Factor IX (or Christmas factor) (EC 220.127.116.11) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.
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: 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 the 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. Formulations include:
- nonacog alfa (trade name BeneFix)
- albutrepenonacog alfa (trade name Idelvion)
- eftrenonacog alfa (trade name Alprolix)
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.
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- "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
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- Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (Feb 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". The Journal of Biological Chemistry. 277 (5): 3622–31. doi:10.1074/jbc.M111202200. PMID 11723140.
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- Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (Oct 1995). "X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9796–800. doi:10.1073/pnas.92.21.9796. PMC 40889. PMID 7568220.
- Freedman SJ, Furie BC, Furie B, Baleja JD (Sep 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.
- Zögg T, Brandstetter H (Dec 2009). "Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa". Structure. 17 (12): 1669–78. doi:10.1016/j.str.2009.10.011. PMID 20004170.
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- "Home: BeneFIX Coagulation Factor IX (Recombinant) Official Site".
- EMA: Idelvion
- "Home: Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] Official Site".
- Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (Oct 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". The New England Journal of Medicine. 361 (17): 1671–5. doi:10.1056/NEJMoa0904377. PMID 19846852.
- Rossi M, Jayaram R, Sayeed R (Sep 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interactive Cardiovascular and Thoracic Surgery. 13 (3): 320–31. doi:10.1510/icvts.2011.272401. PMID 21712351.
- "Home: Factor IX Mutation Database".
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- Sommer SS (Jul 1992). "Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene". FASEB Journal. 6 (10): 2767–74. PMID 1634040.
- Lenting PJ, van Mourik JA, Mertens K (Dec 1998). "The life cycle of coagulation factor VIII in view of its structure and function". Blood. 92 (11): 3983–96. PMID 9834200.
- Lowe GD (Dec 2001). "Factor IX and thrombosis". British Journal of Haematology. 115 (3): 507–13. doi:10.1046/j.1365-2141.2001.03186.x. PMID 11736930.
- O'Connell NM (Jun 2003). "Factor XI deficiency--from molecular genetics to clinical management". Blood Coagulation & Fibrinolysis. 14 Suppl 1: S59–64. doi:10.1097/00001721-200306001-00014. PMID 14567539.
- Du X (May 2007). "Signaling and regulation of the platelet glycoprotein Ib-IX-V complex". Current Opinion in Hematology. 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
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