家族性高胆固醇血症患者低密度脂蛋白受体基因新突变  

Novel mutation of low density lipoprotein receptor gene associated with familial hypercholesterolemia

作　　者：陈立伟[1] 杨明[1] 蔺洁[2] 王绿娅[2] 

机构地区：[1]首都医科大学附属复兴医院心内科,北京100038 [2]北京市心肺血管疾病研究所动脉粥样硬化研究室,100029

出　　处：《中国医师进修杂志》2010年第22期1-4,共4页Chinese Journal of Postgraduates of Medicine

基　　金：国家自然科学基金联合资助（30470722、30771986和30772356）

摘　　要：目的分析一家族性高胆固醇血症（FH）家系低密度脂蛋白受体（LDLR）基因突变类型，明确其突变位点，探讨LDLR基因突变类型与其临床表型的关系以及FH发病的分子病理学机制。方法先证者及家系成员进行血脂测定，并行心电图、心脏和全身大血管彩色多普勒超声等检查，之后采用聚合酶链反应（PCR）联合变性高效液相色谱（DHPLC）技术结合扩增产物直接序列分析，检测LDLR基因启动子和全部18个外显子片段，结果与Gen Bank公布的该基因正常序列比对，找出突变，并检索FH突变数据库（www．ucl．ac．uk／fh）。采用PCR结合限制性内切酶技术，检测载脂蛋白B100（ApoB100）基因Q3500R位点突变，以排除家族性ApoB100缺陷症（FDB）。结果先证者LDLR基因第13外显子存在c．1864G→A错义突变，使得所表达的氨基酸由天冬氨酸→天冬酰胺（Asp622Asn）；该外显子同时发现c．1959c→T（Val653Val）同义突变。在其母亲及外祖母LDLR基因中均发现上述两种突变，其父亲及外祖父也发现Val653Val的同义突变。克隆测序验证上述两种突变。结论国内首次发现Asp622Asn突变；该突变可能是FH发病的分子病理学基础，并导致其严重的临床表型。PCR联合DHPLC技术可用于FH可疑人群的确诊。Objective To analyse the mutation of low density lipoprotein receptor （LDLR） gene associated with familial hypereholesterolemia （FH） and make a discussion on the relationship between genotype and phenotype. Methods The blood fat, electrocardiogram, heart and great vessels color Doppler were examined in propositus and family member. The promoter and all eighteen exons of LDLR gene were investigated by polymerase chain reaction （PCR） ,degenerate high performance liquid chromatogram （DHPLC） and DNA sequence analysis. The results were compared with the normal sequences in GenBank and FH database （www.ucl.uk/fh） to find the mutation. In addition ,the apolipoprotein B100（ApoB100） gene for the known mutations（Q3500R） that cause familial defective ApoB100（FDB ） was detected by directed screening. Results Two novel heterozygous c.1864 G→A （Asp622Asn） and c.1959 C→T（Val 653Val） mutations in the exon 13 of LDLR in promoter were detected. And Asp622Asn mutation segregated with the disease. No mutation Q3500R of ApoB100 was observed. Conclusions The heterozygous c.1864 G→A （Asp622Asn） mutation of LDLR gene is firstly determined in China. The heterozygous c.1864 G→A （Asp622Asn） mutation of LDLR gene is probably responsible for FH. Perhaps it is a particular pathogenesis for Chinese people. PCR-DHPLC could be used for detecting the mutation.

关 键 词：高胆固醇血症 受体 LDL 突变 

分 类 号：R589.2[医药卫生—内分泌]