F X Nottingham and F X Taunton two novel mutations in factor X resulting in loss of functional activity and an interpretation using molecular modelling

We report two novel mutations in the Factor X gene which result in a bleedi ng tendency in two unrelated Caucasian families. Although the mutations occ ur at adjacent codons in exon 8 and result in reduced functional activity w ith normal antigen levels, the patterns of inheritance appear to be quite d istinct. Factor X Nottingham (alanine 404 threonine) appears to be associat ed with an autosomal recessive pattern of inheritance. In contrast, Factor X Taunton (arginine 405 glycine) results in a mode of inheritance consisten t with an autosomal dominant pattern, all five of the heterozygotes in this family being clinically affected. Molecular modelling studies suggest that , in the case of Factor X Nottingham, a drastic conformational change cause s major unfolding of the protein. For Factor X Taunton, less extreme confor mational changes occur causing loss of functional activity such that substr ate binding sites might be maintained. It is proposed that competition with wild type for substrate binding could occur leading to a dominant negative effect.