Abstract
(1) Background: Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. Patients with modest differences in FVII levels may display large differences in clinical severity. The variant p.A354V-p.P464Hfs is associated with reduced FVII antigen and activity. The aim of the study was to investigate the clinical manifestation of this variant and the underlying molecular mechanisms. (2) Methods: Analyses were conducted in 37 homozygous patients. The recombinant variant was produced in mammalian cells. (3) Results: We report a large variation in clinical phenotypes, which points out genetic and acquired components beyond F7 mutations as a source of variability. In contrast, patients displayed similarly reduced FVII plasma levels with antigen higher than its activity. Comparative analysis of the recombinant variant and of plasma samples from a subset of patients indicated the presence of an elongated variant with indistinguishable migration. Treatment of cells with the chemical chaperone 4-phenylbutyrate (4-PBA) improved the intracellular trafficking of the variant and increased its secretion to the conditioned medium up to 2-fold. However, the effect of 4-PBA on biological activity was marginal. (4) Conclusions: Chemical chaperones can be used as biochemical tools to study the intracellular fate of a trafficking-defective FVII variant.
Highlights
Factor (F) VII is a vitamin K-dependent glycoprotein synthesized in the liver that undergoes extensive post-translational modifications prior to secretion [1,2,3]
We recently demonstrated that the chemical chaperone 4-phenylbutyrate (4-PBA) could improve the secretion and biological activity of another recombinant FVII variant characterized by impaired secretion and triggering of endoplasmic reticulum (ER) stress [24]
Because a net effect on secretion of the FVII variant could only be observed in cells treated with 4-PBA, we investigated whether the treatment with this compound could
Summary
Factor (F) VII is a vitamin K-dependent glycoprotein synthesized in the liver that undergoes extensive post-translational modifications prior to secretion [1,2,3]. It is secreted into the blood where it circulates at a concentration of roughly 0.5 μg/mL (10 nM) [4]. The single-chain native FVII is a zymogen that, upon binding to its cofactor, tissue factor (TF), becomes activated, resulting in a two-chained activated molecule (FVIIa). The TF/FVIIa catalytic complex, which is considered the key initiator of blood coagulation, activates downstream clotting factors leading to the production of thrombin, the key effector for the final formation of the clot [6,7].
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