The LDLR c.501C>A is a disease-causing variant in familial hypercholesterolemia

Lipids in Health and Disease

Yingchu Hu¹  Jian Wang¹  Ruoyu Chen²  Shaoyi Lin²  Haochang Hu²  Xiaomin Chen² 

[1] Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang, China;School of Medicine, Ningbo University, Ningbo, Zhejiang, China;Department of Cardiology, Ningbo First Hospital, Ningbo, Zhejiang, China;

关键词: Familial hypercholesterolemia;    Genetic diagnosis;    Whole-exome sequencing;    Heterogeneous genotype;    Homogeneous genotype;    PCSK9 inhibitor;   

DOI  :  10.1186/s12944-021-01536-3

来源: Springer

【 摘 要 】

BackgroundAs an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients.MethodsThe whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months.ResultsAll members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients.ConclusionsLDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.

【 授权许可】

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