Lack of FVIII detection in humans and dogs with an intron-22 inversion challenges hypothesis regarding inhibitor risk.
Hemophilia A
factor VIII
factor VIII coagulant antigen
vascular endothelial cells
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
02 Sep 2024
02 Sep 2024
Historique:
received:
30
06
2024
revised:
03
08
2024
accepted:
05
08
2024
medline:
5
9
2024
pubmed:
5
9
2024
entrez:
5
9
2024
Statut:
aheadofprint
Résumé
Almost half of severe hemophilia A (HA) cases are caused by an intron-22 inversion mutation (Int22Inv), which truncates the 26-exon F8 mRNA after exon 22. Another F8 transcript, F8 To determine if partial FVIII proteins are expressed from intron 22-inverted and/or F8 A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues, and for immunoprecipitation followed by western blots and mass spectrometry-proteomics analysis. Immunofluorescent (IF) staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIII If FVIII is expressed in non-endothelial cells, or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.
Sections du résumé
BACKGROUND
BACKGROUND
Almost half of severe hemophilia A (HA) cases are caused by an intron-22 inversion mutation (Int22Inv), which truncates the 26-exon F8 mRNA after exon 22. Another F8 transcript, F8
OBJECTIVES
OBJECTIVE
To determine if partial FVIII proteins are expressed from intron 22-inverted and/or F8
METHODS
METHODS
A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues, and for immunoprecipitation followed by western blots and mass spectrometry-proteomics analysis.
RESULTS
RESULTS
Immunofluorescent (IF) staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIII
CONCLUSIONS
CONCLUSIONS
If FVIII is expressed in non-endothelial cells, or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.
Identifiants
pubmed: 39233012
pii: S1538-7836(24)00493-8
doi: 10.1016/j.jtha.2024.08.007
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.