reduced fibrinogen clotting
activity, although it retained full hydrolytic activity toward synthetic
substrates. Because previous findings suggested that the functional
defect of prothrombin Himi was caused by an abnormality in the thrombin
portion of the protein, Morishita et al. (1992) amplified the genomic
DNA regions corresponding to exons 8 through 14 and applied
single-strand conformation polymorphism analysis. Two variant conformers
in exon 10 were identified in the proband with this variant: an 8751T-C
transition resulting in a met337-to-thr (M337T) substitution inherited
from the father, and an 8904G-A transition resulting in an arg388-to-his
(R388H; 176930.0007) substitution inherited from the mother.

.0007
DYSPROTHROMBINEMIA PROTHROMBIN HIMI-II
F2, ARG388HIS

This F2 variant is referred to as prothrombin Himi II.

See 176930.0006 and Morishita et al. (1992).

.0008
HYPOPROTHROMBINEMIA
F2, 1-BP INS, 4177T

In a Japanese girl who was compound heterozygous for hypoprothrombinemia
(613679) and dysprothrombinemia, Iwahana et al. (1992) demonstrated a
heterozygous 1-bp insertion (4177insT) in exon 6 of the F2 gene
inherited from her father. This defect was the basis of the
hypoprothrombinemia. The resulting frameshift mutation caused both an
altered amino acid sequence from codon 114 and a premature termination
codon (TGA) at codon 174 in exon 7. Because exon 7 encodes the kringle-2
domain preceding the thrombin sequence, the frameshift led to the null
prothrombin phenotype. The girl was compound heterozygous for 4177insT
and an R418W (176930.0003) substitution, which was the basis of the
dysprothrombinemia (see 613679).

.0009
THROMBOPHILIA DUE TO THROMBIN DEFECT
STROKE, ISCHEMIC, SUSCEPTIBILITY TO, INCLUDED;;
PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 2, INCLUDED
F2, 20210G-A

Rosendaal et al. (1998) presented data from 11 centers and 9 countries,
representing a total of 5,527 tested individuals. Among these, 111
heterozygous carriers of the 20210A mutation were found, yielding an
overall prevalence of 2.0%. In southern Europe, the prevalence was 3.0%,
nearly twice as high as the prevalence in northern Europe (1.7%). The
prothrombin variant appeared to be rare in individuals of Asian and
African descent.

To discern whether the 20210G-A polymorphism originated from a single or
recurrent mutation event, Zivelin et al. (1998) determined allele
frequencies of 4 dimorphisms spanning 16 of 21 kb of the factor II gene
in 133 unrelated Caucasian subjects of Jewish, Austrian, and French
origins who bore factor II 20210A (10 homozygotes and 123 heterozygotes)
and 110 Caucasian controls. Remarkable differences in the allele
frequencies for each dimorphism were observed between the study groups
(p = 0.0007 or less), indicating strong linkage disequilibrium and
suggesting a founder effect. Indeed, a founder haplotype was present in
68% of 20210A mutant alleles and in only 34% of 20210G normal alleles (p
less than 0.0001). These data strongly supported a single origin for the
factor II polymorphism. Because the polymorphism is rare or absent in
non-Caucasian populations, it probably occurred after divergence of
Africans from non-Africans and of Caucasoids from Mongoloid
subpopulations.

Rees et al. (1999) analyzed samples from 22 different non-European
countries and found that the prothrombin 20210G-A variant, like factor V
Leiden (612309.0001), is rare outside Europe. Of 1,811 non-Europeans
tested, they found only 1 individual, in India, who had the mutation in
heterozygous state.

Zivelin et al. (2006) analyzed the frequencies of 5 SNPs and 9
microsatellites flanking the prothrombin gene in 88 homozygotes for
20210A and 66 homozygotes for 20210G. For estimating the age of the
prothrombin 20210G-A mutation, they analyzed linkage disequilibrium
between the mutation and the multiple markers that had been assessed.
The analysis yielded an age estimate of 23,720 years. A similar analysis
was performed for factor V Leiden (612309.0001) yielding an age estimate
of 21,340 years. The occurrence of the 2 mutations in whites toward the
end of the last glaciation and their presently wide distribution in
whites suggested selective evolutionary advantages for which some
evidence was reported (diminished blood loss) or is controversial
(protection against infections). The selected disadvantage from
thrombosis is unlikely because until recent centuries humans did not
live long enough to manifest a meaningful incidence of thrombosis.

Thrombophilia

Poort et al. (1996) found that a common genetic 20210G-A transition in
the 3-prime untranslated region of the prothrombin gene (Degen and
Davie, 1987) was associated with elevated plasma prothrombin levels and
an increased risk of venous thrombosis (THPH1; 188050). The SNP was
found in 18% of probands of families with thrombosis, 6% of unselected
consecutive patients with deep vein thrombosis, and 2% of healthy
controls. Rosendaal et al. (1997) found that the mutation was associated
with a 4-fold increased risk of myocardial infarction in women, while
among men the risk was increased 1.5-fold (Doggen et al., 1998).

Franco et al. (1999) found a frequency of the 20210A allele of 1% in a
400-member healthy control population and 2.7% in 263 patients with
proven premature atherosclerotic disease. All heterozygotes in the
patient group were found to have had a myocardial infarction. In
addition, the data provided evidence for an association of the mutation
with excessive thrombin generation, which may contribute to the
understanding of its role in venous and arterial disease.

Chamouard et al. (1999) studied the frequency of the factor II 20210G-A
mutation in 10 white European patients with idiopathic portal vein
thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The
frequency of the 20210G-A mutation was found to be 40% in idiopathic
portal vein thrombosis compared with 4.8% in controls or patients with
nonidiopathic portal vein thrombosis or deep vein thrombosis. The
frequency of the factor V Leiden mutation (612309.0001) was similar in
subjects with portal vein thrombosis and in controls but was increased
in patients with deep vein thrombosis.

De Stefano et al. (1999) found that patients who were heterozygous for
both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had
a 2.6-fold higher risk of recurrent thrombosis than did carriers of
factor V Leiden alone. Patients who were heterozygous for factor V
Leiden had a risk of recurrent deep venous thrombosis that was similar
to that among patients who had no known mutations in either factor II or
factor V.

In a Spanish family, Corral et al. (1999) identified 3 subjects
homozygous for the 20210A prothrombin mutation who additionally were
heterozygous for factor V Leiden. The combination of the 2 mutations
increased the risk of developing venous thrombotic episodes at an
earlier age. However, even in association with factor V Leiden, the
homozygous condition of the 20210A prothrombin mutation required
additional risk factors to induce a thrombotic event.

Humpert et al. (1999) screened 384 type 1 diabetic patients for the
20210G-A prothrombin polymorphism and detected the variant in 9
patients. There was no increase in the incidence of coronary heart
disease, nephropathy, or retinopathy among diabetic patients carrying
the 20210G-A polymorphism.

Meyer et al. (1999) described a method for simultaneously genotyping for
factor V Leiden and the prothrombin 20210G-A variant by a multiplex
PCR-SSCP assay on whole blood. Prohaska et al. (1999) studied 284
patients with angiographically confirmed coronary artery disease for the
presence of the 20210G-A polymorphism of the prothrombin gene and
compared them with 340 healthy controls. The prevalence of the mutation
was similar in both groups. There was a mild increase in the frequency
of the mutation in a group of 294 venous thrombosis patients compared
with the healthy controls (odds ratio, 2.90; 95% CI, 1.25-6.9).

One of the main factors of sudden hearing impairment, vestibular
disturbance (tinnitus), is generally thought to be an acute labyrinthine
ischemia; the most common mechanism of sudden hearing loss appears to be
impaired cochlear blood circulation. Mercier et al. (1999) provided
evidence that the 20210A allele of the prothrombin gene is a risk factor
for perception deafness. Among 368 patients (median age, 41 years) with
spontaneous deep vein thrombosis, 18 (12 women and 6 men, 38 to 69 years
of age) had also suffered from acute unilateral hearing impairment. Six
of the 18 were heterozygous for the 20210A allele. In a group of 395
nonthrombotic consecutive patients studied in the same laboratory for
hemorrhagic symptoms or thrombocytopenia over the same period of time, 4
had acute unilateral perception deafness; of 395 nonthrombotic and
nonhemorrhagic sex- and age-matched controls, 6 had acute unilateral
perception deafness.

Souto et al. (1999) reported a family illustrating the complexity of
thrombotic disease in relation to the 20210A variant. The pedigree was
ascertained through a proband with idiopathic thrombophilia. The family
members who had a history of thromboembolism were heterozygous carriers
of the 20210A variant. In addition, 4 relatives who were heterozygous as
well as 2 who were homozygous for the 20210A allele failed to show
clinical manifestations. The 2 homozygotes were 51 and 19 years old.

Gehring et al. (2001) demonstrated that the 20210G-A mutation does not
affect the amount of pre-mRNA, the site of 3-prime end cleavage, or the
length of poly(A) tail of the mature mRNA. Rather, Gehring et al. (2001)
demonstrated that the physiologic F2 3-prime end cleavage signal is
inefficient and that F2 20210G-A represents a gain-of-function mutation,
causing increased cleavage site recognition, increased 3-prime end
processing, and increased mRNA accumulation and protein synthesis.
Enhanced mRNA 3-prime end formation efficiency emerges as a novel
principle causing a genetic disorder and explains the role of the F2
20210G-A mutation in the pathogenesis of thrombophilia. Gehring et al.
(2001) concluded that their work illustrates the pathophysiologic
importance of quantitatively minor aberrations of RNA metabolism.

Although the 20210G-A mutation in heterozygous state carries an
increased risk of a first venous thromboembolic episode, De Stefano et
al. (2001) found that the risk of spontaneous recurrent venous
thromboembolism was similar to that in patients with normal genotype.
They concluded that carriers of the prothrombin mutation should be
treated with oral anticoagulants after a first deep venous thrombosis
for a similar length of time as patients with a normal genotype.

Laczika et al. (2002) described a 19-year-old woman with the joint
occurrence of type I antithrombin III deficiency (613118) and a
heterozygous prothrombin 20210G-A mutation, who developed chronic
thromboembolic pulmonary hypertension on the basis of total occlusion of
the right pulmonary artery. Pulmonary vascular patency was restored
successfully by surgical pulmonary thromboendarterectomy performed 24
weeks after the initial clinical presentation.

Segal et al. (2009) provided a metaanalysis of the predictive value of
the prothrombin 20210G-A mutation for venous thromboembolism using a
literature review of 10 relevant articles. Although heterozygosity for
prothrombin 20210G-A in probands conferred a risk of 1.45, the
confidence interval ranged from 0.96 to 2.2, suggesting that the
mutation was not predictive of recurrent venous thromboembolism compared
to those without the mutation. In addition, there was insufficient
evidence regarding the predictive value of homozygosity for prothrombin
20210G-A in probands, and for the predictive value of being a mutation
carrier in relatives of probands with the mutation. It remained unknown
whether testing improved clinical outcomes. Segal et al. (2009)
concluded that there is insufficient evidence to support the hypothesis
that 20210G-A confers a significantly increased risk for venous
thromboembolism in terms of genetic testing.

Ischemic Stroke

In a comprehensive metaanalysis of 19 case-control studies including
3,028 white adult patients, Casas et al. (2004) found a statistically
significant association between ischemic stroke (601367) and the
20210G-A substitution (odds ratio of 1.44).

Budd-Chiari Syndrome

In a 37-year-old Caucasian male with polycythemia vera who had developed
Budd-Chiari syndrome (BDCHS; 600880), Bucciarelli et al. (1998)
identified heterozygosity for the 20210G-A substitution. His paternal
grandmother had died at the age of 60 due to BDCHS, and his father, who
was also heterozygous for the mutation, had had a myocardial infarction
at age 55. Bucciarelli et al. (1998) excluded deficiencies of
antithrombin, protein C, and protein S, as well as the presence of
antiphospholipid syndrome and the factor V Leiden mutation. They
suggested case-control studies to establish if carriers of the 20210G-A
mutation have an increased risk of developing BDCHS.

Oner et al. (1999) described Budd-Chiari syndrome in a patient
heterozygous for both the 20210G-A mutation of F2 and the factor V
Leiden mutation; heterozygosity for the factor V Leiden mutation is a
known susceptibility factor for BDCHS. Oner et al. (1999) referred to
the 20210G-A mutation by the abbreviation PM, presumably for
'prothrombin mutation.'

Susceptibility to Recurrent Pregnancy Loss

Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or
more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128
women without miscarriage and found that heterozygosity for the 20210G-A
mutation of prothrombin was more common in patients with abortions in
the first trimester (p = 0.027; odds ratio, 8.5).

.0010
DYSPROTHROMBINEMIA
F2, GLU300LYS

This F2 variant is referred to as prothrombin Denver I.

Montgomery et al. (1980) described a form of dysprothrombinemia (see
613679) in a proband with a severe hemophilia-like bleeding disorder who
was treated with weekly prophylactic prothrombin replacement. Lefkowitz
et al. (2000) found that the patient was a compound heterozygote for 2
mutations in the F2 gene: glu300-to-lys (E300K) and glu309-to-lys
(E309K; 176930.0011). Factor II activity was 5 units/dl and factor II
antigen was 21 units/dl. The functional defect was apparently in the
activation of zymogen to enzyme.

.0011
DYSPROTHROMBINEMIA
F2, GLU309LYS

This F2 variant is referred to as prothrombin Denver II.

