Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject
dc.contributor.author | Larrea Sebal, Asier | |
dc.contributor.author | Trenti, Chiara | |
dc.contributor.author | Jebari-Benslaiman, Shifa | |
dc.contributor.author | Bertolini, Stefano | |
dc.contributor.author | Calandra, Sebastiano | |
dc.contributor.author | Negri, Emanuele A. | |
dc.contributor.author | Bonelli, Efrem | |
dc.contributor.author | Benito Vicente, Asier | |
dc.contributor.author | Uraga Gracianteparaluceta, Leire | |
dc.contributor.author | Martín Plágaro, César Augusto | |
dc.contributor.author | Fasano, Tommaso | |
dc.date.accessioned | 2023-02-27T14:39:00Z | |
dc.date.available | 2023-02-27T14:39:00Z | |
dc.date.issued | 2023-02-07 | |
dc.identifier.citation | International Journal of Molecular Sciences 24(4) : (2023) // Article ID 3330 | es_ES |
dc.identifier.issn | 1422-0067 | |
dc.identifier.uri | http://hdl.handle.net/10810/60114 | |
dc.description.abstract | Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that led to reduced plasma LDL-C clearance. To date, several PCSK9 gain-of-function (GOF) variants causing FH have been described based on their increased ability to degrade LDLr. On the other hand, mutations that reduce the activity of PCSK9 on LDLr degradation have been described as loss-of-function (LOF) variants. It is therefore important to functionally characterise PCSK9 variants in order to support the genetic diagnosis of FH. The aim of this work is to functionally characterise the p.(Arg160Gln) PCSK9 variant found in a subject suspected to have FH. Different techniques have been combined to determine efficiency of the autocatalytic cleavage, protein expression, effect of the variant on LDLr activity and affinity of the PCSK9 variant for the LDLr. Expression and processing of the p.(Arg160Gln) variant had a result similar to that of WT PCSK9. The effect of p.(Arg160Gln) PCSK9 on LDLr activity is lower than WT PCSK9, with higher values of LDL internalisation (13%) and p.(Arg160Gln) PCSK9 affinity for the LDLr is lower than WT, EC50 8.6 ± 0.8 and 25.9 ± 0.7, respectively. The p.(Arg160Gln) PCSK9 variant is a LOF PCSK9 whose loss of activity is caused by a displacement of the PCSK9 P’ helix, which reduces the stability of the LDLr-PCSK9 complex. | es_ES |
dc.description.sponsorship | This research was funded by Grupos Consolidados Gobierno Vasco 2021, grant number IT1720-22. A.L.-S. was supported by a grant PIF (2019–2020), Gobierno Vasco and partially supported by Fundación Biofísica Bizkaia. S.J-B. was supported by a Margarita Salas Grant 2022 from the University of the Basque Country. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | MDPI | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | familial hypercholesterolemia | es_ES |
dc.subject | PCSK9 | es_ES |
dc.subject | GOF | es_ES |
dc.subject | LOF | es_ES |
dc.subject | characterisation | es_ES |
dc.subject | activity | es_ES |
dc.title | Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.date.updated | 2023-02-24T14:08:48Z | |
dc.rights.holder | © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/). | es_ES |
dc.relation.publisherversion | https://www.mdpi.com/1422-0067/24/4/3330 | es_ES |
dc.identifier.doi | 10.3390/ijms24043330 | |
dc.departamentoes | Bioquímica y biología molecular | |
dc.departamentoeu | Biokimika eta biologia molekularra |
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Except where otherwise noted, this item's license is described as © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).