Abstract
γ-Glutamyl carboxylase (GGCX ) catalyses γ-carboxylation of 15
different vitamin K dependent (VKD) proteins. Pathogenic variants inGGCX 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 aGGCX-/- 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.