Disputation: M.Sc. Elisabeth Andersen – Bleeding disorders

M.Sc. Elisabeth Andersen at the Institute of Clinical Medicine will be defending the thesis "FVII deficiency: from molecular mechanisms to novel therapeutic approaches" for the degree of Philosophiae doctor.

Trial lecture - time and place

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Adjudication committee

  • First opponent: Professor Javier Corral, University of Murcia
  • Second opponent: Professor Björn Dahlbäck, Lund University
  • Third member of the evaluation committee: Professor Britt Nakstad, University of Oslo

Principal Supervisor

Senior Researcher Grethe Skretting, Oslo University Hospital


The aim of this study was to obtain a better understanding of the underlying molecular basis of FVII deficiency to eventually be able to find new therapeutic approaches.

Congenital deficiency of blood coagulation factor (F) VII is a rare bleeding disorder with a prevalence of approximately 1:300.000-1:500.000. It is caused by mutations in the F7 gene resulting in reduced levels of FVII in the blood and/or decreased biological activity.  As of today, bleeding episodes are treated with factor concentrates. However, this therapy requires frequent intravenous administrations and is extremely expensive. In this study, we focused on the four FVII mutations p.G420V, p.I289del, p.Q160R and p.A354Vp.-P464Hfs. They were chosen because they represent different types of mutations with distinct disease pathways. Additionally, the p.Q160R and p.A354V-p.P464Hfs mutations are among the most frequent in the FVII deficient patients. Patients harboring these mutations all experience bleeding symptoms due to both reduced levels and activity of FVII. Both the wild-type and the mutant FVII were expressed in mammalian cell lines and cell studies were performed by different molecular biology techniques.

We found impaired biosynthesis of the mutant FVII proteins and reduced secretion from the cells compared to the wild-type FVII, possibly as a result of misfolding of the FVII protein. Furthermore, we found that the intracellular transport of the FVII mutants was affected. The mutant proteins were not transported to the Golgi apparatus as the wild-type FVII, but were retained inside the endoplasmic reticulum (ER) of the cells causing ER stress.  Chemical chaperones are compounds that enhance the stability of misfolded proteins, enabling them to be secreted from the cells. We therefore tested the effect of various chemical chaperones on the FVII mutants. We found that 4-phenylbutyrate was able to increase the biosynthesis and secretion of FVII from the cells and partially restore the biological activity of the FVII mutants.

The results from these studies indicate that correction of protein misfolding or treatment targeting ER stress responses may represent relevant, novel treatment targets for FVII deficiency.

Additional information

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Published Dec. 4, 2018 7:16 PM - Last modified Dec. 4, 2018 7:16 PM