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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/45228
Title: Factor VII deficiency: Unveiling the cellular and molecular mechanisms underlying three model alterations of the enzyme catalytic domain
Authors: Maria Eugenia Chollet
Elisabeth Andersen
Ellen Skarpen
Christiane F. Myklebust
Christian Koehler
Jens Preben Morth
Ampaiwan Chuansumrit
Mirko Pinotti
Francesco Bernardi
Bernd Thiede
Per Morten Sandset
Grethe Skretting
Oslo University Hospital
Research Institute of Internal Medicine
University of Ferrara
Mahidol University
Universitetet i Oslo
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Mar-2018
Citation: Biochimica et Biophysica Acta - Molecular Basis of Disease. Vol.1864, No.3 (2018), 660-667
Abstract: © 2017 Elsevier B.V. Activated factor (F) VII is a vitamin K-dependent glycoprotein that initiates blood coagulation upon interaction with tissue factor. FVII deficiency is the most common of the rare congenital bleeding disorders. While the mutational pattern has been extensively characterized, the pathogenic molecular mechanisms of mutations, particularly at the intracellular level, have been poorly defined. Here, we aimed at elucidating the mechanisms underlying altered FVII biosynthesis in the presence of three mutation types in the catalytic domain: a missense change, a microdeletion and a frameshift/elongation, associated with severe or moderate to severe phenotypes. Using CHO-K1 cells transiently transfected with expression vectors containing the wild-type FVII cDNA (FVIIwt) or harboring the p.I289del, p.G420V or p.A354V-p.P464Hfs mutations, we found that the secretion of the FVII mutants was severely decreased compared to FVIIwt. The synthesis rate of the mutants was slower than the FVIIwt and delayed, and no degradation of the FVII mutants by proteasomes, lysosomes or cysteine proteases was observed. Confocal immunofluorescence microscopy studies showed that FVII variants were localized into the endoplasmic reticulum (ER) but were not detectable within the Golgi apparatus. These findings suggested that a common pathogenic mechanism, possibly a defective folding of the mutant proteins, was triggered by the FVII mutations. The misfolded state led to impaired trafficking of these proteins causing ER retention, which would explain the low to very low FVII plasma levels observed in patients carrying these mutations.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85038881436&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/45228
ISSN: 1879260X
09254439
Appears in Collections:Scopus 2018

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