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Factor IX

From Wikipedia, the free encyclopedia

F9
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesF9,F9 p22, FIX, HEMB, P19, PTC, THPH8, coagulation factor IX, Blood coagulation factor IX, Christmas Factor
External IDsOMIM:300746;MGI:88384;HomoloGene:106;GeneCards:F9;OMA:F9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2158

14071

Ensembl

ENSG00000101981

ENSMUSG00000031138

UniProt

P00740

P16294

RefSeq (mRNA)

NM_000133
NM_001313913

NM_007979
NM_001305797

RefSeq (protein)

NP_000124
NP_001300842

NP_001292726
NP_032005

Location (UCSC)Chr X: 139.53 – 139.56 MbChr X: 59.04 – 59.08 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Factor IX(EC3.4.21.22), also known asChristmas factor,is one of theserine proteasesinvolved incoagulation;it belongs to peptidase family S1. Deficiency of this protein causeshaemophilia B.

It was discovered in 1952 after a young boy namedStephen Christmaswas found to be lacking this exact factor, leading tohaemophilia.[5]Coagulation factor IX is on theWorld Health Organization's List of Essential Medicines.[6]

Physiology

[edit]
The blood coagulation andProtein Cpathway.

Factor IX is produced as azymogen,an inactive precursor. It is processed to remove thesignal peptide,glycosylatedand then cleaved byfactor XIa(of the contact pathway) orfactor VIIa(of the tissue factor pathway) to produce a two-chain form, where the chains are linked by adisulfide bridge.[7][8]When activated intofactor IXa,in the presence of Ca2+,membrane phospholipids, and a Factor VIII cofactor, it hydrolyses onearginine-isoleucinebond infactor Xto form factor Xa.

Factor IX is inhibited byantithrombin.[7]

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.[9]

Domain architecture

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Factors VII,IX, andXall play key roles inblood coagulationand also share a common domain architecture.[10]The factor IX protein is composed of fourprotein domains:theGla domain,two tandem copies of theEGF domainand a C-terminaltrypsin-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 bindingtissue factor.[10]Wilkinsonet al.conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.[11]

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.[12]The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined byNMR.[13]

Several structures of 'super active' mutants have been solved,[14]which reveal the nature of factor IX activation by other proteins in the clotting cascade.

Genetics

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In human, the F9 gene is located on theX chromosomeat position q27.1.

Because thegenefor factor IX is located on theX chromosome(Xq27.1-q27.2), loss-of-function mutations thereof areX-linked recessive:males experience the disease phenotype much more frequently than females. At least 534 disease-causing mutations in this gene have been discovered.[15]The F9 gene was first cloned in 1982 by Kotoku Kurachi andEarl Davie.[16]

Polly,a transgenic clonedPoll Dorsetsheep carrying the gene for factor IX, was produced by DrIan Wilmutat theRoslin Institutein 1997.[17]

Role in disease

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See also:Prothrombin complex concentrate

Factor IX
INN:nonacog alfa
Clinical data
Trade namesBenefix
License data
ATC code
  • None
Legal status
Legal status
  • AU:S4(Prescription only)
Factor IX
INN:nonacog gamma
Clinical data
Trade namesRixubis
Routes of
administration		Intravenous
ATC code
  • None
Legal status
Legal status
Factor IX
INN:albutrepenonacog alfa
Clinical data
Trade namesIdelvion
License data
ATC code
  • None
Legal status
Legal status
Factor IX
INN:eftrenonacog alfa
Clinical data
Trade namesAlprolix
License data
ATC code
  • None
Legal status
Legal status
  • AU:S4(Prescription only)
  • EU:Rx-only[20]
Factor IX
INN:nonacog beta pegol
Clinical data
Trade namesRefixia
ATC code
  • None
Legal status
Legal status

Deficiency of factor IX causes Christmas disease (hemophilia B).[5]Over 3000 variants of factor IX have been described, affecting 73% of the 461 residues;[22]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.[23] Recombinantfactor IX is used to treat Christmas disease. Formulations include:

  • nonacog alfa (brand name Benefix)[24]
  • nonacog gamma (brand name Rixubis)[18]
  • albutrepenonacog alfa (brand name Idelvion)[25]
  • eftrenonacog alfa (brand name Alprolix)[26]
  • nonacog beta pegol (brand name Refixia)[27]
  • coagulation factor IX [recombinant] (Benefix)[28]
  • coagulation factor IX [recombinant] (Idelvion)[29]
  • coagulation factor IX (recombinant), Fc fusion protein (Alprolix)[30]
  • coagulation factor IX [recombinant] (Ixinity)[31][32]
  • coagulation factor IX [recombinant] (Rebinyn)[33]
  • coagulation factor IX [recombinant] (Rixubis)[34]
  • coagulation factor IX (human) (Alphanine SD)[35]

Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such asdeep vein thrombosis.Thisgain of functionmutation renders the protein hyperfunctional and is associated with familial early-onset thrombophilia.[36]

Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors.Tranexamic acidmay be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.[37]

A list of all the mutations in Factor IX is compiled and maintained by EAHAD.[38]

Coagulation factor IX is on theWorld Health Organization's List of Essential Medicines.[6]

