2018 年第 7 期 第 13 卷

家族性高胆固醇血症患者突变基因及低密度脂蛋白受体活性分析

Low-density lipoprotein receptor function and gene mutation in familial hypercholesterolemia

作者：武文峰孙立元温文慧吴月王绿娅 

英文作者：

单位：100029首都医科大学附属北京安贞医院急诊科（武文峰），皮肤科（孙立元）；100029北京市心肺血管疾病研究所动脉粥样硬化研究室（温文慧、吴月、王绿娅）

英文单位：

关键词：家族性高胆固醇血症；低密度脂蛋白受体；基因突变；黄色瘤

英文关键词：

• 摘要：

• 【摘要】目的    对家族性高胆固醇血症(FH)纯合患者及家系行突变基因检测及低密度脂蛋白受体(LDL-R)活性分析。方法    入选2016年8月首都医科大学附属北京安贞医院高脂血症筛查门诊接诊的1例 12岁男性患者。对纯合子先证者及家系进行血脂、血管超声等检查；提取先证者基因组DNA，采用靶向捕获芯片结合二代测序检测发现突变基因并验证；运用流式细胞仪检测先证者外周血中淋巴细胞LDL-R表达及功能。结果    先证者血清总胆固醇和低密度脂蛋白胆固醇水平明显升高、颈动脉内膜中层增厚；先证者LDL-R基因第8外显子1 129位碱基由G突变为T，导致LDL-R蛋白编码第356位由半胱氨酸取代为甘氨酸（p.C356G），属于杂合错义突变；第9外显子1 268位碱基由T突变为C，导致第402位氨基酸由异亮氨酸取代为苏氨酸（p.I402T），为杂合错义突变。LDL-R的表达量和结合功能显著下降，分别为正常人的48%和40%。结论    纯合先证者LDL-R基因突变分别来源于父亲和母亲的遗传，该突变可能是家系发病的分子基础；C356G也可能是我国FH患者LDL-R基因一种新的突变类型。

• 【Abstract】Objective    To analyze the function of low-density lipoprotein receptor(LDL-R) and gene mutation in a patient with homozygous familial hypercholesterolemia(FH) and his relatives. Methods    A 12 years old boy with hypercholesterolemia admitted in Beijing Anzhen Hospital, Capital Medical University in August 2016 was enrolled; gene detection showed that he was a homozygous type of FH. The proband and his relatives had blood lipid test and vascular ultrasound; gene mutation was detected and verified by targeted capture chip and the second generation DNA sequencing technology; expression and function of LDL-R in peripheral blood lymphocytes were tested by flow cytometry. Results    Levels of serum total cholesterol and low-density lipoprotein cholesterol and  thickness of intima-media wall significantly increased in the proband of FH. The exon 8 of LDL-R gene 1 129 base changed from G to T, the encoded protein was cysteine instead of glycine(p.C356G), which was a heterozygous missense mutation. The 9 exon of LDL-R gene 1 268 base changed from T to C, isoleucine was replaced with threonine(p.I402T), which was a heterozygous missense mutation. Expression and binding function of LDL-R significantly decreased (48% and 40% of normal person respectively). Conclusions    LDL-R gene mutations of the homozygous proband of FH are inherited from mother and father, it may be the molecular basis of the family disease. C356G may be a new mutation type of LDL-R gene in FH patients in China.

  【Key words】Familial hypercholesterolemia；Low-density lipoprotein receptor；Gene mutation;Xanthomata

  【Fund program】National Natural Science Foundation of China（81670811）; Basic and Clinical Scientific Research Cooperation Fund of Capital Medical University(17JL43); President Fund of Beijing Anzhen Hospital, Capital Medical University(2016Z09); Amgen "Progressive Research Fund" Project