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Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S
  1. Jingyi Zhou,
  2. Wenyan Shen,
  3. Yi Gu,
  4. Min Li,
  5. Wei Shen
  1. Department of Laboratory Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
  1. Correspondence to Professor Wei Shen, Department of Laboratory Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200240, China; applessw{at}


Aims Hereditary protein S (PS) deficiency is one of the natural anticoagulant deficiencies causing thrombophilia. We herein described a young male with recurrent deep venous thrombosis, who was diagnosed as type I PS deficiency with compound heterozygous mutations of PROS1 gene. We aimed to analyse the relationship between the genotype and phenotype detection and investigate the pathological mechanisms of PROS1 mutations causing PS deficiency.

Methods Genetic analysis of PROS1 gene was carried out by direct sequencing. Thrombin generation potential and the inhibition function of thrombin generation by plasma PS were detected by thrombin generation test (TGT). The mRNA transcription level of mutant PS in vitro was measured by real-time PCR, while the protein level was evaluated by western blot and ELISA. Cellular distribution of the protein was further analysed by immunofluorescence.

Results Compound heterozygous mutations (PROS1 c.1551_1552delinsG, p.Thr518Argfs*39 and PROS1 c.1681C>T, p.Arg561Trp) were identified in the propositus, and the former one was a novel small indel mutation. TGT results showed impaired inhibition of thrombin generation with the addition of activated protein C in his parents with certain heterozygous mutations. In vitro expression study, p.Thr518Argfs*39 mutant produced truncated protein retained in the cytoplasm, while p.Arg561Trp mutant partially affected the secretion of PS. Both mutations are located in C-terminal sex hormone-binding globulin (SHBG)-like domain of PS.

Conclusions Compound heterozygous mutations identified in the study have strong detrimental effect, causing severe type I PS deficiency in the propositus. SHBG-like domain of PS might play an important role in PS secretion system.

  • deep venous thrombosis
  • mutation
  • protein S deficiency
  • pathological mechanism
  • thrombin generation test

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  • Handling editor Mary Frances McMullin.

  • Contributors JZ designed the study, performed the thrombin generation tests and recombinant protein S (PS) expression experiment, reviewed and interpreted data, and wrote the manuscript. WS performed recombinant PS expression experiment and finished western blot analysis. YG performed the mRNA expression assays and finished the immunofluorescence. ML supervised research, helped to design the study. WS supervised research, helped to design the study and critically revised the manuscript. All the authors approved the final version of the manuscript.

  • Funding This study was supported by National Natural Science Foundation of China (Grant Nos. 81702069 and 81601822) and Cultivation Fund of Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine (Grant No. PYIII-17-012).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Ethics Committee of Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.