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Title: | Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial Hypercholesterolemia in a Chilean population |
Authors: | SANCHEZ, Andrea; BUSTOS, Paulina; HONORATO, Paula; BURGOS, Carlos F.; BARRIGA, Natalia; JANNES, Cinthia E.; SAEZ, Katia; ALONSO, Rodrigo; ASENJO, Sylvia; RADOJKOVIC, Claudia |
Citation: | JOURNAL OF CLINICAL LIPIDOLOGY, v.15, n.2, p.366-+, 2021 |
Abstract: | BACKGROUND: Familial hypercholesterolemia (FH) is an inherited disorder mainly caused by mutations in the LDL receptor (LDL-R) and characterized by elevation of low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. OBJECTIVE: In this study, we evaluated the clinical phenotype of the p.Asp47Asn, described as an uncertain pathogenic variant, and its effect on the structure of LDL-R and ligand interactions with apolipoproteins. METHODS: 27 children and adolescents with suspected FH diagnosis were recruited from a pediatric endocrinology outpatient clinic. Blood samples were collected after 12 h fasting for lipid profile analysis. DNA sequencing was performed for six FH-related genes by Ion Torrent PGM platform and copy number variation by MLPA. For index cases, a familial cascade screening was done restricted to the same mutation found in the index case. In silico analysis were developed to evaluate the binding capacity of LDL-R to apolipoproteins B100 and E. RESULTS: Lipid profile in children and adolescents demonstrated higher LDL-C levels in p.Asp47Asn carriers compared to the wild type genotype. In silico analysis predicted a reduction in the binding capacity of the ligand-binding modules LA1-2 of p.Asp47Asn LDL-R for ApoB100 and ApoE, which was not produced by local structural changes or folding defects but as a consequence of a decreased apparent affinity for both apolipoproteins. CONCLUSION: The clinical phenotype and the structural effects of p.Asp47Asn LDL-R mutation suggest that this variant associates to FH. (C) 2021 Published by Elsevier Inc. on behalf of National Lipid Association. |
Appears in Collections: | Artigos e Materiais de Revistas Científicas - HC/InCor Artigos e Materiais de Revistas Científicas - LIM/13 Artigos e Materiais de Revistas Científicas - ODS/03 |
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