Sandbox Reserved 1482: Difference between revisions

Factor VIII is much studied in order to find a cure for hemophilia A (also written as HEMA), for instance by designing mimicking factors <ref>Ragni MV. Mimicking Factor VIII to Manage the Factor VIII–Deficient State. The New England journal of medicine. 2018 Aug; 379(9): 880-882. doi: 10.1056/NEJMe1808789</ref>.  

== History ==

The C domains belong to the phospholipid-binding discoidin domain family <ref name="wikipedia" />. They are adjacent at the base of the triangular heterotrimer. Moreover, C₁ and C₂ domains are structurally homologous and they have the ability to bind the membrane. Indeed, both C domain protrude three β-hairpin loops with hydrophobic and basic residues in the same direction. Thanks to these loops the factor VIII might interact with the phospholipid bilayer. <ref name="Ngo" />

Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /><ref name="toole">Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC & Kaufman RJ. A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for ''in vitro'' procoagulant activity. Proceedings of the National Academy of Sciences. 1986 Aug; 83(16): 5939-5942. PMID: 3016730 doi  https://doi.org/10.1073/pnas.83.16.5939</ref>. Although factor VIIIa can be formed from at least two cleavages involving Arg372 and Arg1689, fully factor VIIIa is obtained by a third cleavage at Arg740 <ref name="Ngo" />.

The two chain that result are a heavy and a light chains <ref name="Ngo" /><ref name="El" /><ref name="pdb" />.

The <scene name='80/802656/Heavy_chain/4'>heavy chain</scene> has a various size (90 or 120 kDa) <ref name="wikipedia" /><ref name="Binhoreau">Bihoreau N, Fontaine-Aupart MP, Lehegarat A, Desmadril M, Yon JM. First determination of the secondary structure of purified factor VIII light chain. Biochem J. 1992 Nov; 288 ( Pt 1): 35-40. PMID:1445279 doi: 10.1042/bj2880035</ref>. It consists of the A₁-A₂ domains <ref name="wikipedia" /><ref name="El" /><ref name="Binhoreau" />. Both A₁ and A₂ domains are built up of two connected β barrels <ref name="Ngo" />.

The <scene name='80/802656/Light_chain/2'>light chain</scene> has a molecular weight of 80 kDa and is composed of 684 amino acids <ref name="Binhoreau" />. It contains two domains: a unique A domain of 371 amino acids and a duplicated C domain of 153 amino acids and 160 amino acids, respectively <ref name="Binhoreau" />. These domains are ranked in the following order A₃-C₁-C₂ <ref name="wikipedia" /><ref name="Binhoreau" />. It is composed of 42 % irregular structure, 36 % β-strands, and 22 % α-helices <ref name="Binhoreau" />. The C₁ and C₂ domains are defined by a distorted β barrel, while A₃, as well as A₁ and A₂, is composed of two connected β barrels <ref name="Ngo" />. This chain also contains of the major binding site of von Willebrand Factor at its N-terminus <ref name="Binhoreau" />.  

Both chains are non-covalently associated through to a calcium ion to form the active heterodimer <ref name="Ngo" /><ref name="Binhoreau" />. This complex is the pro-coagulant factor VIIIa <ref name="wikipedia" />.  

Although hemophilia A is usually an inherited disease and therefore runs in families <ref name="Srivastava" />, about one-third of people with the disease are caused by a spontaneous mutation <ref name="Srivastava" /> such as misense or nonsense mutations, gene deletions or inversions <ref name="Ngo" />.

====Inheritance====

Thus, because of the recessivity only men are affected by this disease and women are carriers that may pass the gene on to their children (50% chance of transmitting it in each pregnancy). <ref name="Srivastava" />

The risk for boys to carry the disease therefore depends on the carrier status of the mother because affected males transmit the pathogenic variant to all of their daughters and none of their sons <ref name="Konkle" />.

Hemophilia A can be mild, moderate, or severe, depending on the level of Factor VIII clotting activity <ref name="Konkle" /><ref>White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Definitions in hemophilia, Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001 Mar; 85(3): 560. PMID: 11307831</ref>.

The major treatment of the bleeding disorder associated with hemophilia A is the infusion of factor VIII, which leads to the correction of hemostasis <ref name="Srivastava" />.