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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
摘要：
背景：家族性高胆固醇血症（FH）是一种常见的遗传性疾病，可导致胆固醇代谢异常。在这项研究中,我们证实低密度脂蛋白受体（LDLR）中c.415G>A，FH相关基因,通过计算机分析和功能实验，是FH中的致病变体。
方法：使用荷兰脂质临床网络的诊断标准评估先证者及其家人。使用全外显子组和Sanger测序来探索和验证FH相关变体。计算机模拟分析用于评估候选变体的致病性及其对蛋白质稳定性的影响。进行分子和生化方法以检查LDLRc.415G>A变体在体外的作用。
结果：六名参与者中有四名被诊断为FH。据估计，该家族中的LDLRc.415G>A变体可能是致病性的。蛋白质印迹和qPCR表明LDLRc.415G>A不影响蛋白质表达。功能研究表明，该变体可能通过损害LDLR与低密度脂蛋白（LDL）的结合和吸收而导致血脂异常。
结论：LDLRc.415G>A是FH的致病变体；它导致LDLR结合LDL的能力显着降低，导致LDL摄取受损。这些发现扩展了与FH相关的变异谱。
方法：使用荷兰脂质临床网络的诊断标准评估先证者及其家人。使用全外显子组和Sanger测序来探索和验证FH相关变体。计算机模拟分析用于评估候选变体的致病性及其对蛋白质稳定性的影响。进行分子和生化方法以检查LDLRc.415G>A变体在体外的作用。
结果：六名参与者中有四名被诊断为FH。据估计，该家族中的LDLRc.415G>A变体可能是致病性的。蛋白质印迹和qPCR表明LDLRc.415G>A不影响蛋白质表达。功能研究表明，该变体可能通过损害LDLR与低密度脂蛋白（LDL）的结合和吸收而导致血脂异常。
结论：LDLRc.415G>A是FH的致病变体；它导致LDLR结合LDL的能力显着降低，导致LDL摄取受损。这些发现扩展了与FH相关的变异谱。
