Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR
dc.contributor.author | Galicia García, Unai | |
dc.contributor.author | Benito Vicente, Asier | |
dc.contributor.author | Belloso Uribe, Kepa | |
dc.contributor.author | Jebari Benslaiman, Shifa | |
dc.contributor.author | Larrea Sebal, Asier | |
dc.contributor.author | Alonso Estrada, Rocio | |
dc.contributor.author | Aguilo Arce, Joseba | |
dc.contributor.author | Ostolaza Echabe, Elena Amaya | |
dc.contributor.author | Palacios, Lourdes | |
dc.contributor.author | Martín Plágaro, César Augusto | |
dc.date.accessioned | 2020-04-15T10:36:53Z | |
dc.date.available | 2020-04-15T10:36:53Z | |
dc.date.issued | 2020-02-03 | |
dc.identifier.citation | Scientific Reports 10 : (2020) // Article ID 1727 | es_ES |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | http://hdl.handle.net/10810/42716 | |
dc.description.abstract | The primary genetic cause of familial hypercholesterolemia (FH) is related to mutations in the LDLR gene encoding the Low-density Lipoprotein Receptor. LDLR structure is organized in 5 different domains, including an EGF-precursor homology domain that plays a pivotal role in lipoprotein release and receptor recycling. Mutations in this domain constitute 51.7% of the total missense variants described in LDLR. The aim of the present work was to analyse how clinically significant variants in the EGF-precursor homology domain impact LDLR. The activity of sixteen LDLR variants was functionally characterized by determining LDLR expression by Western blot and LDLR expression, LDL binding capacity and uptake, and LDLR recycling activity by flow cytometry in transfected CHO-ldlA7 cells. Of the analysed variants, we found six non-pathogenic LDLR variants and ten pathogenic variants distributed as follow: three class 3 variants; four class 2 variants; and three class 5 variants. These results can be incorporated into clinical management of patients by helping guide the appropriate level of treatment intensity depending on the extent of loss of LDLR activity. This data can also contribute to cascade-screening for pathogenic FH variants. | es_ES |
dc.description.sponsorship | We thank Prof. Monty Krieger for kindly providing CHO-ldlA7 cells. We sincerely thank Haziq Siddiqi (Harvard Medical School) for his critical reading and editing of this manuscript and Professor Katrine T. Schjoldager (Copenhagen Center for Glycomics) for her invaluable research assistance on glycosylation analysis of p.(Ser584Pro) LDLR variant. This work was supported by the Basque Government (Grupos Consolidados IT-1264-19). A.B.-V. was supported by a grant PIF (2014–2015), Gobierno Vasco and DOKBERRI 2019-I. S.J. was supported by a grant PIF (2017–2018), Gobierno Vasco. U.G-G. and R.A-E. were supported by Fundación Biofísica Bizkaia | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.title | Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://www.nature.com/articles/s41598-020-58734-9 | es_ES |
dc.identifier.doi | 10.1038/s41598-020-58734-9 | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |
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