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Functional characterization of two protein C variants causing type I deficiency via cellular degradation or retention

Ibuki Yasuda1, Satomi Nagaya1, Rikuto Yui1

  • 1Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa, 920-0942, Japan.

International Journal of Hematology
|September 24, 2025
PubMed

Insights

Two protein C (PC) gene variants, L173P and V241L, cause hereditary thrombotic disorders by impairing PC secretion. L173P leads to degradation, while V241L causes ER retention, revealing distinct molecular defects in type I PC deficiency.

Area of Science:

  • Genetics
  • Molecular Biology
  • Hematology

Background:

  • Hereditary protein C (PC) deficiency is a genetic thrombotic disorder.
  • It is caused by mutations in the PC gene (PROC).
  • Understanding the molecular mechanisms of PC deficiency is crucial for managing thrombosis.

Purpose of the Study:

  • To investigate the functional consequences of two PROC variants (L173P and V241L) found in Japanese families with venous thrombosis.
  • To elucidate the distinct intracellular mechanisms leading to type I PC deficiency caused by these variants.

Main Methods:

  • Constructed PC expression vectors for wild-type and variant proteins (PC-L173P, PC-V241L).
  • Expressed vectors in human embryonic kidney 293 cells.
  • Analyzed cell lysates and supernatants using Western blotting and evaluated intracellular trafficking.

Main Results:

  • Both PC-L173P and PC-V241L showed significantly reduced extracellular secretion compared to wild-type PC.
  • PC-L173P underwent proteasome-mediated intracellular degradation.
  • PC-V241L accumulated within the endoplasmic reticulum, indicating retention.

Conclusions:

  • Type I PC deficiency can result from distinct secretion defects, including intracellular degradation and ER retention.
  • The differing intracellular fates of PC-L173P and PC-V241L are likely due to mutation site and amino acid properties.
  • These findings highlight the heterogeneity in the molecular pathophysiology of type I PC deficiency.

Keywords:
Endoplasmic reticulum retentionEndoplasmic reticulum-associated degradationMissense variantProtein C deficiencySecretion defect

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