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Gene Review

F9  -  coagulation factor IX

Homo sapiens

Synonyms: Christmas factor, Coagulation factor IX, FIX, HEMB, P19, ...
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Disease relevance of F9


High impact information on F9

  • Factor IX (Christmas factor), a vitamin K-dependent plasma protein made in the liver, functions in the middle phase of the intrinsic pathway of blood coagulation [5].
  • Infusion of recombinant activated human Factor VII (rhFVIIa), driving procoagulant reactions independently of human FVIII (hFVIII) or hFIX, has been successful in such patients and could in theory provide hemostasis in all hemophilia patients [6].
  • Human Factor IX (Christmas factor) was isolated from the plasma of a patient with mild hemophilia B [7].
  • Purification and characterization of an abnormal factor IX (Christmas factor) molecule. Factor IX Chapel Hill [7].
  • Statistical analysis of the pedigrees gave a maximum lod score of 3.10 at a recombination fraction of 0.11, demonstrating a linkage between a manic depressive locus and the F9 locus in the Xq27 region [8].

Chemical compound and disease context of F9


Biological context of F9

  • By scanning a total of 1.5 megabases of deep intronic regions of F9 in the genomic DNA from 84 individuals, 42 neutral polymorphisms were found in 23 haplotypes that differed by at least 11 mutations from the ancestral primate haplotype [1].
  • Human Factor IX (Christmas factor) is a single-chain plasma glycoprotein (mol wt 57,000) that participates in the middle phase of the intrinsic pathway of blood coagulation [12].
  • A cDNA library prepared from human liver has been screened for factor IX (Christmas factor), a clotting factor that participates in the middle phase of blood coagulation [13].
  • Administration of only 1 x 10(10) scAAV particles led to expression of hFIX at supraphysiologic levels (8I U/mL) and correction of the bleeding diathesis in FIX knock-out mice [14].
  • By comparison of this structure to that of the Gla domain bound to calcium ions, we localize the membrane binding site to a highly ordered structure including residues 1-11 of the Gla domain [15].

Anatomical context of F9

  • Our results suggest that factor IX Gla-domain mediated binding to endothelial cells/collagen IV plays a role in controlling factor IX concentration in the blood [16].
  • Portal vein injections of each vector alone, a combination of both vectors, or a hFIX control vector were performed in C57BL/6 mice [17].
  • Both proteins interact with membranes; TF is an integral membrane protein, while fVIIa binds reversibly to phospholipid surfaces via its Gla domain [18].
  • We established a cell line (hPTC) from the tissue of papillary thyroid cancer surgically excised from a 27-year-old female patient [19].
  • Consistent with this, binding of gla-domain-deleted FVIIa to hepatocytes was markedly diminished [20].

Associations of F9 with chemical compounds

  • One such antibody, 10C12, recognizes the calcium-stabilized form of the Gla domain of Factor IX [21].
  • Recombinant factor IX bound to factor XIa with a K(d) of 107 nm, whereas factor IX with a factor VII Gla domain (rFIX/VII-Gla) and factor IX expressed in the presence of warfarin (rFIX-desgamma) did not bind [22].
  • These results indicate that the NH2 terminus of the Gla domain, specifically including leucine 6 and phenylalanine 9 in the hydrophobic patch, is the contact surface on Factor IX that interacts with the phospholipid bilayer [15].
  • Lack of the gamma-carboxyglutamic acid (Gla)-domain (des-(1-38)-VIIa) resulted in a 10- to 30-fold increase of the Kd for the interaction, as did blocking the Gla-domain by Fab fragments of a specific monoclonal antibody [23].
  • These proteins present at their amino-terminal extremity a gamma-carboxyglutamic acid containing domain (Gla domain), followed by two epidermal growth factor-like (EGF1 and EGF2) domains, an activation peptide, and a serine protease domain [24].

