Compound heterozygous protein C deficiency caused by two 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 deficiency was analyzed. Two different point mutations, each located in a different allele, were detected to reveal that the patient is a compound heterozygote. Mutation of Arg-178 (CGG) to Gln (CAG) [mutation I] was detected in exon VII, in the vicinity of activation peptide cleavage 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 bond formation in the catalytic domain of the heavy chain. The alteration of Cys-331 to Arg disables the formation of the disulfide bond and would alter the protein conformation. Transient expression assays using COS-7 cells transfected with protein C expression vectors containing each one of these two mutations suggested that each of the two mutations would lead to the protein C deficiency by an impairment of secretion of the respective mutant proteins.
Sugahara
Y
Y
First Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Miura
O
O
Hirosawa
S
S
Aoki
N
N
D000483:Alleles; D001120:Arginine / Q000235:genetics*; D001483:Base Sequence; D003545:Cysteine / Q000235:genetics*; D005973:Glutamine / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011486:Protein C / Q000235:genetics / Q000502:physiology; D020151:Protein C Deficiency; D012636:Secretory Rate / Q000235:genetics; D014162:Transfection
D011486:Protein C; D005973:Glutamine; D001120:Arginine; D003545:Cysteine