F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes
| Autor: | Alessio Branchini, Massimo Morfini, Barbara Lunghi, Donata Belvini, Paolo Radossi, Loredana Bury, Maria Luisa Serino, Paola Giordano, Dorina Cultrera, Angelo Claudio Molinari, Mariasanta Napolitano, Elisabetta Bigagli, Giancarlo Castaman, Mirko Pinotti, Francesco Bernardi, Paola Agostini, Chiara Biasioli, Teresa Maria Caimi, Filomena Daniele, Alfredo Dragani, Donato Gemmati, Paolo Gresele, Silvia Linari, Gina Rossetti, Cristina Santoro, Rita Santoro, Gianluca Sottilotta, Johanna Svahn |
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| Přispěvatelé: | Branchini, Alessio, Morfini, Massimo, Lunghi, Barbara, Belvini, Donata, Radossi, Paolo, Bury, Loredana, Serino, Maria Luisa, Giordano, Paola, Cultrera, Dorina, Molinari, Angelo Claudio, Napolitano, Mariasanta, Bigagli, Elisabetta, Castaman, Giancarlo, Pinotti, Mirko, Bernardi, Francesco |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
pharmacogenetics Mutation Missense Socio-culturale Alpha (ethology) aemophilia B recombinant proteins Hemophilia B law.invention Factor IX Antigen law Internal medicine Genotype medicine Missense mutation Humans Haemophilia B pharmacokinetic Beta (finance) Chemistry Hematology medicine.disease Endocrinology Phenotype factor IX activation hemophilia B pharmacokinetics Recombinant DNA Female Blood Coagulation Tests recombinant protein medicine.drug |
| Zdroj: | Journal of thrombosis and haemostasis : JTH. 20(1) |
| ISSN: | 1538-7836 |
| Popis: | Background Circulating 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. Objectives To 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). Methods We 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). Results The 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. Conclusions FIX 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. |
| Databáze: | OpenAIRE |
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