Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia

Haochang Hu,Shuangshuang Wang,Shaoyi Lin,Jun Ma,Tian Shu,Ruoyu Chen,Jian Wang,Xiaomin Chen

doi:10.3389/fgene.2021.762587

Abstract

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.

Highlights

Familial hypercholesterolemia (FH) is a common autosomal genetic disorder mainly caused by pathogenic mutations in genes encoding low-density lipoprotein receptor (LDLR), apolipoprotein B (ApoB) and proprotein convertase subtilisin kexin 9 (PCSK9) (Benn et al, 2016)
As a membrane protein on the surface of liver cells, LDLR is the key point of lowdensity lipoprotein cholesterol (LDLC) metabolism
The pathogenic variants in LDLR could directly lead to protein dysfunction and Disease-Causing Mutations in familial hypercholesterolemia (FH)

Summary

Introduction

Familial hypercholesterolemia (FH) is a common autosomal genetic disorder mainly caused by pathogenic mutations in genes encoding low-density lipoprotein receptor (LDLR), apolipoprotein B (ApoB) and proprotein convertase subtilisin kexin 9 (PCSK9) (Benn et al, 2016). A meta-analysis of 11 million subjects illustrated that the prevalence of FH in the general population is 0.32%, while the prevalence of FH in ischemic heart disease and premature ischemic heart disease patients is 3.2 and 6.7%, respectively (Beheshti et al, 2020). European and American guidelines suggest that FH patients should be identified as early as possible so that LDLC lowering treatment can be started early in life in order to improve the patient’s prognosis (Piepoli et al, 2016; Grundy et al, 2019). As a membrane protein on the surface of liver cells, LDLR is the key point of LDLC metabolism. The LDLR subsequently returns to the surface of liver cells for recycling (van de Sluis et al, 2017; Chemello et al, 2021). The pathogenic variants in LDLR could directly lead to protein dysfunction and Disease-Causing Mutations in FH

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Conclusion