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 amido lytic and clotting functional assays, was investigated by direct seque ncing of PCR fragments derived from the coding portion of the protein C gene. A G (8856) to A transition was noted in the patient which was not present in healthy controls. This mutation is predicted to cause t he substitution of Ser for Gly 381, an evolutionarily conserved residu e in the substrate binding pocket of serine-proteases (Gly 216, chymot rypsin numbering). A computer model of the structure of the serine-pro tease domain indicates that the properties of the altered protein C mo lecule can be explained on the basis of steric hindrance between the s ubstituted serine and the substrate arginine side chains.