Defective cofactor function of FVIIIa variant

Stable Identifier
R-HSA-9672396
Type
Pathway
Species
Homo sapiens
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Factor VIII (FVIII) in its activated form, FVIIIa, acts as a cofactor to the serine protease FIXa, in the conversion of the zymogen FX to the active enzyme (FXa). Missense mutations within the S577-Q584 region of FVIII have been associated with mild/moderate hemophilia A (HA) (Amano K et al. 1998; Celie PH et al. 1999; Jenkins PV et al. 2002). A functional assay demonstrated that the mutations S577F, V578A, D579A, and Q584R interfere with FVIIIa:FIXa-mediated stimulation of FX activation thus the effect of the mutations is to reduce the cofactor potential of FVIII in FXa generation. The Reactome event describes failed generation of FXa as the functional consequence of the FIXa interaction with HA-associated FVIIIa variants due to reduced ability of defective FVIII to act as a cofactor for FIXa within the intrinsic tenase complex.

Literature References
PubMed ID Title Journal Year
9427707 The molecular basis for cross-reacting material-positive hemophilia A due to missense mutations within the A2-domain of factor VIII

Amano, K, Sarkar, R, Pemberton, S, Kemball-Cook, G, Kazazian, HH, Kaufman, RJ

Blood 1998
12091341 Mutations associated with hemophilia A in the 558-565 loop of the factor VIIIa A2 subunit alter the catalytic activity of the factor Xase complex

Jenkins, PV, Freas, J, Schmidt, KM, Zhou, Q, Fay, PJ

Blood 2002
10468875 Substitution of Arg527 and Arg531 in factor VIII associated with mild haemophilia A: characterization in terms of subunit interaction and cofactor function

Celie, PH, Van Stempvoort, G, Jorieux, S, Mazurier, C, van Mourik, JA, Mertens, K

Br. J. Haematol. 1999
Participants
Participant Of
Disease
Name Identifier Synonyms
factor VIII deficiency 12134 Congenital factor VIII disorder, Subhemophilia, Hemophilia A
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