A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins

Br J Haematol. 1998 Dec;103(4):1051-60. doi: 10.1046/j.1365-2141.1998.01122.x.


A variety of mutations are found in haemophilia A families. Those with circulating, dysfunctional protein can provide insights into structural determinants of factor VIII function. A molecular model based upon the crystal structure of the homologous A domains in caeruloplasmin enables predictions of molecular consequences of mutations. To identify haemophilic mutations in coding regions for three A domains of factor VIII and predict amino acid substitutions important for coagulant cofactor function, amplified DNA fragments from 188 unrelated haemophilia A families were screened for heteroduplex formation. Exons 1-19 were examined. 65 families were positive for 58 distinct mutations (39 novel) on DNA sequencing. 12 were non-missense mutations. 38 missense mutations were found in patients that circulate or potentially circulate dysfunctional factor VIII protein and are in an A domain molecular model. Of these 38, 12 have identical residues among all known species of factors V, VIII and caeruloplasmin. These 38 mutations have been localized onto a factor VIII A domain molecular model. Of these, 19 are in coiled, 15 in beta-pleated sheet, and two each in turns and alpha-helical structures. 15 substituted residues are on the surface, nine are partially on the surface and 14 are buried within the model structure. Mutant side-chain substitutions were inserted to predict changes in surface groups or, for buried residues, potential surface areas whose structure is probably disrupted by the substitution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Exons / genetics
  • Factor VIII / genetics*
  • Female
  • Hemophilia A / genetics*
  • Humans
  • Male
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Pedigree
  • Polymerase Chain Reaction / methods
  • Sequence Homology, Amino Acid
  • src Homology Domains


  • Factor VIII