Evidence map›Paper›PMID 37393002›Full record

ArticleJournal of thrombosis and haemostasis : JTH2023

Molecular basis of inherited protein C deficiency results from genetic variations in the signal peptide and propeptide regions.

Qing Cao, Zhenyu Hao, Cheng Li, Xuejie Chen, Meng Gao, Nan Jiang, Hongli Liu, Yan Shen, Haiping Yang, Shujuan Zhang and 4 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of thrombosis and haemostasis : JTH, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 9 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Protein C deficiency with recurrent systemic thrombosis associated with compound heterozygousAmerican heart journal plus : cardiology research and practice · 2025
    Article
  5. Article
  6. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 5 institutions in 2 countries.

Qing CaoHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA.
Zhenyu HaoCollege of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, People's Republic of China.
Cheng LiHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.
Xuejie ChenDepartment of Biology, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Meng GaoHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.
Nan JiangCollege of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, People's Republic of China.
Hongli LiuHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; Department of Cell Biology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
Yan ShenHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.
Haiping YangHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China.
Shujuan ZhangDepartment of Cell Biology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
Aiying YangDepartment of Cell Biology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
Weikai LiDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address: weikai@wustl.edu.
Jian-Ke TieDepartment of Biology, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: jktie@email.unc.edu.
Guomin ShenHenan International Joint Laboratory of Thrombosis and Hemostasis, Henan University of Science and Technology, Luoyang, Henan, People's Republic of China; Department of Cell Biology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China. Electronic address: shenba433@163.com.
Henan University of Science and Technology · CNHarbin Medical University · CNUniversity of North Carolina at Chapel Hill · USYangzhou University · CNWashington University in St. Louis · US

Funding

STRUCTURAL AND FUNCTIONAL BASIS OF THE VITAMIN K CYCLER01HL121718 · NHLBI · WASHINGTON UNIVERSITY · PI Weikai Li · 2014 to 2026
$5.2M
Characterization of enzymes in the vitamin K cycleR01HL131690 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI STAFFORD, DARREL W, TIE, JIANKE · 2016 to 2023
$4.0M
STRUCTURAL BASIS OF SCHNYDER CORNEAL DYSTROPHYR21EY028705 · NEI · WASHINGTON UNIVERSITY · PI LI, WEIKAI, WEISS, JAYNE S · 2018 to 2019
$424k
NEI NIH HHS R21 EY028705NHLBI NIH HHS R01 HL121718NHLBI NIH HHS R01 HL131690
6 · The paper itself

Abstract

backgroundInherited protein C deficiency (PCD) caused by mutations in protein C (PC) gene (PROC) increases the risk of thrombosis. Missense mutations in PC's signal peptide and propeptide have been reported in patients with PCD, but their pathogenic mechanisms, except mutations in R42 residue, remain unclear.

objectivesTo investigate the pathogenic mechanisms of inherited PCD caused by 11 naturally occurring missense mutations in PC's signal peptide and propeptide.

methodsUsing cell-based assays, we evaluated the impact of these mutations on various aspects such as activities and antigens of secreted PC, intracellular PC expression, subcellular localization of a reporter protein, and propeptide cleavage. Additionally, we investigated their effect on pre-messenger RNA (pre-mRNA) splicing using a minigene splicing assay.

resultsOur data revealed that certain missense mutations (L9P, R32C, R40C, R38W, and R42C) disrupted PC secretion by impeding cotranslational translocation to the endoplasmic reticulum or causing endoplasmic reticulum retention. Additionally, some mutations (R38W and R42L/H/S) resulted in abnormal propeptide cleavage. However, a few missense mutations (Q3P, W14G, and V26M) did not account for PCD. Using a minigene splicing assay, we observed that several variations (c.8A>C, c.76G>A, c.94C>T, and c.112C>T) increased the incidence of aberrant pre-mRNA splicing.

conclusionOur findings suggest that variations in PC's signal peptide and propeptide have varying effects on the biological process of PC, including posttranscriptional pre-mRNA splicing, translation, and posttranslational processing. Additionally, a variation could affect the biological process of PC at multiple levels. Except for W14G, our results provide a clear understanding of the relationship between PROC genotype and inherited PCD.

Indexed as

Protein C DeficiencyHumansMutationMutation, MissenseProtein Sorting SignalsRNA, MessengerRNA PrecursorsRNA SplicingThrombophiliaProtein Sorting SignalsRNA, MessengerRNA Precursorsaberrant pre-mRNA splicinginherited protein C deficiency (PCD)missense mutationpathogenic mechanismsignal peptide and propeptidethrombophilia

Identifiers

PMID37393002
PMCPMC10592384
OpenAlexW4382562105

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.