Genotype-phenotype correlation in combined deficiency of factor V and factor VIII

Blood. 2008 Jun 15;111(12):5592-600. doi: 10.1182/blood-2007-10-113951. Epub 2008 Apr 7.


Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV. Combining the current data together with all previous published reports, we performed a genotype-phenotype analysis comparing patients with MCFD2 mutations with those with LMAN1 mutations. A previously unappreciated difference is observed between these 2 classes of patients in the distribution of plasma levels for FV and factor VIII (FVIII). Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations. No differences in distribution of factor levels are observed by sex. These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets / physiology
  • COS Cells
  • Chlorocebus aethiops
  • Factor V / metabolism
  • Factor V Deficiency / blood
  • Factor V Deficiency / genetics*
  • Factor VIII / metabolism
  • Family Health
  • Female
  • Gene Deletion
  • Genes, Recessive
  • Genotype
  • Hemophilia A / blood
  • Hemophilia A / genetics*
  • Humans
  • Male
  • Mannose-Binding Lectins / genetics*
  • Mannose-Binding Lectins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation, Missense
  • Phenotype
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism


  • LMAN1 protein, human
  • MCFD2 protein, human
  • Mannose-Binding Lectins
  • Membrane Proteins
  • Vesicular Transport Proteins
  • Factor V
  • Factor VIII