The molecular basis of haemophilia A and B

Most families with haemophilia A or B carry gene defects of independent origin. Haemophilia B is mostly due to small changes in the factor IX gene affecting either its transcription, mRNA maturation, mRNA translation or the fine structure of factor IX. Only 2-3% of patients show gross deletions or rearrangements. The great variety of missense mutations reported to cause haemophilia B indicates that this multidomain protein is highly constrained. Less is known about the factor VIII gene as fully efficient mutation detection procedures only became available in 1991. This, however, led to the discovery that almost half the severe cases of haemophilia A or a fifth of all cases are due to frequently occurring inversions caused by homologous intra-chromosome (-chromatid) recombination between repeated sequences 9.5 kb long. Of the three repeats one is in intron 22 of the factor VIII gene and two are 400-500 kb more telomeric. They are 99.8% similar to each other. The spectrum of the other haemophilia A mutations is similar to that of haemophilia B. Since 1983 mounting evidence has shown that in both haemophilias the nature of the mutation is important in predisposing to the inhibitor complication. With regard to genetic counselling the best way to provide this service is through the construction of national confidential databases of mutations and pedigrees, as indicated by work in the UK on haemophilia B now being extended to haemophilia A.