Publication: Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency
Issued Date
2018-04-01
Resource Type
ISSN
03406245
Other identifier(s)
2-s2.0-85044929541
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Thrombosis and Haemostasis. Vol.118, No.4 (2018), 664-675
Suggested Citation
Elisabeth Andersen, Maria Eugenia Chollet, Christiane Filion Myklebust, Mirko Pinotti, Francesco Bernardi, Ampaiwan Chuansumrit, Ellen Skarpen, Per Morten Sandset, Grethe Skretting Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency. Thrombosis and Haemostasis. Vol.118, No.4 (2018), 664-675. doi:10.1055/s-0038-1637690 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46803
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency
Abstract
© 2018 Schattauer. Congenital factor (F) VII deficiency is a bleeding disorder caused by a heterogeneous pattern of mutations in the F7 gene. Protein misfolding due to mutations is a strong candidate mechanism to produce the highly represented type I FVII deficiency forms, characterized by a concomitant deficiency of FVII antigen and activity. Misfolded proteins can accumulate within the endoplasmic reticulum (ER) causing ER stress with subsequent activation of the unfolded protein response (UPR). So far, there are limited data on this important issue in FVII deficiency. In this study, we chose as candidate FVII model mutations, the p.Q160R, p.I289del and p.A354V-p.P464Hfs, which are all associated with severe to moderate type I FVII deficiency. In vitro expression of the recombinant (r) mutants rFVII-160R, rFVII-289del or rFVII-354V-464Hfs, which are characterized by either amino acid substitution, deletion, or by an extended carboxyl terminus, demonstrated inefficient secretion of the mutant proteins, probably caused by intracellular retention and association with ER chaperones. Both ER stress and UPR were activated following expression of all FVII mutants, with the highest response for rFVII-289del and rFVII-354V-464Hfs. These data unravel new knowledge on pathogenic mechanisms leading to FVII deficiency, and support the investigation of pharmaceutical modulators of ER stress and UPR as therapeutic agents.