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

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in gamma-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the gamma-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 gamma-carboxylation of VKD proteins, where clotting factors are sufficiently gamma-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.

Automated summary

VKCFD1 is a rare hereditary bleeding disorder caused by mutations in the GGCX gene. In addition to bleeding, patients may develop non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and cardiac defects. Recent studies have found that GGCX mutations affect the gamma-carboxylation of VKD proteins, leading to the development of diverse phenotypes. Mineralization defects are the major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients.