Titre

Molecular basis of coagulation factor V deficiency caused by the R1698W inter-domain mutation.

Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Calzavarini, S.
Auteure/Auteur
Villoutreix, B.O.
Auteure/Auteur
Lunghi, B.
Auteure/Auteur
Livaja, R.
Auteure/Auteur
Bernardi, F.
Auteure/Auteur
Dahlbäck, B.
Auteure/Auteur
Liens vers les unités
ISSN
0340-6245
Statut éditorial
Publié
Date de publication
2013
Volume
110
Numéro
1
Première page
31
Dernière page/numéro d’article
38
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article Publication Status: ppublish
Résumé
Coagulation factor V (FV) deficiency is characterised by variable bleeding phenotypes and heterogeneous mutations. To add new insights into the FV genotype-phenotype relationship, we characterised the R1698W change in the A3 domain, at the poorly investigated interface with the A2 domain. The FV R1698W mutation was responsible for a markedly reduced expression level (10% of FV-WT) and specific activity in thrombin generation (0.39). Interestingly, the FVa1698W showed rapid activity decay upon activation due to increased dissociation rate between the heavy and light chains. The importance of the size and charge of the residue at position 1698 was investigated by three additional recombinant mutants, FVR1698A, FVR1698Q, and FVR1698E. FVR1698A and FVR1698Q expression (30 and 45% of FV-WT), specific activity (both 0.57) and stability were all reduced. Noticeably, FVR1698E showed normal activity and stability despite poor expression (10% of FV-WT). These data indicate the essential role of R1698 for normal biosynthetic process and support local flexibility for positively or negatively charged residues to produce stable and functional A3-A2 domain interactions. Their experimental alteration produces a gradient of FV defects, which help to interpret the wide spectrum of phenotypes in FV-deficient patients.
PID Serval
serval:BIB_828CDE251F10
DOI
PMID
WOS
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Date de création
2013-08-11T07:40:52.370Z
Date de création dans IRIS
2025-05-20T20:58:21Z