As 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. The 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. All 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. LDLR 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.

中文翻译：

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LDLR c.501C>A 是家族性高胆固醇血症的致病变异

作为一种常染色体显性遗传疾病，家族性高胆固醇血症（FH）主要归因于低密度脂蛋白受体（LDLR）基因的致病变异。本研究旨在探讨 LDLR c.501C>A 变异在 FH 中的分子机制，并评估前蛋白转化酶枯草杆菌蛋白酶 kexin 9 型 (PCSK9) 抑制剂治疗 FH 患者的疗效。对两个家族进行全外显子组测序以鉴定致病变异，并通过 Sanger 测序验证。通过蛋白质印迹和共聚焦显微镜在 HEK293 细胞中进一步探索了 LDLR 变体的功能。此外，对两名先证者的 PCSK9 抑制剂治疗效果进行了为期 3 个月的评估。具有 LDLR c.501C>A 变体的两个家族的所有成员都显示出高水平的 LDLC。本研究证实了临床表型与 LDLR 变异之间的关系。计算机和体外分析均显示 LDLR c.501C>A 变体降低了 LDLR 表达和 LDL 摄取。PCSK9抑制剂治疗使先证者1的血脂水平降低了24.91%。然而，该治疗对先证者2无效。后续研究表明，PCSK9抑制剂治疗对患者的降脂作用能力较低。LDLR c.501C>一个变异可能对 FH 有致病性。PCSK9 抑制剂治疗不是治疗 LDLR c.501C>A 变异的 FH 患者的高效选择。PCSK9抑制剂治疗使先证者1的血脂水平降低了24.91%。然而，该治疗对先证者2无效。后续研究表明，PCSK9抑制剂治疗对患者的降脂作用能力较低。LDLR c.501C>一个变异可能对 FH 有致病性。PCSK9 抑制剂治疗不是治疗 LDLR c.501C>A 变异的 FH 患者的高效选择。PCSK9抑制剂治疗使先证者1的血脂水平降低了24.91%。然而，该治疗对先证者2无效。后续研究表明，PCSK9抑制剂治疗对患者的降脂作用能力较低。LDLR c.501C>一个变异可能对 FH 有致病性。PCSK9 抑制剂治疗不是治疗 LDLR c.501C>A 变异的 FH 患者的高效选择。