Caracterización funcional de la variante D47N del receptor de lipoproteína de baja densidad y su correlación con los niveles de colesterol LDL en plasma de personas portadoras de Hipercolesterolemia Familiar.
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Date
2025
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Universidad de Concepción
Abstract
La Hipercolesterolemia Familiar (HF) es una alteración genética autosómica dominante caracterizada por elevados niveles plasmáticos de colesterol de lipoproteína de baja densidad (LDL) desde muy temprana edad, lo cual se asocia a un alto riesgo de desarrollo de enfermedades cardiovasculares (ECV) prematuras. Esta mutaciones se vinculan a genes que codifican para PSCK9, apolipoproteína B y, > 80% al gen del receptor de LDL (LDLR). Un estudio de pesquisa de HF en la región del Biobío, se relevó la segunda variante más frecuente, p.Asp47Asn (D47N) del LDLR, la cual clasifica como una variante de patogenicidad incierta. Sin embargo, se ha descrito una alteración significativa en niveles de colesterol en sangre de pacientes portadores, lo que les confiere mayor riesgo de desarrollo de ECV precoz, haciendo necesario determinar cómo la presencia de esta variante afecta la función del LDLR.
Por esta razón, el presente estudio propuso contribuir a establecer la patogenicidad de la variante D47N por medio de ensayos funcionales ex vivo con células proveniente de pacientes. Para ello, técnicas de Biología Celular y Molecular se emplearon en macrófagos derivados de monocitos obtenidos de sangre venosa de portadores de la variante. De esta caracterización se obtuvieron diferencias significativas frente al control wild-type, también presentó características similares a mutaciones de clase 3, sugiriendo que se podría estar en presencia de una variante patogénica.
Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL C) from a very early age, which is associated with a high risk of developing premature cardiovascular diseases (CVD). These mutations are linked to genes encoding PCSK9, apolipoprotein B, and >80% to the LDL receptor (LDLR) gene. A FH screening study in the Biobío region revealed the second most frequent variant, p.Asp47Asn (D47N) of the LDLR, which is classified as a variant of uncertain pathogenicity. However, a significant alteration in cholesterol levels in the blood of carrier patients has been described, conferring a higher risk of early CVD development, making it necessary to determine how the presence of this variant affects LDLR function. For this reason, the present study proposed to contribute to establishing the pathogenicity of the D47N variant through ex vivo functional assays with cells from patients. To this end, Cellular and Molecular Biology techniques were employed in macrophages derived from monocytes obtained from venous blood of variant carriers. This characterization yielded significant differences compared to the wild type control, also presenting characteristics similar to class 3 mutations, suggesting that we could be in the presence of a pathogenic variant.
Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL C) from a very early age, which is associated with a high risk of developing premature cardiovascular diseases (CVD). These mutations are linked to genes encoding PCSK9, apolipoprotein B, and >80% to the LDL receptor (LDLR) gene. A FH screening study in the Biobío region revealed the second most frequent variant, p.Asp47Asn (D47N) of the LDLR, which is classified as a variant of uncertain pathogenicity. However, a significant alteration in cholesterol levels in the blood of carrier patients has been described, conferring a higher risk of early CVD development, making it necessary to determine how the presence of this variant affects LDLR function. For this reason, the present study proposed to contribute to establishing the pathogenicity of the D47N variant through ex vivo functional assays with cells from patients. To this end, Cellular and Molecular Biology techniques were employed in macrophages derived from monocytes obtained from venous blood of variant carriers. This characterization yielded significant differences compared to the wild type control, also presenting characteristics similar to class 3 mutations, suggesting that we could be in the presence of a pathogenic variant.
Description
Tesis presentada para optar al grado de Magíster en Bioquímica Clínica e Inmunología
Keywords
Hiperlipoproteinemia tipo II, Liproteínas ldl colesterol, Lipoproteínas Análisis