See (176930.0010) and Lefkowitz et al. (2000).

.0012
DYSPROTHROMBINEMIA
F2, ARG382HIS

Akhavan et al. (2000) described a homozygous arg382-to-his (R382H)
substitution in the prothrombin gene of an Iranian girl with
dysprothrombinemia (see 613679). The only symptoms were sporadic
ecchymosis and 1 episode of buttock hematoma following a major trauma. A
substitution in this residue had been identified in the compound
heterozygous dysprothrombins Quick I (R382C; 176930.0004) and Corpus
Christi.

Akhavan et al. (2002) investigated the functional properties of the
R382H mutant protein. Their experiments showed that the R382H
substitution drastically affected both the procoagulant and the
anticoagulant functions of thrombin as well as its inhibition by heparin
cofactor II (142360). The mild hemorrhagic phenotype may be explained by
abnormalities that ultimately counterbalance each other.

.0013
DYSPROTHROMBINEMIA
F2, ASP552GLU

This F2 variant is referred to as prothrombin Saint-Denis.

In a male newborn with dysprothrombinemia (see 613679), Rouy et al.
(2006) identified a new prothrombin variant, with a point mutation at
nucleotide 20029 resulting in an asp552-to-glu (D552E) substitution.
Prothrombin levels were reduced in each of 3 assays. The substitution
did not affect the rate of prothrombin conversion to thrombin, but
altered thrombin activity. Amino acid 552 had been involved in the
allosteric transition, which is induced by sodium binding to thrombin.
This was the first known amino acid substitution at this site to result
in dysprothrombinemia. The male newborn was referred because of fetal
pulmonary hypertension and left ventricular failure, which resolved
spontaneously. The father and mother, who were first cousins, had a
slight decrease in prothrombin activity and normal levels of prothrombin
antigen. No abnormal bleeding was observed in the proband at birth or in
the first 30 months of his life, and both parents were asymptomatic.

.0014
HYPOPROTHROMBINEMIA
F2, TYR44CYS

In a patient with congenital prothrombin deficiency (613679) and severe
bleeding tendency, Poort et al. (1994) identified a homozygous A-to-G
transition in exon 3 of the F2 gene, resulting in a tyr44-to-cys (Y44C)
substitution. Laboratory studies showed factor II activity at about 2%
and antigen levels at about 5%. Both parents were heterozygous for the
mutation. Further family studies revealed complete cosegregation of the
mutation with the prothrombin deficiency. Five homozygous brothers and
sisters of the propositus were clinically affected with severe
hemorrhages, including epistaxis, soft tissue, muscle, and joint
bleedings in all, and severe menorrhagia in the 2 women.

Lancellotti and De Cristofaro (2009) noted that the Y44C mutation
resulted from a 1305A-G change and affected the kringle-1 domain. The
mutation was found in the family with hypoprothrombinemia reported by
Van Creveld (1954).

.0015
THROMBOPHILIA DUE TO THROMBIN DEFECT
F2, ARG596LEU

In affected members of a Japanese family with recurrent thrombophilia
due to thrombin defect (188050), Miyawaki et al. (2012) identified a
heterozygous 1787G-T transversion in the F2 gene, resulting in an
arg596-to-leu (R596L) substitution within the sodium-binding region of
thrombin and also in 1 of the antithrombin-binding sites. The mutation
was not found in unaffected family members or in 100 control
individuals. In vitro ELISA studies showed that the mutant prothrombin
did not form a complex with antithrombin (SERPINC1; 107300) even when
heparin was added. A thrombin generation assay showed that the mutant
prothrombin activity was lower than wildtype, but its inactivation in
reconstituted plasma was exceedingly slow. Miyawaki et al. (2012)
concluded that although the procoagulant activity of mutant prothrombin
was somewhat impaired due to disruption of the sodium-binding site, the
antithrombin:thrombin complex was considerably impaired due to
disruption of that binding site, causing continued facilitation of
coagulation. The findings indicated that R596L was a gain-of-function
mutation resulting in the resistance to antithrombin, and conferring
susceptibility to thrombosis. The mutant variant was termed 'prothrombin
Yukuhashi.'

*FIELD* SA
Board et al. (1982); Degen et al. (1983); Henriksen and Owen (1987);
Iwahana et al. (1992)
*FIELD* RF
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2. Akhavan, S.; Mannucci, P. M.; Lak, M.; Mancuso, G.; Mazzucconi,
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and three-dimensional structural analysis of nine novel mutations
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2000.

3. Banfield, D. K.; MacGillivray, R. T. A.: Partial characterization
of vertebrate prothrombin cDNAs: amplification and sequence analysis
of the B chain of thrombin from nine different species. Proc. Nat.
Acad. Sci. 89: 2779-2783, 1992.

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5. Board, P. G.; Coggan, M.; Pidcock, M. E.: Genetic heterogeneity
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6. Board, P. G.; Shaw, D. C.: Determination of the amino acid substitution
in human prothrombin type 3 (157 glu-to-lys) and the localization
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7. Bucciarelli, P.; Franchi, F.; Alatri, A.; Bettini, P.; Moia, M.
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8. Casas, J. P.; Hingorani, A. D.; Bautista, L. E.; Sharma, P.: Meta-analysis
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9. Celikel, R.; McClintock, R. A.; Roberts, J. R.; Mendolicchio, G.
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10. Chamouard, P.; Pencreach, E.; Maloisel, F.; Grunebaum, L.; Ardizzone,
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11. Corral, J.; Zuazu-Jausoro, I.; Rivera, J.; Gonzalez-Conejero,
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14. Degen, S. J. F.; Schaefer, L. A.; Jamison, C. S.; Grant, S. G.;
Fitzgibbon, J. J.; Pai, J.-A.; Chapman, V. M.; Elliott, R. W.: Characterization
of the cDNA coding for mouse prothrombin and localization of the gene
on mouse chromosome 2. DNA Cell Biol. 9: 487-498, 1990.

15. De Stefano, V.; Martinelli, I.; Mannucci, P. M.; Paciaroni, K.;
Chiusolo, P.; Casorelli, I.; Rossi, E.; Leone, G.: The risk of recurrent
deep venous thrombosis among heterozygous carriers of both factor
V Leiden and the G20210A prothrombin mutation. New Eng. J. Med. 341:
801-806, 1999.

16. De Stefano, V.; Martinelli, I.; Mannucci, P. M.; Paciaroni, K.;
Rossi, E.; Chiusolo, P.; Casorelli, I.; Leone, G.: The risk of recurrent
venous thromboembolism among heterozygous carriers of the G20210A
prothrombin gene mutation. Brit. J. Haemat. 113: 630-635, 2001.

17. Doggen, C. J. M.; Cats, V. M.; Bertina, R. M.; Rosendaal, F. R.
: Interaction of coagulation defects and cardiovascular risk factors:
increased risk of myocardial infarction associated with factor V Leiden
or prothrombin 20210A. Circulation 97: 1037-1041, 1998.

18. Dumas, J. J.; Kumar, R.; Seehra, J.; Somers, W. S.; Mosyak, L.
: Crystal structure of the Gp1b-alpha-thrombin complex essential for
platelet aggregation. Science 301: 222-226, 2003.

19. Franco, R. F.; Trip, M. D.; ten Cate, H.; van den Ende, A.; Prins,
M. H.; Kastelein, J. J. P.; Reitsma, P. H.: The 20210G-A mutation
in the 3-prime-untranslated region of the prothrombin gene and the
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1999.

20. Gehring, N. H.; Frede, U.; Neu-Yilik, G.; Hundsdoerfer, P.; Vetter,
B.; Hentze, M. W.; Kulozik, A. E.: Increased efficiency of mRNA 3-prime
end formation: a new genetic mechanism contributing to hereditary
thrombophilia. Nature Genet. 28: 389-392, 2001.

21. Girolami, A.; Scarano, L.; Saggiorato, G.; Girolami, B.; Bertomoro,
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22. Henriksen, R. A.; Mann, K. G.: Identification of the primary
structural defect in the dysthrombin thrombin Quick I: substitution
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23. Henriksen, R. A.; Mann, K. G.: Substitution of valine for glycine-558
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24. Henriksen, R. A.; Owen, W. G.: Characterization of the catalytic
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25. Humpert, P. M.; Isermann, B.; Rudofsky, G.; Ziegler, R.; Bierhaus,
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26. Inomoto, T.; Shirakami, A.; Kawauchi, S.; Shigekiyo, T.; Saito,
S.; Miyoshi, K.; Morita, T.; Iwanaga, S.: Prothrombin Tokushima:
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27. Iwahana, H.; Yoshimoto, K.; Shigekiyo, T.; Shirakami, A.; Saito,
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28. Iwahana, H.; Yoshimoto, K.; Shigekiyo, T.; Shirakami, A.; Saito,
S.; Itakura, M.: Detection of a single base substitution of the gene
for prothrombin Tokushima: the application of PCR-SSCP for the genetic
and molecular analysis of dysprothrombinemia. Int. J. Hemat. 55:
93-100, 1992.

29. Kroh, H. K.; Panizzi, P.; Bock, P. E.: Von Willebrand factor-binding
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30. Laczika, K.; Lang, I. M.; Quehenberger, P.; Mannhalter, C.; Muhm,
M.; Klepetko, W.; Kyrle, P. A.: Unilateral chronic thromboembolic
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286-289, 2002.

31. Lancellotti, S.; De Cristofaro, R.: Congenital prothrombin deficiency. Semin.
Thromb. Hemost. 35: 367-381, 2009.

32. Lefkowitz, J. B.; Haver, T.; Clarke, S.; Jacobson, L.; Weller,
A.; Nuss, R.; Manco-Johnson, M.; Hathaway, W. E.: The prothrombin
Denver patient has two different prothrombin point mutations resulting
in glu300-to-lys and glu309-to-lys substitutions. Brit. J. Haemat. 108:
182-187, 2000.

33. Martinelli, I.; Bucciarelli, P.; Margaglione, M.; De Stefano,
V.; Castaman, G.; Mannucci, P. M.: The risk of venous thromboembolism
in family members with mutations in the genes of factor V or prothrombin
or both. Brit. J. Haemat 111: 1223-1229, 2000.

34. Martinelli, I.; Sacchi, E.; Landi, G.; Taioli, E.; Duca, F.; Mannucci,
P. M.: High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene
mutation and in users of oral contraceptives. New Eng. J. Med. 338:
1793-1797, 1998.

35. Meeks, S. L.; Abshire, T. C.: Abnormalities of prothrombin: a
review of the pathophysiology, diagnosis, and treatment. Haemophilia 14:
1159-1163, 2008.

36. Mercier, E.; Quere, I.; Chabert, R.; Lallemant, J.-G.; Daures,
J.-P.; Berlan, J.; Gris, J.-C.: The 20210A allele of the prothrombin
gene is an independent risk factor for perception deafness in patients
with venous thromboembolic antecedents. (Letter) Blood 93: 3150-3152,
1999.

37. Meyer, M.; Kutscher, G.; Vogel, G.: Simultaneous genotyping for
factor V Leiden and prothrombin G20210A variant by a multiplex PCR-SSCP
assay on whole blood. (Letter) Thromb. Haemost. 81: 162-163, 1999.

38. Miyata, T.; Morita, T.; Inomoto, T.; Kawauchi, S.; Shirakami,
A.; Iwanaga, S.: Prothrombin Tokushima, a replacement of arginine-418
by tryptophan that impairs the fibrinogen clotting activity of derived
thrombin Tokushima. Biochemistry 26: 1117-1122, 1987.

39. Miyawaki, Y.; Suzuki, A.; Fujita, J.; Maki, A.; Okuyama, E.; Murata,
M.; Takagi, A.; Murate, T.; Kunishima, S.; Sakai, M.; Okamoto, K.;
Matsushita, T.; Naoe, T.; Saito, H.; Kojima, T.: Thrombosis from
a prothrombin mutation conveying antithrombin resistance. New Eng.
J. Med. 366: 2390-2396, 2012.

40. Montgomery, R. R.; Corrigan, J. J.; Clarke, S.; Johnson, J.:
Prothrombin Denver: a new dysprothrombinemia. (Abstract) Circulation 62
(suppl. III): 279 only, 1980.

41. Morishita, E.; Saito, M.; Kumabashiri, I.; Asakura, H.; Matsuda,
T.; Yamaguchi, K.: Prothrombin Himi: a compound heterozygote for
two dysfunctional prothrombin molecules (met-337-to-thr and arg-388-to-his). Blood 80:
2275-2280, 1992.

42. Oner, A. F.; Arslan, S.; Caksen, H.; Ceylan, A.: Budd-Chiari
syndrome in a patient heterozygous for both factor V Leiden and the
G20210A mutation on the prothrombin gene. (Letter) Thromb. Haemost. 82:
1366-1367, 1999.

43. Owen, C. A., Jr.; Henriksen, R. A.; McDuffie, F. C.; Mann, K.
G.: Prothrombin Quick: a newly identified dysprothrombinemia. Mayo
Clin. Proc. 53: 29-33, 1978.

44. Pihusch, R.; Buchholz, T.; Lohse, P.; Rubsamen, H.; Rogenhofer,
N.; Hasbargen, U.; Hiller, E.; Thaler, C. J.: Thrombophilic gene
mutations and recurrent spontaneous abortion: prothrombin mutation
increases the risk in the first trimester. Am. J. Reprod. Immunol. 46:
124-131, 2001.

