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LDLR variants functional characterization: Contribution to variant classification

2021-06-10Journal article Restricted access
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dc.contributor.authorAlves, Ana Catarina
dc.contributor.authorAzevedo, Sílvia
dc.contributor.authorBenito-Vicente, Asier
dc.contributor.authorGraça, Rafael
dc.contributor.authorGalicia-Garcia, Unai
dc.contributor.authorBarros, Patrícia
dc.contributor.authorJordan, Peter
dc.contributor.authorMartin, Cesar
dc.contributor.authorBourbon, Mafalda
dc.date.accessioned2022-01-31T17:32:57Z
dc.date.available2022-01-31T17:32:57Z
dc.date.issued2021-06-10
dc.description.abstractBackground and aims: Familial hypercholesterolaemia (FH) is an autosomal disorder of lipid metabolism presenting with increased cardiovascular risk. LDLR mutations are the cause of disease in 90% of the cases but functional studies have only been performed for about 15% of all LDLR variants. In the Portuguese Familial Hypercholesterolemia Study (PFHS), 142 unique LDLR alterations were identified and 44 (30%) lack functional characterization. The aim of the present work is to increase evidence for variant classification by performing functional characterization of 13 LDLR missense alterations found in Portugal and in 20 other countries. Methods: Different LDLR mutants were generated by site-directed mutagenesis and expressed in CHO-ldlA7 cells lacking endogenous expression of LDLR. To determine the effects of alterations on LDLR function, cell surface expression, binding and uptake of FITC-LDL were assessed by flow cytometry and Western blot. Results: Of the 13 variants studied 7 were shown to affect LDLR function - expression, binding or uptake, with rates lower than 60%: p.(Cys184Tyr), p.(Gly207_Ser213del); p.(His211Asp); p.(Asp221Tyr); p.(Glu288Lys); p.(Gly592Glu) and p.(Asp601Val)). The remaining 6 variants do not alter the LDLR function. Conclusions: These studies contributed to an update of these variants classification: from the 9 variants classified as variants of unknown significance, 7 have reached now a final classification and 3 variants have improved classification from likely pathogenic to pathogenic. In Portugal, an additional 55 patients received an FH definite diagnosis thanks to these studies. Since only likely pathogenic and pathogenic variants are clinically actionable, this work shows the importance of functional studies for variant classification.pt_PT
dc.description.abstractHighlights: This work shows the importance of functional studies for variant classification, since only likely pathogenic and pathogenic variants are clinically actionable; This work contributed to an update of 10 variants classification; Variants presented in this work were also found in 20 different countries and many other patients worldwide will benefit from these; Functional studies are very important to add evidence to reach a final classification with the ACMG algorithm.pt_PT
dc.description.sponsorshipFunding was obtained from UID/MULTI/04046/2019 Research Unit grant from FCT, Portugal (to BioISI) and for the Basque Government (Grupos Consolidados IT-1264-19). UGG was supported by Fundacion ´ Biofísica Bizkaia. ABV. was supported by Programa de especializacion ´ de Personal Investigador Doctor en la UPV/EHU (2019) 2019–2020.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAtherosclerosis. 2021 Jul;329:14-21. doi: 10.1016/j.atherosclerosis.2021.06.001. Epub 2021 Jun 10.pt_PT
dc.identifier.doi10.1016/j.atherosclerosis.2021.06.001pt_PT
dc.identifier.issn0021-9150
dc.identifier.urihttp://hdl.handle.net/10400.18/7901
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevier/ European Atherosclerosis Societypt_PT
dc.relationBiosystems & Integrative Sciences Institute
dc.relation.publisherversionhttps://www.atherosclerosis-journal.com/article/S0021-9150(21)00272-0/fulltextpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectFamilial Hypercholesterolemiapt_PT
dc.subjectFunctional Studiespt_PT
dc.subjectLDLRpt_PT
dc.subjectMolecular Diagnosispt_PT
dc.subjectVariantspt_PT
dc.subjectHypercholesterolaemiapt_PT
dc.subjectRecetor LDLpt_PT
dc.subjectMutagénesept_PT
dc.subjectDoenças Cardio e Cérebro-vascularespt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleLDLR variants functional characterization: Contribution to variant classificationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.citation.endPage21pt_PT
oaire.citation.startPage14pt_PT
oaire.citation.titleAtherosclerosispt_PT
oaire.citation.volume329pt_PT
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication35168786-8dfc-4a00-9759-dab3669fe1ae
relation.isProjectOfPublication.latestForDiscovery35168786-8dfc-4a00-9759-dab3669fe1ae

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