GGCX variants leading to biallelic deficiency to γ-carboxylate GRP cause skin laxity in VKCFD1 patients.

Abstract

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.

• Authors: Suvoshree Ghosh, Katrin Kraus, Arijit Biswas, Jens Müller, Francesco Forin, Heike Singer, Klara Höning, Veit Hornung, Matthias Watzka, Johannes Oldenburg, Katrin J Czogalla-Nitsche
• Journal: Human mutation (Hum Mutat) Vol. 43 Issue 1 Pg. 42-55 (01 2022) ISSN: 1098-1004 [Electronic] United States
• PMID: 34816548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Human Mutation published by Wiley Periodicals LLC.

Chemical References

• Carboxy-Lyases
• GGCX protein, human
• Carbon-Carbon Ligases
• glutamyl carboxylase

Topics

• Blood Coagulation Disorders, Inherited (genetics)
• Carbon-Carbon Ligases (chemistry, genetics, metabolism)
• Carboxy-Lyases
• Humans
• Mutation