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Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial
Andrea Sánchez1, Paulina Bustos1, Paula Honorato1
1Departamento de Bioquímica Clínica e Inmunología, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile.
Insights
The p.Asp47Asn LDL receptor (LDL-R) mutation in familial hypercholesterolemia (FH) increases LDL-C levels and reduces LDL-R binding capacity. This variant is associated with FH, impacting cardiovascular health.
Area of Science:
- Genetics
- Biochemistry
- Cardiology
Background:
- Familial hypercholesterolemia (FH) is an inherited disorder.
- It is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease.
- Mutations in the LDL receptor (LDL-R) are a primary cause of FH.
Purpose of the Study:
- Evaluate the clinical phenotype of the p.Asp47Asn variant.
- Assess the variant's effect on LDL-R structure and apolipoprotein binding.
- Determine the association of the p.Asp47Asn variant with FH.
Main Methods:
- Recruited 27 children and adolescents with suspected FH.
- Performed lipid profile analysis and DNA sequencing of FH-related genes.
- Utilized in silico analysis to evaluate LDL-R binding capacity to apolipoproteins.
Main Results:
- p.Asp47Asn carriers showed higher LDL-C levels compared to wild-type.
- In silico analysis predicted reduced binding capacity of p.Asp47Asn LDL-R for ApoB100 and ApoE.
- This reduction was due to decreased apparent affinity, not structural defects.
Conclusions:
- The p.Asp47Asn LDL-R mutation is associated with FH.
- The variant impacts LDL-R function and lipid levels.
- Clinical phenotype and structural effects support its role in FH.
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.
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