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

Elisabeth Andersen; Maria Eugenia Chollet; Christiane Filion Myklebust; Mirko Pinotti; Francesco Bernardi; Ampaiwan Chuansumrit; Ellen Skarpen; Per Morten Sandset; Grethe Skretting

doi:10.1055/s-0038-1637690

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

³Institute of Clinical Medicine, University of Oslo, Oslo, Norway

,

Maria Eugenia Chollet

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

,

Christiane Filion Myklebust

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

,

Mirko Pinotti

⁴Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, Ferrara, Italy

,

Francesco Bernardi

⁴Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, Ferrara, Italy

,

Ampaiwan Chuansumrit

⁵International Hemophilia Training Center, Mahidol University, Ramathibodi Hospital, Bangkok, Thailand

,

Ellen Skarpen

⁶Core Facility for Advanced Light Microscopy, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

,

Per Morten Sandset

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

³Institute of Clinical Medicine, University of Oslo, Oslo, Norway

,

Grethe Skretting

¹Department of Haematology, Oslo University Hospital, Oslo, Norway

²Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway

› Institutsangaben

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

Volltext

Referenzen

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