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GGCX Mutations Lead to Different γ-carboxylation Status of Vitamin K Dependent Coagulation Proteins

1Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany, 2Institute of Molecular Medicine, Bonn, Germany, 3Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany

Abstract Number: PB0689

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Rare Bleeding Disorders

Background: Vitamin K Dependent Coagulation Factor Deficiency type 1 (VKCFD1) is a rare bleeding disorder caused by mutations in γ-glutamyl carboxylase (GGCX) gene, which is characterized by spontaneous bleeding due to under γ-carboxylated vitamin K dependent (VKD) clotting factors.

Aims: The aim of this study is to categorize 22 reported GGCX mutations into responders and non-responders to vitamin K (K1) treatment with respect to VKD clotting factors.  

Methods: The cDNAs of GGCX together with F2, F7, F9, F10 or Protein C (PC) were cloned into a bicistronic vector, which was transfected into GGCX-/- cells, and treated with different K1 concentrations to determine γ-carboxylation by ELISA. Moreover, an in silico GGCX model was generated to visualize the localization of heterogeneous mutations.

Results: Elevated K1 concentrations increase γ-carboxylation of VKD clotting factors for most mutations. GGCX:p.(M174R) and GGCX:p.(F299S) show loss-of-function in γ-carboxylation for all clotting factors at any K1 concentration. Mutations GGCX:p.(R83P), GGCX:p.(R83W), GGCX:p.(D153G), GGCX:p.(L394R), GGCX:p.(H404P) and GGCX:p.(S300F) are low responding mutations, which showed reduced levels of γ-carboxylation compared to wild-type at high K1 concentration. Certain mutants show a differential effect on γ-carboxylation. GGCX:p.(R485P) γ-carboxylates FX, FVII and FIX as wild-type, whereas FII is γ-carboxylated to a lower level.  Mutation GGCX:p.(G558R) and GGCX:p.(T591K) cannot γ-carboxylate FX to any level, whereas it increases slightly for FII. These differential mutations are located close to the propeptide binding site in our GGCX in silico model.  

Conclusions: Therapy with K1 will lead to normal coagulation for most mutations. Low responding mutations are difficult to treat with K1. Therefore, patients with low responding mutation in homozygous form or in combination with a loss-of-function mutation should be treated with Prothrombin Complex Concentrate. The close location of GGCX:p.(R485P), GGCX:p.(G558R), and GGCX:p.(T591K) to the propeptide binding site in our GGCX in silico model might be responsible for the differential responses to the clotting factors.
​PNG

To cite this abstract in AMA style:

Ghosh S, Mueller J, Biswas A, Höning K, Hornung V, Forin F, Watzka M, Czogalla kJ, Oldenburg J. GGCX Mutations Lead to Different γ-carboxylation Status of Vitamin K Dependent Coagulation Proteins [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/ggcx-mutations-lead-to-different-%ce%b3-carboxylation-status-of-vitamin-k-dependent-coagulation-proteins/. Accessed October 2, 2023.

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