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Antithrombin deficiency in three Japanese families: one novel and two reported point mutations in the antithrombin
Keiko Maruyama1, Eriko Morishita, Megumi Karato
1Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Insights
Three novel mutations in the antithrombin (AT) gene were identified in patients with thrombosis. Two mutations, A459D and P112R, cause Type I AT deficiency, while R56C causes Type II HBS deficiency.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Inherited antithrombin (AT) deficiency increases the risk of familial venous thromboembolic disease.
- Analysis of the AT gene (SERPINC1) was performed in three unrelated patients with AT deficiency and thrombosis.
Observation:
- Three distinct heterozygous mutations were identified: p.56Arginine → Cysteine (R56C), p.459Alanine → Aspartic acid (A459D), and p.112 Proline → Arginine (P112R).
- In vitro expression showed R56C mutant had near-wild-type AT antigen levels, while A459D and P112R mutants had significantly decreased levels.
- R56C mutant exhibited reduced AT activity with shorter incubation, but comparable activity to wild-type with increased incubation.
Findings:
- The R56C mutant is associated with Type II Heparin Binding Site (HBS) deficiency.
- The A459D and P112R mutants are classified as Type I AT deficiency.
Implications:
- These findings expand the understanding of genotype-phenotype correlations in antithrombin deficiency.
- Identification of specific mutations aids in diagnosing and managing patients with inherited thrombophilia.
Introduction:
Inherited antithrombin (AT) deficiency is associated with a predisposition to familial venous thromboembolic disease. We analyzed the AT gene in three unrelated patients with an AT deficiency who developed thrombosis.
Materials And Methods:
We analyzed the SERPINC1 gene in three patients. Additionally, we expressed the three mutants in the COS-1 cells and compared their secretion rates and levels of AT activity with those of the wild-type (WT).
Results:
We identified three distinct heterozygous mutations of c.2534C>T: p.56Arginine → Cysteine (R56C), c.13398C>A: p.459Alanine → Aspartic acid (A459D) and c.2703C>G: p.112 Proline → Arginine (P112R). In the in vitro expression experiments, the AT antigen levels in the conditioned media (CM) of the R56C mutant were nearly equal to those of WT. In contrast, the AT antigen levels in the CM of the A459D and P112R mutants were significantly decreased. The AT activity of R56C was decreased in association with a shorter incubation time in a FXa inhibition assay and a thrombin inhibition-based activity test. However, the AT activity of R56C was comparable to that of WT when the incubation time was increased.
Conclusions:
We concluded that the R56C mutant is responsible for type II HBS deficiency. We considered that the A459D and P112R mutants can be classified as belonging to the type I AT deficiency.
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