References

[edit]
  1. ^abcGRCh38: Ensembl release 89: ENSG00000101981–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000031138–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abBiggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR (Dec 1952)."Christmas disease: a condition previously mistaken for haemophilia".British Medical Journal.2(4799): 1378–82.doi:10.1136/bmj.2.4799.1378.PMC2022306.PMID12997790.
  6. ^abWorld Health Organization(2019).World Health Organization model list of essential medicines: 21st list 2019.Geneva: World Health Organization.hdl:10665/325771.WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^abDi Scipio RG, Kurachi K, Davie EW (Jun 1978)."Activation of human factor IX (Christmas factor)".The Journal of Clinical Investigation.61(6): 1528–38.doi:10.1172/JCI109073.PMC372679.PMID659613.
  8. ^Taran LD (Jul 1997). "Factor IX of the blood coagulation system: a review".Biochemistry. Biokhimiia.62(7): 685–93.PMID9331959.
  9. ^Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (Sep 1995)."Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice".Blood.86(6): 2198–205.doi:10.1182/blood.V86.6.2198.bloodjournal8662198.PMID7662969.
  10. ^abZhong 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.PMID11723140.
  11. ^Wilkinson FH, Ahmad SS, Walsh PN (Feb 2002)."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.doi:10.1074/jbc.M107753200.PMID11714704.
  12. ^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.Bibcode:1995PNAS...92.9796B.doi:10.1073/pnas.92.21.9796.PMC40889.PMID7568220.
  13. ^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.PMID7547952.
  14. ^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.PMID20004170.
  15. ^Šimčíková D, Heneberg P (December 2019)."Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases".Scientific Reports.9(1): 18577.Bibcode:2019NatSR...918577S.doi:10.1038/s41598-019-54976-4.PMC6901466.PMID31819097.
  16. ^Kurachi K, Davie EW (Nov 1982)."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.Bibcode:1982PNAS...79.6461K.doi:10.1073/pnas.79.21.6461.PMC347146.PMID6959130.
  17. ^Nicholl D. (2002).An Introduction to Genetic Engineering Second Edition.Cambridge University Press. p. 257.
  18. ^ab"Rixubis EPAR".European Medicines Agency(EMA).19 December 2014.Retrieved1 June2024.
  19. ^"Health Canada New Drug Authorizations: 2016 Highlights".Health Canada.14 March 2017.Retrieved7 April2024.
  20. ^"Alprolix EPAR".European Medicines Agency(EMA).8 June 2007.Retrieved7 June2024.
  21. ^"Refixia (Novo Nordisk Pharmaceuticals Pty Ltd)".Therapeutic Goods Administration (TGA).13 September 2024.Retrieved15 September2024.
  22. ^Goodeve AC (2015)."Hemophilia B: Molecular pathogenesis and mutation analysis".Journal of Thrombosis and Haemostasis.13(7): 1184–1195.doi:10.1111/jth.12958.PMC4496316.PMID25851415.
  23. ^Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP (Jan 1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis".Thrombosis and Haemostasis.67(1): 63–5.doi:10.1055/s-0038-1648381.PMID1615485.S2CID25251813.
  24. ^"Benefix EPAR".European Medicines Agency(EMA).17 September 2018.Archivedfrom the original on 17 June 2020.Retrieved17 June2020.
  25. ^"Idelvion EPAR".European Medicines Agency(EMA).17 September 2018.Archivedfrom the original on 17 June 2020.Retrieved17 June2020.
  26. ^"Alprolix EPAR".European Medicines Agency(EMA).17 September 2018.Archivedfrom the original on 11 August 2020.Retrieved17 June2020.
  27. ^"Refixia EPAR".European Medicines Agency(EMA).17 September 2018.Archivedfrom the original on 18 June 2020.Retrieved17 June2020.
  28. ^"Benefix (coagulation factor ix- recombinant kit".DailyMed.1 March 2023.Archivedfrom the original on 29 January 2023.Retrieved23 March2024.
  29. ^"Idelvion- coagulation factor ix recombinant human kit".DailyMed.30 June 2023.Archivedfrom the original on 27 January 2023.Retrieved23 March2024.
  30. ^"Alprolix (coagulation factor ix- recombinant, fc fusion protein kit".DailyMed.25 May 2023.Archivedfrom the original on 7 February 2023.Retrieved23 March2024.
  31. ^"Ixinity (coagulation factor ix- recombinant kit".DailyMed.23 February 2021.Archivedfrom the original on 28 September 2023.Retrieved23 March2024.
  32. ^"Ixinity (coagulation factor ix- recombinant kit".DailyMed.9 January 2024.Archivedfrom the original on 3 December 2022.Retrieved23 March2024.
  33. ^"Rebinyn ((coagulation factor ix- recombinant, glycopegylated kit".DailyMed.11 August 2022.Archivedfrom the original on 29 November 2022.Retrieved23 March2024.
  34. ^"Rixubis (coagulation factor ix- recombinant kit".DailyMed.22 March 2023.Archivedfrom the original on 2 July 2022.Retrieved23 March2024.
  35. ^"Alphanine SD (coagulation factor ix- human kit".DailyMed.18 January 2024.Archivedfrom the original on 18 February 2024.Retrieved23 March2024.
  36. ^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.hdl:11577/2438365.PMID19846852.
  37. ^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.PMID21712351.
  38. ^"Home: EAHAD Factor 9 Gene Variant Database".Archivedfrom the original on 2020-10-28.Retrieved2020-10-23.

Further reading

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