A mutation adjacent to the beta cleavage site of factor IX (valine 182 to leucine) results in mild haemophilia Bm.

The genetic basis of a mild form of haemophilia Bm has been investigated. The patient under investigation has a mild bleeding disorder and has never experienced spontaneous bleeds. Factor IX coagulant activity (FIX:C) was 0.15 units/ml and factor IX antigen (FIX:Ag) 1.32 units/ml. The prothrombin time performed with an ox brain thromboplastin was 65 s (normal plasma 31 s). Studies of the abnormal factor IX protein in this patient showed a normal molecular weight and normal calcium binding properties. Activation of the mutant factor IX with factor XIa showed normal proteolytic cleavage. DNA sequence from the eight factor IX exons and flanking introns was amplified from this patient using the polymerase chain reaction. The amplified material was subjected to direct chain termination nucleotide sequencing. The only nucleotide sequence alteration found was a G----C transversion at nucleotide 20,524, changing the amino acid encoded at residue 182 from valine to leucine. This residue is one amino acid removed from the beta cleavage site of factor IX. This residue is highly conserved in other vitamin K dependent serine proteases and we propose that its alteration in this patient is responsible for his mild haemophilic phenotype, and for the abnormal interaction of this factor IX protein with the extrinsic system of coagulation.