Titre :

Identification of von Willebrand factor D4 domain mutations in patients of Afro‐Caribbean descent: In vitro characterization

Auteur(s) :

Dubois, Marie‐daniéla [Auteur]
Hémostase, Inflammation, Thrombose [HITH - U1176 Inserm - CHU Bicêtre]
Vulnérabilité cardiovasculaire, pathologie métabolique et endocrinienne [VCPME]
Peyron, Ivan [Auteur]
Hémostase, Inflammation, Thrombose [HITH - U1176 Inserm - CHU Bicêtre]
Pierre-Louis, Olivier‐nicolas [Auteur]
Vulnérabilité cardiovasculaire, pathologie métabolique et endocrinienne [VCPME]
Pierre-Louis, Serge [Auteur]
Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique] [CHU de Martinique]
Rabout, Johalène [Auteur]
Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique] [CHU de Martinique]
Boisseau, Pierre [Auteur]
Centre Hospitalier Universitaire de Nantes = Nantes University Hospital [CHU Nantes]
de Jong, Annika [Auteur]
Susen, Sophie [Auteur]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U 1011 [RNMCD]
Goudemand, Jenny [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Neviere, Rémi [Auteur]
Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique] [CHU de Martinique]
Fuseau, Pascal [Auteur]
Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique] [CHU de Martinique]
Christophe, Olivier [Auteur]
Hémostase, Inflammation, Thrombose [HITH - U1176 Inserm - CHU Bicêtre]
Lenting, Peter [Auteur]
Hémostase, Inflammation, Thrombose [HITH - U1176 Inserm - CHU Bicêtre]
Denis, Cécile [Auteur]
Hémostase, Inflammation, Thrombose [HITH - U1176 Inserm - CHU Bicêtre]
Casari, Caterina [Auteur]
Hémostase, Inflammation, Thrombose [HITH - U1176 Inserm - CHU Bicêtre]

Titre de la revue :

Research and Practice in Thrombosis and Haemostasis

Pagination :

e12737

Éditeur :

Wiley

Date de publication :

2022

ISSN :

2475-0379

Mot(s)-clé(s) en anglais :

binding assays
intracellular retention
recombinant proteins
von Willebrand disease
von Willebrand factor

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Hématologie
Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire/Génomique, Transcriptomique et Protéomique [q-bio.GN]
Sciences du Vivant [q-bio]/Génétique/Génétique humaine

Résumé en anglais : [en]

Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene (VWF) revealed the presence of multiple variants located throughout the gene, including variants located in the ...
Lire la suite >Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene (VWF) revealed the presence of multiple variants located throughout the gene, including variants located in the D4 domain of VWF: p.(Pro2145Thrfs*5) in one patient and p.(Cys2216Phefs*9) in the other patient. Interestingly, D4 variants have not been studied often.Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/secretion and functions using in vitro assays.Methods: Recombinant VWF (rVWF), mutant or wild-type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild-type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated.Results: Homozygous expression of the p.(Cys2216Phefs*9)-rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild-type-rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)-rVWF exhibited reduced binding to type III collagen and αIIbβ3 integrin compared to wild-type-rVWF.Conclusions: We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (RNMCD) - U1011

Source :

Harvested from HAL