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<p>Hereditary protein C (PC) deficiency is an inherited thrombophilic disorder caused by variants in the PC gene (<i>PROC</i>). We identified a novel <i>PROC</i> variant, c.302G&gt;T, p.Cys101Phe (C101F), in a patient with type I PC deficiency. We analyzed the intracellular dynamics of the C101F variant of PC (PC-C101F) to elucidate the pathogenic mechanism underlying this condition. Wild-type PC (PC-WT) and PC-C101F were transiently expressed in HEK293 cells for expression and functional analyses. The PC antigen levels in the cell lysate and culture supernatant of PC-C101F-expressing cells were significantly lower than those of PC-WT-expressing cells. In cycloheximide (CHX) chase experiments, the intracellular PC antigen level gradually decreased in PC-C101F-expressing cells, but remained stable at 0 and 6&#xa0;h in the presence of CHX/MG132. No significant difference in co-localization with the endoplasmic reticulum was observed between PC-C101F and PC-WT. 101Cys forms a disulfide bond with 106Cys, which is crucial for maintaining the conformation of PC. PC-C101F likely results in protein misfolding and proteasomal degradation, leading to type I PC deficiency. These findings highlight the importance of cysteine residues in the three-dimensional structure of PC and provide insight into the mechanism of type I PC deficiency.</p>

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The novel protein C variant p.C101F results in early intracellular degradation that drives type I protein C deficiency

  • 期刊论文

  • 发表日期：

    2025年2月10日

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  • Rikuto Yui,
  • Satomi Nagaya,
  • Ibuki Yasuda,
  • Tomoki Togashi,
  • Yuika Kikuchi,
  • Kengo Saito,
  • Makiko Meguro-Horike,
  • Shin-Ichi Horike,
  • Hiroshi Kawasaki,
  • Hidekazu Nishikii,
  • Eriko Morishita

摘要

Hereditary protein C (PC) deficiency is an inherited thrombophilic disorder caused by variants in the PC gene (PROC). We identified a novel PROC variant, c.302G>T, p.Cys101Phe (C101F), in a patient with type I PC deficiency. We analyzed the intracellular dynamics of the C101F variant of PC (PC-C101F) to elucidate the pathogenic mechanism underlying this condition. Wild-type PC (PC-WT) and PC-C101F were transiently expressed in HEK293 cells for expression and functional analyses. The PC antigen levels in the cell lysate and culture supernatant of PC-C101F-expressing cells were significantly lower than those of PC-WT-expressing cells. In cycloheximide (CHX) chase experiments, the intracellular PC antigen level gradually decreased in PC-C101F-expressing cells, but remained stable at 0 and 6 h in the presence of CHX/MG132. No significant difference in co-localization with the endoplasmic reticulum was observed between PC-C101F and PC-WT. 101Cys forms a disulfide bond with 106Cys, which is crucial for maintaining the conformation of PC. PC-C101F likely results in protein misfolding and proteasomal degradation, leading to type I PC deficiency. These findings highlight the importance of cysteine residues in the three-dimensional structure of PC and provide insight into the mechanism of type I PC deficiency.