Factor VI359T: a novel mutation associated with thrombosis and resistance to activated protein C

Research output: Contribution to journalArticle

Abstract

We report a kindred in which two siblings suffered spontaneous venous thromboses in the second decade of life. Further investigation showed reduced coagulation factor V (FV) activity and activated protein C resistance (APCR) ratio but no other thrombophilic abnormalities. The reduction in APCR ratio persisted in a modified APCR assay in which FV activity was normalized between test and control plasmas. Analysis of the FV gene showed that the thrombotic individuals had a complex genotype that included two novel point mutations c.529G>T and c.1250T>C resulting in FV E119X and FV I359T substitutions inherited on different alleles. Individuals in the kindred with FV E119X or FV I359T substitutions alone were asymptomatic. We suggest that the FV I359T substitution confers pro-thrombotic risk and APCR, but that this is only clinically manifest when co-inherited with the FV E119X allele. The FV I359T substitution creates a new consensus sequence for N-linked glycosylation within the FV heavy chain and we speculate that this abnormal glycosylation may disrupt activated protein C-mediated proteolysis of the variant FV and FVa.

Details

Authors
  • AD Mumford
  • JH McVey
  • CV Morse
  • K Gomez
  • Mårten Steen
  • Eva Norström
  • EGD Tuddenham
  • Björn Dahlbäck
  • PHB Bolton-Maggs
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology

Keywords

  • thrombosis, factor V, mutation, activated protein C resistance
Original languageEnglish
Pages (from-to)496-501
JournalBritish Journal of Haematology
Volume123
Issue number3
Publication statusPublished - 2003
Publication categoryResearch
Peer-reviewedYes