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Article

The Factor VII Variant p.A354V-p.P464Hfs: Clinical versus Intracellular and Biochemical Phenotypes Induced by Chemical Chaperones

by
Elisabeth Andersen
1,2,*,
Maria Eugenia Chollet
1,2,
Francesco Bernardi
3,
Alessio Branchini
3,
Marcello Baroni
3,
Guglielmo Mariani
4,5,
Alberto Dolce
6,
Angelika Batorova
7,
Ellen Skarpen
8,
Christiane Filion Myklebust
1,2,
Grethe Skretting
1,2 and
Per Morten Sandset
1,2,9,*
1
Department of Haematology, Oslo University Hospital, 0450 Oslo, Norway
2
Research Institute of Internal Medicine, Oslo University Hospital, 0450 Oslo, Norway
3
Department of Life Sciences and Biotechnology and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
4
Faculty of Science and Technology, Westminster University, London W1B 2HW, UK
5
Seven Treatment Evaluation Registry [STER] Study Group, 0450 Oslo, Norway
6
National Institute of Statistics, 90100 Palermo, Italy
7
The National Haemophilia Centre, Institute of Haematology and Blood Transfusion, School of Medicine of Comenius University, University Hospital, 813 72 Bratislava, Slovakia
8
Core Facility for Advanced Light Microscopy, Institute for Cancer Research, Oslo University Hospital, 0379 Oslo, Norway
9
Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2021, 11(13), 5762; https://doi.org/10.3390/app11135762
Submission received: 1 May 2021 / Revised: 19 June 2021 / Accepted: 20 June 2021 / Published: 22 June 2021
(This article belongs to the Special Issue Characterization of Molecular Mechanisms and Tailored Correction Approaches for Inherited Disorders)
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Abstract

(1) Background: Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. Patients with modest differences in FVII levels may display large differences in clinical severity. The variant p.A354V-p.P464Hfs is associated with reduced FVII antigen and activity. The aim of the study was to investigate the clinical manifestation of this variant and the underlying molecular mechanisms. (2) Methods: Analyses were conducted in 37 homozygous patients. The recombinant variant was produced in mammalian cells. (3) Results: We report a large variation in clinical phenotypes, which points out genetic and acquired components beyond F7 mutations as a source of variability. In contrast, patients displayed similarly reduced FVII plasma levels with antigen higher than its activity. Comparative analysis of the recombinant variant and of plasma samples from a subset of patients indicated the presence of an elongated variant with indistinguishable migration. Treatment of cells with the chemical chaperone 4-phenylbutyrate (4-PBA) improved the intracellular trafficking of the variant and increased its secretion to the conditioned medium up to 2-fold. However, the effect of 4-PBA on biological activity was marginal. (4) Conclusions: Chemical chaperones can be used as biochemical tools to study the intracellular fate of a trafficking-defective FVII variant.
Keywords: factor VII deficiency; chemical chaperones; mutations; protein misfolding; endoplasmic reticulum; trafficking factor VII deficiency; chemical chaperones; mutations; protein misfolding; endoplasmic reticulum; trafficking

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MDPI and ACS Style

Andersen, E.; Chollet, M.E.; Bernardi, F.; Branchini, A.; Baroni, M.; Mariani, G.; Dolce, A.; Batorova, A.; Skarpen, E.; Myklebust, C.F.; et al. The Factor VII Variant p.A354V-p.P464Hfs: Clinical versus Intracellular and Biochemical Phenotypes Induced by Chemical Chaperones. Appl. Sci. 2021, 11, 5762. https://doi.org/10.3390/app11135762

AMA Style

Andersen E, Chollet ME, Bernardi F, Branchini A, Baroni M, Mariani G, Dolce A, Batorova A, Skarpen E, Myklebust CF, et al. The Factor VII Variant p.A354V-p.P464Hfs: Clinical versus Intracellular and Biochemical Phenotypes Induced by Chemical Chaperones. Applied Sciences. 2021; 11(13):5762. https://doi.org/10.3390/app11135762

Chicago/Turabian Style

Andersen, Elisabeth, Maria Eugenia Chollet, Francesco Bernardi, Alessio Branchini, Marcello Baroni, Guglielmo Mariani, Alberto Dolce, Angelika Batorova, Ellen Skarpen, Christiane Filion Myklebust, and et al. 2021. "The Factor VII Variant p.A354V-p.P464Hfs: Clinical versus Intracellular and Biochemical Phenotypes Induced by Chemical Chaperones" Applied Sciences 11, no. 13: 5762. https://doi.org/10.3390/app11135762

APA Style

Andersen, E., Chollet, M. E., Bernardi, F., Branchini, A., Baroni, M., Mariani, G., Dolce, A., Batorova, A., Skarpen, E., Myklebust, C. F., Skretting, G., & Sandset, P. M. (2021). The Factor VII Variant p.A354V-p.P464Hfs: Clinical versus Intracellular and Biochemical Phenotypes Induced by Chemical Chaperones. Applied Sciences, 11(13), 5762. https://doi.org/10.3390/app11135762

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