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Functional profiling of LDLR variants: Important evidence for variant classification: Functional profiling of LDLR variants

2022-08Journal article Restricted access
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dc.contributor.authorGraça, Rafael
dc.contributor.authorAlves, Ana Catarina
dc.contributor.authorZimon, Magdalena
dc.contributor.authorPepperkok, Rainer
dc.contributor.authorBourbon, Mafalda
dc.date.accessioned2023-01-27T14:23:40Z
dc.date.available2023-01-27T14:23:40Z
dc.date.issued2022-08
dc.description.abstractBackground: Familial Hypercholesterolemia (FH) is a semidominant disorder of the lipid metabolism associated with premature atherosclerosis and coronary heart disease. So far, about 3,000 unique LDLR variants have been described, most of which lack functional evidence proving their effect on LDLR function, despite the important role that functional studies play in variant classification. Objective: In this work, we aimed to functionally characterize 13 rare missense variants, identified worldwide and in Portugal, in clinical FH patients. Methods: LDLR-deficient CHO-ldlA7 cells were transfected with plasmids carrying different LDLR variants generated by site-directed mutagenesis. LDLR activity and expression were assessed by FACS. Results: 11/13 variants affect LDLR function (p.Cys109Phe; p.Cys143Arg; p.Glu267Lys; p.Cys352Ser; p.Ile451Thr; p.His485Gln; p.Asp492Asn; p.Val500Ala; p.Gly529Arg; p.Phe614Ile; p.Glu626Lys) and 2/13 are inconclusive (p.Arg81Cys; p.Gly98Arg;). Conclusion: Of the 13 variants studied, 8 were classified as VUS by ACMG criteria, but for 7 of these 8, our functional studies were able to reassign them as Likely pathogenic or Pathogenic. For an accurate diagnosis, an effort must be made to improve functional characterization of putative disease-causing variants.pt_PT
dc.description.abstractHighlights: 13 rare LDLR missense variants were functionally characterised; Our results identified 11 additional functionally abnormal LDLR variants; 22 patients received a definite diagnosis with the new functional data.pt_PT
dc.description.sponsorshipR.G acknowledges his PhD fellowship funded by the Science and Technology Foundation (PD/BD/131427/2017).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Clin Lipidol. 2022 Jul-Aug;16(4):516-524. doi: 10.1016/j.jacl.2022.04.005. Epub 2022 Apr 30.pt_PT
dc.identifier.doi10.1016/j.jacl.2022.04.005pt_PT
dc.identifier.issn1933-2874
dc.identifier.urihttp://hdl.handle.net/10400.18/8463
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationFunctional genomics in familial dyslipidaemia
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S1933287422000757pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectFamilial Hypercholesterolemiapt_PT
dc.subjectLDL Receptorpt_PT
dc.subjectFunctional Studiespt_PT
dc.subjectDefinitive Diagnosispt_PT
dc.subjectDoenças Cardio e Cérebro-vascularespt_PT
dc.titleFunctional profiling of LDLR variants: Important evidence for variant classification: Functional profiling of LDLR variantspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleFunctional genomics in familial dyslipidaemia
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F131427%2F2017/PT
oaire.citation.endPage524pt_PT
oaire.citation.issue4pt_PT
oaire.citation.startPage516pt_PT
oaire.citation.titleJournal of Clinical Lipidologypt_PT
oaire.citation.volume16pt_PT
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.isProjectOfPublication0d42d91a-b315-4173-bab7-c2b1f093d3f1
relation.isProjectOfPublication.latestForDiscovery0d42d91a-b315-4173-bab7-c2b1f093d3f1

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