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Details on Person Coagulation factor VIII (FVIII) encoded by the F8 gene is sy...

Class:IdSummation:9665830
_displayNameCoagulation factor VIII (FVIII) encoded by the F8 gene is sy...
_timestamp2020-01-13 20:25:27
created[InstanceEdit:9665826] Shamovsky, Veronica, 2019-11-01
literatureReference[LiteratureReference:9661611] Molecular cloning of a cDNA encoding human antihaemophilic factor
[LiteratureReference:9661667] Expression of active human factor VIII from recombinant DNA clones
[LiteratureReference:9661682] Biosynthesis, assembly and secretion of coagulation factor VIII
[LiteratureReference:9661613] Post-translational modifications required for coagulation factor secretion and function
[LiteratureReference:9665828] Factor VIII/V C-domain swaps reveal discrete C-domain roles in factor VIII function and intracellular trafficking
[LiteratureReference:9662340] A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor
[LiteratureReference:9665800] Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development
[LiteratureReference:9665840] Mild hemophilia A patient with novel Pro1809Leu mutation develops an anti-C2 antibody inhibiting allogeneic but not autologous factor VIII activity
[LiteratureReference:9665814] Storage of factor VIII variants with impaired von Willebrand factor binding in Weibel-Palade bodies in endothelial cells
[LiteratureReference:9665821] Surface-exposed hemophilic mutations across the factor VIII C2 domain have variable effects on stability and binding activities
[LiteratureReference:9665833] Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure
[LiteratureReference:9665837] Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A
[LiteratureReference:9667090] Interaction Between the a3 Region of Factor VIII and the TIL'E' Domains of the von Willebrand Factor
[LiteratureReference:9667085] The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von willebrand factor
[LiteratureReference:9667091] A human antibody directed to the factor VIII C1 domain inhibits factor VIII cofactor activity and binding to von Willebrand factor
[LiteratureReference:9668020] Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor
modified[InstanceEdit:9666389] Shamovsky, Veronica, 2019-11-05
[InstanceEdit:9667082] Shamovsky, Veronica, 2019-11-07
[InstanceEdit:9668074] Shamovsky, Veronica, 2019-11-19
[InstanceEdit:9668146] Shamovsky, Veronica, 2019-11-19
[InstanceEdit:9674512] Shamovsky, Veronica, 2020-01-13
textCoagulation factor VIII (FVIII) encoded by the F8 gene is synthesized as a 19 amino acid signal peptide followed by 2332 amino acids and includes the A1-A2-B-A3-C1-C2 structural domains (Toole JJ et al. 1984; Wood WI et al. 1984). Upon secretion from the cell, FVIII is cleaved at two sites in the B-domain to form a heterodimer consisting of the heavy chain containing the A1-A2-B domains in a metal ion-dependent complex with the light chain consisting of the A3-C1-C2 domains (Kaufman RJ et al. 1997; Kaufman RJ 1998). The heterodimer circulates in a tight complex with the multimeric glycoprotein von Willebrand Factor (vWF), which is essential for maintaining stable levels of FVIII in the circulation (reviewed by Pipe SW et al. 2016). The structurally homologous C1 and C2 domains of FVIII are believed to have specific functions in interactions with vWF (Pratt KP et al. 1999; Jacquemin M et al. 2000a,b; Ebberink EH et al. 2017). The acidic subdomain a3 of the light chain also controls FVIII binding to vWF (Saenko EL & Scandella D 1997; Dagil L et al. 2019). Sulfation at Tyr1699 in the a3 subdomain was required for high affinity interaction with vWF (Leyte A et al. 1991).

Genetic mutations in the F8 gene can compromise FVIII binding to vWF thus decreasing FVIII values in the plasma causing hemophilia A (HEMA), an X-linked recessive bleeding disorder (Higuchi M et al. 1990; Liu ML et L. 2000; Jacquemin M et al. 2000b; Spiegel PC et al. 2004; d'Oiron R et al. 2004; van den Biggelaar M et al. 2011; Yada K et al. 2015). This Reactome event describes reduced FVIII interaction with vWF caused by the defective Tyr1699 sulfation site (Y1699F) in a3 of FVIII or by mutations in the C domains of FVIII (S2138Y, P2319L, R2169H, R2323H etc.) found in HEMA patients.

(summation)[FailedReaction:9665809] F8 variant does not bind von Willebrand factor [Homo sapiens]
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