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

Autor: Veit Hornung, Heike Singer, Klara Höning, Katrin J. Czogalla-Nitsche, Katrin Kraus, S Ghosh, Arijit Biswas, Johannes Oldenburg, Jens Müller, Francesco Forin, Matthias Watzka
Rok vydání: 2021
Předmět:
Zdroj: Human Mutation. 43:42-55
ISSN: 1098-1004
1059-7794
Popis: γ-Glutamyl carboxylase (GGCX) catalyses 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-haemorrhagic phenotypes remain elusive. Therefore, we analyzed the effect of 22 GGCX pathogenic variants on γ-carboxylation of six non-haemostatic VKD proteins (UCMA/GRP, MGP, BGLAP, GAS6, PRGP1, TMG4) in a GGCX-/- HEK293T cell line by a functional ELISA. We observed that biallelic deficiency to γ-carboxylate Gla-rich protein lead to the development of skin laxity. Markedly reduced level of γ-carboxylated MGP is crucial but not exclusive for causing facial dysmorphologies. Moreover, we identified the vitamin K hydroquinone binding site in GGCX in an in silico model by docking studies, which was further validated by functional assays. Variants affecting this site result into loss-of-function or severely diminished ability to γ-carboxylate VKD proteins and hence are involved in the most severe phenotypes. This genotype-phenotype analysis will help to develop new treatment options for VKCFD1 patients, where individualized therapy with γ-carboxylated VKD proteins may represent a promising strategy.
Databáze: OpenAIRE
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