45. Poort, S. R.; Michiels, J. J.; Reitsma, P. H.; Bertina, R. M.
: Homozygosity for a novel missense mutation in the prothrombin gene
causing a severe bleeding disorder. Thromb. Haemost. 72: 819-824,
1994.

46. Poort, S. R.; Rosendaal, F. R.; Reitsma, P. H.; Bertina, R. M.
: A common genetic variation in the 3-prime-untranslated region of
the prothrombin gene is associated with elevated plasma prothrombin
levels and an increase in venous thrombosis. Blood 88: 3698-3703,
1996.

47. Prohaska, W.; Schmidt, M.; Mannebach, H.; Gleichmann, U.; Kleesiek,
K.: The prevalence of the prothrombin 20210G-A mutation is not increased
in angiographically confirmed coronary artery disease. (Letter) Thromb.
Haemost. 81: 161-162, 1999.

48. Quick, A. J.; Hussey, C. V.: Hereditary hypoprothrombinemias. Lancet 279279:
173-177, 1962. Note: Originally Volume 1.

49. Quick, A. J.; Pisciotta, A. V.; Hussey, C. V.: Congenital hypoprothrombinemic
states. Arch. Intern. Med. 95: 2-14, 1955.

50. Rabiet, M.-J.; Elion, J.; Benarous, R.; Labie, D.; Josso, F.:
Activation of prothrombin Barcelona: evidence for active high molecular
weight intermediates. Biochim. Biophys. Acta 584: 66-75, 1979.

51. Rabiet, M.-J.; Furie, B. C.; Furie, B.: Molecular defect of prothrombin
Barcelona: substitution of cysteine for arginine at residue 273. J.
Biol. Chem. 261: 15045-15048, 1986.

52. Rees, D. C.; Chapman, N. H.; Webster, M. T.; Guerreiro, J. F.;
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J. Haemat. 105: 564-566, 1999.

53. Rosendaal, F. R.; Doggen, C. J. M.; Zivelin, A.; Arruda, V. R.;
Aiach, M.; Siscovick, D. S.; Hillarp, A.; Watzke, H. H.; Bernardi,
F.; Cumming, A. M.; Preston, F. E.; Reitsma, P. H.: Geographic distribution
of the 20210 G to A prothrombin variant. Thromb. Haemost. 79: 706-708,
1998.

54. Rosendaal, F. R.; Siscovick, D. S.; Schwartz, S. M.; Psaty, B.
M.; Raghunathan, T. E.; Vos, H. L.: A common prothrombin variant
(20210 G to A) increases the risk of myocardial infarction in young
women. Blood 90: 1747-1750, 1997.

55. Rouy, S.; Vidaud, D.; Alessandri, J.-L.; Dautzenberg, M.-D.; Venisse,
L.; Guillin, M.-C.; Bezeaud, A.: Prothrombin Saint-Denis: a natural
variant with a point mutation resulting in asp to glu substitution
at position 552 in prothrombin. Brit. J. Haemat. 132: 770-773, 2006.

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

57. Royle, N. J.; Irwin, D. M.; Koschinsky, M. L.; MacGillivray, R.
T. A.; Hamerton, J. L.: Human genes encoding prothrombin and ceruloplasmin
map to 11p11-q12 and 3q21-24, respectively. Somat. Cell Molec. Genet. 13:
285-292, 1987.

58. Sakai, M.; Urano, H.; Iinuma, A.; Okamoto, K.; Ohsato, K.; Shirahata,
A.: A family with multiple thrombosis including infancy occurrence. J.
UOEH 23: 297-305, 2001. Note: Article in Japanese.

59. Segal, J. B.; Brotman, D. J.; Necochea, A. J.; Emadi, A.; Samal,
L.; Wilson, L. M.; Crim, M. T.; Bass, E. B.: Predictive value of
factor V Leiden and prothrombin G20210A in adults with venous thromboembolism
and in family members of those with a mutation: a systematic review. JAMA 301:
2472-2485, 2009.

60. Shirakami, A.; Kawauchi, S.: Congenital dysprothrombinemia. Acta
Haemat. Jpn. 47: 1697-1704, 1984.

61. Shirakami, A.; Kawauchi, S.; Shigekiyo, T.; Ono, H.; Kataoka,
K.; Miyoshi, K.; Yura, Y.: Prothrombin Tokushima: a family with heterozygosity
for dysprothrombin and hypoprothrombin. (Abstract) Acta Haemat. Jpn. 46:
589 only, 1983.

62. Souto, J. C.; Mateo, J.; Soria, J. M.; Llobet, D.; Coll, I.; Borrell,
M.; Fontcuberta, J.: Homozygotes for prothrombin gene 20210 A allele
in a thrombophilic family without clinical manifestations of venous
thromboembolism. Haematologica 84: 627-632, 1999.

63. Sun, W. Y.; Witte, D. P.; Degen, J. L.; Colbert, M. C.; Burkart,
M. C.; Holmback, K.; Xiao, Q.; Bugge, T. H.; Degen, S. J. F.: Prothrombin
deficiency results in embryonic and neonatal lethality in mice. Proc.
Nat. Acad. Sci. 95: 7597-7602, 1998.

64. Van Creveld, S.: Congenital idiopathic hypoprothrombinemia. Acta
Paediat. Suppl. 43: 245-255, 1954.

65. Zivelin, A.; Mor-Cohen, R.; Kovalsky, V.; Kornbrot, N.; Conard,
J.; Peyvandi, F.; Kyrle, P. A.; Bertina, R.; Peyvandi, F.; Emmerich,
J.; Seligsohn, U.: Prothrombin 20210G-A is an ancestral prothrombotic
mutation that occurred in whites approximately 24,000 years ago. Blood 107:
4666-4668, 2006.

66. Zivelin, A.; Rosenberg, N.; Faier, S.; Kornbrot, N.; Peretz, H.;
Mannhalter, C.; Horellou, M. H.; Seligsohn, U.: A single genetic
origin for the common prothrombotic G20210A polymorphism in the prothrombin
gene. Blood 92: 1119-1124, 1998.

*FIELD* CN
Cassandra L. Kniffin - updated: 6/20/2012
Marla J. F. O'Neill - updated: 12/13/2011
Carol A. Bocchini - updated: 1/5/2011
Cassandra L. Kniffin - updated: 1/3/2011
Victor A. McKusick - updated: 9/28/2006
Victor A. McKusick - updated: 6/9/2006
Cassandra L. Kniffin - updated: 6/10/2005
Ada Hamosh - updated: 1/5/2004
Victor A. McKusick - updated: 10/16/2002
Victor A. McKusick - updated: 10/8/2002
Victor A. McKusick - updated: 11/7/2001
Victor A. McKusick - updated: 9/20/2001
Ada Hamosh - updated: 7/13/2001
Victor A. McKusick - updated: 2/26/2001
Victor A. McKusick - updated: 6/7/2000
Victor A. McKusick - updated: 2/24/2000
Victor A. McKusick - updated: 2/1/2000
Victor A. McKusick - updated: 1/10/2000
George E. Tiller - updated: 11/16/1999
Victor A. McKusick - updated: 7/13/1999
Ada Hamosh - updated: 5/18/1999
Victor A. McKusick - updated: 3/25/1999
Victor A. McKusick - updated: 9/29/1998
Victor A. McKusick - updated: 8/21/1998
Victor A. McKusick - updated: 6/25/1998
Victor A. McKusick - updated: 6/10/1998

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 06/20/2012
ckniffin: 6/20/2012
carol: 3/1/2012
carol: 2/28/2012
alopez: 12/13/2011
carol: 7/19/2011
carol: 4/8/2011
carol: 4/7/2011
carol: 2/11/2011
terry: 1/5/2011
carol: 1/5/2011
carol: 1/4/2011
ckniffin: 1/3/2011
carol: 11/18/2009
ckniffin: 11/11/2009
alopez: 6/16/2009
terry: 5/4/2009
carol: 10/8/2008
carol: 9/29/2008
carol: 10/3/2006
terry: 9/28/2006
alopez: 7/5/2006
terry: 6/9/2006
carol: 6/13/2005
ckniffin: 6/10/2005
carol: 3/17/2004
cwells: 1/7/2004
terry: 1/5/2004
tkritzer: 11/19/2002
tkritzer: 11/1/2002
tkritzer: 10/22/2002
terry: 10/16/2002
carol: 10/16/2002
tkritzer: 10/14/2002
terry: 10/8/2002
carol: 11/26/2001
mcapotos: 11/16/2001
terry: 11/7/2001
carol: 10/12/2001
mcapotos: 9/27/2001
mcapotos: 9/21/2001
terry: 9/20/2001
alopez: 8/2/2001
alopez: 7/16/2001
terry: 7/13/2001
mcapotos: 3/6/2001
mcapotos: 3/2/2001
terry: 2/26/2001
mcapotos: 2/13/2001
carol: 7/6/2000
mcapotos: 6/28/2000
mcapotos: 6/23/2000
terry: 6/7/2000
alopez: 3/22/2000
alopez: 3/21/2000
mcapotos: 3/17/2000
mcapotos: 3/1/2000
terry: 2/24/2000
mcapotos: 2/14/2000
mcapotos: 2/9/2000
terry: 2/1/2000
mcapotos: 1/20/2000
mcapotos: 1/19/2000
terry: 1/10/2000
alopez: 11/16/1999
carol: 7/23/1999
jlewis: 7/21/1999
terry: 7/13/1999
alopez: 5/24/1999
terry: 5/18/1999
mgross: 4/2/1999
mgross: 3/31/1999
terry: 3/25/1999
terry: 10/1/1998
carol: 9/30/1998
terry: 9/29/1998
carol: 8/24/1998
terry: 8/21/1998
dholmes: 7/22/1998
alopez: 6/26/1998
terry: 6/25/1998
terry: 6/11/1998
dholmes: 6/10/1998
terry: 8/8/1997
carol: 6/20/1997
mark: 6/14/1997
mark: 6/25/1996
mimadm: 2/25/1995
davew: 8/19/1994
terry: 7/15/1994
warfield: 3/11/1994
carol: 7/13/1993
carol: 1/21/1993

MIM 188050
*RECORD*
*FIELD* NO
188050
*FIELD* TI
#188050 THROMBOPHILIA DUE TO THROMBIN DEFECT; THPH1
;;THROMBOPHILIA DUE TO FACTOR 2 DEFECT;;
read moreVENOUS THROMBOSIS;;
VENOUS THROMBOEMBOLISM
THROMBOSIS, PROTECTION AGAINST, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because susceptibility to
thrombophilia (THPH1) can be caused by heterozygous mutation in the the
thrombin gene (F2; 176930) on chromosome 11.

DESCRIPTION

Thrombophilia is a multifactorial disorder of inappropriate clot
formation resulting from an interaction of genetic, acquired, and
circumstantial predisposing factors. Venous thromboembolism most
commonly manifests as deep vein thrombosis, which may progress to
pulmonary embolism if the clot dislodges and travels to the lung. Other
manifestations include thromboses of the cerebral or visceral veins and
recurrent pregnancy loss (summary by Seligsohn and Lubetsky, 2001 and
Varga and Kujovich, 2012).

- Genetic Heterogeneity of Thrombophilia

THPH2 (188055) is caused by mutation in the F5 gene (612309) on
chromosome 1q23; THPH3 (176860) and THPH4 (612304) are both caused by
mutation in the PROC gene (612283) on 2q; THPH5 (612336) and THPH6
(614514) are caused by mutation in the PROS1 gene (176880) on 3q11;
THPH7 (613118) is caused by mutation in the AT3 gene (107300) on
1q23-q25; THPH8 (300807) is caused by mutation in the F9 gene (300746)
on Xq27; THPH9 (612348) is associated with decreased release of tissue
plasminogen activator (PLAT; 173370); THPH10 (612356) is caused by
mutation in the HCF2 gene (142360) on 22q11; THPH11 (613116) is caused
by mutation in the HRG gene (142640) on 3q27; and THPH12 (614486) is
associated with variation in the THBD gene (188040) on 20p11.

Susceptibility to thrombosis has also been associated with variation in
additional genes, including MTHFR (607093.0003); F13B (134580.0003);
plasminogen activator inhibitor (SERPINE1; 173360); SERPINA10 (605271);
and several genes encoding fibrinogen (FGA, 134820; FGB, 134830; FGG,
134850). Variation in the KNG1 (612358) and HABP2 (603924) genes has
also been reported.

Protection against venous thrombosis is associated with variation in the
F13A1 gene (134570) on 6p25.

CLINICAL FEATURES

Miyawaki et al. (2012) reported a Japanese family, originating from
Yukuhashi in the northern part of the Kyushu islands, with recurrent
thrombophilia. The family had originally been reported by Sakai et al.
(2001). There were at least 9 affected individuals spanning 3
generations. The proband had onset of recurrent deep vein thrombosis at
age 11 years, and many affected family members had onset of deep vein
thrombosis or pulmonary embolism before age 50 years.

MAPPING

- Associations Pending Confirmation

In a multistage study using a collection of 5,862 cases with venous
thrombosis and 7,112 healthy controls, Morange et al. (2010) identified
a locus on chromosome 6p24.1 as a susceptibility locus for venous
thrombosis. The C allele of the single-nucleotide polymorphism (SNP)
dbSNP rs169713, which resides 92 kb 5-prime of the HIVEP1 gene (194540),
was associated with an increased risk for venous thrombosis, with an
odds ratio of 1.2 (95% confidence interval 1.13-1.27, P = 2.86 x
10(-9)). HIVEP1 codes for a protein that participates in the
transcriptional regulation of inflammatory target genes by binding
specific DNA sequences in their promoter and enhancer regions. Morange
et al. (2010) concluded that these results identified a locus involved
in venous thrombosis susceptibility that lies outside the traditional
coagulation/fibrinolysis pathway.