Physical interactions of F9

  • The masking of the mutational effect by the presence of phospholipid shows a critical importance of Xa Gla-domain interactions in stabilizing the quaternary TF-VIIa-Xa-TFPI complex [25].
  • The endothelial PC receptor binds the Gla domain of PC and stimulates the activation [26].
  • The Gla domain is instrumental in the binding of protein S to phospholipid, whereas the thrombin-sensitive region and the first EGF-like domain may be directly involved in protein-protein interactions on the phospholipid surface [27].
  • This indicates that the N-terminal residues of the FVII Gla domain are important for the structural integrity of the peptide, and implicates the Gla domain per se in a direct interaction with phospholipid-bound FX [28].
  • A protein C chimera with the prothrombin Gla domain and aromatic stack failed to bind to EPCR detectably [29].

Regulatory relationships of F9

  • Enhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C [30].

Other interactions of F9

  • Reactions requiring all 4 contact phase factors, including PTA, such as surface-induced generation of plasmin activity (amidolysis of H-D-val-leu-lys-pNa) and activated Christmas factor (factor IXa) activity, were defective [31].
  • The study of this FX deficiency provides an "in vivo" and "in vitro" model for the investigation of Gla domain interactions [32].
  • The results of the NMR and SAXS measurements reported in this paper confirm our previous result that the Gla domain is folded also in its apo state when linked to the EGF domain [Sunnerhagen, M., et al. (1995) Nat. Struct. Biol. 2, 504-509] [33].
  • The protein exhibits a high-affinity calcium binding site in the first EGF-like domain, in addition to calcium binding in the Gla domain [34].
  • This contrasts with the paucity of markers (other than the fragile X locus) between the F9 gene in q27 and the G6PD cluster in q28, which are separated by about 30% recombination [35].

Analytical, diagnostic and therapeutic context of F9

  • For AAV-mediated hemophilia B (HB) gene therapy, we have overcome this obstacle by constructing a liver-restricted mini-human factor IX (hFIX) expression cassette that can be packaged as complementary dimers within individual AAV particles [14].
  • Carrier detection and prenatal diagnosis are possible by direct or indirect genetic analysis of the F8 or F9 genes [36].
  • Partial hepatectomy resulted in a 4- to 6-fold increase (P < 0.005) in serum hFIX of up to 350 ng/mL compared with the nonhepatectomized counterparts [4].
  • The protease from Russell's viper venom that activates factor X (Stuart factor), factor IX (Christmas factor), and protein C was purified by gel filtration on Sephadex G-150 and QAE-Sephadex A-50 column chromatography [37].
  • Site-directed mutagenesis of charged residue side chains in the VIIa Gla-domain identified Arg-36 as being important for macromolecular substrate docking [38].


