X-Linked Thrombophilia with a Mutant Factor IX (Factor IX Padua)
Open accessAbstract
We report a case of juvenile thrombophilia associated with a substitution of leucine for arginine at position 338 (R338L) in the factor IX gene (factor IX-R338L). The level of the mutant factor IX protein in plasma was normal, but the clotting activity of factor IX from the proband was approximately eight times the normal level. In vitro, recombinant factor IX-R338L had a specific activity that was 5 to 10 times as high as that in the recombinant wild-type factor IX. The R338 substitution causes a gain-of-function mutation, resulting in factor IX that is hyperfunctional.
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All HA clinical trials use a B-domain-deleted FVIII transgene, and HB trials have universally adapted the FIX-Padua (FIX-R338L) transgene, which affords approximately 8-fold greater specific activity relative to wild-type FIX.
“All HA clinical trials use a B-domain-deleted FVIII (BDD-FVIII) transgene, which retains full procoagulant function while meeting AAV packaging constraints (∼4.7 kb) and enhancing expression.187, 188, 189”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [192]
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- Authors
- Simioni, P., Tormene, D., Tognin, G., Gavasso, S., Bulato, C., Iacobelli, N. P., Finn, J. D., Spiezia, L., Radu, C., & Arruda, V. R.
- Affiliations
- University of Padua (IT)
- Children's Hospital of Philadelphia (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-10-22
- Volume
- 361
- Issue
- 17
- Pages
- 1671-1675
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1976452565
- Cited by
- 394
- References
- 0
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 39 · 2023: 26 · 2022: 34 · 2021: 26 · 2020: 22 · 2019: 26 · 2018: 31 · 2017: 28 · 2016: 14 · 2015: 22 · 2014: 17 · 2013: 19 · 2012: 14
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (P01 HL64910)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- factor IX, gain-of-function mutations, hypercoagulability, thrombophilia, coagulation factor activity
- MeSH terms
- DNA Mutational Analysis, Factor IX, Female, Genotype, Humans, Male, Pedigree, Point Mutation, Thrombophilia, Mutation, Missense, Genetic Diseases, X-Linked, Young Adult
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