Protein C deficiency caused by homozygosity for a novel PROC D180G mutation--in vitro expression and structural analysis of the mutation.
Homozygosity for a novel D180G mutation in the protease domain of protein C, associated with plasma protein C activity and antigen levels of 8% of normal was identified in a thrombosis prone family. Transient expression of protein C in HK-293 cells and analysis of protein C antigen in culture media and cell lysates showed that the secretion of mutant protein as compared with wild-type protein was reduced by 79% while the intracellular contents were similar. Computer analysis of the X-ray structure of activated protein C and of a theoretical model of the zymogen predicts that the mutation destabilises the molecule locally. Our results are compatible with a relatively unstable mutant molecule that could be trapped inside the cell and degraded. However, if secreted the mutant molecule could have a relatively normal catalytic activity and structure consistent with the plasma levels of protein C activity and the late onset of thrombosis.
D000328:Adult; D005192:Family Health; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D011486:Protein C / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020151:Protein C Deficiency / Q000209:etiology / Q000235:genetics*; D011487:Protein Conformation; D013927:Thrombosis / Q000209:etiology / Q000235:genetics; D014162:Transfection
D011486:Protein C