Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia
Novel LDLR variants affecting low density lipoprotein metabolism identified in familial hypercholesterolemia
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DOI：
10.1007/s11033-023-09169-8
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发表时间：
2024-12-01
影响因子：
2.8
通讯作者：
Jin，Liping
中科院分区：
文献类型：
--
作者：
Wang，Miao;Hong，Ling;Jin，Liping
家族性高胆固醇血症（FH）是一种常染色体显性遗传的脂代谢疾病，主要由低密度脂蛋白受体（LDLR）基因突变引起。FH患者的基因检测有助于精确诊断和治疗，从而降低冠心病（CHD）和其他相关疾病的风险。本研究的目的是确定致病基因突变，在中国FH家庭，揭示致病性和这些突变的机制。方法和resultsWhole外显子组测序在一个严重的脂代谢功能障碍的患者寻求生育指导，从中国FH家庭。在家族中鉴定出两种LDLR变体c.1875 C > G（p.N625K;新变体）和c.1448G > A（p.W483*）。野生型和突变型LDLR构建体通过定点诱变技术建立。通过细胞转染进行功能研究，以评价检测到的变体对LDLR活性的影响。这两种变体被证明影响LDL的摄取和结合，导致胆固醇清除率不同程度地降低。根据美国医学遗传学和基因组学学会（ACMG）标准和指南，W 483 * 变异体被归类为“致病性”，而N625 K变异体被归类为“VUS”。
BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant disease of lipid metabolism mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Genetic detection of patients with FH help with precise diagnosis and treatment, thus reducing the risk of coronary heart disease (CHD) and other related diseases. The study aimed to identify the causative gene mutations in a Chinese FH family and reveal the pathogenicity and the mechanism of these mutations.Methods and resultsWhole exome sequencing was performed in a patient with severe lipid metabolism dysfunction seeking fertility guidance from a Chinese FH family. Two LDLR variants c.1875 C > G (p.N625K; novel variant) and c.1448G > A (p.W483*) were identified in the family. Wildtype and mutant LDLR constructs were established by the site-direct mutagenesis technique. Functional studies were carried out by cell transfection to evaluate the impact of detected variants on LDLR activity. The two variants were proven to affect LDL uptake and binding, resulting in cholesterol clearance reduction to different degrees. According to The American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines, the W483* variant was classified as “Pathogenic”, while the N625K variant as “VUS”.ConclusionsOur results provide novel experimental evidence of functional alteration byLDLRvariants identified in our study and expand the mutational spectrum ofLDLRmutation induced FH.