Symptomatic type II protein C deficiency caused by a missense mutation (Gly 381-->Ser) in the substrate-binding pocket.

A patient with recurrent deep vein thrombosis and heterozygous type II deficiency, characterized by reduced protein C activity in both amidolytic and clotting functional assays, was investigated by direct sequencing of PCR fragments derived from the coding portion of the protein C gene. AG (8856) to A transition was noted in the patient which was not present in healthy controls. This mutation is predicted to cause the substitution of Ser for Gly 381, an evolutionari'y conserved residue in the substrate binding pocket of serine-proteases (Gly 216, chymotrypsin numbering). A computer model of the structure of the serine-protease domain indicates that the properties of the altered protein C molecule can be explained on the basis of steric hindrance between the substituted serine and the substrate arginine side chains.