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Partial F8gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia

Authors :
Simioni, Paolo
Cagnin, Stefano
Sartorello, Francesca
Sales, Gabriele
Pagani, Luca
Bulato, Cristiana
Gavasso, Sabrina
Nuzzo, Francesca
Chemello, Francesco
Radu, Claudia M.
Tormene, Daniela
Spiezia, Luca
Hackeng, Tilman M.
Campello, Elena
Castoldi, Elisabetta
Source :
Blood; April 2021, Vol. 137 Issue: 17 p2383-2393, 11p
Publication Year :
2021

Abstract

High coagulation factor VIII (FVIII) levels comprise a common risk factor for venous thromboembolism (VTE), but the underlying genetic determinants are largely unknown. We investigated the molecular bases of high FVIII levels in 2 Italian families with severe thrombophilia. The proband of the first family had a history of recurrent VTE before age 50 years, with extremely and persistently elevated FVIII antigen and activity levels (>400%) as the only thrombophilic defects. Genetic analysis revealed a 23.4-kb tandem duplication of the proximal portion of the F8gene (promoter, exon 1, and a large part of intron 1), which cosegregated with high FVIII levels in the family and was absent in 103 normal controls. Targeted screening of 50 unrelated VTE patients with FVIII levels ≥250% identified a second thrombophilic family with the same F8rearrangement on the same genetic background, suggesting a founder effect. Carriers of the duplication from both families showed a twofold or greater upregulation of F8messenger RNA, consistent with the presence of open chromatin signatures and enhancer elements within the duplicated region. Testing of these sequences in a luciferase reporter assay pinpointed a 927-bp region of F8intron 1 associated with >45-fold increased reporter activity in endothelial cells, potentially mediating the F8transcriptional enhancement observed in carriers of the duplication. In summary, we report the first thrombophilic defect in the F8gene (designated FVIII Padua) associated with markedly elevated FVIII levels and severe thrombophilia in 2 Italian families.

Details

Language :
English
ISSN :
00064971 and 15280020
Volume :
137
Issue :
17
Database :
Supplemental Index
Journal :
Blood
Publication Type :
Periodical
Accession number :
ejs56042065
Full Text :
https://doi.org/10.1182/blood.2020008168