COMPOUND HETEROZYGOUS PROTEIN-C DEFICIENCY CAUSED BY 2 MUTATIONS, ARG-178 TO GLN AND CYS-331 TO ARG, LEADING TO IMPAIRED SECRETION OF MUTANT PROTEIN-C

The protein C gene in a patient apparently homozygous for protein C de ficiency was analyzed. Two different point mutations, each located in a different allele, were detected to reveal that the patient is a comp ound heterozygote. Mutation of Arg-178 (CGG) to Gin (CAG) [mutation I] was detected in exon VII: in the vicinity of activation peptide cleav age site by thrombin. Mutation of Cys-331 (TGC) to Arg (CGC) [mutation II] was found in exon IX, at one of the sites involved in disulfide b ond formation in the catalytic domain of the heavy chain. The alterati on of Cys-331 to Arg disables the formation of the disulfide bond and would alter the protein conformation. Transient expression assays usin g COS-7 cells transfected with protein C expression vectors containing each one of these two mutations suggested that each of the two mutati ons would lead to the protein C deficiency by an impairment of secreti on of the respective mutant proteins.