Defective F8 secretion

Stable Identifier
Homo sapiens
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Hemophilia A (HA) is a bleeding disorder caused by lack of or a defective factor VIII (FVIII) protein and results from defects in the F8 gene (Peyvandi F et al. 2016).

In healthy individuals, FVIII is synthesized as a large glycoprotein of 2351 amino acids with a discrete domain structure: A1-A2-B-A3-C1-C2 (Wood WI et al. 1984; Vehar GA et al. 1984; Toole JJ et al. 1984). Upon synthesis, FVIII is translocated into the lumen of the endoplasmic reticulum (ER), where it undergoes extensive processing including cleavage of a signal peptide and N-linked glycosylation at asparagine residues (Kaufman RJ et al. 1988, 1997; Kaufman RJ 1998). In the ER lumen of mammalian cells FVIII interacts with the protein chaperones calnexin (CNX), calreticulin (CRT), and immunoglobulin-binding protein (BiP or GRP78) that facilitate proper folding of proteins prior to trafficking to the Golgi compartment (Marquette KA et al. 1995; Swaroop M et al. 1997; Pipe SW et al. 1998; Kaufman RJ et al. 1997; Kaufman RJ 1998). Trafficking from the ER to the Golgi compartment is facilitated by LMAN1 and multiple combined factor deficiency 2 (MCFD2) cargo receptor complex (Zhang B et al. 2005; Zheng, C et al. 2010, 2013). Within the Golgi apparatus, FVIII is subject to further processing, including modification of the N-linked oligosaccharides to complex-type structures, O-linked glycosylation, and sulfation of specific Tyr-residues (Kaufman RJ 1998). 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 Reactome event describes defects within the secretory pathway due to mutations in the F8 gene that can impair FVIII synthesis, folding, intracellular processing and transport which result in a lack or reduced levels of the plasma FVIII protein. The module includes also an event of defective post-translational tyrosine sulfonation of FVIII in the Golgi apparatus that is required for the optimal interaction between the secreted FVIII and the von Willebrand factor (VWF).

Literature References
PubMed ID Title Journal Year
10691849 Intracellular accumulation of factor VIII induced by missense mutations Arg593-->Cys and Asn618-->Ser explains cross-reacting material-reduced haemophilia A

Peters, M, Timmermans, SM, De Laaf, RT, van Mourik, JA, Voorberg, J, Roelse, JC

Br. J. Haematol. 2000
29444815 Molecular mechanisms of missense mutations that generate ectopic N-glycosylation sites in coagulation factor VIII

Zhu, M, Gilmore, R, Zhang, B, Zhu, X, Yang, R, Misra, S, Cannon, MV, Wei, W

Biochem. J. 2018
11380445 Stable recombinant expression and characterization of the two haemophilic factor VIII variants C329S (CRM(-)) and G1948D (CRM(r))

Tuddenham, EG, David, D, McVey, JH, Saenko, EL, Kemball-Cook, G, Johnson, DJ, Santos, IM

Br. J. Haematol. 2001
2107542 Mutations and a polymorphism in the factor VIII gene discovered by denaturing gradient gel electrophoresis

Kogan, S, Gitschier, J

Proc. Natl. Acad. Sci. U.S.A. 1990
28327546 Missense mutations near the N-glycosylation site of the A2 domain lead to various intracellular trafficking defects in coagulation factor VIII

Zhu, M, Zheng, C, Zhang, B, Yang, R, Zhu, X, Misra, S, Wei, W

Sci Rep 2017
8810344 Factor VIII C2 domain missense mutations exhibit defective trafficking of biologically functional proteins

Kaufman, RJ, Pipe, SW

J. Biol. Chem. 1996
8836140 Intracellular retention of a factor VIII protein with an Arg2307-->Gln mutation as a cause of haemophilia A

De Laaf, RT, van Mourik, JA, Voorberg, J, Koster, PM

Biochem. J. 1996
Name Identifier Synonyms
factor VIII deficiency DOID:12134 Congenital factor VIII disorder, Subhemophilia, Hemophilia A
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