CHARACTERIZATION OF A SPLICING MUTATION IN THE FACTOR-VIII GENE AT THE RNA LEVEL

Haemophilia A is an X-linked bleeding disorder caused by mutations in the coagulation factor VIII (FVIII) gene. The identification and chara cterization of naturally occurring disease-producing mutations allows the recognition of new mechanisms of pathogenesis in haemophilia A. An alysis of the illegitimately transcribed FVIII mRNA in a severely affe cted patient has revealed that the A-->G transition at position -2 of the acceptor splice site of intron 4 results in the skipping of exon 5 in 90% of the processed pre-mRNA. Another minor mRNA species arising from the skipping of exons 4 and 5 has also been observed. The skippin g of exon 5 predicts the removal of the corresponding 13 amino acids f rom the A1 domain of FVIII. A novel missense mutation, C329S, in exon 8 of FVIII gene has been identified in another patient.