Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/7939 |
Resumo: | This article belongs to the Special Issue mRNA Metabolism in Health and Disease. |
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Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional PhenotypesACMG ClassificationLDLRFamilial HypercholesterolemiaFunctional CharacterizationInitiation CodonGenómica FuncionalGenómica Funcional e EstruturalDoenças GenéticasDoenças Cardio e Cérebro-vascularesThis article belongs to the Special Issue mRNA Metabolism in Health and Disease.Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, characterized by increased levels of total and LDL plasma cholesterol, which leads to premature atherosclerosis and coronary heart disease. FH phenotype has considerable genetic heterogeneity and phenotypic variability, depending on LDL receptor activity and lifestyle. To improve diagnosis and patient management, here, we characterized two single nucleotide missense substitutions at Methionine 1 of the human LDLR gene (c.1A>T/p.(Met1Leu) and c.1A>C/p.(Met1Leu)). We used a combination of Western blot, flow cytometry, and luciferase assays to determine the effects of both variants on the expression, activity, and synthesis of LDLR. Our data show that both variants can mediate translation initiation, although the expression of variant c.1A>T is very low. Both variants are in the translation initiation codon and codify for the same amino acid p.(Met1Leu), yet they lead to different levels of impairment on LDLR expression and activity, corroborating different efficiencies of the translation initiation at these non-canonical initiation codons. The functional data of these variants allowed for an improved American College of Medical Genetics (ACMG) classification for both variants, which can allow a more personalized choice of the lipid-lowering treatment and dyslipidemia management, ultimately improving patients' prognosis.The authors acknowledge Fundação para a Ciência e a Tecnologia (Ph.D. scholarship no. SFRH/PD/BD/131427/2017 and SFRH/PD/BD/114392/2016).MDPIRepositório Científico do Instituto Nacional de SaúdeGraça, RafaelFernandes, RafaelAlves, Ana catarinaMenezes, JulianeRomão, LuísaBourbon, Mafalda2022-02-07T16:15:39Z2021-09-142021-09-14T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/7939engBiomedicines. 2021 Sep 14;9(9):1219. doi: 10.3390/biomedicines90912192227-905910.3390/biomedicines9091219info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:42:22Zoai:repositorio.insa.pt:10400.18/7939Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:42:43.674555Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
title |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
spellingShingle |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes Graça, Rafael ACMG Classification LDLR Familial Hypercholesterolemia Functional Characterization Initiation Codon Genómica Funcional Genómica Funcional e Estrutural Doenças Genéticas Doenças Cardio e Cérebro-vasculares |
title_short |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
title_full |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
title_fullStr |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
title_full_unstemmed |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
title_sort |
Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes |
author |
Graça, Rafael |
author_facet |
Graça, Rafael Fernandes, Rafael Alves, Ana catarina Menezes, Juliane Romão, Luísa Bourbon, Mafalda |
author_role |
author |
author2 |
Fernandes, Rafael Alves, Ana catarina Menezes, Juliane Romão, Luísa Bourbon, Mafalda |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Graça, Rafael Fernandes, Rafael Alves, Ana catarina Menezes, Juliane Romão, Luísa Bourbon, Mafalda |
dc.subject.por.fl_str_mv |
ACMG Classification LDLR Familial Hypercholesterolemia Functional Characterization Initiation Codon Genómica Funcional Genómica Funcional e Estrutural Doenças Genéticas Doenças Cardio e Cérebro-vasculares |
topic |
ACMG Classification LDLR Familial Hypercholesterolemia Functional Characterization Initiation Codon Genómica Funcional Genómica Funcional e Estrutural Doenças Genéticas Doenças Cardio e Cérebro-vasculares |
description |
This article belongs to the Special Issue mRNA Metabolism in Health and Disease. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-09-14 2021-09-14T00:00:00Z 2022-02-07T16:15:39Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/7939 |
url |
http://hdl.handle.net/10400.18/7939 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Biomedicines. 2021 Sep 14;9(9):1219. doi: 10.3390/biomedicines9091219 2227-9059 10.3390/biomedicines9091219 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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