GGCX mutations show different responses to vitamin K thereby determining the severity of the hemorrhagic phenotype in VKCFD1 patients.

Abstract

BACKGROUND:

Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-glutamyl carboxylase (GGCX). VKCFD1 patients are treated life-long with high doses of vitamin K in order to correct the bleeding phenotype. However, normalization of clotting factor activities cannot be achieved for all VKCFD1 patients.

OBJECTIVE:

The current study aims to investigate the responsiveness to vitamin K for all reported GGCX mutations with respect to clotting factors in order to optimize treatment.

METHODS:

This study developed an assay using genetically engineered GGCX-/- cells, in which GGCX mutations were analyzed with respect to their ability to γ-carboxylate vitamin K dependent pro-coagulatory and anti-coagulatory clotting factors by ELISA. Additionally, factor VII activity was measured in order to proof protein functionality. For specific GGCX mutations immunofluorescent staining was performed to assess the intracellular localization of clotting factors with respect to GGCX wild-type and mutations.

RESULTS:

All GGCX mutations were categorized into responder and low responder mutations, thereby determining the efficiency of vitamin K supplementation. Most VKCFD1 patients have at least one vitamin K responsive GGCX allele that is able to γ-carboxylate clotting factors. In few patients, the hemorrhagic phenotype cannot be reversed by vitamin K administration because GGCX mutations on both alleles affect either structural or catalytically important sites thereby resulting in residual ability to γ-carboxylate clotting factors.

CONCLUSION:

With these new functional data we can predict the hemorrhagic outcome of each VKCFD1 genotype, thus recommending treatments with either vitamin K or prothrombin complex concentrate.

• Authors: Suvoshree Ghosh, Katrin Kraus, Arijit Biswas, Jens Müller, Anna-Lena Buhl, Francesco Forin, Heike Singer, Klara Höning, Veit Hornung, Matthias Watzka, Katrin J Czogalla-Nitsche, Johannes Oldenburg
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 19 Issue 6 Pg. 1412-1424 (06 2021) ISSN: 1538-7836 [Electronic] England
• PMID: 33590680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

Chemical References

• Vitamin K
• Vitamin K 1
• Vitamin K Epoxide Reductases
• Carbon-Carbon Ligases
• glutamyl carboxylase

Topics

• Carbon-Carbon Ligases (genetics)
• Humans
• Mutation
• Phenotype
• Vitamin K
• Vitamin K 1
• Vitamin K Epoxide Reductases (genetics)