Factor IX

Factor IX (Template:EC number), also known as Christmas factor, 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.<ref name="PMD12997790">Template:Cite journal</ref> Coagulation factor IX is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref>

Physiology

File:Coagulation full.svg

The blood coagulation and Protein C pathway.

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.<ref name="pmid659613">Template:Cite journal</ref><ref name="pmid9331959">Template:Cite journal</ref> 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.<ref name="pmid659613" />

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.<ref name="pmid7662969">Template:Cite journal</ref>

Domain architecture

Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.<ref name="pmid11723140">Template:Cite journal</ref> 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.

File:Factor IX.png

Human factor IX protein domain architecture, where each protein domain is represented by a coloured box

The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor.<ref name="pmid11723140"/> 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.<ref name="pmid11714704">Template:Cite journal</ref>

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.<ref name="pmid7568220">Template:Cite journal</ref> The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.<ref name="pmid7547952">Template:Cite journal</ref>

Several structures of 'super active' mutants have been solved,<ref name="pmid20004170">Template:Cite journal</ref> which reveal the nature of factor IX activation by other proteins in the clotting cascade.

Genetics

File:F9 gene location.png

In human, the F9 gene is located on the X chromosome at position q27.1.

Because the gene for factor IX is located on the X chromosome (Xq27.1-q27.2), 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.<ref name = "Šimčíková_2019 - supplementary table S7">Template:Cite journal</ref> The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite book</ref>

Role in disease

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Deficiency of factor IX causes Christmas disease (hemophilia B).<ref name="PMD12997790" /> Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Recombinant factor IX is used to treat Christmas disease. Formulations include:

• nonacog alfa (brand name Benefix)<ref>{{#invoke:citation/CS1|citation

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• nonacog gamma (brand name Rixubis)<ref name="Rixubis EPAR" />
• albutrepenonacog alfa (brand name Idelvion)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• eftrenonacog alfa (brand name Alprolix)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• nonacog beta pegol (brand name Refixia)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• coagulation factor IX [recombinant] (Benefix)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• coagulation factor IX [recombinant] (Idelvion)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• coagulation factor IX (recombinant), Fc fusion protein (Alprolix)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• coagulation factor IX [recombinant] (Ixinity)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• coagulation factor IX [recombinant] (Rebinyn)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• coagulation factor IX [recombinant] (Rixubis)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• coagulation factor IX (human) (Alphanine SD)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

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.<ref name="pmid19846852">Template:Cite journal</ref>

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.<ref name="pmid21712351">Template:Cite journal</ref>

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.<ref name="urlHome: EAHAD Factor 9 Gene Variant Database">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Coagulation factor IX is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st" />

Further reading

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External links

• Template:PDBe-KB2
• GeneReviews/NCBI/NIH/UW entry on Hemophilia B
• The MEROPS online database for peptidases and their inhibitors: S01.214 Template:Webarchive