INHERITANCE

In general, thrombophilia is a complex (multifactorial) trait. The genes
involved in complex traits are, for the most part, susceptibility genes,
not genes that represent the primary cause of the disorder, as in the
case of mendelian disorders. Mendelian disorders fit the model which
might be referred to as mendelian/garrodian; complex, or multifactorial,
traits follow the galtonian/fisherian model. Archibald Garrod's
conception of metabolic blocks in a biochemical pathway caused by a
mendelizing mutation obtains for the inborn errors of metabolism which
he first described and named. Francis Galton (1822-1911) conceived the
notion of multiple genetic factors involved in quantitative traits such
as intelligence and stature. His disciples argued against the relevance
of mendelism in relation to quantitative traits, indeed in relation to
most inherited traits. Fisher (1918) showed that the behavior of
quantitative traits is consistent with collaboration of multiple genetic
factors, each behaving in a mendelian manner.

Schafer (1999) discussed venous thrombosis as a chronic and polygenic
disease.

The transmission pattern in the Japanese family with recurrent
thrombophilia due to an F2 mutation reported by Sakai et al. (2001) and
Miyawaki et al. (2012) was consistent with autosomal dominant
inheritance.

CLINICAL MANAGEMENT

Kearon et al. (1999) presented evidence suggesting that patients with a
first episode of idiopathic venous embolism should be treated with
anticoagulant agents for longer than 3 months.

MOLECULAR GENETICS

Poort et al. (1996) found that a common 20210G-A transition in the
3-prime untranslated region of the prothrombin gene (176930.0009) was
associated with elevated plasma prothrombin levels and an increased risk
of venous thrombosis. The SNP was found in 18% of probands of families
with thrombosis, 6% of unselected consecutive patients with deep vein
thrombosis, and 2% of healthy controls.

Chamouard et al. (1999) studied the frequency of the factor II 20210G-A
mutation in 10 white European patients with idiopathic portal vein
thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The
frequency of the 20210G-A mutation was found to be 40% in idiopathic
portal vein thrombosis compared with 4.8% in controls or patients with
nonidiopathic portal vein thrombosis or deep vein thrombosis.

De Stefano et al. (1999) found that patients who were heterozygous for
both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had
a 2.6-fold higher risk of recurrent thrombosis than did carriers of
factor V Leiden alone. Patients who were heterozygous for factor V
Leiden had a risk of recurrent deep venous thrombosis that was similar
to that among patients who had no known mutations in either factor II or
factor V.

In a Spanish family, Corral et al. (1999) identified 3 subjects
homozygous for the 20210A prothrombin mutation who were also
heterozygous for factor V Leiden. The combination of the 2 mutations
increased the risk of developing venous thrombotic episodes at an
earlier age. However, even in association with factor V Leiden, the
homozygous condition of the 20210A prothrombin mutation required
additional risk factors to induce a thrombotic event.

In affected members of a Japanese family with recurrent thrombophilia,
Miyawaki et al. (2012) identified a heterozygous mutation in the F2 gene
(R596L; 176930.0015). The family had originally been reported by Sakai
et al. (2001). In vitro ELISA studies showed that the mutant prothrombin
did not form a complex with antithrombin (SERPINC1; 107300) even when
heparin was added. A thrombin generation assay showed that the mutant
prothrombin activity was lower than wildtype, but its inactivation in
reconstituted plasma was exceedingly slow. Miyawaki et al. (2012)
concluded that although the procoagulant activity of the R596L mutant
prothrombin was somewhat impaired, the antithrombin:thrombin complex was
considerably impaired, causing continued facilitation of coagulation.
The findings indicated that R596L was a gain-of-function mutation
resulting in the resistance to antithrombin, and conferring
susceptibility to thrombosis. The mutant variant was termed 'prothrombin
Yukuhashi.'

*FIELD* RF
1. Chamouard, P.; Pencreach, E.; Maloisel, F.; Grunebaum, L.; Ardizzone,
J.-F.; Meyer, A.; Gaub, M.-P.; Goetz, J.; Baumann, R.; Uring-Lambert,
B.; Levy, S.; Dufour, P.; Hauptmann, G.; Oudet, P.: Frequent factor
II G20210A mutation in idiopathic portal vein thrombosis. Gastroenterology 116:
144-148, 1999.

2. Corral, J.; Zuazu-Jausoro, I.; Rivera, J.; Gonzalez-Conejero, R.;
Ferrer, F.; Vicente, V.: Clinical and analytical relevance of the
combination of prothrombin 20210A/A and factor V Leiden: results from
a large family. Brit. J. Haemat. 105: 560-563, 1999.

3. De Stefano, V.; Martinelli, I.; Mannucci, P. M.; Paciaroni, K.;
Chiusolo, P.; Casorelli, I.; Rossi, E.; Leone, G.: The risk of recurrent
deep venous thrombosis among heterozygous carriers of both factor
V Leiden and the G20210A prothrombin mutation. New Eng. J. Med. 341:
801-806, 1999.

4. Fisher, R. A.: Correlation between relatives on the supposition
of mendelian inheritance. Trans. Roy. Soc. Edinburgh 52: 399-433,
1918.

5. Kearon, C.; Gent, M.; Hirsh, J.; Weitz, J.; Kovacs, M. J.; Anderson,
D. R.; Turpie, A. G.; Green, D.; Ginsberg, J. S.; Wells, P.; MacKinnon,
B.; Julian, J. A.: A comparison of three months of anticoagulation
with extended anticoagulation for a first episode of idiopathic venous
thromboembolism. New Eng. J. Med. 340: 901-907, 1999. Note: Erratum:
New Eng. J. Med. 341: 298 only, 1999.

6. Miyawaki, Y.; Suzuki, A.; Fujita, J.; Maki, A.; Okuyama, E.; Murata,
M.; Takagi, A.; Murate, T.; Kunishima, S.; Sakai, M.; Okamoto, K.;
Matsushita, T.; Naoe, T.; Saito, H.; Kojima, T.: Thrombosis from
a prothrombin mutation conveying antithrombin resistance. New Eng.
J. Med. 366: 2390-2396, 2012.

7. Morange, P.-E.; Bezemer, I.; Saut, N.; Bare, L.; Burgos, G.; Brocheton,
J.; Durand, H.; Biron-Andreani, C.; Schved, J.-F.; Pernod, G.; Galan,
P.; Drouet, L.; and 17 others: A follow-up study of a genome-wide
association scan identifies a susceptibility locus for venous thrombosis
on chromosome 6p24.1. Am. J. Hum. Genet. 86: 592-595, 2010. Note:
Erratum: Am. J. Hum. Genet. 86: 655 only, 2010.

8. Poort, S. R.; Rosendaal, F. R.; Reitsma, P. H.; Bertina, R. M.
: A common genetic variation in the 3-prime-untranslated region of
the prothrombin gene is associated with elevated plasma prothrombin
levels and an increase in venous thrombosis. Blood 88: 3698-3703,
1996.

9. Sakai, M.; Urano, H.; Iinuma, A.; Okamoto, K.; Ohsato, K.; Shirahata,
A.: A family with multiple thrombosis including infancy occurrence. J.
UOEH 23: 297-305, 2001. Note: Article in Japanese.

10. Schafer, A. I.: Venous thrombosis as a chronic disease. (Editorial) New
Eng. J. Med. 340: 955-956, 1999.

11. Seligsohn, U.; Lubetsky, A.: Genetic susceptibility to venous
thrombosis. New Eng. J. Med. 344: 1222-1231, 2001.

12. Varga, E. A.; Kujovich, J. L.: Management of inherited thrombophilia:
guide for genetics professionals. Clin. Genet. 81: 7-17, 2012.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Vascular];
Thrombosis, recurrent;
Deep vein thrombosis

RESPIRATORY:
[Lung];
Pulmonary embolism

NEUROLOGIC:
[Central nervous system];
Cerebral thrombosis

MISCELLANEOUS:
Onset in childhood

MOLECULAR BASIS:
Caused by mutation in the coagulation factor 2 gene (F2, 176930.0009)

*FIELD* CN
Cassandra L. Kniffin - revised: 6/20/2012

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

*FIELD* ED
joanna: 07/05/2012
ckniffin: 6/20/2012

*FIELD* CN
Cassandra L. Kniffin - updated: 6/20/2012
Cassandra L. Kniffin - updated: 2/23/2012
Ada Hamosh - updated: 6/14/2010
Victor A. McKusick - updated: 2/28/2002
Victor A. McKusick - updated: 5/10/2001
Victor A. McKusick - updated: 4/5/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
terry: 03/14/2013
carol: 6/20/2012
ckniffin: 6/20/2012
carol: 3/1/2012
carol: 2/28/2012
ckniffin: 2/23/2012
carol: 11/2/2011
wwang: 8/10/2011
ckniffin: 8/1/2011
ckniffin: 4/8/2011
carol: 11/15/2010
alopez: 9/10/2010
alopez: 6/18/2010
terry: 6/14/2010
ckniffin: 11/10/2009
carol: 9/12/2008
wwang: 5/18/2006
ckniffin: 5/17/2006
tkritzer: 3/11/2004
cwells: 3/5/2002
cwells: 3/4/2002
terry: 2/28/2002
terry: 5/10/2001
mgross: 4/6/1999
carol: 4/5/1999
mimadm: 5/10/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
marie: 12/16/1986

MIM 601367
*RECORD*
*FIELD* NO
601367
*FIELD* TI
#601367 STROKE, ISCHEMIC
;;CEREBROVASCULAR ACCIDENT;;
CEREBRAL INFARCTION
*FIELD* TX
read moreA number sign (#) is used with this entry because common variants in
several genes have been associated with increased susceptibility to
development of ischemic stroke (see MOLECULAR GENETICS).

A locus for susceptibility to ischemic stroke has been mapped to
chromosome 5q12 (STRK1; 606799).

Several conditions in which stroke occurs are inherited in a classic
mendelian pattern. As reviewed by Tournier-Lasserve (2002), these
monogenic disorders have a low prevalence but a high risk for stroke in
mutation carriers. The genes that have been identified include APP
(104760), BRI (603904), and CST3 (604312), causing autosomal dominant
amyloid angiopathies; NOTCH3 (600276), causing cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL; 125310); and KRIT1 (604214), causing cavernous angioma
(116860).

DESCRIPTION

A stroke is an acute neurologic event leading to death of neural tissue
of the brain and resulting in loss of motor, sensory and/or cognitive
function. It is said to be the third leading cause of death in the
United States. Gunel and Lifton (1996) noted that about 20% of strokes
are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes,
resulting from vascular occlusion, account for the majority of strokes.

Bersano et al. (2008) reviewed genetic polymorphisms that have been
implicated in the development of stroke. Candidate genes include those
involved in hemostasis (see, e.g., F5; 612309), the
renin-angiotensin-aldosterone system (see, e.g., ACE; 106180),
homocysteine (see, e.g., MTHFR; 607093), and lipoprotein metabolism
(see, e.g., APOE; 107741).

See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; 614519).

OTHER FEATURES

Among 512 Korean patients with ischemic stroke, Bang et al. (2005) found
a significant association between intracranial atherosclerotic stroke
(143 patients) and components of the metabolic syndrome (AOMS1; 605552),
compared to those with extracranial atherosclerotic stroke (77 patients)
and those with nonatherosclerotic stroke (292 patients). The association
was particularly strong with regard to hypertension, abdominal obesity,
and HDL cholesterol levels.

Campbell et al. (2006) found that increased serum levels of soluble
vascular adhesion molecule-1 (VCAM1; 192225) predicted recurrent
ischemic stroke in a study of 252 patients. A smaller but similar trend
was noted for serum levels of N-terminal pro-B-type natriuretic peptide
(NPPB; 600295). Patients in the highest quarters for both sVCAM1 and
NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke
compared to patients in the lowest quarters for both biologic markers.

Among 195 nondemented stroke survivors over age 75 years who were
followed for 2 years for cognitive decline and 5 years for survival,
Martin-Ruiz et al. (2006) found that longer telomeres in peripheral
blood mononuclear cells (see 609113) was associated with decreased risk
for death (p = 0.04) and dementia (p = 0.002) and with a smaller
reduction in Mini-Mental State Examination score (p = 0.04). The authors
suggested that peripheral leukocyte telomere length may serve as a
biomarker for long-term stroke outcomes.

INHERITANCE

- Genetic Factors

Ischemic stroke is considered to be a highly complex disease consisting
of a group of heterogeneous disorders with multiple genetic and
environmental risk factors, and can therefore be viewed as a paradigm
for late-onset, complex polygenic diseases (see Dominiczak and McBride,
2003).

Several lines of evidence support a role for genetic factors in the
pathogenesis of stroke. These include studies of twins (Brass et al.,
1992) and familial aggregation (Brass and Shaker, 1991). Both
environmental and genetic risk factors for ischemic stroke have been
well characterized (Sacco et al., 1997). Chief among these are age (the
single most important risk factor), hypertension, cardiac disease,
sickle cell disease, and hyperhomocysteinemia. Intimal-medial thickness
of the common and internal carotid arteries is strongly correlated with
cerebrovascular accidents. Duggirala et al. (1996) demonstrated high
heritability, with 66 to 74.9% of the total variation being accounted
for by genetic factors and the remainder being attributable to
covariates such as lipids, diabetes, blood pressure, and smoking.

