{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:04:17Z","timestamp":1784869457914,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003086","name":"Grupos Consolidados Gobierno Vasco 2021","doi-asserted-by":"publisher","award":["IT1720-22"],"award-info":[{"award-number":["IT1720-22"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PIF","award":["IT1720-22"],"award-info":[{"award-number":["IT1720-22"]}]},{"name":"Fundaci\u00f3n Biof\u00edsica Bizkaia","award":["IT1720-22"],"award-info":[{"award-number":["IT1720-22"]}]},{"name":"University of the Basque Country","award":["IT1720-22"],"award-info":[{"award-number":["IT1720-22"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u00b1 0.8 and 25.9 \u00b1 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\u2019 helix, which reduces the stability of the LDLr-PCSK9 complex.<\/jats:p>","DOI":"10.3390\/ijms24043330","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:01:45Z","timestamp":1675825305000},"page":"3330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9107-4299","authenticated-orcid":false,"given":"Asier","family":"Larrea-Sebal","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universidad del Pa\u00eds Vasco UPV\/EHU, 48080 Bilbao, Spain"},{"name":"Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Cient\u00edficas (UPV\/EHU, CSIC), 48940 Leioa, Spain"},{"name":"Fundaci\u00f3n Biofisika Bizkaia, 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Trenti","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Unit, Azienda USL\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifa","family":"Jebari-Benslaiman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universidad del Pa\u00eds Vasco UPV\/EHU, 48080 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Bertolini","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Calandra","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5828-6510","authenticated-orcid":false,"given":"Emanuele A.","family":"Negri","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Unit, Azienda USL\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efrem","family":"Bonelli","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Unit, Azienda USL\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asier","family":"Benito-Vicente","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universidad del Pa\u00eds Vasco UPV\/EHU, 48080 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leire","family":"Uraga-Gracianteparaluceta","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universidad del Pa\u00eds Vasco UPV\/EHU, 48080 Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4087-8729","authenticated-orcid":false,"given":"C\u00e9sar","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Universidad del Pa\u00eds Vasco UPV\/EHU, 48080 Bilbao, Spain"},{"name":"Department of Molecular Biophysics, Biofisika Institute, University of Basque Country and Consejo Superior de Investigaciones Cient\u00edficas (UPV\/EHU, CSIC), 48940 Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Fasano","sequence":"additional","affiliation":[{"name":"Clinical Pathology Unit, AUSL Romagna, 47521 Cesena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Benito-Vicente, A., Uribe, K.B., Jebari, S., Galicia-Garcia, U., Ostolaza, H., and Martin, C. 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