Hemophilia A results from a broad spectrum of mutations that occur along the entire length of the F8 gene causing diverse molecular phenotypes that result in similar disease states (Peyvandi F et al. 2016). Together with missense mutations being the most common type of mutations in hemophilia A, a relatively frequent cause is ascribable to nonsense and splice site mutations, deletions/insertions and promoter mutations (Hakeos WH et al. 2002; Wei W et al. 2017; Jacquemin M et al. 2000; Amano K et al. 1998; Gilbert GE et al. 2012; Pahl S et al. 2014; Peyvandi F et al. 2016). In addition, the inversion of intron 1 or 22 in the F8 gene is responsible for approximately half of severely affected hemophilia A patients (Antonarakis SE et al. 1995). Although specific FVIII missense mutations correlate with defects including decreased secretion or stability and specific functional impairment of FVIII, the mechanisms of the majority of missense mutations are poorly understood (Hakeos WH et al. 2002; Wei W et al. 2017, 2018; Jacquemin M et al. 2000; Amano K et al. 1998; Gilbert GE et al. 2012; Pahl S et al. 2014). The Reactome module describes several molecular mechanisms underlying hemophilia A which include:(1) low-level secretion of defective FVIII molecule as a result of impaired FVIII folding and intracellular processing, (2) reduced ability of FVIII variants to bind to von Willebrand factor (VWF) that leads to instability of FVIII variants in the plasma, (3) abnormal interaction of defective FVIII with FIXa. Defects in FVIII activity may also result in potentially slowing down FVIII activation by thrombin or altering stability of activated FVIIIa.
d'Oiron, R, Jacquemin, M, Peerlinck, K, De Maeyer, M, Saint-Remy, JM, Lavend'homme, R
Babiker, HM, Salen, P
Factor VIII and Factor IX Subcommittee, -, Aledort, LM, Rosendaal, F, White, GC, Lusher, JM, Ingerslev, J, Rothschild, C
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