Catto (2001) reviewed evidence that stroke has a genetic basis and that
the hemostatic system is an important risk factor for stroke. He
evaluated the genetic regulation of a number of these hemostatic
proteins.

PATHOGENESIS

Ischemic strokes can be further subdivided into large vessel strokes and
those resulting from the occlusion of small intracerebral vessels. The
majority of large vessel ischemic strokes are caused by thromboemboli
arising from the carotid artery, aortic arch, or heart (Delanty and
Vaughan, 1997). Small vessel strokes are associated with lipohyalinosis
of small intracranial blood vessels observed as lacunae and
leukoaraiosis on magnetic resonances imaging of the brain. Lacunar
infarctions are associated with diabetes mellitus, hypertension, and
disorders such as CADASIL (Pantoni and Garcia, 1997).

- Hypertension

The importance of hypertension in stroke pathogenesis has conclusively
been shown by large randomized prospective trials, demonstrating that
treatment of hypertension reduces the risk of stroke by at least 40%
(MacMahon et al., 1990). Hypertension not only accelerates
atherosclerosis in the large arteries but also affects smaller
penetrating arteries of the brain by a process known as lipohyalinosis
or fibrinoid necrosis. This process weakens the vessel wall, and
extravasation of blood through the disintegrating wall follows.
Ultimately, this results either in thrombosis or in rupture of the
vessel wall. Gunel and Lifton (1996) stated that not all hypertensive
individuals develop lipohyalinosis, and lipohyalinosis has also been
reported in normotensive individuals. These observations raise the
possibility that genetic predisposition may be important in the
pathogenesis of stroke. Such predisposition may include not only genes
contributing to elevated blood pressure but also genes acting
independently of blood pressure.

MAPPING

See ATFB5 (611494) for discussion of an association between SNPs at
chromosome 4q25 and the cardioembolic subtype of ischemic stroke.

- Associations Pending Confirmation

In a genomewide association study of 4 large cohorts including 19,602
Caucasians in whom 1,544 incident strokes (1,164 ischemic strokes)
developed over an average follow-up of 11 years, Ikram et al. (2009)
found linkage to dbSNP rs11833579 and dbSNP rs12425791 on chromosome
12p13 near or within the NINJ2 gene (607297). Both SNPs showed
significant associations with total stroke (p = 4.8 x 10(-9) and p = 1.5
x 10(-8), respectively) and ischemic stroke (p = 2.3 x 10(-10) and p =
2.6 x 10(-9), respectively). A significant association with dbSNP
rs12425791 was replicated in 3 additional cohorts, yielding an overall
hazard ratio of 1.29 (p = 1.1 x 10(-9)). However, the International
Stroke Genetics Consortium and Wellcome Trust Case-Control Consortium 2
(2010) failed to replicate an association between ischemic stroke and
the variants dbSNP rs11833579 and dbSNP rs12425791 on 12p13 in a
combined sample of 8,637 cases and 8,733 controls of European ancestry,
as well as in a population-based genomewide cohort study of 278 ischemic
strokes among 22,054 participants.

Matsushita et al. (2010) specifically examined the association of dbSNP
rs11833579 and dbSNP rs12425791 with ischemic stroke in a case-control
study of 3,784 Japanese patients and 3,102 Japanese controls. After
adjustment for age and cardiovascular risk factors, dbSNP rs12425791 was
significantly associated with atherothrombotic stroke (p = 0.0084; odds
ratio of 1.15) in the total cohort. However, after sex stratification,
the association was no longer significant for males (p = 0.086) and
showed only a weak association with females (p = 0.027). There was no
association between stroke and dbSNP rs11833579 in any of the
comparisons.

Matsushita et al. (2010) performed a large case-control association
study and a replication study in a total of 2,775 cases with
atherothrombotic stroke and 2,839 controls. Through the analysis in 860
cases and 860 age- and sex-matched controls, the SNP dbSNP rs2280887 in
ARHGEF10 (608136) was significantly associated with atherothrombotic
stroke even after the adjustment of multiple testing by a permutation
test. The association was replicated in an independent set of 1,915
cases and 1,979 controls. Subsequent fine mapping found another 3 SNPs
that showed similar association due to strong linkage disequilibrium to
dbSNP rs2280887. In the functional analyses of these 4 highly associated
SNPs, dbSNP rs4376531 affected ARHGEF10 transcriptional activity due to
a difference in SP1 (189906)-binding affinity. In a small GTPase
activity assay, the gene product of ARHGEF10 specifically activated RHOA
(165390). A population-based cohort study revealed that subjects with
dbSNP rs4376531 CC or CG had an increased incidence of ischemic stroke
(P = 0.033). The authors suggested that the functional SNP of ARHGEF10
confers susceptibility to atherothrombotic stroke.

Chen et al. (2010) identified a single-nucleotide polymorphism (SNP),
dbSNP rs2507800, within the 3-prime untranslated region (UTR) of
angiopoietin-1 (ANGPT1; 601667) that influences regulation of
angiopoietin-1 by miR211 (613753). The A allele of dbSNP rs2507800, but
not the T allele, suppressed angiopoietin-1 translation by facilitating
miR211 binding. Subjects carrying the TT genotype had higher plasma
angiopoietin-1 levels than those with the A allele. The association of
the variant with stroke was tested in 438 stroke patients and 890
controls, and replicated in an independent population of 1791 stroke
patients and 1843 controls. The TT genotype resulted in a significant
reduction in overall stroke risk (p = 0.0003), ischemic stroke (p =
0.007) and hemorrhagic stroke (p = 0.007). These results were confirmed
in an independent study. The authors concluded that the TT genotype of
dbSNP rs2507800 in the 3-prime UTR of angiopoietin-1 might reduce the
risk of stroke by interfering with miR211 binding.

MOLECULAR GENETICS

Zee et al. (2004) collected DNA samples at baseline in a prospective
cohort of 14,916 initially healthy American men. The authors then
genotyped 92 polymorphisms from 56 candidate genes among 319 individuals
who subsequently developed ischemic stroke and among 2,092 individuals
who remained free of reported cardiovascular disease over a mean
follow-up period of 13.2 years. Two polymorphisms related to
inflammation, val640-to-leu in the SELP gene (173610.0002) and a 582C-T
transition in the IL4 gene (147780), were found to be independent
predictors of thromboembolic stroke (odds ratio of 1.63, P = 0.001, and
odds ratio of 1.40, P = 0.003, respectively).

Casas et al. (2004) performed a comprehensive metaanalysis of 120
case-control studies of genetic associations in ischemic stroke in white
adults and determined the pooled odds ratios (OR) conferred by specific
genetic changes. Statistically significant associations were identified
for 4 polymorphisms: factor V Leiden (R506Q; 612309.0001, OR of 1.33);
methylenetetrahydrofolate reductase (A222V; 607093.0003, OR of 1.24);
prothrombin (20210G-A; 176930.0009, OR of 1.44); and
angiotensin-converting enzyme (insertion/deletion, OR of 1.21). These
were also the most investigated candidate genes, including 4,588, 3,387,
3,028, and 2,990 cases, respectively. No statistically significant
association with ischemic stroke was detected for the 3 next most
investigated genes: factor VIII (300841), apolipoprotein E (107741), and
human platelet antigen type 1 (173470). Casas et al. (2004) concluded
that although there is no single gene with a major effect, common
variants in several genes contribute to the risk of stroke.

In a genomewide scan of 296 multiplex Icelandic families including 713
individuals with myocardial infarction (608557), Helgadottir et al.
(2004) found suggestive linkage to chromosome 13q12-q13. By analysis of
a candidate gene in the region, ALOX5AP (603700), they identified a
4-SNP haplotype, 'HapA' (defined by SG13S25, SG13S114, SG13S89, and
SG13S32), that conferred a nearly 2 times greater risk of myocardial
infarction and stroke. Another 4-SNP haplotype, 'HapB', was associated
only with myocardial infarction.

To assess further the contribution of the ALOX5AP variants HapA and HapB
in a population outside Iceland, Helgadottir et al. (2005) genotyped 7
SNPs that defined both of these haplotypes from 450 patients with
ischemic stroke and 710 controls from Aberdeenshire, Scotland. The
haplotype that was at-risk in Iceland, HapA, had significantly greater
frequency in Scottish patients than in controls. The carrier frequency
in patients and controls was 33.4% and 26.4%, respectively, which
resulted in a relative risk of 1.36 under the assumption of a
multiplicative model (p = 0.007). They did not detect association
between HapB and ischemic stroke in the Scottish cohort. However, HapB
was overrepresented in male patients.

Fornage et al. (2005) genotyped 12 SNPs in the EPHX2 gene (132811) in
315 stroke patients and 1,021 controls from the ARIC study and
identified 2 common EPHX2 haplotypes that were associated with increased
and decreased risk of ischemic stroke in African Americans (adjusted p
less than 0.04). In whites, 2 different common haplotypes showed
suggestive evidence for association with ischemic stroke risk but, as in
African Americans, these relationships were in opposite direction.
Fornage et al. (2005) suggested that multiple variants may exist within
or near the EPHX2 gene, with greatly contrasting relationships to
ischemic stroke incidence.

In large studies in Japan, Kubo et al. (2007) demonstrated association
between cerebral infarction (ischemic stroke) and a nonsynonymous SNP in
the PRKCH gene (V374I; 605437.0001), which caused enhancement of PKC
activity in transfected 293T cells. Furthermore, Kubo et al. (2007)
found that PKC-eta was expressed mainly in vascular endothelial cells
and foamy macrophages in human atherosclerotic lesions, and its
expression increased as the lesion type progressed. These results
supported a role for PRKCH in the pathogenesis of cerebral infarction.

Berger et al. (2007) performed 2 large case-control studies involving
1,901 hospitalized stroke patients and 1,747 regional population
controls and found that the E298D polymorphism of the NOS3 gene
(153729.0001) was significantly associated with ischemic stroke
independent of age, gender, hypertension, diabetes, and
hypercholesterolemia.

Zacho et al. (2008) studied 10,276 persons from a general population
cohort, including 1,786 in whom ischemic heart disease developed (see
607339) and 741 in whom ischemic cerebrovascular disease developed, and
an additional 31,992 persons from a cross-sectional general population
study, of whom 2,521 had ischemic heart disease and 1,483 had ischemic
cerebrovascular disease. Finally, Zacho et al. (2008) compared 2,238
patients with ischemic heart disease with 4,474 control subjects and 612
patients with ischemic cerebrovascular disease with 1,224 control
subjects. Zacho et al. (2008) measured levels of high-sensitivity
C-reactive protein (CRP: 123260) and conducted genotyping for 4 CRP
polymorphisms and 2 apolipoprotein E polymorphisms (dbSNP rs429358 and
dbSNP rs7412). The risk of ischemic heart disease and ischemic
cerebrovascular disease was increased by a factor of 1.6 and 1.3,
respectively, in persons who had CRP levels above 3 mg per liter, as
compared with persons who had CRP levels below 1 mg per liter. Genotype
combinations of the 4 CRP polymorphisms dbSNP rs1205, dbSNP 1130864,
dbSNP rs3091244, and dbSNP rs3093077 were associated with an increase in
CRP levels up to 64%, resulting in a theoretically predicted increased
risk of up to 32% for ischemic heart disease and up to 25% for ischemic
cerebrovascular disease. However, these genotype combinations were not
associated with an increased risk of ischemic vascular disease. In
contrast, Zacho et al. (2008) found that apolipoprotein E genotypes were
associated with both elevated cholesterol levels and increased risk of
ischemic heart disease. Zacho et al. (2008) concluded that polymorphisms
in the CRP gene are associated with marked increases in CRP levels, but
that these are not in themselves associated with an increased risk of
ischemic vascular disease.

ANIMAL MODEL

Rubattu et al. (1996) reported the chromosomal mapping of quantitative
trait loci (QTLs) contributing to stroke in a rat model of this complex
disorder of multifactorial and polygenic etiology. Using the
stroke-prone spontaneously hypertensive rat (SHRSP) as a model organism,
they mated it with the stroke-resistant spontaneously hypertensive rat
(SHR) and performed a genomewide screen in the resultant F2 cohort where
latency until stroke, but not hypertension (a major confounder),
segregated. They identified 3 major QTLs: STR1, STR2, and STR3, with lod
scores of 7.4, 4.7, and 3.0, respectively. These 3 QTLs accounted for
28% of the overall phenotypic variants. STR1 mapped to rat chromosome 1
and strongly affected latency to stroke in a recessive mode, accounting
for 17.3% of overall phenotypic variants in the cross studied.
Additional consideration of age-adjusted blood pressure values as a
covariate had no effects on the resultant statistic, indicating to
Rubattu et al. (1996) that this locus acts independently of blood
pressure. STR2, on the other hand, conferred a significant protective
effect against stroke in the presence of SHRSP alleles. STR2 accounted
for 9.6% of overall variants in stroke latency. The peak protective
effect mapped close to the gene coding for atrial natriuretic factor
(ANF; 108780) on rat chromosome 5. In the rat, as in man and mouse, the
gene for brain natriuretic factor, BNF, colocalizes with ANF. STR3, a
locus linked to rat chromosome 4, conferred a similar, but less
significant, recessive effect on preventing stroke in the presence of 2
SHRSP-derived alleles.

