Biology:Factor IX

From HandWiki
Short description: Protein involved in blood clotting in humans

Template:Cs1 config

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Factor IX (or Christmas factor) (EC 3.4.21.22) 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.[1]

Coagulation factor IX is on the World Health Organization's List of Essential Medicines.[2]

Physiology

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.[3][4] 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.[3]

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.[5]

Domain architecture

Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.[6] 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.

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.[6] 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.[7]

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.[8] The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.[9]

Several structures of 'super active' mutants have been solved,[10] which reveal the nature of factor IX activation by other proteins in the clotting cascade.

Genetics

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

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. At least 534 disease-causing mutations in this gene have been discovered.[11] The F9 gene was first cloned in 1982 by Kotoku Kurachi and Earl Davie.[12]

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.[13]

Role in disease

Deficiency of factor IX causes Christmas disease (hemophilia B).[1] Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;[14] 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.[15] Recombinant factor IX is used to treat Christmas disease. Formulations include:

  • nonacog alfa (brand name BeneFix)[16]
  • albutrepenonacog alfa (brand name Idelvion)[17]
  • eftrenonacog alfa (brand name Alprolix)[18]
  • nonacog beta pegol (brand name Refixia)[19]

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.[20]

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.[21]

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.[22]

Coagulation factor IX is on the World Health Organization's List of Essential Medicines.[2]

References

  1. ↑ 1.0 1.1 "Christmas disease: a condition previously mistaken for haemophilia". British Medical Journal 2 (4799): 1378–82. Dec 1952. doi:10.1136/bmj.2.4799.1378. PMID 12997790. 
  2. ↑ 2.0 2.1 World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  3. ↑ 3.0 3.1 "Activation of human factor IX (Christmas factor)". The Journal of Clinical Investigation 61 (6): 1528–38. Jun 1978. doi:10.1172/JCI109073. PMID 659613. 
  4. ↑ "Factor IX of the blood coagulation system: a review". Biochemistry. Biokhimiia 62 (7): 685–93. Jul 1997. PMID 9331959. 
  5. ↑ "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood 86 (6): 2198–205. Sep 1995. doi:10.1182/blood.V86.6.2198.bloodjournal8662198. PMID 7662969. 
  6. ↑ 6.0 6.1 "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. Feb 2002. doi:10.1074/jbc.M111202200. PMID 11723140. 
  7. ↑ "The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex". The Journal of Biological Chemistry 277 (8): 5734–41. Feb 2002. doi:10.1074/jbc.M107753200. PMID 11714704. 
  8. ↑ "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. Oct 1995. doi:10.1073/pnas.92.21.9796. PMID 7568220. Bibcode: 1995PNAS...92.9796B. 
  9. ↑ "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry 34 (38): 12126–37. Sep 1995. doi:10.1021/bi00038a005. PMID 7547952. 
  10. ↑ "Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa". Structure 17 (12): 1669–78. Dec 2009. doi:10.1016/j.str.2009.10.011. PMID 20004170. 
  11. ↑ "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports 9 (1): 18577. December 2019. doi:10.1038/s41598-019-54976-4. PMID 31819097. Bibcode: 2019NatSR...918577S. 
  12. ↑ "Isolation and characterization of a cDNA coding for human factor IX". Proceedings of the National Academy of Sciences of the United States of America 79 (21): 6461–4. Nov 1982. doi:10.1073/pnas.79.21.6461. PMID 6959130. Bibcode: 1982PNAS...79.6461K. 
  13. ↑ Nicholl D. (2002). An Introduction to Genetic Engineering Second Edition. Cambridge University Press. p. 257. 
  14. ↑ Goodeve, A. C. (2015). "Hemophilia B: Molecular pathogenesis and mutation analysis". Journal of Thrombosis and Haemostasis 13 (7): 1184–1195. doi:10.1111/jth.12958. PMID 25851415. 
  15. ↑ "Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis". Thrombosis and Haemostasis 67 (1): 63–5. Jan 1992. doi:10.1055/s-0038-1648381. PMID 1615485. 
  16. ↑ "BeneFIX EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/benefix. 
  17. ↑ "Idelvion EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/idelvion. 
  18. ↑ "Alprolix EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/alprolix. 
  19. ↑ "Refixia EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/refixia. 
  20. ↑ "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". The New England Journal of Medicine 361 (17): 1671–5. Oct 2009. doi:10.1056/NEJMoa0904377. PMID 19846852. 
  21. ↑ "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interactive Cardiovascular and Thoracic Surgery 13 (3): 320–31. Sep 2011. doi:10.1510/icvts.2011.272401. PMID 21712351. 
  22. ↑ "Home: EAHAD Factor 9 Gene Variant Database". https://f9-db.eahad.org/. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Factor_IX&oldid=3572849"