|Coagulation factor IX|
PDB rendering based on .
|Symbols||; FIX; HEMB; P19; PTC; THPH8|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Factor IX (or Christmas factor) (EC 126.96.36.199) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to hemophilia.
Factor IX is produced as a zymogen, an inactive precursor. It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa.
Factor IX expression increases with age in humans and mice. In mouse models mutations within the promoter region of factor IX have an age-dependent phenotype.
Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture. The factor IX protein is composed of four protein domains. These are the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.
The N-terminal EGF domain has been shown to at least in part be responsible for binding Tissue factor. Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the Factor X activating complex.
The structures of all four domains have been solved. A structure of the two EGF domains and trypsin like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.
Several structures of 'super active' mutants have been solved  which reveal the nature of Factor IX activation by other proteins in the clotting cascade.
The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie.
Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B). Over 100 mutations of factor IX have been described; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas' DNA, revealing a mutation which changed a cysteine to a serine. Recombinant factor IX is used to treat Christmas disease, and is commercially available as BeneFIX. Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis.
Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.
A list of all the mutations in Factor IX is compiled and maintained at the Factor IX mutation database maintained at the University College London.
- Biggs, R; Douglas, AS; MacFarlane, RG; Dacie, JV; Pitney, WR; Merskey, C.; O'Brien, J. R. (1952). "Christmas Disease". British Medical Journal 2 (4799): 1378–82. doi:10.1136/bmj.2.4799.1378. PMC 2022306. PMID 12997790.
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- Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (1995). "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood 86 (6): 2198–205. PMID 7662969.
- Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (February 2002). "The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor". J. Biol. Chem. 277 (5): 3622–31. doi:10.1074/jbc.M111202200. PMID 11723140.
- Wilkinson FH, Ahmad SS, Walsh PN (February 2002). "The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex". J. Biol. Chem. 277 (8): 5734–41. doi:10.1074/jbc.M107753200. PMID 11714704.
- Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (October 1995). "X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9796–800. doi:10.1073/pnas.92.21.9796. PMC 40889. PMID 7568220.
- Freedman SJ, Furie BC, Furie B, Baleja JD (September 1995). "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry 34 (38): 12126–37. doi:10.1021/bi00038a005. PMID 7547952.
- Zogg T, Brandstetter H, (2009). "Structural Basis of the Cofactor- and Substrate-Assisted Activation of Human Coagulation Factor Ixa". Structure 17 (12): 1669–1678. doi:10.1016/j.str.2009.10.011. PMID 20004170.
- Kurachi K, Davie E (1982). "Isolation and characterization of a cDNA coding for human factor IX". Proc Natl Acad Sci USA 79 (21): 6461–4. doi:10.1073/pnas.79.21.6461. PMC 347146. PMID 6959130.
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- Taylor, S. A.; Duffin, J.; Cameron, C.; Teitel, J.; Garvey, B.; Lillicrap, D. P. (1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): From clinical recognition to molecular pathogenesis". Thrombosis and haemostasis 67 (1): 63–65. PMID 1615485.
- "Home: BeneFIX Coagulation Factor IX (Recombinant) Official Site".
- Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (October 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". N. Engl. J. Med. 361 (17): 1671–5. doi:10.1056/NEJMoa0904377. PMID 19846852.
- Rossi M, Jayaram R, Sayeed R (September 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interact Cardiovasc Thorac Surg 13 (3): 320–31. doi:10.1510/icvts.2011.272401. PMID 21712351.
- "Home: Factor IX Mutation Database".
- Davie EW, Fujikawa K (1975). "Basic mechanisms in blood coagulation". Annu. Rev. Biochem. 44: 799–829. doi:10.1146/annurev.bi.44.070175.004055. PMID 237463.
- Sommer SS (1992). "Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene". FASEB J. 6 (10): 2767–74. PMID 1634040.
- Lenting PJ, van Mourik JA, Mertens K (1999). "The life cycle of coagulation factor VIII in view of its structure and function". Blood 92 (11): 3983–96. PMID 9834200.
- Lowe GD (2002). "Factor IX and thrombosis". Br. J. Haematol. 115 (3): 507–13. doi:10.1046/j.1365-2141.2001.03186.x. PMID 11736930.
- O'Connell NM (2004). "Factor XI deficiency--from molecular genetics to clinical management". Blood Coagul. Fibrinolysis. 14 Suppl 1: S59–64. PMID 14567539.
- Du X (2007). "Signaling and regulation of the platelet glycoprotein Ib-IX-V complex". Curr. Opin. Hematol. 14 (3): 262–9. doi:10.1097/MOH.0b013e3280dce51a. PMID 17414217.
- GeneReviews/NCBI/NIH/UW entry on Hemophilia B
- The MEROPS online database for peptidases and their inhibitors: S01.214
- An X(-mas) Factor that gets our vote- QUite Interesting PDB Structure article at PDBe