Factor IX


Factor IX is one of the serine proteases involved in coagulation; 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. Coagulation factor IX is on the World Health Organization's List of Essential Medicines.

Physiology

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 or factor VIIa 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 is inhibited by antithrombin.
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.

Domain architecture

, 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.
Image:Factor IX.png|thumb|Human factor IX protein domain architecture, where each protein domain is represented by a coloured box|400px|left
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-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.

Genetics

Because the gene for factor IX is located on the X chromosome, loss-of-function mutations thereof are X-linked recessive: males experience the disease phenotype much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered. The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.
Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997.

Role in disease

Deficiency of factor IX causes the blood clotting disorder haemophilia B. Named after Stephen Christmas, it is also known as Christmas disease.
Recombinant
  • nonacog alfa
  • nonacog gamma
  • albutrepenonacog alfa
  • eftrenonacog alfa
  • nonacog beta pegol
  • coagulation factor IX
  • coagulation factor IX
  • coagulation factor IX, Fc fusion protein
  • coagulation factor IX
  • coagulation factor IX
  • coagulation factor IX
  • coagulation factor IX
Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis. This gain of function mutation renders the protein hyperfunctional and is associated with familial early-onset thrombophilia.
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 by EAHAD.
Coagulation factor IX is on the World Health Organization's List of Essential Medicines.