Characterization of Two Variants at Met 1 of the Human LDLR Gene Encoding the Same Amino Acid but Causing Different Functional Phenotypes

Detalhes bibliográficos
Autor(a) principal: Graça, Rafael
Data de Publicação: 2021
Outros Autores: Fernandes, Rafael, Alves, Ana catarina, Menezes, Juliane, Romão, Luísa, Bourbon, Mafalda
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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spelling 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
dc.format.none.fl_str_mv 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
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection 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
repository.mail.fl_str_mv
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