Building on the work of Rubattu et al. (1996), Jeffs et al. (1997)
designed studies to identify the genetic component responsible for large
infarct volumes in the SHRSP in response to a focal ischemic insult by
performing a genome scan in a F2 cross derived from the SHRSP and the
normotensive reference rat strain WKY. They identified a highly
significant QTL on rat chromosome 5 with a lod score of 16.6 that
accounted for 67% of the total variance, colocalized with the genes
encoding the atrial and brain natriuretic factors (see 108780 and
600295), and was blood pressure independent.

In a rat model of ischemic stroke, Simard et al. (2006) found
upregulation of the cation channel regulatory subunit Sur1 (600509) in
ischemic neurons, astrocytes, and capillaries. Upregulation of Sur1 was
linked to activation of the transcription factor Sp1 (189906) and was
associated with expression of functional nonselective cation channels,
which they called the NC(Ca-ATP) channel, but not K(ATP) channels.
Treatment with low-dose glibenclamide, which blocks Sur1 and the
NC(Ca-ATP) channel, reduced cerebral edema, infarct volume, and
mortality by 50%. Simard et al. (2006) concluded that the NC(Ca-ATP)
channel is involved in the development of cerebral edema and that
targeting Sur1 may provide a new therapeutic approach to stroke.

Arboleda-Velasquez et al. (2008) found that Notch3 knockout increased
susceptibility of mice to ischemic challenge. Notch3-null mice showed
larger ischemic lesions, more neurologic deficits, increased mortality,
more severe cerebral blood flow deficits, and more frequent spontaneous
periinfarct depolarizations compared with wildtype mice. Microarray
analysis revealed over 600 differentially regulated genes, and all genes
that regulate muscle contraction were downregulated.

*FIELD* RF
1. Arboleda-Velasquez, J. F.; Zhou, Z.; Shin, H. K.; Louvi, A.; Kim,
H.-H.; Savitz, S. I.; Liao, J. K.; Salomone, S.; Ayata, C.; Moskowitz,
M. A.; Artavanis-Tsakonas, S.: Linking Notch signaling to ischemic
stroke. Proc. Nat. Acad. Sci. 105: 4856-4861, 2008.

2. Bang, O. Y.; Kim, J. W.; Lee, J. H.; Lee, M. A.; Lee, P. H.; Joo,
I. S.; Huh, K.: Association of the metabolic syndrome with intracranial
atherosclerotic stroke. Neurology 65: 296-298, 2005.

3. Berger, K.; Stogbauer, F.; Stoll, M.; Wellmann, J.; Huge, A.; Cheng,
S.; Kessler, C.; John, U.; Assmann, G.; Ringelstein, E. B.; Funke,
H.: The glu298asp polymorphism in the nitric oxide synthase 3 gene
is associated with the risk of ischemic stroke in two large independent
case-control studies. Hum. Genet. 121: 169-178, 2007.

4. Bersano, A.; Ballabio, E.; Bresolin, N.; Candelise, L.: Genetic
polymorphisms for the study of multifactorial stroke. Hum. Mutat. 29:
776-795, 2008.

5. Brass, L. M.; Isaacsohn, J. L.; Merikangas, K. R.; Robinette, C.
D.: A study of twins and stroke. Stroke 23: 221-223, 1992.

6. Brass, L. M.; Shaker, L. A.: Family history in patients with transient
ischemic attacks. Stroke 22: 837-841, 1991.

7. Campbell, D. J.; Woodward, M.; Chalmers, J. P.; Colman, S. A.;
Jenkins, A. J.; Kemp, B. E.; Neal, B. C.; Patel, A.; MacMahon, S.
W.: Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type
natriuretic peptide in predicting ischemic stroke in patients with
cerebrovascular disease. Arch. Neurol. 63: 60-65, 2006.

8. Casas, J. P.; Hingorani, A. D.; Bautista, L. E.; Sharma, P.: Meta-analysis
of genetic studies in ischemic stroke: thirty-two genes involving
approximately 18000 cases and 58000 controls. Arch. Neurol. 61:
1652-1662, 2004.

9. Catto, A. J.: Genetic aspects of the hemostatic system in cerebrovascular
disease. Neurology 57 (suppl. 2): S24-S30, 2001.

10. Chen, J.; Yang, T.; Yu, H.; Sun, K.; Shi, Y.; Song, W.; Bai, Y.;
Wang, X.; Lou, K.; Song, Y.; Zhang, Y.; Hui, R.: A functional variant
in the 3-prime-UTR of angiopoietin-1 might reduce stroke risk by interfering
with the binding efficiency of microRNA 211. Hum. Molec. Genet. 19:
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11. Delanty, N.; Vaughan, C. J.: Vascular effects of statins in stroke. Stroke 28:
2315-2320, 1997.

12. Dominiczak, A. F.; McBride, M. W.: Genetics of common polygenic
stroke. Nature Genet. 35: 116-117, 2003.

13. Duggirala, R.; Villalpando, C. G.; O'Leary, D. H.; Stern, M. P.;
Blangero, J.: Genetic basis of variation in carotid artery wall thickness. Stroke 27:
833-837, 1996.

14. Fornage, M.; Lee, C. R.; Doris, P. A.; Bray, M. S.; Heiss, G.;
Zeldin, D. C.; Boerwinkle, E.: The soluble epoxide hydrolase gene
harbors sequence variation associated with susceptibility to and protection
from incident ischemic stroke. Hum. Molec. Genet. 14: 2829-2837,
2005.

15. Gunel, M.; Lifton, R. P.: Counting strokes. Nature Genet. 13:
384-385, 1996.

16. Helgadottir, A.; Gretarsdottir, S.; St. Clair, D.; Manolescu,
A.; Cheung, J.; Thorleifsson, G.; Pasdar, A.; Grant, S. F. A.; Whalley,
L. J.; Hakonarson, H.; Thorsteinsdottir, U.; Kong, A.; Gulcher, J.;
Stefansson, K.; MacLeod, M. J.: Association between the gene encoding
5-lipoxygenase-activating protein and stroke replicated in a Scottish
population. Am. J. Hum. Genet. 76: 505-509, 2005.

17. Helgadottir, A.; Manolescu, A.; Thorleifsson, G.; Gretarsdottir,
S.; Jonsdottir, H.; Thorsteinsdottir, U.; Samani, N. J.; Gudmundsson,
G.; Grant, S. F. A.; Thorgeirsson, G.; Sveinbjornsdottir, S.; Valdimarsson,
E. M.; and 14 others: The gene encoding 5-lipoxygenase activating
protein confers risk of myocardial infarction and stroke. Nature
Genet. 36: 233-239, 2004.

18. Ikram, M. A.; Seshadri, S.; Bis, J. C.; Fornage, M.; DeStefano,
A. L.; Aulchenko, Y. S.; Debette, S.; Lumley, T.; Folsom, A. R.; van
den Herik, E. G.; Bos, M. J.; Beiser, A.; and 34 others: Genomewide
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19. International Stroke Genetics Consortium; Wellcome Trust Case-Control
Consortium 2: Failure to validate association between 12p13 variants
and ischemic stroke. (Letter) New Eng. J. Med. 362: 1547-1550, 2010.

20. Jeffs, B.; Clark, J. S.; Anderson, N. H.; Gratton, J.; Brosnan,
M. J.; Gauguier, D.; Reid, J. L.; Macrae, I. M.; Dominiczak, A. F.
: Sensitivity to cerebral ischaemic insult in a rat model of stroke
is determined by a single genetic locus. Nature Genet. 16: 364-367,
1997.

21. Kubo, M.; Hata, J.; Ninomiya, T.; Matsuda, K.; Yonemoto, K.; Nakano,
T.; Matsushita, T.; Yamazaki, K.; Ohnishi, Y.; Saito, S.; Kitazono,
T.; Ibayashi, S.; Sueishi, K.; Iida, M.; Nakamura, Y.; Kiyohara, Y.
: A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the
risk of cerebral infarction. Nature Genet. 39: 212-217, 2007.

22. MacMahon, S.; Peto, R.; Cutler, J.; Collins, R.; Sorlie, P.; Neaton,
J.; Abbott, R.; Godwin, J.; Dyer, A.; Stamler, J.: Blood pressure,
stroke, and coronary heart disease. Part 1, prolonged differences
in blood pressure: prospective observational studies corrected for
the regression dilution bias. Lancet 335: 765-774, 1990.

23. Martin-Ruiz, C.; Dickinson, H. O.; Keys, B.; Rowan, E.; Kenny,
R. A.; von Zglinicki, T.: Telomere length predicts poststroke mortality,
dementia, and cognitive decline. Ann. Neurol. 60: 174-180, 2006.

24. Matsushita, T.; Askikawa,, K.; Yonemoto, K.; Hirakawa, Y.; Hata,
J.; Amitani, H.; Doi, Y.; Ninomiya, T.; Kitazono, T.; Ibayashi, S.;
Iida, M.; Nakamura, Y.; Kiyohara, Y.; Kubo, M.: Functional SNP of
ARHGEF10 confers risk of atherothrombotic stroke. Hum. Molec. Genet. 19:
1137-1146, 2010.

25. Matsushita, T.; Umeno, J.; Hirakawa, Y.; Yonemoto, K.; Ashikawa,
K.; Amitani, H.; Ninomiya, T.; Hata, J.; Doi, Y.; Kitazono, T.; Iida,
M.; Nakamura, Y.; Kiyohara, Y.; Kubo, M.: Association study of the
polymorphisms on chromosome 12p13 with atherothrombotic stroke in
the Japanese population. J. Hum. Genet. 55: 473-476, 2010.

26. Pantoni, L.; Garcia, J. H.: Pathogenesis of leukoaraiosis: a
review. Stroke 28: 652-659, 1997.

27. Rubattu, S.; Volpe, M.; Kreutz, R.; Ganten, U.; Ganten, D.; Lindpaintner,
K.: Chromosomal mapping of quantitative trait loci contributing to
stroke in a rat model of complex human disease. Nature Genet. 13:
429-434, 1996.

28. Sacco, R. L.; Benjamin, E. J.; Broderick, J. P.; Dyken, M.; Easton,
J. D.; Feinberg, W. M.; Goldstein, L. B.; Gorelick, P. B.; Howard,
G.; Kittner, S. J.; Manolio, T. A.; Whisnant, J. P.; Wolf, P. A.:
Risk factors. Stroke 28: 1507-1517, 1997.

29. Simard, J. M.; Chen, M.; Tarasov, K. V.; Bhatta, S.; Ivanova,
S.; Melnitchenko, L.; Tsymbalyuk, N.; West, G. A.; Gerzanich, V.:
Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral
edema after ischemic stroke. Nature Med. 12: 433-440, 2006.

30. Tournier-Lasserve, E.: New players in the genetics of stroke. New
Eng. J. Med. 347: 1711-1712, 2002.

31. Zacho, J.; Tybjaerg,-Hansen, A.; Jensen, J. S.; Grande, P.; Sillesen,
H.; Nordestgaard, B. G.: Genetically elevated C-reactive protein
and ischemic vascular disease. New Eng. J. Med. 359: 1897-1908,
2008.

32. Zee, R. Y. L.; Cook, N. R.; Cheng, S.; Reynolds, R.; Erlich, H.
A.; Lindpaintner, K.; Ridker, P. M.: Polymorphism in the P-selectin
and interleukin-4 genes as determinants of stroke: a population-based,
prospective genetic analysis. Hum. Molec. Genet. 13: 389-396, 2004.

