Journal
CELL AND BIOSCIENCE
Volume 9, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13578-019-0333-8
Keywords
Factor VII deficiency; Chemical chaperones; Mutations; Protein misfolding; Endoplasmic reticulum; Trafficking
Categories
Funding
- Oslo University Hospital
- University of Oslo
- South-Eastern Norway Regional Health Authority
- FondoAteneoRicerca from the Ferrara University-Italy
Ask authors/readers for more resources
Background Congenital coagulation factor (F) VII deficiency is a rare bleeding disorder caused by mutations in the F7 gene. The missense factor FVII variant p.Q160R is the disease-causing mutation in all Norwegian FVII deficient patients and results in reduced biological activity and antigen levels of FVII in patient plasma. Previous in vitro studies on this variant demonstrated impaired intracellular trafficking and reduced secretion, possibly due to protein misfolding. The aim of the study was therefore to assess the impact of chemical chaperones on cellular processing and secretion of this variant using a cell model based on overexpression of the recombinant protein. Results Through screening of compounds, we identified 4-phenylbutyrate (4-PBA) to increase the secretion of recombinant (r) FVII-160R by similar to 2.5-fold. Additionally, treatment with 4-PBA resulted in a modest increase in specific biological activity. Intracellular localization studies revealed that upon treatment with 4-PBA, rFVII-160R was secreted through Golgi and Golgi reassembly-stacking protein (GRASP)-structures. Conclusions The present study demonstrates that the chemical chaperone 4-PBA, restores intracellular trafficking and increases the secretion of a missense FVII variant with functional properties in the extrinsic coagulation pathway.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available