Severe factor VII deficiency caused by a novel mutation His(348) to Gln inthe catalytic domain

Factor VII is a vitamin K-dependent zymogen that plays a key role in the in itiation of the extrinsic pathway. A severe factor VII deficiency was ident ified in a 45-year old male whose plasma factor VII antigen was less than 6 0 ng/ml and expressed 5.2% of normal factor VII activity. DNA sequence anal ysis of the patient's factor VII gene showed a thymidine to guanine transve rsion at nucleotide 10968 in exon Vm that results in a novel amino acid sub stitution of His(348) to Gln. The patient was homozygous for this mutation, whereas some of his family members were heterozygous. Both wild type and m utant factor VII were transiently expressed in COS-1 cells. The level of se creted mutant factor VII antigen was only 11.0% of the level of wild type f actor VII. In CHO cells stably transfected with the mutant factor VII, only 37.3% of the total labeled FVII was secreted into the conditioned media an d the remainder was retained inside the cells. These data suggest this muta tion leads to factor VII deficiency due to the impaired secretion of the mo lecule.