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Variantes no gene APOB associadas a hipobetalipoproteinemia e hipercolesterolemia familiar: estudos funcionais e relação genótipo/fenótipo
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As dislipidemias são um grupo de patologias caracterizadas por alterações no perfil lipídico, podendo incluir fenótipos de hiperlipidemia ou hipolipidemia. A apolipoproteína B (apoB), principal componente proteico do colesterol LDL (c-LDL), desempenha um papel essencial na regulação dos níveis de colesterol no sangue. Variantes no gene APOB estão associadas a condições distintas como a hipercolesterolemia familiar (FH) e a hipobetalipoproteinemia familiar (FHBL).
A FH caracteriza-se por níveis elevados de c-LDL, que podem levar ao desenvolvimento de aterosclerose e doença coronária prematura. Por outro lado, a FHBL apresenta níveis reduzidos de c-LDL e está associada a complicações hepáticas, nutricionais e neurológicas. A compreensão dos efeitos das variantes no gene APOB é fundamental, sendo os estudos funcionais uma ferramenta indispensável, especialmente com o avanço da sequenciação de nova geração (NGS), que permite a análise completa
do gene.
O presente trabalho visou realizar estudos funcionais de variantes no gene APOB associadas a estas duas patologias, com o objetivo de aprofundar o conhecimento sobre os mecanismos moleculares subjacentes. A análise de variantes descritas na base de dados ClinVar revelou um elevado número associado tanto à FH como à FHBL, com muitas classificadas como variantes de significado clínico incerto (VUS).
Foram realizados ensaios funcionais utilizando citometria de fluxo a partir de LDL de indivíduos com variantes no gene APOB associadas à hipercolesterolemia. Os resultados não
identificaram nenhuma das variantes analisadas como causadora do fenótipo observado nos indivíduos. Consequentemente, não foi possível alterar a classificação destas variantes, que permanecem de significado incerto. Adicionalmente, foram analisados casos de FHBL e discutidas possíveis abordagens para estudos funcionais futuros. Este trabalho reforça a relevância de estudos funcionais para esclarecer o papel das variantes no gene APOB nas dislipidemias, contribuindo para um melhor diagnóstico e caracterização destas condições.
Dyslipidemias are a group of pathologies characterized by alterations in the lipid profile, which may include phenotypes of hyperlipidemia or hypolipidemia. Apolipoprotein B (apoB), the main protein component of LDL cholesterol (LDL-c), plays a crucial role in regulating blood cholesterol levels. Genetic variants in the APOB gene are associated with distinct conditions such as familial hypercholesterolemia (FH) and familial hypobetalipoproteinemia (FHBL). FH is characterized by elevated LDL-c levels, which can lead to the development of atherosclerosis and premature coronary artery disease. On the other hand, FHBL presents itself with reduced LDL-c levels and is associated with hepatic, nutritional, and neurological complications. Understanding the effects of variants in the APOB gene is essential, and functional studies are an indispensable tool, especially with the growing use of next generation sequencing (NGS), which allows the analysis of the full gene sequence. The present work aimed to conduct functional analysis of variants in the APOB gene associated with these two conditions, with the goal of deepening the knowledge of the underlying molecular mechanisms. Analysis of variants described in the ClinVar database revealed a high number of variants associated with both FH and FHBL, many of which were classified as variants of uncertain significance (VUS). Functional assays were performed using flow cytometry on LDL from individuals with APOB variants associated with hypercholesterolemia. The results did not identify any of the analysed variants as causative of the observed phenotype in these individuals. Consequently, it was not possible to change the previous classification of these variants, which remains as VUS. Additionally, cases of FHBL were analysed, and potential approaches for future functional studies were discussed. This work reinforces the importance of functional studies to clarify the role of APOB gene variants in dyslipidemias, contributing to a better diagnosis and characterization of these conditions.
Dyslipidemias are a group of pathologies characterized by alterations in the lipid profile, which may include phenotypes of hyperlipidemia or hypolipidemia. Apolipoprotein B (apoB), the main protein component of LDL cholesterol (LDL-c), plays a crucial role in regulating blood cholesterol levels. Genetic variants in the APOB gene are associated with distinct conditions such as familial hypercholesterolemia (FH) and familial hypobetalipoproteinemia (FHBL). FH is characterized by elevated LDL-c levels, which can lead to the development of atherosclerosis and premature coronary artery disease. On the other hand, FHBL presents itself with reduced LDL-c levels and is associated with hepatic, nutritional, and neurological complications. Understanding the effects of variants in the APOB gene is essential, and functional studies are an indispensable tool, especially with the growing use of next generation sequencing (NGS), which allows the analysis of the full gene sequence. The present work aimed to conduct functional analysis of variants in the APOB gene associated with these two conditions, with the goal of deepening the knowledge of the underlying molecular mechanisms. Analysis of variants described in the ClinVar database revealed a high number of variants associated with both FH and FHBL, many of which were classified as variants of uncertain significance (VUS). Functional assays were performed using flow cytometry on LDL from individuals with APOB variants associated with hypercholesterolemia. The results did not identify any of the analysed variants as causative of the observed phenotype in these individuals. Consequently, it was not possible to change the previous classification of these variants, which remains as VUS. Additionally, cases of FHBL were analysed, and potential approaches for future functional studies were discussed. This work reinforces the importance of functional studies to clarify the role of APOB gene variants in dyslipidemias, contributing to a better diagnosis and characterization of these conditions.
Descrição
Dissertação de Mestrado em Biologia Molecular e Genética, apresentada à Faculdade de Ciências, Universidade de Lisboa, 2025. http://hdl.handle.net/10400.5/100267
Palavras-chave
LDL Apolipoproteína B Hipercolesterolemia Hipobetalipoproteinemia Estudos Funcionais Doenças Cardio e Cérebro-vasculares Apolipoprotein B Hypercholesterolemia Hypobetalipoproteinemia Functional Studies
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Sem licença CC