Evaluación funcional del receptor de LDL de la variante D47N en personas con hipercolesterolemia familiar.
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Date
2024
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Universidad de Concepción
Abstract
La Hipercolesterolemia Familiar (HF) es una alteración genética autosómica dominante caracterizada por presentar elevados niveles plasmáticos de colesterol de LDL (c-LDL) desde muy temprana edad, asociándose a un alto riesgo de desarrollo de enfermedades cardiovasculares ateroscleróticas prematuras. Esta enfermedad está asociada a mutaciones vinculadas a genes que codifican para la pro-proteína PSCK9, apolipoproteína B (Apo B) y, cerca de un 90%, al receptor de LDL (LDLR). Por medio de una pesquisa de HF en la región del Biobío, quedó en evidencia que la segunda variante con más frecuencia en la población es la mutación p.Asp47Asn (D47N) del LDLR, la cual se clasifica como una variante de patogenicidad incierta. Sin embargo, se ha descrito una alteración significativa de los niveles de colesterol en sangre en los pacientes que la portan, por lo que hace necesario determinar cómo afecta la presencia de esta variante en la funcionalidad del LDLR en pacientes portadores de esta enfermedad. Por todo lo anteriormente descrito, el presente estudio propone evaluar la funcionalidad del LDLR con la mutación D47N de HF para contribuir a establecer la patogenicidad de esta mutación. Para ello, por medio de uso de macrófagos derivados de monocitos purificados de muestra de pacientes portadores en ensayos inmunocitoquímicos y de citometría de flujo, se determinaron niveles de expresión, localización subcelular y transporte de LDL en esta variante del LDLR. Todos estos antecedentes sugiriendo que corresponde a una mutación de clase III, la cual afecta la localización y expresión del LDLR.
Familial hypercholesterolemia (FH) is an autosomal dominant genetic alteration characterized by high plasma levels of LDL cholesterol (c-LDL) from a very early age, associated with a high risk of developing premature atherosclerotic cardiovascular diseases. These mutations are produced in genes that code for pro-protein PSCK9, apolipoprotein B (Apo B) and about 90% the LDL receptor (LDLR). Through research study of FH in the Biobío region, it became clear that the second most frequent variant in the population is the p.Asp47Asn (D47N) mutation of LDLR, which is classified as an uncertain pathogenic variant. However, a significant alteration in blood cholesterol levels has been described in patients who carry it, so it is necessary to determine how the presence of this variant affects the functionality of LDLR in patients with this disease. For all of the above, the present study proposes to evaluate the functionality of LDLR with the D47N mutation of HF to help establish the pathogenicity of this mutation. To do this, through the use of macrophages derived from purified monocytes from samples of carrier patients in immunocytochemical and flow cytometry assays, expression levels, subcellular localization and LDL transport were determined in this variant of LDLR, suggesting that it corresponds to a class III mutation, which affects the localization and expression of LDLR.
Familial hypercholesterolemia (FH) is an autosomal dominant genetic alteration characterized by high plasma levels of LDL cholesterol (c-LDL) from a very early age, associated with a high risk of developing premature atherosclerotic cardiovascular diseases. These mutations are produced in genes that code for pro-protein PSCK9, apolipoprotein B (Apo B) and about 90% the LDL receptor (LDLR). Through research study of FH in the Biobío region, it became clear that the second most frequent variant in the population is the p.Asp47Asn (D47N) mutation of LDLR, which is classified as an uncertain pathogenic variant. However, a significant alteration in blood cholesterol levels has been described in patients who carry it, so it is necessary to determine how the presence of this variant affects the functionality of LDLR in patients with this disease. For all of the above, the present study proposes to evaluate the functionality of LDLR with the D47N mutation of HF to help establish the pathogenicity of this mutation. To do this, through the use of macrophages derived from purified monocytes from samples of carrier patients in immunocytochemical and flow cytometry assays, expression levels, subcellular localization and LDL transport were determined in this variant of LDLR, suggesting that it corresponds to a class III mutation, which affects the localization and expression of LDLR.
Description
Tesis presentada para optar al título de Bioquímico/a.
Keywords
Hiperlipoproteinemia Tipo II, LDL-Colesterol, Enfermedades cardiovasculares, Citofluorometría de flujo