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.