Of four mutations in the factor VII gene in Tunisian patients, one novel mutation (Ser339Phe) in three unrelated families abrogates factor X activation

Hereditary factor VII (FVII) deficiency is a rare bleeding disorder. Dysfunctional FVII variants characterized by normal or reduced levels of FVII antigen and discordantly low FVII activity have been described. In this study, seven unrelated Tunisian patients with FVII deficiency were examined. Molecular analysis revealed that three probands harbored a novel Ser339Phe mutation, one proband was inferred to have a novel splice site mutation in intron 2, c.226-2 A>G and three probands had two previously described mutations, Arg304Gln and Cys310Phe. Expression of Ser339Phe in baby hamster kidney cells yielded secretion of FVII antigen at a concentration of 225 ± 50 ng/ml, compared with 181 ± 47 ng/ml in cells transfected with wild-type FVII but with no demonstrable FVII activity. FVII Ser339Phe bound to tissue factor similarly to the binding of commercial recombinant activated FVII or recombinant wild-type FVII and was normally activated by activated factor X. The major defect of FVII Ser339Phe was its inability to activate factor X in the presence of tissue factor. Modeling predicted that the substitution of Ser339 by Phe abrogated substrate docking.