*FIELD* CS

Neuro:
Stroke;
Motor, sensory and/or cognitive function loss

Inheritance:
Multifactorial predisposition

*FIELD* CD
John F. Jackson: 10/03/1997

*FIELD* CN
George E. Tiller - updated: 08/08/2013
George E. Tiller - updated: 11/10/2011
Cassandra L. Kniffin - updated: 8/18/2010
Cassandra L. Kniffin - updated: 4/22/2010
George E. Tiller - updated: 4/22/2009
Marla J. F. O'Neill - updated: 3/3/2009
Ada Hamosh - updated: 11/24/2008
Marla J. F. O'Neill - updated: 10/16/2008
Patricia A. Hartz - updated: 9/4/2008
Cassandra L. Kniffin - updated: 6/26/2008
Marla J. F. O'Neill - updated: 8/27/2007
Cassandra L. Kniffin - updated: 7/30/2007
Victor A. McKusick - updated: 2/23/2007
George E. Tiller - updated: 12/4/2006
Cassandra L. Kniffin - updated: 7/14/2006
Cassandra L. Kniffin - updated: 5/15/2006
Cassandra L. Kniffin - updated: 10/31/2005
Cassandra L. Kniffin - reorganized: 6/13/2005
Cassandra L. Kniffin - updated: 6/10/2005
Cassandra L. Kniffin - updated: 4/12/2005
Victor A. McKusick - updated: 10/1/2003
Victor A. McKusick - updated: 12/13/2002
Victor A. McKusick - updated: 3/21/2002
Victor A. McKusick - updated: 11/9/2001
Orest Hurko - updated: 4/6/1998
Victor A. McKusick - updated: 8/1/1997

*FIELD* CD
Victor A. McKusick: 8/9/1996

*FIELD* ED
alopez: 08/08/2013
carol: 3/7/2012
ckniffin: 3/5/2012
alopez: 11/21/2011
terry: 11/10/2011
carol: 4/7/2011
terry: 3/22/2011
carol: 3/10/2011
wwang: 8/24/2010
ckniffin: 8/18/2010
alopez: 4/23/2010
ckniffin: 4/22/2010
wwang: 7/30/2009
ckniffin: 7/14/2009
wwang: 5/8/2009
terry: 4/22/2009
terry: 3/3/2009
alopez: 12/15/2008
terry: 11/24/2008
carol: 10/17/2008
carol: 10/16/2008
carol: 10/9/2008
carol: 10/8/2008
wwang: 9/4/2008
wwang: 7/2/2008
ckniffin: 6/26/2008
wwang: 8/27/2007
wwang: 8/22/2007
ckniffin: 7/30/2007
alopez: 3/8/2007
terry: 2/23/2007
wwang: 12/4/2006
terry: 12/4/2006
carol: 7/19/2006
ckniffin: 7/14/2006
wwang: 5/24/2006
ckniffin: 5/15/2006
wwang: 11/3/2005
ckniffin: 10/31/2005
carol: 6/13/2005
ckniffin: 6/10/2005
wwang: 4/25/2005
wwang: 4/14/2005
ckniffin: 4/12/2005
alopez: 10/7/2003
terry: 10/1/2003
tkritzer: 12/16/2002
terry: 12/13/2002
alopez: 3/27/2002
terry: 3/21/2002
carol: 11/12/2001
terry: 11/9/2001
dkim: 12/10/1998
carol: 6/22/1998
terry: 6/1/1998
terry: 4/6/1998
terry: 8/5/1997
terry: 8/1/1997
mark: 7/8/1997
terry: 11/25/1996
jamie: 10/23/1996
jamie: 10/18/1996
jamie: 10/16/1996
mark: 8/30/1996
terry: 8/9/1996
mark: 8/9/1996

MIM 613679
*RECORD*
*FIELD* NO
613679
*FIELD* TI
#613679 PROTHROMBIN DEFICIENCY, CONGENITAL
;;HYPOPROTHROMBINEMIA
DYSPROTHROMBINEMIA, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because congenital prothrombin
deficiency is caused by homozygous or compound heterozygous mutation in
the gene encoding coagulation factor II, also known as prothrombin (F2;
176930).

DESCRIPTION

Prothrombin deficiency is an extremely rare autosomal recessive bleeding
disorder characterized by low levels of circulating prothrombin; it
affects about 1 in 2,000,000 individuals. There are 2 main types: type I
deficiency, known as true prothrombin deficiency or
'hypoprothrombinemia,' is defined as plasma levels of prothrombin being
less than 10% of normal with a concomitant decrease in activity. These
patients have severe bleeding from birth, including umbilical cord
hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding,
hemarthroses, intracranial bleeding, gastrointestinal bleeding, and
menorrhagia. Type II deficiency, known as 'dysprothrombinemia,' is
characterized by normal or low-normal synthesis of a dysfunctional
protein. Bleeding symptoms are more variable, depending on the amount of
residual functional activity. Variant prothrombin gene alleles can
result in 'hypoprothrombinemia' or 'dysprothrombinemia,' and individuals
who are compound heterozygous for these 2 types of alleles have variable
manifestations. Heterozygous mutation carriers, who have plasma levels
between 40 and 60% of normal, are usually asymptomatic, but can show
bleeding after tooth extraction or surgical procedures (review by
Lancellotti and De Cristofaro, 2009).

CLINICAL FEATURES

Quick and Hussey (1962) described congenital hypoprothrombinemia. In a
patient reported by Quick and Hussey (1962), Lanchantin et al. (1968)
found no identifiable prothrombin protein, consistent with true
deficiency or hypoprothrombinemia. This finding was distinct from a
related disorder, dysprothrombinemia, in which a biologically
dysfunctional protein can been detected by immunoassay.

Poort et al. (1994) reported a family with congenital prothrombin
deficiency and severe bleeding. Clinical features included epistaxis and
soft tissue, muscle, and joint bleedings in all, and severe menorrhagia
in the 2 women. Laboratory studies of the proband showed factor II
activity of about 2% and antigen levels of about 5% of normal controls,
consistent with hypoprothrombinemia.

Rubio et al. (1983) reported a 5-year-old Cuban girl who presented with
umbilical bleeding after birth, followed by easy bruising and bleeding
tendency throughout her life. Laboratory studies showed prolonged
prothrombin and partial thromboplastin times. Prothrombin activity was
less than 10% of normal, but immunologic studies showed about 50%
protein levels. Family studies showed that the father had approximately
50% prothrombin activity and antigen, whereas the mother had 45%
prothrombin activity and almost 100% prothrombin antigen. Rubio et al.
(1983) concluded that the girl was compound heterozygous for a true
prothrombin deficiency allele inherited from the father and for an
abnormal dysprothrombinemia allele inherited from the mother. The
hypoprothrombinemia allele was called prothrombin Habana.

Rocha et al. (1986) reported a 21-year-old Spanish man, born of
consanguineous parents, who presented simultaneously with hemarthrosis
of the left knee and an extensive hematoma following a minor trauma.
Prothrombin time and activated partial thromboplastin time were
prolonged. Prothrombin activity was very low (range 7 to 23% by various
methods), whereas antigen levels were low-normal (64%), consistent with
dysprothrombinemia. Both parents had about 50% reduced prothrombin
activity. The variant, which showed an abnormal band on immunodiffusion,
was termed prothrombin Segovia. Rocha et al. (1986) stated that only 15
families with structural abnormalities of prothrombin had been
described.

Dumont et al. (1987) described a newborn girl with congenital
dysprothrombinemia who presented severe bleeding from the second day of
life. Routine coagulation tests showed very prolonged prothrombin time
and activated partial thromboplastin time, with prothrombin activity
ranging from 2 to 35%. The prothrombin antigen level was 47% and showed
abnormal migration on immunoelectrophoresis. Tests of thrombin
generation showed that the abnormal prothrombin was slowly and
incompletely activated. Family studies showed both the abnormal and
normal prothrombin in the father, mother, and brother. The proposita was
thought to be homozygous for a 'lazy' dysprothrombin, termed prothrombin
Poissy.

Lutze et al. (1989) described a family in which 7 members in 3
generations had an abnormal prothrombin. Five of the 7 persons had a
slightly increased bleeding tendency manifested especially in more
marked or prolonged posttraumatic and postoperative bleeding. Laboratory
studies showed decreased clotting activity compared to antigen levels.
The variant was referred to as prothrombin Magdeburg.

BIOCHEMICAL FEATURES

Shapiro et al. (1969) reported a large kindred in which 11 individuals
had normal immunoreactive prothrombin antigen, but half-normal biologic
prothrombin activity, consistent with dysprothrombinemia. They referred
to the defective molecule as prothrombin Cardeza.

Shapiro et al. (1974) discussed 3 prothrombin variants--Barcelona
(176930.0002), Cardeza, and San Juan. They presented evidence that San
Juan is in fact an example of a genetic compound, i.e., the parents were
heterozygous for different prothrombin variants. Prothrombin Barcelona
appeared to be an example of mutation at the cleavage site between the
'pro' and 'thrombin' parts of the molecule (Rabiet et al., 1979).

In an editorial on variants of vitamin K-dependent coagulation factors,
Bertina et al. (1979) stated that 9 defective variants of factor II
(F2), 5 variants of factor X (F10; 613872), and many variants of factor
IX (F9; 300746) had been identified.

Board et al. (1982) referenced the functionally abnormal prothrombins
that had been reported, noting that functional abnormality was more
likely to occur with a mutation affecting the enzymatically active part
of the molecule or at sites where activated factor X either splits off
the initial profragment or activates the thrombin molecule.

Inomoto et al. (1987) stated that only 16 prothrombin variants leading
to congenital dysprothrombinemia had been reported. All
dysprothrombinemia variants were characterized by a decrease in the
functional level of prothrombin relative to the antigenic level of
prothrombin. Five of the prothrombin variants had been purified and
characterized. Prothrombin Barcelona (176930.0002) and prothrombin
Madrid were found to have specific impairment of 1 of the 2 factor
Xa-catalyzed cleavages, whereas prothrombin Quick (176930.0004;
176930.0005), prothrombin Metz, and prothrombin Salakta had a defect
confined to the thrombin portion of the molecule. Inomoto et al. (1987)
described the first case of dysprothrombinemia in Japan; the prothrombin
variant Tokushima (176930.0003) also had a defect in the thrombin
portion. The patient was a compound heterozygote; the mother had a
dysprothrombinemia allele and the father had a hypoprothrombinemia
allele (176930.0008).

Valls-de-Ruiz et al. (1987) described a Mexican Mestizo family in which
a mother and all 3 of her children had a functionally normal but
structurally abnormal prothrombin variant, termed 'Mexico City.'
Laboratory studies showed an abnormal cleavage of the prothrombin
molecule by factor Xa, despite a functionally normal thrombin molecule.
The family also had multiple exostoses (133700), which was molecularly
unrelated to the prothrombin variant.

INHERITANCE

Josso et al. (1962) reported 2 affected offspring with
hypoprothrombinemia who were born of first-cousins, suggesting autosomal
recessive inheritance.

MOLECULAR GENETICS

In affected members of a family with congenital prothrombin deficiency,
Poort et al. (1994) identified a homozygous mutation in the F2 gene
(Y44C; 176930.0014).

The allelic variants causing dysprothrombinemia are usually indicated
according to the city or area where they were described for the first
time: see, e.g., prothrombin Barcelona (176930.0002) and prothrombin
Tokushima (176930.0003). The abnormalities are usually caused by a
defect in activation of the protease, such as prothrombin Barcelona, or
a defect in the protease itself, such as prothrombin Quick (176930.0004;
176930.0005) and prothrombin Tokushima (reviews by Girolami et al., 1998
and Lancellotti and De Cristofaro, 2009).

Montgomery et al. (1980) described a form of dysprothrombinemia that
they referred to as prothrombin Denver. The proband had a severe
hemophilia-like bleeding disorder treated with weekly prophylactic
factor replacement. Lefkowitz et al. (2000) found that the patient was a
compound heterozygote for 2 mutations in the F2 gene: glu300-to-lys
(E300K; 176930.0010 and E309K; 176930.0011).

In an Iranian girl with a mild form of dysprothrombinemia characterized
sporadic ecchymosis and 1 episode of buttock hematoma following a major
trauma, Akhavan et al. (2000) identified a homozygous substitution in
the prothrombin gene (R382H; 176930.0012).

*FIELD* SA
Girolami (1971); Girolami et al. (1974); Iwahana et al. (1992); Iwahana
et al. (1992); Josso et al. (1971); Josso et al. (1982); Kattlove
et al. (1970); Meeks and Abshire (2008); Morishita et al. (1992);
Owen et al. (1978); Pool et al. (1962); Quick et al. (1955); Rabiet
et al. (1984); Segal et al. (2009); Shirakami and Kawauchi (1984);
Shirakami et al. (1983); Smith et al. (1981); Van Creveld (1954);
Weinger et al. (1980)
*FIELD* RF
1. Akhavan, S.; Mannucci, P. M.; Lak, M.; Mancuso, G.; Mazzucconi,
M. G.; Rocino, A.; Jenkins, P. V.; Perkins, S. J.: Identification
and three-dimensional structural analysis of nine novel mutations
in patients with prothrombin deficiency. Thromb. Haemost. 84: 989-997,
2000.

2. Bertina, R. M.; Briet, E.; Veltkamp, J. J.: Variants of vitamin
K dependent coagulation factors. (Editorial) Acta Haemat. 62: 1-3,
1979.

3. Board, P. G.; Coggan, M.; Pidcock, M. E.: Genetic heterogeneity
of human prothrombin (FII). Ann. Hum. Genet. 46: 1-9, 1982.

4. Dumont, M.-D.; Tapon-Bretaudiere, J.; Fischer, A.-M.; Bros, A.;
Chassevent, J.; Aufeuvre, J.-P.: Prothrombin Poissy: a new variant
of human prothrombin. Brit. J. Haemat. 66: 239-243, 1987.

5. Girolami, A.: The hereditary transmission of congenital 'true'
hypoprothrombinaemia. Brit. J. Haemat. 21: 695-704, 1971.

6. Girolami, A.; Bareggi, G.; Brunetti, A.; Sticchi, A.: Prothrombin
Padua: a new congenital dysprothrombinemia. J. Lab. Clin. Med. 84:
654-666, 1974.

7. Girolami, A.; Scarano, L.; Saggiorato, G.; Girolami, B.; Bertomoro,
A.; Marchiori, A.: Congenital deficiencies and abnormalities of prothrombin. Blood
Coagul. Fibrinolysis 9: 557-569, 1998.

8. Inomoto, T.; Shirakami, A.; Kawauchi, S.; Shigekiyo, T.; Saito,
S.; Miyoshi, K.; Morita, T.; Iwanaga, S.: Prothrombin Tokushima:
characterization of dysfunctional thrombin derived from a variant
of human prothrombin. Blood 69: 565-569, 1987.

9. Iwahana, H.; Yoshimoto, K.; Shigekiyo, T.; Shirakami, A.; Saito,
S.; Itakura, M.: Molecular and genetic analysis of a compound heterozygote
for dysprothrombinemia of prothrombin Tokushima and hypoprothrombinemia. Am.
J. Hum. Genet. 51: 1386-1395, 1992.

