| Autor: |
Ghosh, Suvoshree, Kraus, Katrin, Biswas, Arijit, Müller, Jens, Forin, Francesco, Singer, Heike, Höning, Klara, Hornung, Veit, Watzka, Matthias, Oldenburg, Johannes, Czogalla‐Nitsche, Katrin J. |
| Zdroj: |
Human Mutation; Jan2022, Vol. 43 Issue 1, p42-55, 14p |
| Abstrakt: |
γ‐Glutamyl carboxylase (GGCX) catalyzes the γ‐carboxylation of 15 different vitamin K dependent (VKD) proteins. Pathogenic variants in GGCX cause a rare hereditary bleeding disorder called Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1). In addition to bleedings, some VKCFD1 patients develop skin laxity and skeletal dysmorphologies. However, the pathophysiological mechanisms underlying these non‐hemorrhagic phenotypes remain elusive. Therefore, we have analyzed 20 pathogenic GGCX variants on their ability to γ‐carboxylate six non‐hemostatic VKD proteins in an in vitro assay, where GGCX variants were expressed in GGCX‐/‐ cells and levels of γ‐carboxylated co‐expressed VKD proteins were detected by a functional ELISA. We observed that GGCX variants causing markedly reduced γ‐carboxylation of Gla rich protein (GRP) in vitro were reported in patients with skin laxity. Reduced levels of γ‐carboxylated Matrix gla protein (MGP) are not exclusive for causing skeletal dysmorphologies in VKCFD1 patients. In silico docking of vitamin K hydroquinone on a GGCX model revealed a binding site, which was validated by in vitro assays. GGCX variants affecting this site result in disability to γ‐carboxylate VKD proteins and hence are involved in the most severe phenotypes. This genotype‐phenotype analysis will help to understand the development of non‐hemorrhagic phenotypes and hence improve treatment in VKCFD1 patients. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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