Factor IX

Factor IX (or Christmas factor) is one of the is_associated_with::serine proteases of the is_associated_with::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 is_associated_with::Stephen Christmas was found to be lacking this exact factor, leading to is_associated_with::hemophilia.

Physiology


Factor IX is produced as a is_associated_with::zymogen, an inactive precursor. It is processed to remove the is_associated_with::signal peptide, glycosylated and then cleaved by is_associated_with::factor XIa (of the contact pathway) or is_associated_with::factor VIIa (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a is_associated_with::disulfide bridge. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one is_associated_with::arginine-is_associated_with::isoleucine bond in is_associated_with::factor X to form factor Xa.

Factor IX is inhibited by is_associated_with::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
Factors VII, IX, and X all play key roles in is_associated_with::blood coagulation and also share a common domain architecture. The factor IX protein is composed of four is_associated_with::protein domains: the is_associated_with::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 is_associated_with::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 is_associated_with::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
The is_associated_with::gene for factor IX is located on the is_associated_with::X chromosome (Xq27.1-q27.2) and is therefore is_associated_with::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.

Polly, a transgenic cloned is_associated_with::Poll Dorset sheep carrying the gene for factor IX, was produced by Dr is_associated_with::Ian Wilmut at the is_associated_with::Roslin Institute in 1997.

Role in disease
Deficiency of factor IX causes Christmas disease (is_associated_with::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 and Alprolix. Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as is_associated_with::deep vein thrombosis.

Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. is_associated_with::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.