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.
Highlights
Introduction γGlutamyl carboxylase (GGCX) is a post translational modifying enzyme and the only one that γ-carboxylates vitamin K dependent (VKD) proteins at specific glutamic acid (Glu) residues to γ-carboxyglutamic acid residues (Gla) [1,2,3]
We correlated the γ-carboxylation values obtained from this in vitro assay with the genotype of VKCFD1 patients harboring a non-hemorrhagic phenotype. By this we mainly identified that γ-glutamyl carboxylase (GGCX) mutations with markedly reduced ability to γ-carboxylate Gla-rich protein (GRP) in our in vitro assay are reported in VKCFD1 patients that developed skin hyperlaxity
We have recently reported that under-carboxylation of GRP by specific GGCX mutations are associated with skin hyperlaxity in VKCFD1 patients [61]
Summary
Physiological calcification is crucial for maintaining tissue homeostasis, which is depending on the proper regulation of both pro and anti-mineralization factors [25]. The imbalance in mineralization causes ectopic calcification leading to diverse pathological phenotypes. Two VKD proteins, MGP and GRP, are known to function, as calcification inhibitors and under-carboxylation of these proteins are associated with pathological calcification
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