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Thromb Haemost 2018; 118(04): 664-675
DOI: 10.1055/s-0038-1637690
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency

Elisabeth Andersen
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
3   Institute of Clinical Medicine, University of Oslo, Oslo, Norway
,
Maria Eugenia Chollet
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
,
Christiane Filion Myklebust
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
,
Mirko Pinotti
4   Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, Ferrara, Italy
,
Francesco Bernardi
4   Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, Ferrara, Italy
,
Ampaiwan Chuansumrit
5   International Hemophilia Training Center, Mahidol University, Ramathibodi Hospital, Bangkok, Thailand
,
Ellen Skarpen
6   Core Facility for Advanced Light Microscopy, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
,
Per Morten Sandset
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
3   Institute of Clinical Medicine, University of Oslo, Oslo, Norway
,
Grethe Skretting
1   Department of Haematology, Oslo University Hospital, Oslo, Norway
2   Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
› Author Affiliations Funding The study was supported by grants from the South-Eastern Norway Regional Health Authority.
Further Information

Publication History

18 May 2017

14 January 2018

Publication Date:
04 April 2018 (online)

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Abstract

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.

Keywords

factor VII deficiency - endoplasmic reticulum stress - unfolded protein response

Supplementary Material

 

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