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Clinical and Molecular Characterization of Nine Novel Antithrombin Mutations
Judit Kállai1,2, Réka Gindele1, Krisztina Pénzes-Daku1
1Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
International Journal of Molecular Sciences
|March 13, 2024
Summary
This study identified nine novel antithrombin (AT) mutations, revealing six cause type I AT deficiency through impaired synthesis or secretion, and two suggest type II AT deficiency. The findings enhance understanding of AT deficiency's genetic basis.
Area of Science:
- Genetics and Molecular Biology
- Hematology and Thrombosis
Background:
- Antithrombin (AT) deficiency (ATD) is a severe inherited thrombophilia.
- Understanding novel SERPINC1 mutations is crucial for diagnosing and managing ATD.
- Genotype-phenotype correlations in ATD require further elucidation.
Purpose of the Study:
- To identify and characterize novel mutations in the SERPINC1 gene.
- To investigate the genotype-phenotype correlations of these new AT mutations.
- To elucidate the pathogenic mechanisms underlying different types of AT deficiency.
Main Methods:
- Expression of nine novel mutant antithrombin (AT) proteins in HEK293 cells.
- Detection of wild-type and mutant AT using Western blotting, N-Glycosidase F digestion, and ELISA.
- Analysis of AT mRNA expression via RT-qPCR, functional studies (AT activity, heparin binding via SPR), and in silico methods.
Main Results:
- Six novel mutations were confirmed to cause Type I ATD due to altered protein synthesis or secretion.
- Two mutations suggested Type II ATD, involving heparin-binding site defects or pleiotropic effects.
- The pathogenic role of one mutation (p.Arg14Lys) remained equivocal.
Conclusions:
- This study provides in vitro evidence for the pathogenic nature of novel SERPINC1 mutations.
- The findings contribute to a better understanding of the molecular basis of antithrombin deficiency.
- Characterization of these mutations aids in predicting clinical phenotypes and guiding patient management.
