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Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism

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Abstract

Objective: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. Methods: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. Results: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). Conclusion: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

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No datasets were generated or analysed during the current study.

References

  1. Liu S, Yu F, Luo S et al (2020) Phenotypic and genotypic analysis of a heterozygous deletion mutation in a family with inherited protein C deficiency. Chin J Med Genet 37(10):1108–1112. https://doi.org/10.3760/cmaJ.c. n511374-20190625-00312

    Article  Google Scholar 

  2. Griffin JH, Evatt B, Zimmerman TS et al (1981) Deficiency of protein C in congenital thrombotic disease. J Clin Invest 68(5):1370–1373. https://doi.org/10.1172/jci110385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen C, Yang L, Villoutreix BO et al (2017) Gly74Ser mutation in protein C causes thrombosis due to a defect in protein S-dependent anticoagulant function. Thromb Haemost 117(7):1358–1369. https://doi.org/10.1160/TH17-01-0043

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yang L, Zhu L, Yang X et al (2012) Genetic analysis of genetic protein C deficiency caused by complex heterozygous protein C gene mutation. Chin J Med Genet 29(5):515–518. https://doi.org/10.3760/cma. J.i SSN. 1003–9406. 2012.05. 003

  5. **e H, ** Y, Yang L et al (2021) A family investigation of genetic protein S deficiency caused by homozygous variation. Chin J Tuberculosis Respiratory 44(4):360–364. https://doi.org/10.3760/cma.j.N112147-20200511-00584

    Article  CAS  Google Scholar 

  6. Dinarvand P, Moser KA (2019) Protein C Deficiency. Arch Pathol Lab Med 143(10):1281–1285. https://doi.org/10.5858/arpa.2017-0403-RS

    Article  CAS  PubMed  Google Scholar 

  7. Lu Y, Giri H, Villoutreix BO et al (2020) Gly197Arg mutation in protein C causes recurrent thrombosis in a heterozygous carrier. Thromb Haemost 18(5):1141–1153. https://doi.org/10.1111/jth.14777

    Article  CAS  Google Scholar 

  8. Martos L, Fernández-Pardo Á, López-Fernández MF et al (2019) Identification of 58 mutations (26 Novel) in 94 of 109 symptomatic Spanish probands with protein C. Defic Thromb Haemost 119(9):1409–1418. https://doi.org/10.1055/s-0039-1692440

    Article  Google Scholar 

  9. Noiri JI, Matsuzoe H, Nagaya S et al (2022) A case of venous thromboembolism caused by protein C deficiency due to a novel gene mutation. J Cardiol Cases 26(5):360–363. https://doi.org/10.1016/j.jccase.2022.07.012

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cooper PC, Hill M, Maclean RM (2012) The phenotypic and genetic assessment of protein C deficiency. Int J Lab Hematol 34(4):336–346. https://doi.org/10.1111/j.1751-553X

    Article  CAS  PubMed  Google Scholar 

  11. Boonyawat K, Angchaisuksiri P (2022) Thrombosis and anticoagulation: clinical issues of special importance to hematologists who practice in Asia. Hematol Am Soc Hematol Educ Program 2022(1):474–480. https://doi.org/10.1182/hematology.2022000383

    Article  Google Scholar 

  12. Zhou RF, Cai XH, **e S et al (2007) Molecular mechanisms of protein C deficiency caused by C64W and F139V mutations. Chin J Hematol 28(3):156–159. https://doi.org/10.3760/j:issn:0253-2727.2007.03.004

    Article  CAS  Google Scholar 

  13. Ding Q, Yang L, Hassanian SM et al (2013) Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. Thromb Haemost 109(4):614–624. https://doi.org/10.1160/TH12-10-0760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Soria JM, Morell M, Estivill X et al (1996) Recurrence of the PROC gene mutation R178Q: independent origins in Spanish protein C deficiency patients. Hum Mutat 8(1):71–73. https://doi.org/10.1002/(SICI)1098-1004(1996)8:1<71::AID-HUMU10>3.0.CO;2-O

    Article  CAS  PubMed  Google Scholar 

  15. Kuismanen K, Levo A, Vahtera E et al (2006) Genetic background of type I protein C deficiency in Finland. Thromb Res 118(5):603–609. https://doi.org/10.1016/j.thromres.2005.10.009

    Article  CAS  PubMed  Google Scholar 

  16. Miyata T, Sakata T, Yasumuro Y et al (1998) Genetic analysis of protein C deficiency in nineteen Japanese families: five recurrent defects can explain half of the deficiencies. Thromb Res 92(4):181–187. https://doi.org/10.1016/s0049-3848(98)00131-5

    Article  CAS  PubMed  Google Scholar 

  17. Sasaki M, Tokonami F, Tsuji S et al (1989) [A case of recurrent multiple cerebral infarctions with protein C abnormality]. Rinsho Shinkeigaku 29(9):1136–1139

    CAS  PubMed  Google Scholar 

  18. Tahir F, Majid Z, Bin Arif T et al (2020) Cerebral infarction followed by Myocardial Infarction in a Young Adult with Protein C and S Deficiency. Cureus 12(1):e6665. https://doi.org/10.7759/cureus.6665

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li P, Qin C (Cureus) Recurrent cerebellar infarction associated with hereditary heterozygous protein C deficiency in a 35yearold woman (eds) A case report and genetic study on the pedigree. Exp Ther Med 16(3):2677–2681. https://doi.org/10.3892/etm

  20. Chiasakul T, De Jesus E, Tong J et al (2019) Inherited Thrombophilia and the risk of arterial ischemic stroke: a systematic review and Meta-analysis. J Am Heart Assoc 8(19):e012877. https://doi.org/10.1161/JAHA.119.012877

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li ZY, Zhang LP, Li B et al (2020) [Hereditary protein S deficiency: survey results from a Chinese pedigree]. Chin J Cardiovasc Dis 48(10):831–836. https://doi.org/10.3760/cma.j.cn112148-20200816-00647

    Article  CAS  Google Scholar 

  22. Thrombosis and Haemostasis Group Haematology Branch Chinese Medical Association (2021) Chinese guidelines for the diagnosis and prevention of thrombophilia (2021 edition). 42(11):881–888. https://doi.org/10.3760/cma.j.issn.0253-2727.2021.11.001

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Acknowledgements

We would like to express our gratitude to the donor, relatives and allothers who made this study possible.

Funding

This study was supported by grants from the project of Science and Technology Plan Fund of Wenzhou City(Y20180136).

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Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital, Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325003, China

    Xuanyu Chen, Chengxiang Yuan, Beilei Hu, Chunxing Lu, Yujia Wang, Zhao Han & Ming Zou

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  1. Xuanyu Chen
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  2. Chengxiang Yuan
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Contributions

Chen Xuanyu: designed the study, conducted experiments, wrote the paper. Yuan Chengxiang: obtained data. Lu Chunxing and Wang Yujia: analysed clinical and experimental data. Zou Ming and Han Zhao: supervisied the paper, reviewed the paper, supported contributions; Beilei Hu: supervised the paper, reviewed the paper, supported contributions, obtained research funding.

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Correspondence to Ming Zou.

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Chen, X., Yuan, C., Hu, B. et al. Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism. Ann Hematol 103, 2145–2155 (2024). https://doi.org/10.1007/s00277-024-05674-3

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