Meta-Biol

• Pathways

Factor IX (FIX) is a vitamin K-dependent trypsin-like serine protease zymogen in plasma, which upon activation to its active form (FIXa), binds to cofactor VIIIa (FVIIIa) on negatively charged membrane surfaces in the presence of Ca2+ to activate factor X (FX) in the intrinsic pathway of the blood clotting cascade (Davie EW et al. 1991; Ngo JC et al. 2008). FIX deficiency is associated with mild to severe bleeding in hemophilia B (HB) patients (Rallapalli PM et al. 2013). HB is caused by a wide range of mutations that can include point mutations (nonsense and missense), insertions, deletions and other complex rearrangements of the F9 gene (Rallapalli PM et al. 2013). Exons 7 and 8 encode the catalytic domain of FIX, which is responsible for the subsequent activation of FX in the coagulation cascade. Disease-causing mutations at these exons 7 and 8 produce dysfunctional FIX with impaired clotting enzyme activity (Usharani P et al. 1985: Attree O et al. 1989; Bajaj SP et al. 1990; Spitzer SG et al. 1990; Ludwig M et al. 1992; Lu Q et al. 2015). The Reactome event describes failed generation of FXa as the functional consequence of the defective serine protease activity of hemophilia B (HB)-associated FIX variants such as G363R & G363E (Lu Q et al. 2015), G357E (Miyata T et al. 1991), A436V (Usharani P et al. 1985), I443T (Hamaguchi N et al. 1991), G409V (Bajaj SP et al. 1990), D410H and S411G (Ludwig M et al. 1992).