The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes

Abstract

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients.

Keywords: GGCX; GRP/UCMA; MGP; VKCFD1.

Figure 1

Evaluation of under-carboxylated MGP and GRP in the development of non-hemostatic VKCFD1 phenotypes. The schematic shows the genotype of VKCFD1 patients that were reported with skin hyper-laxity, skeletal dysmorphologies, congenital cardiac abnormalities and/or atherosclerosis. GGCX mutations that showed reduced ability to carboxylate MGP or GRP in vitro are highlighted in green (for MGP) or blue color (GRP). GGCX mutations in black color showed γ-carboxylation levels above 50% in vitro. Multiple factors could be associated with skeletal dysmorphologies such as under-carboxylated MGP, VKORC1:c.-1639 AA polymorphism and nutritional uptake by the mother during pregnancy. The biallelic reduction to γ-carboxylate GRP is associated with the PXE-like phenotype in VKCFD1 patients. Congenital cardiac abnormalities are associated with multiple factors such as ucMGP, nutritional uptake during pregnancy or other not yet identified factors. In the two patients with subclinical atherosclerosis low levels of γ-carboxylated GRP could be the reason for developing this phenotype.