ArticleJournal of thrombosis and haemostasis : JTH2022
F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes.
Article in Journal of thrombosis and haemostasis : JTH, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 29 citations in OpenAlex.
- Molecular mechanisms and therapeutic strategies for the recurrent F9 (c.520 + 13 A > G) variant in hemophilia B.Human genomics · 2026Article
- Article
- Tailored collagen binding of albumin-fused hyperactive coagulation factor IX dictates in vivo distribution and functional properties.Nature communications · 2025Article
- "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
- Blood Coagulation Factor IX: Structure, Function, and Regulation.IUBMB life · 2025Review
- Gene Dosage ofGenes · 2024Article
- Managing Relevant Clinical Conditions of Hemophilia A/B Patients.Hematology reports · 2023Article
- Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency.Thrombosis journal · 2023Article
- Variant spectrum ofFrontiers in genetics · 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
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Authors and funding
16 authors at 8 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundCirculating dysfunctional factor IX (FIX) might modulate distribution of infused FIX in hemophilia B (HB) patients. Recurrent substitutions at FIX activation sites (R191-R226, >300 patients) are associated with variable FIX activity and antigen (FIXag) levels.
objectivesTo investigate the (1) expression of a complete panel of missense mutations at FIX activation sites and (2) contribution of F9 genotypes on the FIX pharmacokinetics (PK).
methodsWe checked FIX activity and antigen and activity assays in plasma and after recombinant expression of FIX variants and performed an analysis of infused FIX PK parameters in patients (n = 30), mostly enrolled in the F9 Genotype and PK HB Italian Study (GePKHIS; EudraCT ID2017-003902-42).
resultsThe variable FIXag amounts and good relation between biosynthesis and activity of multiple R191 variants results in graded moderate-to-mild severity of the R191C>L>P>H substitutions. Recombinant expression may predict the absence in the HB mutation database of the benign R191Q/W/K and R226K substitutions. Equivalent changes at R191/R226 produced higher FIXag levels for R226Q/W/P substitutions, as also observed in p.R226W female carrier plasma. Pharmacokinetics analysis in patients suggested that infused FIX Alpha distribution and Beta elimination phases positively correlated with endogenous FIXag levels. Mean residence time was particularly prolonged (79.4 h, 95% confidence interval 44.3-114.5) in patients (n = 7) with the R191/R226 substitutions, which in regression analysis were independent predictors (β coefficient 0.699, P = .004) of Beta half-life, potentially prolonged by the increasing over time ratio between endogenous and infused FIX.
conclusionsFIX activity and antigen levels and specific features of the dysfunctional R191/R226 variants may exert pleiotropic effects both on HB patients' phenotypes and substitutive treatment.
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