Antithrombin-p.Ala416Pro: the second reported case in Japan
Toshio Shigekiyo1, Etsuko Sekimoto, Hironobu Shibata
1Department of Hematology, Tokushima Prefectural Central Hospital, Japan.
Insights
Recurrent deep vein thrombosis in a family was linked to a novel antithrombin (AT) gene mutation. This AT-p.Ala416Pro mutation caused type IIa AT deficiency, affecting heparin cofactor activity.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Recurrent deep venous thrombosis (DVT) can be associated with inherited thrombophilias.
- Antithrombin (AT) deficiency is a rare genetic disorder predisposing individuals to venous thromboembolism.
- Type IIa AT deficiency is characterized by normal AT antigen levels but reduced heparin cofactor activity.
Purpose of the Study:
- To investigate the genetic basis of recurrent deep venous thrombosis in a family with suspected antithrombin deficiency.
- To identify the specific mutation responsible for type IIa AT deficiency within the family.
Main Methods:
- Clinical evaluation of patients with recurrent DVT.
- Assay of antithrombin (AT) antigen and heparin cofactor activity levels.
- Genetic analysis of the AT gene, including nucleotide sequencing of exon 7.
Main Results:
- The affected family members exhibited low AT heparin cofactor activity with normal AT antigen levels.
- A novel single nucleotide substitution (c.1246 G>C) in exon 7 of the AT gene was identified, leading to the p.Ala416Pro mutation.
- This AT-p.Ala416Pro mutation was present in affected individuals (father, aunt, patient) but not in an unaffected sister.
Conclusions:
- The identified AT-p.Ala416Pro mutation is the causative genetic defect for type IIa AT deficiency in this family.
- This mutation impairs AT's heparin cofactor activity, leading to an increased risk of venous thrombosis.
- Genetic testing is crucial for diagnosing inherited thrombophilias and guiding family screening.
Abstract:
A 42-year-old man was referred to our department due to recurrent deep venous thrombosis. He, his father and his aunt had low antithrombin (AT) heparin cofactor activity and progressive AT activity levels with normal AT antigen levels. A single nucleotide substitution of G to C was found at nucleotide position c.1246 in exon 7 of the patient's AT gene, resulting in a p.Ala416Pro mutation of AT. The same mutation was identified in his father and aunt, but not his sister, who had a normal AT level. These results show that the AT-p.Ala416Pro mutation was responsible for type IIa AT deficiency in this family.
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