Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses

Thromb Haemost. 2002 Feb;87(2):273-6.


Heteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII: of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Amino Acid Substitution
  • Codon / genetics
  • Codon, Nonsense
  • DNA Mutational Analysis
  • Exons / genetics
  • Factor VIII / genetics*
  • Factor VIII / immunology
  • Female
  • Gene Deletion
  • Hemophilia A / genetics*
  • Hemophilia A / immunology
  • Heteroduplex Analysis*
  • Humans
  • Isoantibodies / immunology*
  • Male
  • Mutation*
  • Mutation, Missense
  • Nucleic Acid Heteroduplexes / genetics
  • RNA Splice Sites / genetics


  • Codon
  • Codon, Nonsense
  • Isoantibodies
  • Nucleic Acid Heteroduplexes
  • RNA Splice Sites
  • Factor VIII