Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial Hypercholesterolemia in a Chilean population
Autor: | Paula Honorato, Natalia Barriga, Paulina Bustos, Sylvia Asenjo, Andrea Sanchez, Claudia Radojkovic, Katia Sáez, Carlos F. Burgos, Cinthia E. Jannes, Rodrigo Alonso |
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Rok vydání: | 2021 |
Předmět: |
Adult
Apolipoprotein E medicine.medical_specialty Adolescent DNA Copy Number Variations Apolipoprotein B Endocrinology Diabetes and Metabolism Population Familial hypercholesterolemia 030204 cardiovascular system & hematology Hyperlipoproteinemia Type II 03 medical and health sciences 0302 clinical medicine Internal medicine Genotype Internal Medicine medicine Humans Outpatient clinic 030212 general & internal medicine education education.field_of_study Nutrition and Dietetics biology medicine.diagnostic_test business.industry medicine.disease Phenotype Endocrinology Receptors LDL LDL receptor biology.protein lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine Lipid profile business |
Zdroj: | Journal of Clinical Lipidology. 15:366-374.e1 |
ISSN: | 1933-2874 |
Popis: | 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. |
Databáze: | OpenAIRE |
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