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The following is a summary of “Novel protein C variant p.C101F results in early intracellular degradation that drives type I protein C deficiency,” published in the February 2025 issue of the International Journal of Hematology by Yui et al.
Researchers conducted a retrospective study and identified a novel PC gene (PROC) variant, c.302G>T, p.Cys101Phe (C101F), in a patient with type I protein C (PC) deficiency, an inherited thrombophilic disorder caused by variants in the PROC.
They analyzed PC-C101F intracellular dynamics to determine its pathogenic mechanism. They transiently expressed PC-WT and PC-C101F in HEK293 cells for expression and functional analyses. PC antigen levels in the lysate and supernatant of PC-C101F-expressing cells were significantly lower than in PC-WT-expressing cells. In cycloheximide (CHX) chase experiments, intracellular PC antigen levels decreased in PC-C101F-expressing cells but remained stable at 0 and 6 h with CHX/MG132. No significant difference in endoplasmic reticulum co-localization was observed between PC-C101F and PC-WT.
The results showed 101Cys formed a disulfide bond with 106Cys, crucial for PC conformation.
Investigators found PC-C101F led to protein misfolding and proteasomal degradation, causing type I PC deficiency. They highlighted the role of cysteine residues in PC structure and disease mechanism.
Source: link.springer.com/article/10.1007/s12185-025-03943-z
