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Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency

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Abstract

We report three heterozygous PROS1 mutations that caused type I protein S deficiency in three unrelated Chinese families. We measured protein S activity and antigen levels for all participants, screened them for mutations in the PROS1 gene. And we employed the calibrated automated thrombin generation (CAT) method to investigate thrombin generation. Numerous bioinformatics tools were utilized to analyze the conservation, pathogenicity of mutation, and spatial structure of the protein S. Phenotyping analysis indicated that all three probands exhibited simultaneous reduced levels of PS:A, TPS:Ag, and FPS:Ag. Genetic testing revealed that proband A harbored a heterozygous c.458_458delA (p.Lys153Serfs*6) mutation in exon 5, proband B carried a heterozygous c.1687C>T (p.Gln563stop) mutation in exon 14, and proband C exhibited a heterozygous c.200A>C (p.Glu67Ala) mutation in exon 2. Bioinformatic analysis predicted that the p.Lys153Serfs*6 frameshift mutation and the p.Gln563stop nonsense mutation in the protein S were classified as “disease-causing.” The identification of the novel mutation p.Lys153Serfs*6 in PROS1 enriches the Human Genome Database. Our research suggests that these three mutations (p.Lys153Serfs*6, p.Gln563stop, and p.Glu67Ala) are possibly responsible for the decreased level of protein S in the three families. Furthermore, the evidence also supports the notion that individuals who are asymptomatic but have a family history of PSD can benefit from genetic analysis of the PROS1 gene.

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Data availability

The data that support the conclusions of this study are available from the corresponding author upon request. Further inquiries can be directed to the corresponding author.

Abbreviations

PROS1 gene:

protein S1 gene

PSD:

protein S deficiency

CAT:

calibrated automated thrombin generation

PS:A:

protein S activity

TPS:Ag:

total protein S antigen

FPS:Ag:

free protein S antigen

PC:

protein C

APC:

activated PC

TFPI:

tissue factor inhibitor

VTE:

venous thromboembolism

MRI:

magnetic resonance imaging

CT:

computed tomography

PE:

pulmonary embolism

MRV:

magnetic resonance venography

PT:

prothrombin time

APTT:

activated partial thromboplastin time

D-D:

D-dimer

PC:A:

protein C activity

AT:A:

anti-thrombin activity

PPP:

platelet-poor plasma

ELISA:

enzyme-linked immunosorbent assay

TGT:

thrombin generation test

ETP:

endogenous thrombin potential

sTM:

soluble recombinant human thrombomodulin

PCR:

polymerase chain reaction

PDB:

Protein Data Bank

EGF:

epidermal growth factor

LGR:

liver growth factor

TSR:

thrombin-sensitive region

PF:

purpura fulminans

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Funding

This work was funded by the Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province (2022E10022) and the Science and Technology Plan Fund of Wenzhou (Y20220125).

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Authors and Affiliations

  1. Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Fei Xu, Xingxing Zhou, Yanhui Jin, Lihong Yang, Jingye Pan & Mingshan Wang

  2. Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, Ouhai District, Wenzhou, Zhejiang, 325000, China

    Xiaoli Chen

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  1. Fei Xu
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  2. Xingxing Zhou
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  3. Yanhui Jin
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  4. Lihong Yang
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  7. Xiaoli Chen
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Contributions

All the authors have made significant contributions to the study’s conception and design, data acquisition, analysis and interpretation, as well as to the drafting and critical revision of the manuscript for important intellectual content. Furthermore, all the authors have provided their final approval for the submitted version of the article.

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Correspondence to Xiaoli Chen.

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Xu, F., Zhou, X., Jin, Y. et al. Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency. Ann Hematol 103, 653–662 (2024). https://doi.org/10.1007/s00277-023-05607-6

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  • DOI: https://doi.org/10.1007/s00277-023-05607-6

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