10. Iwahana, H.; Yoshimoto, K.; Shigekiyo, T.; Shirakami, A.; Saito,
S.; Itakura, M.: Detection of a single base substitution of the gene
for prothrombin Tokushima: the application of PCR-SSCP for the genetic
and molecular analysis of dysprothrombinemia. Int. J. Hemat. 55:
93-100, 1992.

11. Josso, F.; Monasterio De Sanchez, J.; Lavergne, J. M.; Menache,
D.; Soulier, J. P.: Congenital abnormality of the prothrombin molecule
(factor II) in four siblings: prothrombin Barcelona. Blood 38: 9-16,
1971.

12. Josso, F.; Rio, Y.; Beguin, S.: A new variant of human prothrombin:
prothrombin Metz, demonstration in a family showing double heterozygosity
for congenital hypoprothrombinemia and dysprothrombinemia. Haemostasis 12:
309-316, 1982.

13. Josso, P.; Prou-Wartelle, O.; Soulier, J.-P.: Etude d'un cas
d'hypoprothrombinemie congenitale. Nouv. Rev. Franc. Hemat. 2: 647-672,
1962.

14. Kattlove, H. E.; Shapiro, S. S.; Spivack, M.: Hereditary prothrombin
deficiency. New Eng. J. Med. 282: 57-61, 1970.

15. Lancellotti, S.; De Cristofaro, R.: Congenital prothrombin deficiency. Semin.
Thromb. Hemost. 35: 367-381, 2009.

16. Lanchantin, G. F.; Hart, D. W.; Friedmann, J. A.; Saavedra, N.
V.; Mehl, J. W.: Amino acid composition of human plasma prothrombin. J.
Biol. Chem. 243: 5479-5485, 1968.

17. Lefkowitz, J. B.; Haver, T.; Clarke, S.; Jacobson, L.; Weller,
A.; Nuss, R.; Manco-Johnson, M.; Hathaway, W. E.: The prothrombin
Denver patient has two different prothrombin point mutations resulting
in glu300-to-lys and glu309-to-lys substitutions. Brit. J. Haemat. 108:
182-187, 2000.

18. Lutze, G.; Frick, U.; Topfer, G.; Urbahn, H.: Hereditaere Dysprothrombinaemie
mit geringer Blutungsneigung (Prothrombin Magdeburg). Dtsch. Med.
Wschr. 114: 288-292, 1989.

19. Meeks, S. L.; Abshire, T. C.: Abnormalities of prothrombin: a
review of the pathophysiology, diagnosis, and treatment. Haemophilia 14:
1159-1163, 2008.

20. Montgomery, R. R.; Corrigan, J. J.; Clarke, S.; Johnson, J.:
Prothrombin Denver: a new dysprothrombinemia. (Abstract) Circulation 62
(suppl. III): 279 only, 1980.

21. Morishita, E.; Saito, M.; Kumabashiri, I.; Asakura, H.; Matsuda,
T.; Yamaguchi, K.: Prothrombin Himi: a compound heterozygote for
two dysfunctional prothrombin molecules (met-337-to-thr and arg-388-to-his). Blood 80:
2275-2280, 1992.

22. Owen, C. A., Jr.; Henriksen, R. A.; McDuffie, F. C.; Mann, K.
G.: Prothrombin Quick: a newly identified dysprothrombinemia. Mayo
Clin. Proc. 53: 29-33, 1978.

23. Pool, J. G.; Desai, R.; Kropatkin, M. L.: Severe congenital hypoprothrombinemia
in a Negro boy. Thromb. Diath. Haemorrh. 8: 235-240, 1962.

24. Poort, S. R.; Michiels, J. J.; Reitsma, P. H.; Bertina, R. M.
: Homozygosity for a novel missense mutation in the prothrombin gene
causing a severe bleeding disorder. Thromb. Haemost. 72: 819-824,
1994.

25. Quick, A. J.; Hussey, C. V.: Hereditary hypoprothrombinemias. Lancet 279:
173-177, 1962. Note: Originally Volume 1.

26. Quick, A. J.; Pisciotta, A. V.; Hussey, C. V.: Congenital hypoprothrombinemic
states. Arch. Intern. Med. 95: 2-14, 1955.

27. Rabiet, M.-J.; Elion, J.; Benarous, R.; Labie, D.; Josso, F.:
Activation of prothrombin Barcelona: evidence for active high molecular
weight intermediates. Biochim. Biophys. Acta 584: 66-75, 1979.

28. Rabiet, M. J.; Jandrot-Perrus, M.; Boissel, J. P.; Elion, J.;
Josso, F.: Thrombin Metz: characterization of the dysfunctional thrombin
derived from a variant of human prothrombin. Blood 63: 927-934,
1984.

29. Rocha, E.; Paramo, J. A.; Bascones, C.; Fisac, P. R.; Cuesta,
B.; Fernandez, J.: Prothrombin Segovia: a new congenital abnormality
of prothrombin. Scand. J. Haemat. 36: 444-449, 1986.

30. Rubio, R.; Almagro, D.; Cruz, A.; Corral, J. F.: Prothrombin
Habana: a new dysfunctional molecule of human prothrombin associated
with a true prothrombin deficiency. Brit. J. Haemat. 54: 553-560,
1983.

31. Segal, J. B.; Brotman, D. J.; Necochea, A. J.; Emadi, A.; Samal,
L.; Wilson, L. M.; Crim, M. T.; Bass, E. B.: Predictive value of
factor V Leiden and prothrombin G20210A in adults with venous thromboembolism
and in family members of those with a mutation: a systematic review. JAMA 301:
2472-2485, 2009.

32. Shapiro, S. S.; Maldonado, N. I.; Fradera, J.; McCord, S.: Prothrombin
San Juan: a complex new dysprothrombinemia. (Abstract) J. Clin. Invest. 53:
73A only, 1974.

33. Shapiro, S. S.; Martinez, J.; Holburn, R. R.: Congenital dysprothrombinemia:
an inherited structural disorder of human prothrombin. J. Clin. Invest. 48:
2251-2259, 1969.

34. Shirakami, A.; Kawauchi, S.: Congenital dysprothrombinemia. Acta
Haemat. Jpn. 47: 1697-1704, 1984.

35. Shirakami, A.; Kawauchi, S.; Shigekiyo, T.; Ono, H.; Kataoka,
K.; Miyoshi, K.; Yura, Y.: Prothrombin Tokushima: a family with heterozygosity
for dysprothrombin and hypoprothrombin. (Abstract) Acta Haemat. Jpn. 46:
589 only, 1983.

36. Smith, L. G.; Coone, L. A. H.; Kitchens, C. S.: Prothrombin Gainesville:
a dysprothrombinemia in a pair of identical twins. Am. J. Hemat. 11:
223-231, 1981.

37. Valls-de-Ruiz, M.; Ruiz-Arguelles, A.; Ruiz-Arguelles, G. J.;
Ambriz, R.: Prothrombin 'Mexico City,' an asymptomatic autosomal
dominant prothrombin variant. Am. J. Hemat. 24: 229-240, 1987.

38. Van Creveld, S.: Congenital idiopathic hypoprothrombinemia. Acta
Paediat. Suppl. 43: 245-255, 1954.

39. Weinger, R. S.; Rudy, C.; Moake, J. L.; Olson, J. D.; Cimo, P.
L.: Prothrombin Houston: a dysprothrombin identifiable by crossed
immunoelectrofocusing and abnormal Echis carinatus venom activation. Blood 55:
811-816, 1980.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Nose];
Epistaxis;
[Mouth];
Gingival bleeding

GENITOURINARY:
[Internal genitalia, female];
Menorrhagia

ABDOMEN:
[Gastrointestinal];
Gastrointestinal bleeding

SKELETAL:
Hemarthroses

SKIN, NAILS, HAIR:
[Skin];
Ecchymosis;
Easy bruising

MUSCLE, SOFT TISSUE:
Hematomas;
Umbilical cord hemorrhage

NEUROLOGIC:
[Central nervous system];
Intracranial bleeding

HEMATOLOGY:
Bleeding tendency due to defect in prothrombin and inability to form
fibrin clot;
Prolonged bleeding time;
Prolonged prothrombin time;
Prolonged activated partial thromboplastin time;
Decreased F2 antigen levels (in some patients);
Decreased F2 activity

MISCELLANEOUS:
Onset at birth;
Prevalence of true hypoprothrombinemia is 1 in 2 million;
Variable severity;
Bleeding after trauma or surgery;
Some heterozygous carriers may have mild manifestations

MOLECULAR BASIS:
Caused by mutation in the coagulation factor II gene (F2, 176930.0001)

*FIELD* CD
Cassandra L. Kniffin: 1/3/2011

*FIELD* ED
joanna: 11/30/2012
joanna: 7/17/2012
ckniffin: 1/3/2011

*FIELD* CD
Cassandra L. Kniffin: 12/27/2010

*FIELD* ED
carol: 04/08/2011
terry: 2/28/2011
carol: 1/4/2011
ckniffin: 1/3/2011

MIM 614390
*RECORD*
*FIELD* NO
614390
*FIELD* TI
#614390 PREGNANCY LOSS, RECURRENT, SUSCEPTIBILITY TO, 2; RPRGL2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moresusceptibility to recurrent pregnancy loss can be caused by mutation in
the coagulation factor II gene (F2; 176930) on chromosome 11p11-q12.

For a discussion of genetic heterogeneity of susceptibility to recurrent
pregnancy loss, see RPRGL1 (614389).

DESCRIPTION

Miscarriage, the commonest complication of pregnancy, is the spontaneous
loss of a pregnancy before the fetus has reached viability. The term
therefore includes all pregnancy losses from the time of conception
until 24 weeks of gestation. Recurrent miscarriage, defined as 3 or more
consecutive pregnancy losses, affects about 1% of couples; when defined
as 2 or more losses, the scale of the problem increases to 5% of all
couples trying to conceive (summary by Rai and Regan, 2006).

Pregnancy losses have traditionally been designated 'spontaneous
abortions' if they occur before 20 weeks' gestation and 'stillbirths' if
they occur after 20 weeks. Subtypes of spontaneous abortions can be
further distinguished on the basis of embryonic development and include
anembryonic loss in the first 5 weeks after conception (so-called
'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal
loss from 10 weeks' gestation through the remainder of the pregnancy.
These distinctions are important because the causes of pregnancy loss
vary over gestational ages, with anembryonic losses being more likely to
be associated with chromosomal abnormalities, for example. Possible
etiologies for recurrent pregnancy loss include uterine anatomic
abnormalities, cytogenetic abnormalities in the parents or fetus, single
gene disorders, thrombophilic conditions, and immunologic or endocrine
factors as well as environmental or infectious agents (summary by Warren
and Silver, 2008).

MOLECULAR GENETICS

Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or
more consecutive spontaneous abortions compared to 128 women without
miscarriage and found that heterozygosity for the 20210G-A mutation of
prothrombin was more common in patients with abortions in the first
trimester (p = 0.027; odds ratio, 8.5). None of the patients had
deficiencies of antithrombin, protein C, or protein S. Patients with
elevated anticardiolipin antibodies were considered to have the
antiphospholipid syndrome (107320) and were excluded from the study;
patients with chromosomal abnormalities were also excluded. No
relationship to recurrent spontaneous abortion was found with mutations
in the other clotting factors studied, including factor V Leiden
(612309.0001), the 677C-T mutation of MTHFR (607093.0003), the 1565C-T
polymorphism of GP3A (173470.0006), and the -455G-A polymorphism of the
FGB gene (134830.0008). Pihusch et al. (2001) noted that the prothrombin
20210G-A mutation causes only a moderately thrombophilic state, and in
contrast to factor V Leiden, it is associated with problems of both the
venous and arterial systems. In this respect, the 20210G-A mutation may
resemble the antiphospholipid syndrome, which has been well documented
to cause abortions as well as arterial and venous thromboses.
Furthermore, in addition to fibrin generation, thrombin also activates
tissue components represented in the placenta and induces cellular
responses. Increased prothrombin levels may affect placental function by
influencing pivotal mechanisms such as cell adhesion, smooth muscle
proliferation, and vasculogenesis.

*FIELD* RF
1. Pihusch, R.; Buchholz, T.; Lohse, P.; Rubsamen, H.; Rogenhofer,
N.; Hasbargen, U.; Hiller, E.; Thaler, C. J.: Thrombophilic gene
mutations and recurrent spontaneous abortion: prothrombin mutation
increases the risk in the first trimester. Am. J. Reprod. Immunol. 46:
124-131, 2001.

2. Rai, R.; Regan, L.: Recurrent miscarriage. Lancet 368: 601-611,
2006.

3. Warren, J. E.; Silver, R. M.: Genetics of pregnancy loss. Clin.
Obstet. Gynec. 51: 84-95, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GENITOURINARY:
[Internal genitalia, female];
Spontaneous abortion, recurrent

MOLECULAR BASIS:
Caused by mutation in the coagulation factor II gene (F2, 176930.0009)

*FIELD* CD
Marla J. F. O'Neill: 12/13/2011

*FIELD* ED
joanna: 10/03/2013
joanna: 12/13/2011

*FIELD* CD
Marla J. F. O'Neill: 12/12/2011

*FIELD* ED
terry: 05/07/2012
joanna: 2/23/2012
alopez: 12/13/2011

RBCC Red Blood Cell Collection

Full text data of F2