Dysfunctional Factor VII Variant (FVII Tondabayashi) with R79Q: Determination of Mutated Site with Monoclonal Anti-Human Factor VII Antibody (B101/B1)

Abstract

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder that occurs in roughly 1 out of 500 000 people. Although some patients with homozygous FVII deficiency have a life-long tendency to bleed, a coincident thromboembolic complication has been reported (1) . In general, the bleeding tendency of FVII deficiency is not as severe as that of hemophilia. The clinical features are quite variable, with a rather poor correlation between measured coagulation activity and clinical bleeding tendency (2) . In laboratory testing, FVII deficiency has been divided into three types: cross-reactive material (CRM)− type, with decreased synthesis of the FVII molecule; CRM+, with decreased FVII activity but an antigen concentration within reference values; and CRMR, with reduced synthesis of FVII (3) . Specific FVII variants have been characterized as FVII molecules that give different procoagulant activities using tissue factor (TF) from various sources, such as human, rabbit, and bovine brain TF (4)(5)(6) . Some of the dysfunctional FVII variants possess either an Arg 79-to-Gln substitution in the first epidermal growth factor (EGF)-like domain or an Arg 353-to-Gln substitution in the catalytic domain of FVII (7)(8)(9)(10)(11) . In the present study, using an ELISA with the monoclonal antibody that recognizes a specific epitope located in the three-dimensional structure near position 79 in the first EGF-like domain of human FVII (12) , we determined the mutated site of a dysfunctional FVII variant that possessed different FVII activity with human placental TF than with rabbit and ox brain TF. The propositus was a 12-year-old girl with FVII deficiency. She was born at 36 weeks gestation, had no hemorrhagic problems, and showed no evidence of abnormal hepatic function either at birth or later. Her parents were …