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Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
Compound heterozygous mutations identified in severe type I protein S deficiency impaired the secretion of protein S
Jingyi Zhou1, Wenyan Shen1, Yi Gu1
1Department of Laboratory Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Insights
Hereditary protein S (PS) deficiency, a cause of thrombophilia, was linked to compound heterozygous PROS1 mutations in a young male. These mutations impaired PS function and secretion, highlighting the SHBG-like domain's role.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Hereditary protein S (PS) deficiency is a known cause of thrombophilia.
- Type I PS deficiency is characterized by reduced PS levels and anticoagulant function.
- Understanding PROS1 mutations is crucial for diagnosing and managing thrombotic disorders.
Observation:
- A young male presented with recurrent deep venous thrombosis.
- He was diagnosed with type I PS deficiency due to compound heterozygous mutations in the PROS1 gene.
Findings:
- Two PROS1 mutations, a novel indel (c.1551_1552delinsG) and a missense mutation (c.1681C>T), were identified.
- The novel mutation resulted in a truncated protein retained in the cytoplasm.
- The missense mutation partially impaired protein S secretion.
- Both mutations are in the C-terminal SHBG-like domain, affecting thrombin generation inhibition.
Implications:
- Compound heterozygous mutations in PROS1 can cause severe type I PS deficiency.
- The SHBG-like domain of protein S is critical for its secretion and function.
- This study highlights the importance of genetic analysis in diagnosing and understanding thrombophilia.
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.
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