  1. Mutations in the factor IX gene (F9) during the past 150 years have relative rates similar to ancient mutations. Feng, J., Drost, J.B., Scaringe, W.A., Liu, Q., Sommer, S.S. Hum. Mutat. (2002) [Pubmed]
  2. Linkage analysis of bipolar illness with X-chromosome DNA markers: a susceptibility gene in Xq27-q28 cannot be excluded. De bruyn, A., Raeymaekers, P., Mendelbaum, K., Sandkuijl, L.A., Raes, G., Delvenne, V., Hirsch, D., Staner, L., Mendlewicz, J., Van Broeckhoven, C. Am. J. Med. Genet. (1994) [Pubmed]
  3. Sequence analysis of a Molluscum contagiosum virus DNA region which includes the gene encoding protein kinase 2 and other genes with unique organization. Martin-Gallardo, A., Moratilla, M., Funes, J.M., Agromayor, M., Nuñez, A., Varas, A.J., Collado, M., Valencia, A., Lopez-Estebaranz, J.L., Esteban, M. Virus Genes (1996) [Pubmed]
  4. Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver. Park, F., Ohashi, K., Kay, M.A. Blood (2000) [Pubmed]
  5. Active gamma-carboxylated human factor IX expressed using recombinant DNA techniques. de la Salle, H., Altenburger, W., Elkaim, R., Dott, K., Dieterlé, A., Drillien, R., Cazenave, J.P., Tolstoshev, P., Lecocq, J.P. Nature (1985) [Pubmed]
  6. Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII. Margaritis, P., Arruda, V.R., Aljamali, M., Camire, R.M., Schlachterman, A., High, K.A. J. Clin. Invest. (2004) [Pubmed]
  7. Purification and characterization of an abnormal factor IX (Christmas factor) molecule. Factor IX Chapel Hill. Chung, K.S., Madar, D.A., Goldsmith, J.C., Kingdon, H.S., Roberts, H.R. J. Clin. Invest. (1978) [Pubmed]
  8. Polymorphic DNA marker on X chromosome and manic depression. Mendlewicz, J., Simon, P., Sevy, S., Charon, F., Brocas, H., Legros, S., Vassart, G. Lancet (1987) [Pubmed]
  9. Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency. Akhavan, S., Mannucci, P.M., Lak, M., Mancuso, G., Mazzucconi, M.G., Rocino, A., Jenkins, P.V., Perkins, S.J. Thromb. Haemost. (2000) [Pubmed]
  10. Crystal matrix protein--getting blood out of a stone. Stapleton, A.M., Ryall, R.L. Mineral and electrolyte metabolism. (1994) [Pubmed]
  11. Anticoagulant-induced pseudothrombocytopenia occurring after transcatheter arterial embolization for hepatocellular carcinoma. Yoshikawa, T., Nakanishi, K., Maruta, T., Takenaka, D., Hirota, S., Matsumoto, S., Saigo, K., Ohno, Y., Fujii, M., Sugimura, K. Jpn. J. Clin. Oncol. (2006) [Pubmed]
  12. Activation of human factor IX (Christmas factor). Di Scipio, R.G., Kurachi, K., Davie, E.W. J. Clin. Invest. (1978) [Pubmed]
  13. Isolation and characterization of a cDNA coding for human factor IX. Kurachi, K., Davie, E.W. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  14. Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Nathwani, A.C., Gray, J.T., Ng, C.Y., Zhou, J., Spence, Y., Waddington, S.N., Tuddenham, E.G., Kemball-Cook, G., McIntosh, J., Boon-Spijker, M., Mertens, K., Davidoff, A.M. Blood (2006) [Pubmed]
  15. Identification of the phospholipid binding site in the vitamin K-dependent blood coagulation protein factor IX. Freedman, S.J., Blostein, M.D., Baleja, J.D., Jacobs, M., Furie, B.C., Furie, B. J. Biol. Chem. (1996) [Pubmed]
  16. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Gui, T., Lin, H.F., Jin, D.Y., Hoffman, M., Straight, D.L., Roberts, H.R., Stafford, D.W. Blood (2002) [Pubmed]
  17. Coexpression of factor VIII heavy and light chain adeno-associated viral vectors produces biologically active protein. Burton, M., Nakai, H., Colosi, P., Cunningham, J., Mitchell, R., Couto, L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  18. Tissue factor positions and maintains the factor VIIa active site far above the membrane surface even in the absence of the factor VIIa Gla domain. A fluorescence resonance energy transfer study. McCallum, C.D., Su, B., Neuenschwander, P.F., Morrissey, J.H., Johnson, A.E. J. Biol. Chem. (1997) [Pubmed]
  19. Growth regulation of the human papillary thyroid cancer cell line by protein tyrosine kinase and cAMP-dependent protein kinase. Hishinuma, A., Yamanaka, T., Kasai, K., So, S., Bamba, N., Shimoda, S.I. Endocr. J. (1994) [Pubmed]
