# LDLR c.415G > A causes familial hypercholesterolemia by weakening LDLR binding to LDL

## TL;DR

This study identifies a genetic variant in the LDLR gene that causes familial hypercholesterolemia by reducing the receptor's ability to bind LDL.

## Contribution

The study confirms the pathogenicity of the LDLR c.415G > A variant and shows it impairs LDL binding.

## Key findings

- The LDLR c.415G > A variant is likely pathogenic in familial hypercholesterolemia.
- The variant does not affect LDLR protein expression but weakens LDL binding.
- This finding expands the known genetic variants associated with FH.

## Abstract

Familial hypercholesterolemia (FH) is a prevalent hereditary disease that can cause aberrant cholesterol metabolism. In this study, we confirmed that c.415G > A in low-density lipoprotein receptor (LDLR), an FH-related gene, is a pathogenic variant in FH by in silico analysis and functional experiments.

The proband and his family were evaluated using the diagnostic criteria of the Dutch Lipid Clinic Network. Whole-exome and Sanger sequencing were used to explore and validate FH-related variants. In silico analyses were used to evaluate the pathogenicity of the candidate variant and its impact on protein stability. Molecular and biochemical methods were performed to examine the effects of the LDLR c.415G > A variant in vitro.

Four of six participants had a diagnosis of FH. It was estimated that the LDLR c.415G > A variant in this family was likely pathogenic. Western blotting and qPCR suggested that LDLR c.415G > A does not affect protein expression. Functional studies showed that this variant may lead to dyslipidemia by impairing the binding and absorption of LDLR to low-density lipoprotein ( LDL).

LDLR c.415G > A is a pathogenic variant in FH; it causes a significant reduction in LDLR’s capacity to bind LDL, resulting in impaired LDL uptake. These findings expand the spectrum of variants associated with FH.

The online version contains supplementary material available at 10.1186/s12944-024-02068-2.