Two novel mutations in severe factor VII deficiency

We have characterized the molecular defect in two families with severe factor VII (FVII) deficiency. In family I, the proband was found to be homozygous for a novel 18 bp deletion in exon 8 (g.10896-10913del) resulting in the in-frame deletion of six amino acids in the serine protease domain. Molecular modelling suggests the deletion is likely to disrupt folding of the FVII molecule. The reduced FVII antigen (21 U/dl) and negligible activity (0.4 U/dl) in the patient's plasma indicated that the deletion affected both the secretion/stability and function of the mutant protein. In family II, the proband was found to be a compound heterozygote for a novel missense mutation (g.7884G>A; FVII G117R) in exon 5 encoding the EGF2 domain of FVII and a nonsense mutation (g.8960C>T; FVII R152X) in exon 6. Extensive sequence comparison in a wide evolutionary context suggested that the Gly117 residue is critical for structure of FVII. The grossly reduced FVII antigen (1.1 U/dl) and activity (0.4 U/dl) plasma values indicate the mutation primarily affected the folding/secretion or stability of the protein.