  20. Factor VIIa binding and internalization in hepatocytes. Hjortoe, G., Sorensen, B.B., Petersen, L.C., Rao, L.V. J. Thromb. Haemost. (2005) [Pubmed]
  21. Crystal structure of the calcium-stabilized human factor IX Gla domain bound to a conformation-specific anti-factor IX antibody. Huang, M., Furie, B.C., Furie, B. J. Biol. Chem. (2004) [Pubmed]
  22. The factor IX gamma-carboxyglutamic acid (Gla) domain is involved in interactions between factor IX and factor XIa. Aktimur, A., Gabriel, M.A., Gailani, D., Toomey, J.R. J. Biol. Chem. (2003) [Pubmed]
  23. Characterization of factor VII association with tissue factor in solution. High and low affinity calcium binding sites in factor VII contribute to functionally distinct interactions. Ruf, W., Kalnik, M.W., Lund-Hansen, T., Edgington, T.S. J. Biol. Chem. (1991) [Pubmed]
  24. Role of the Gla and first epidermal growth factor-like domains of factor X in the prothrombinase and tissue factor-factor VIIa complexes. Thiec, F., Cherel, G., Christophe, O.D. J. Biol. Chem. (2003) [Pubmed]
  25. The role of catalytic cleft and exosite residues of factor VIIa for complex formation with tissue factor pathway inhibitor. Iakhiaev, A., Ruf, W., Rao, L.V. Thromb. Haemost. (2001) [Pubmed]
  26. Molecular recognition in the protein C anticoagulant pathway. Dahlbäck, B., Villoutreix, B.O. J. Thromb. Haemost. (2003) [Pubmed]
  27. Characterization of functionally important domains in human vitamin K-dependent protein S using monoclonal antibodies. Dahlbäck, B., Hildebrand, B., Malm, J. J. Biol. Chem. (1990) [Pubmed]
  28. Synthesis and characterization of wild-type and variant gamma-carboxyglutamic acid-containing domains of factor VII. Martin, D.M., O'Brien, D.P., Tuddenham, E.G., Byfield, P.G. Biochemistry (1993) [Pubmed]
  29. The interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C. Regan, L.M., Mollica, J.S., Rezaie, A.R., Esmon, C.T. J. Biol. Chem. (1997) [Pubmed]
  30. Enhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C. Sun, Y.H., Tran, S., Norstrøm, E.A., Dahlbäck, B. J. Biol. Chem. (2004) [Pubmed]
  31. A unique precipitating autoantibody against plasma thromboplastin antecedent associated with multiple apparent plasma clotting factor deficiencies in a patient with systemic lupus erythematosus. Poon, M.C., Saito, H., Koopman, W.J. Blood (1984) [Pubmed]
  32. Reduced activation of the Gla19Ala FX variant via the extrinsic coagulation pathway results in symptomatic CRMred FX deficiency. Pinotti, M., Marchetti, G., Baroni, M., Cinotti, F., Morfini, M., Bernardi, F. Thromb. Haemost. (2002) [Pubmed]
  33. The relative orientation of Gla and EGF domains in coagulation factor X is altered by Ca2+ binding to the first EGF domain. A combined NMR-small angle X-ray scattering study. Sunnerhagen, M., Olah, G.A., Stenflo, J., Forsén, S., Drakenberg, T., Trewhella, J. Biochemistry (1996) [Pubmed]
  34. Sequence-specific 1H NMR assignments, secondary structure, and location of the calcium binding site in the first epidermal growth factor like domain of blood coagulation factor IX. Huang, L.H., Cheng, H., Pardi, A., Tam, J.P., Sweeney, W.V. Biochemistry (1991) [Pubmed]
  35. Multipoint genetic mapping of the Xq26-q28 region in families with fragile X mental retardation and in normal families reveals tight linkage of markers in q26-q27. Oberlé, I., Camerino, G., Wrogemann, K., Arveiler, B., Hanauer, A., Raimondi, E., Mandel, J.L. Hum. Genet. (1987) [Pubmed]
  36. Carrier detection and prenatal diagnosis of hemophilia in developing countries. Peyvandi, F. Semin. Thromb. Hemost. (2005) [Pubmed]
  37. Factor X activating enzyme from Russell's viper venom: isolation and characterization. Kisiel, W., Hermodson, M.A., Davie, E.W. Biochemistry (1976) [Pubmed]
  38. Importance of factor VIIa Gla-domain residue Arg-36 for recognition of the macromolecular substrate factor X Gla-domain. Ruf, W., Shobe, J., Rao, S.M., Dickinson, C.D., Olson, A., Edgington, T.S. Biochemistry (1999) [Pubmed]
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