Identification and characterization of a novel variant in C-terminal region of Antithrombin (Ala427Thr) associated with type II AT deficiency leading to polymer formation.
Antithrombin
Molecular dynamics simulation
Mutations
Polymerization
Thrombosis
Journal
Journal of thrombosis and thrombolysis
ISSN: 1573-742X
Titre abrégé: J Thromb Thrombolysis
Pays: Netherlands
ID NLM: 9502018
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
pubmed:
6
2
2020
medline:
5
8
2021
entrez:
6
2
2020
Statut:
ppublish
Résumé
Antithrombin (AT) deficiency is a rare but strong risk factor for the thrombosis development. Mutations in gene encoding AT (SERPINC1) have provided a detailed understanding of AT deficiency and subsequent development of thrombotic complications. In the present study, we describe a case of thrombotic patient with reduced AT activity and normal AT antigen levels. AT deficiency in the patient was explained by the presence of heterozygous mutation g.13397A>G (Ala427Thr) in exon 6 of SERPINC1. Reduced APTT and TT with normal PT were observed. The mutation was found to be absent in healthy controls (n = 62). In vitro purification and characterization of variant AT showed significant decrease in fluorescence emission intensity, decreased bis-ANS fluorescence emission, changes in secondary structure and presence of polymerized AT in patient's plasma as assessed by fluorescence, circular dichroism and transmission electron microscopy respectively. Furthermore, molecular dynamics simulation studies showed altered conformation due to Ala427Thr substitution. Our study shows that genetic screening should be carried out in AT deficient patients in addition to the routinely used functional assays to understand the molecular basis of disease development.
Identifiants
pubmed: 32020514
doi: 10.1007/s11239-020-02048-0
pii: 10.1007/s11239-020-02048-0
doi:
Substances chimiques
SERPINC1 protein, human
0
Antithrombin III
9000-94-6
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
678-685Subventions
Organisme : Indian Council of Medical Research
ID : 52/2/2009-BMS
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