家族性高胆固醇血症低密度脂蛋白受体基因突变分析  

Mutation analysis of low density lipoprotein receptor gene in patient and his family with familial hypercholesterolemia

作　　者：文莉[1] 彭文辉[1] 韩雪更[1] 李海玲[1] 闻静[1] 崔世涛[2] 魏毅东[1] 李伟明[1] 徐亚伟[1] 

机构地区：[1]同济大学附属上海市第十人民医院心血管内科,上海200072 [2]同济大学附属上海市第十人民医院心胸外科

出　　处：《临床心血管病杂志》2011年第6期452-457,共6页Journal of Clinical Cardiology

基　　金：上海市科委重点项目基金资助(No:09JC1412000)

摘　　要：目的:检测1例家族性高胆固醇血症(FH)先证者及其4代家系成员低密度脂蛋白受体(LDL-R)基因突变,探讨该家族FH可能发病分子机制。方法:收集先证者及其家系成员临床资料和基因组DNA,以基因组DNA为模板,用PCR方法扩增LDL-R基因的启动子和全部18个外显子,PCR产物进行限制性内切酶技术结合DNA测序,核苷酸序列分析结果与Gen Bank比对寻找突变;采用PCR-DNA测序技术检测apoB100基因R3500Q、R3531C和R3500W位点以及枯草溶菌素转化酶9(PCSK9)基因,以排除家族性apoB100缺陷症和PC-SK9基因突变。结果:先证者及其部分家系成员第6号外显子发生Cys276X杂合无义突变,为半胱氨酸改变为提前终止密码子,使终止密码子在第276位提前出现,为致病性突变,国内尚无报道;另外,第15号外显子发生Arg744Arg同义突变。其母未发现上述突变,未检测出患者及其家系apoB100基因R3500Q、R3531C和R3500W突变以及枯草溶菌素转化酶9基因突变。结论:此患者及家系LDL-R基因存在Cys276X无义突变,可能是FH的致病突变,该突变是我国FH患者LDLR基因的一种新突变类型。Objective：To identify the mutation of low density lipoprotein receptor（LDL-R） gene in the proband and his family members of 4 generations,and discuss the molecular pathologic mechanism.Method：Blood samples and clinical data were collected from the proband and his familial members.DNA were extracted from blood and investigated for mutations of promoter and all eighteen exons of LDL-R gene.Screening was carried out by using polymerase chain reaction（PCR）,combined with DNA sequence analysis and restriction fragment length polymorphism（PCR-RFLP）.Then the results from nucleotide sequence analysis were compared to the Gene Bank for mutation.In addition,we screened the apolipoprotein B gene（apoB） for known mutations（R3500Q、R3531C and R3500W） that cause familial defective apoB100（FDB） and proprotein convertase subtilisin/kexin type 9（PCSK9） gene by PCR-DNA sequence analysis.Result：The proband and 2 members of paternal relatives showed a novel Cys276X heterozygosis mutation in exon 6 of LDLR gene which introduced the change from cysteine to a new stop codon,but not his mother.No mutations R3500Q,R3531C,R3500W of apoB100 and PCSK9 were observed.Conclusion：The presence of the novel mutation at Cys276X in LDL-R gene may be the cause of FH.As far as we known,it was a new pathogenetic genotype in Chinese people.

关 键 词：高胆固醇血症 家族性 脂蛋白受体 低密度 基因突变 脱氧核糖核苷酸测序 

分 类 号：R541.6[医药卫生—心血管疾病]