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Anton Stepanov
Anton Stepanov

GRP Development Fixed

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.

GRP Development

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UCMA (alternatively named GRP) is a novel member of the family of γ-carboxyglutamate (Gla) containing proteins that is mainly expressed in cartilage. We have used the zebrafish as a model organism to study UCMA function. Due to the whole genome duplication two Ucma genes are present in zebrafish, ucmaa and ucmab, located on chromosomes 25 and 4, respectively. UCMA gene structure, alternative splicing and protein sequence are highly conserved between mammals and zebrafish and Ucmaa and Ucmab are expressed in zebrafish skeletal tissues. Ucmaa is first detected in the notochord at 18 hpf and expression continues during notochord development. In addition, it is widely present in the developing craniofacial cartilage. In contrast, the weakly expressed Ucmab can be first detected at specific sites in the craniofacial cartilage at 96 hpf, but not in notochord. Knockdown of ucmaa leads to severe growth retardation and perturbance of skeletal development. The cartilage of the morphants has a decreased aggrecan and collagen II content. Similar malformations were observed when glutamate γ-carboxylation was inhibited by warfarin treatment, indicating that glutamate γ-carboxylation is crucial for Ucma function and pointing to a role of UCMA in the pathogenesis of "warfarin embryopathies" and other human skeletal diseases.

Therefore, results from both studies eliminate the hypothesis that under-carboxylated MGP is the sole causative determinant for developing skeletal defects in patients. We assume that the development of skeletal defects is attributed to various factors as for example nutritional uptake of the mother during pregnancy, polymorphisms in VKORC1 gene, or other epigenetic factors. Maternal nutrition during pregnancy is crucial for the normal development of the offspring. Since vitamin K is supplied by food, insufficient intrauterine transfer of vitamin K or insufficient transfer of γ-carboxylated VKD proteins might lead to skeletal defects in the offspring. This hypothesis is supported by one case report harboring the genotype GGCX:p.(S284P);p.(W315X) [7], where the mother of the patient developed hyperemesis gravidarum with a weight loss of 7 kgs in the first trimester. GGCX:p.(S284P) showed 134% γ-carboxylation for MGP in vitro by Hao et al. and 102% by our group. However, the offspring developed skeletal defects, despite having theoretically sufficient amounts of γ-carboxylated MGP. This case report shows the importance of nutritional uptake during pregnancy.

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.

The age of onset for skin hyper-laxity was reported to be around 18 years and at later age [19]. Therefore, early-stage monitoring and vitamin K enriched diet might prevent or postpone the onset of skin laxity for the patients harboring GGCX mutations that effect γ-carboxylation of GRP mildly. However, our recent in vitro study showed that GGCX mutations, reported in VKCFD1 patients diagnosed with a PXE-like phenotype, do not respond with increasing levels of γ-carboxylated GRP after treatment with increasing vitamin K concentrations. Therefore, theoretically VKCFD1 patients might also not show greatly enhanced γ-carboxylated GRP values under vitamin K enriched diet. In this case, other treatment options than only vitamin K administration are needed to rescue the development of skin folding and hyper-laxity. Viegas et al. have proposed a treatment strategy to inhibit vascular calcification by a nanotechnology-based method, where human γ-carboxylated GRP is loaded into extracellular vesicles [64]. This system was capable of reducing extracellular matrix calcium deposits in calcifying VSMCs in vitro. However, it remains to be elucidated whether this innovative system will prevent skin hyperlaxity.

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In 2019, the Northwest Area Committee convened a Taskforce to address this GRP accessibility by finding out more about who uses GRPs and how they use them. The Taskforce developed a survey that generated valuable feedback around GRP best practices, common users, and ways to innovate the GRP development and publication process. A key outcome of the survey for Washington is the new GRP format hosted on this website. This change was important to address the efficiency and sustainability of GRP development today and into the future. 041b061a72

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