ArticleBlood2017
Specific factor IX mRNA and protein features favor drug-induced readthrough over recurrent nonsense mutations.
Article in Blood, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Ribosomal read through as an alternative therapy for patients with hemophilia with nonsense mutations.Journal of thrombosis and haemostasis : JTH · 2026Article
- "An integrated multitool analysis contributes elements to interpreting unclassified factor IX missense variants associated with hemophilia B": comment from Lee et al.Journal of thrombosis and haemostasis : JTH · 2025Article
- Review
- Enhanced procoagulant activity of select hemophilia B causing factor IX variants with emicizumab.Blood · 2024Article
- Molecular pathogenesis of a novel Met394Thr variant causing hemophilia B.Molecular genetics & genomic medicine · 2023Article
- Translational readthrough atHaematologica · 2023Article
- The Molecular Basis of FIX Deficiency in Hemophilia B.International journal of molecular sciences · 2022Review
- F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes.Journal of thrombosis and haemostasis : JTH · 2022Article
- Fusion of engineered albumin with factor IX Padua extends half-life and improves coagulant activity.British journal of haematology · 2021Article
- Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants.Blood advances · 2021Article
- Molecular Insights into Determinants of Translational Readthrough and Implications for Nonsense Suppression Approaches.International journal of molecular sciences · 2020Review
- Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems.International journal of molecular sciences · 2020Article
- Translational readthrough ofRNA biology · 2020Article
- Variable readthrough responsiveness of nonsense mutations in hemophilia A.Haematologica · 2020Article
- Identification of candidate nonsense mutations of FVIII for ribosomal readthrough therapy.Haematologica · 2019Article
- Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies.International journal of molecular sciences · 2019Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug-induced readthrough over premature stop codons (PTCs) is a potentially attractive therapy for genetic disorders, but a wide outcome variability has been observed. Through expression studies, we investigated the responsiveness to the readthrough-inducing drug geneticin of 11 rationally selected factor IX (FIX) nonsense mutations, present in 70% (324/469) of hemophilia B (HB) patients with PTCs. Among the predicted readthrough-permissive TGA variants, only 2 (p.W240X and p.R384X) responded with a remarkable rescue of FIX activity. The amounts of rescued full-length FIX protein for the p.W240X (∼9% of recombinant FIX [rFIX]-wild-type [WT]) slightly exceeded activity (5.2 ± 0.6%). FIX antigen for the p.R384X (1.9 ± 0.3%) was remarkably lower than activity (7.5 ± 0.7%). Data indicate novel specific mechanisms producing functional rescue: (1) prevalent reinsertion of the authentic residue (tryptophan), reverting the nonsense effects for the p.W240X, and (2) gain-of-function for the p.R384X, supported by the fourfold increased activity of the most probable readthrough-mediated missense variant (rFIX-R384W). For most PTCs, impaired secretion/function produced by readthrough-mediated amino acid substitutions prevented a significant functional rescue, which requires combinations of favorable FIX messenger RNA (mRNA) sequence and protein features. This rational approach, applicable to other coagulation disorders, helps with interpreting the poor response reported in the few investigated HB patients, and identifies candidate patients eligible for treatment.
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