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Functional characterization of Factor V-Ile359Thr, a novel mutation associated with thrombosis.

In English

Författare

Summary, in English

A missense mutation, FV-IIe359Thr (FV Liverpool), associated with thrombosis has recently been described. This mutation creates an additional potential N-linked glycosylation site (Asn-X-Ser/Thr) in factor V (FV) at Asn357 that could interfere with secretion and/or protein interactions. To investigate the molecular pathology of FV-IIe359Thr, the mutation was created by site-directed mutagenesis and expressed together with other mutations that could help explain the phenotype (FV-Arg306GIn/IIe359Thr/Arg679GIn, FV-IIe359Thr/Arg506GIn/Arg679GIn, and FV-Asn357GIn/IIe359Thr). The FV-IIe359Thr was secreted normally and had full procoagulant activity. Western blot analysis showed that FV-IIe359Thr migrated more slowly, while the FV-Asn357GIn/IIe359Thr was indistinguishable from FV-wild type (FV-WT), indicating that FV-IIe359Thr was expressed with an additional carbohydrate chain. Activated protein C (APC)-mediated inactivation in an FVa degradation assay showed that the IIe359Thr mutation significantly reduced the cleavage at Arg306 both in the presence and absence of protein S, whereas the cleavage at Arg506 was unaffected. When tested in an FVIIIa degradation assay, the FV-IIe359Thr variant exhibited equally low APC cofactor activity as FV Leiden (FVArg506GIn). In conclusion, the IIe359Thr mutation appears to affect anticoagulation by 2 mechanisms, impeding the APCmediated down-regulation of the FVa molecule and additionally being a poor APC cofactor for the down-regulation of FVIIIa. These findings explain the association of the FV-IIe359Thr mutation with thrombosis. (C) 2004 by The American Society of Hematology.

Publiceringsår

2004

Språk

Engelska

Sidor

3381-3387

Publikation/Tidskrift/Serie

Blood

Volym

103

Issue

9

Dokumenttyp

Artikel i tidskrift

Förlag

American Society of Hematology

Ämne

  • Hematology

Status

Published

Forskningsgrupp

  • Clinical Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1528-0020