title: Factor VIII Ise (R2159C) in a patient with mild hemophilia A, an abnormal factor VIII with retention of function but modification of C2 epitopes.
abstract: We found a patient with mild hemophilia A who had no detectable factor VIII antigen (FVIII:Ag), as shown by two-site ELISA using inhibitor alloantibodies (TK). We then analyzed A2, A2/B, and C2 antigen of the patient's DDAVP-induced FVIII using several anti-FVIII monoclonal antibodies. Factor VIII activity (FVIII:C) was increased from 12 to 42 U/dl by the administration of DDAVP. The DDAVP-induced increases in the A2 and A2/B antigens were 40 and 36 U/dl, respectively. However, the increase in the C2 antigen was only 7.5 U/dl. SSCP analysis and subsequent sequencing demonstrated an Arg to Cys transition at codon 2159. The anti-FVIII:C titer of monoclonal antibody, NMC-VIII/5 which recognized the C2 domain, against normal plasma was 450 Bethesda U/mg of IgG. However, the titer against DDAVP-treated patient's plasma was only 15 Bethesda U/mg. We also tested DDAVP-induced increase in the FVIII:Ag in another mild hemophilia A patient with the same mutation at Arg2159. Increase in his C2 antigen levels was only 19% of those in the A2 and A2/B antigen. We designate this abnormal FVIII as FVIII Ise. Our results show that a missense mutation at Arg2159 to Cys modifies the antigenicity of the C2 domain.
authors.affiliation: Department of Pediatrics, Nara Medical University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Shima
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.forename: K
authors.initials: K
authors.lastname: Kagawa
authors.forename: K
authors.initials: K
authors.lastname: Fukutake
authors.forename: S
authors.initials: S
authors.lastname: Kamisue
authors.forename: H
authors.initials: H
authors.lastname: Nakai
authors.forename: S
authors.initials: S
authors.lastname: Morichika
authors.forename: I
authors.initials: I
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Gale
authors.forename: E G
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: A
authors.initials: A
authors.lastname: Yoshioka
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D001120:Arginine; D001483:Base Sequence; D003545:Cysteine; D017931:DNA Primers; D003894:Deamino Arginine Vasopressin; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000032:analysis / Q000737:chemistry; D005091:Exons; D005169:Factor VIII / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D006801:Humans; D007518:Isoantibodies; D008297:Male; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D014841:von Willebrand Factor / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D000939:Epitopes; D007518:Isoantibodies; C107159:factor VIII Ise; D014841:von Willebrand Factor; D005169:Factor VIII; D001120:Arginine; D003894:Deamino Arginine Vasopressin; D003545:Cysteine