GGCX mutations show different responses to vitamin K thereby determining the severity of the hemorrhagic phenotype in VKCFD1 patients
| Autor: | Katrin Kraus, Arijit Biswas, Francesco Forin, Jens Müller, Heike Singer, Anna-Lena Buhl, Matthias Watzka, Johannes Oldenburg, S Ghosh, Klara Höning, Veit Hornung, Katrin J. Czogalla-Nitsche |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Vitamin K Coagulation Factor Deficiency 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine Vitamin K Epoxide Reductases Internal medicine Genotype Humans Medicine Allele Clotting factor business.industry Vitamin K 1 Hematology Prothrombin complex concentrate Phenotype Pyruvate carboxylase Endocrinology Carbon-Carbon Ligases Mutation VKORC1 business medicine.drug |
| Zdroj: | Journal of Thrombosis and Haemostasis. 19:1412-1424 |
| ISSN: | 1538-7836 |
| Popis: | 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, where 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, FVII 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 into 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. |
| Databáze: | OpenAIRE |
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