SERPINC1 c.1247dupC: a novel SERPINC1 gene mutation associated with familial thrombosis results in a secretion defect and quantitative antithrombin deficiency.

Frameshift mutation Hereditary antithrombin deficiency Secretion defect Thrombosis

Journal

Thrombosis journal
ISSN: 1477-9560
Titre abrégé: Thromb J
Pays: England
ID NLM: 101170542

Informations de publication

Date de publication:
12 Feb 2024
Historique:
received: 31 08 2023
accepted: 01 02 2024
medline: 13 2 2024
pubmed: 13 2 2024
entrez: 12 2 2024
Statut: epublish

Résumé

Antithrombin (AT) is an important anticoagulant in hemostasis. We describe here the characterization of a novel AT mutation associated with clinically relevant thrombosis. A pair of sisters with confirmed type I AT protein deficiency was genetically analyzed on suspicion of an inherited SERPINC1 mutation. A frameshift mutation, c.1247dupC, was identified and the effect of this mutation was examined on the cellular and molecular level. Plasmids for the expression of wild-type (WT) and mutated SERPINC1 coding sequence (CDS) fused to green fluorescent protein (GFP) or hemagglutinin (HA) tag were transfected into HEK293T cells. Subcellular localization and secretion of the respective fusion proteins were analyzed by confocal laser scanning microscopy and Western blot. The c.1247dupC mutation results in a frameshift in the CDS of the SERPINC1 gene and a subsequently altered amino acid sequence (p.Ser417LysfsTer48). This alteration affects the C-terminus of the AT antigen and results in impaired secretion as confirmed by GFP- and HA-tagged mutant AT analyzed in HEK293T cells. The p.Ser417LysfsTer48 mutation leads to impaired secretion, thus resulting in a quantitative AT deficiency. This is in line with the type I AT deficiency observed in the patients.

Sections du résumé

BACKGROUND BACKGROUND
Antithrombin (AT) is an important anticoagulant in hemostasis. We describe here the characterization of a novel AT mutation associated with clinically relevant thrombosis. A pair of sisters with confirmed type I AT protein deficiency was genetically analyzed on suspicion of an inherited SERPINC1 mutation. A frameshift mutation, c.1247dupC, was identified and the effect of this mutation was examined on the cellular and molecular level.
METHODS METHODS
Plasmids for the expression of wild-type (WT) and mutated SERPINC1 coding sequence (CDS) fused to green fluorescent protein (GFP) or hemagglutinin (HA) tag were transfected into HEK293T cells. Subcellular localization and secretion of the respective fusion proteins were analyzed by confocal laser scanning microscopy and Western blot.
RESULTS RESULTS
The c.1247dupC mutation results in a frameshift in the CDS of the SERPINC1 gene and a subsequently altered amino acid sequence (p.Ser417LysfsTer48). This alteration affects the C-terminus of the AT antigen and results in impaired secretion as confirmed by GFP- and HA-tagged mutant AT analyzed in HEK293T cells.
CONCLUSION CONCLUSIONS
The p.Ser417LysfsTer48 mutation leads to impaired secretion, thus resulting in a quantitative AT deficiency. This is in line with the type I AT deficiency observed in the patients.

Identifiants

DOI: 10.1186/s12959-024-00589-5 PMID: 38347553
pubmed: 38347553
doi: 10.1186/s12959-024-00589-5
pii: 10.1186/s12959-024-00589-5
doi:

Types de publication

Journal Article

Langues

eng

Pagination

19

Informations de copyright

© 2024. The Author(s).

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Auteurs

Maximilian Ruf (M)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Sarah Cunningham (S)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Alexandra Wandersee (A)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Regine Brox (R)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Susanne Achenbach (S)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Julian Strobel (J)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Holger Hackstein (H)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany.

Sabine Schneider (S)

Department of Transfusion Medicine and Hemostaseology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Krankenhausstr. 12, 91054, Erlangen, Germany. sabine.schneider@uk-erlangen.de.

Classifications MeSH