Novel factor V C2-domain mutation (R2074H) in two families with factor V deficiency and bleeding

Thromb Haemost. 2002 Feb;87(2):294-9.

Abstract

The molecular basis of Factor V deficiency has been defined in few patients only. We report a homozygous nucleotide change (G6395A) in two Tunisian probands with Factor V deficiency and bleeding episodes. This substitution results in the replacement of an arginine (R) by a histidine (H) in amino acid position 2074, located in the Factor V C2-domain. Mutations in this protein domain have not previously been described. Several lines of evidence support that this sequence variant is indeed disease causing: 1) Crystal structures of Factor V and molecular C2-domain modeling studies of H2074 suggest that the conserved R2074 is required for correct folding; 2) Structure-function studies of selective Factor V mutants (R2074A) demonstrate the importance of R2074 for structural stability of the Factor V C2-domain and for cofactor activity (1); 3) In Factor VIII, point mutations in codon 2209, which corresponds to position 2074 in Factor V, cause hemophilia A.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution*
  • Consanguinity
  • Diseases in Twins
  • Factor V / chemistry
  • Factor V / genetics*
  • Factor V Deficiency / genetics*
  • Female
  • Humans
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense*
  • Pedigree
  • Point Mutation*
  • Protein Conformation
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Tunisia

Substances

  • Factor V