Factor VII R110C: a novel missense mutation (Arg110Cys) in the second epidermal growth factor-like domain causing...

This report describes the findings of a genetic analysis of the factor VII (FVII) gene in a Japanese, male patient with FVII deficiency. The proband showed FVII activity level of 25% and FVII antigen level of 28% of the normal value, but he had no severe bleeding episodes. We identified the mutation by direct sequencing of polymerase chain reaction products representing all exons except 1b and their flanking intronic regions of his FVII gene. We detected a single point mutation, a C-->T substitution at nucleotide position 7863 in exon 5, which results in an amino acid replacement of Arg (CGC) to Cys (TGC) at codon 110 in the second epidermal growth factor-like domain. Homozygosity was confirmed in the propositus by loss of a site for the restriction endonuclease Eco47III. Furthermore, his parents, who had moderately reduced levels of factor VII activity and antigen, carried this mutation site as a heterozygote. Although the Arg11O residue is located distal to the tissue factor (TF) in the soluble TF-FVIIa crystal structure, we infer that the replacement of the positively charged and larger Arg residue with a neutral Cys residue may be likely to impair proper folding, resulting in destabilization of the protein structure.