Figure 1. Evaluation of γ-carboxylation of non-haemostatic VKD
proteins
(a) Under normal physiological condition, GGCX γ-carboxylates specific
Glu residues located in VKD proteins to Gla residues rendering them
active. VKD proteins which undergoes γ-carboxylation includes both
haemostatic (FII, FVII, FIX, FX, PC, PS and PZ) and non-haemostatic
proteins (GRP, MGP, BGLAP, GAS6, PRGPs, and TMGs). (b) Evaluation of
γ-carboxylation for VKD non-haemostatic proteins (GRP, MGP, BGLAP,
PRGP1, TMG4, and GAS6) by GGCX wt with a functional ELISA detecting GLA
residues. In the dose-response curves the y-axis represents normalized
γ-carboxylation (%) and the x-axis represents K1 concentrations
[0.1-100 µM]. (c) Pathological variants in GGCX lead to
uncarboxylated or partially γ-carboxylated VKD proteins, which are
inactive. Patients harboring these GGCX variants develop a rare
bleeding disorder called VKCFD1. Several VKCFD1 patients are diagnosed
with non-haemorrhagic phenotype f.e. PXE-like phenotype, facial
dysmorphologies and/or cardiac abnormalities. Until now the potential
non-haemostatic VKD protein/s responsible for developing these
non-haemorrhagic pathological conditions is unknown.