FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2846905651> ?p ?o ?g. }

• W2846905651 endingPage "2043" @default.
• W2846905651 startingPage "2035" @default.
• W2846905651 abstract "Essentials•Missense mutations often impair protein folding, and thus intracellular trafficking and secretion.•Cellular models of severe type I hemophilia B were challenged with chaperone‐like compounds.•Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q.•The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype.AcknowledgementsThis study was financially supported by an unconditioned research grant from Pfizer (EuroAspire project WI199905 to A. Branchini.). Pfizer had no role in study design, data analysis and interpretation of results. The authors would like to thank Dr R. Mari for technical assistance in performing coagulation assays.PfizerWI199905Summary: BackgroundMissense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone‐like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications.ObjectivesTo rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone‐like compounds.MethodsExpression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone‐like compounds.ResultsAs a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild‐type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX‐294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild‐type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype.ConclusionsAltogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable ‘personalized’ therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy. Essentials•Missense mutations often impair protein folding, and thus intracellular trafficking and secretion.•Cellular models of severe type I hemophilia B were challenged with chaperone‐like compounds.•Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q.•The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype.AcknowledgementsThis study was financially supported by an unconditioned research grant from Pfizer (EuroAspire project WI199905 to A. Branchini.). Pfizer had no role in study design, data analysis and interpretation of results. The authors would like to thank Dr R. Mari for technical assistance in performing coagulation assays.PfizerWI199905 •Missense mutations often impair protein folding, and thus intracellular trafficking and secretion.•Cellular models of severe type I hemophilia B were challenged with chaperone‐like compounds.•Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q.•The increased coagulant activity levels (∼3%) of p.R294Q would ameliorate the bleeding phenotype. This study was financially supported by an unconditioned research grant from Pfizer (EuroAspire project WI199905 to A. Branchini.). Pfizer had no role in study design, data analysis and interpretation of results. The authors would like to thank Dr R. Mari for technical assistance in performing coagulation assays.PfizerWI199905 Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone‐like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone‐like compounds. Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone‐like compounds. As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild‐type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 ± 0.1% to 1.5 ± 0.3%) only of the rFIX‐294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild‐type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 ± 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable ‘personalized’ therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy." @default.
• W2846905651 created "2018-07-19" @default.
• W2846905651 creator A5029202139 @default.
• W2846905651 creator A5034161065 @default.
• W2846905651 creator A5036886312 @default.
• W2846905651 creator A5045527190 @default.
• W2846905651 creator A5057403590 @default.
• W2846905651 creator A5057798051 @default.
• W2846905651 creator A5065155407 @default.
• W2846905651 creator A5070894673 @default.
• W2846905651 creator A5083337792 @default.
• W2846905651 creator A5087028468 @default.
• W2846905651 date "2018-10-01" @default.
• W2846905651 modified "2023-10-11" @default.
• W2846905651 title "The chaperone‐like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation" @default.
• W2846905651 cites W1574609405 @default.
• W2846905651 cites W1586981128 @default.
• W2846905651 cites W1693223774 @default.
• W2846905651 cites W1968520813 @default.
• W2846905651 cites W1971513339 @default.
• W2846905651 cites W1973388870 @default.
• W2846905651 cites W1990178743 @default.
• W2846905651 cites W200415659 @default.
• W2846905651 cites W2028591711 @default.
• W2846905651 cites W2031763961 @default.
• W2846905651 cites W2047386174 @default.
• W2846905651 cites W2060905042 @default.
• W2846905651 cites W2065631672 @default.
• W2846905651 cites W2066304010 @default.
• W2846905651 cites W2076159058 @default.
• W2846905651 cites W2078855449 @default.
• W2846905651 cites W2088791759 @default.
• W2846905651 cites W2092376035 @default.
• W2846905651 cites W2096966529 @default.
• W2846905651 cites W2107646622 @default.
• W2846905651 cites W2111256689 @default.
• W2846905651 cites W2115034875 @default.
• W2846905651 cites W2119974575 @default.
• W2846905651 cites W2162468986 @default.
• W2846905651 cites W2409614280 @default.
• W2846905651 cites W2513447995 @default.
• W2846905651 cites W2588272004 @default.
• W2846905651 cites W2769858709 @default.
• W2846905651 cites W2791632640 @default.
• W2846905651 cites W410189575 @default.
• W2846905651 doi "https://doi.org/10.1111/jth.14236" @default.
• W2846905651 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29993188" @default.
• W2846905651 hasPublicationYear "2018" @default.
• W2846905651 type Work @default.
• W2846905651 sameAs 2846905651 @default.
• W2846905651 citedByCount "14" @default.
• W2846905651 countsByYear W28469056512019 @default.
• W2846905651 countsByYear W28469056512020 @default.
• W2846905651 countsByYear W28469056512021 @default.
• W2846905651 countsByYear W28469056512022 @default.
• W2846905651 countsByYear W28469056512023 @default.
• W2846905651 crossrefType "journal-article" @default.
• W2846905651 hasAuthorship W2846905651A5029202139 @default.
• W2846905651 hasAuthorship W2846905651A5034161065 @default.
• W2846905651 hasAuthorship W2846905651A5036886312 @default.
• W2846905651 hasAuthorship W2846905651A5045527190 @default.
• W2846905651 hasAuthorship W2846905651A5057403590 @default.
• W2846905651 hasAuthorship W2846905651A5057798051 @default.
• W2846905651 hasAuthorship W2846905651A5065155407 @default.
• W2846905651 hasAuthorship W2846905651A5070894673 @default.
• W2846905651 hasAuthorship W2846905651A5083337792 @default.
• W2846905651 hasAuthorship W2846905651A5087028468 @default.
• W2846905651 hasBestOaLocation W28469056511 @default.
• W2846905651 hasConcept C104317684 @default.
• W2846905651 hasConcept C127716648 @default.
• W2846905651 hasConcept C134018914 @default.
• W2846905651 hasConcept C139447449 @default.
• W2846905651 hasConcept C142724271 @default.
• W2846905651 hasConcept C143065580 @default.
• W2846905651 hasConcept C158617107 @default.
• W2846905651 hasConcept C185592680 @default.
• W2846905651 hasConcept C2775962898 @default.
• W2846905651 hasConcept C2778043179 @default.
• W2846905651 hasConcept C2909310144 @default.
• W2846905651 hasConcept C49039625 @default.
• W2846905651 hasConcept C55493867 @default.
• W2846905651 hasConcept C61397870 @default.
• W2846905651 hasConcept C71924100 @default.
• W2846905651 hasConcept C75563809 @default.
• W2846905651 hasConcept C79879829 @default.
• W2846905651 hasConcept C86803240 @default.
• W2846905651 hasConcept C95444343 @default.
• W2846905651 hasConceptScore W2846905651C104317684 @default.
• W2846905651 hasConceptScore W2846905651C127716648 @default.
• W2846905651 hasConceptScore W2846905651C134018914 @default.
• W2846905651 hasConceptScore W2846905651C139447449 @default.
• W2846905651 hasConceptScore W2846905651C142724271 @default.
• W2846905651 hasConceptScore W2846905651C143065580 @default.
• W2846905651 hasConceptScore W2846905651C158617107 @default.
• W2846905651 hasConceptScore W2846905651C185592680 @default.
• W2846905651 hasConceptScore W2846905651C2775962898 @default.
• W2846905651 hasConceptScore W2846905651C2778043179 @default.
• W2846905651 hasConceptScore W2846905651C2909310144 @default.

• next