家族性高胆固醇血症患者低密度脂蛋白受体基因复合纯合突变一例

Explortion of low density lipoprotein receptor gene mutations in a Chinese patient with familial compound homozygous hypercholesterolemia

目的 检测家族性高胆固醇血症 (FH)患者低密度脂蛋白受体 (LDL R)基因点突变 ,分析基因型与临床表型间的关系 ,探讨其分子病理机制。方法 以 1例临床诊断为FH纯合子患儿及其父母的基因组DNA为模板 ,用降落PCR方法 ,在同一程序中分别对LDL R基因的启动子和全部 18个外显子片段进行扩增 ,琼脂糖凝胶电泳检测 ,扩增产物直接进行核苷酸序列分析 ,并检索FH突变数据库 (www ucl ac uk/fh)。此外采用PCR 限制性内切酶技术 ,检测载脂蛋白 (Apo)B10 0 基因Q35 0 0R突变 ,以排除家族性ApoB10 0 缺陷症。结果 该患儿及其父亲第 4外显子发生Cys12 2 →Tyr(C12 2Y)杂合错义突变 ,同时患儿及其母第 9外显子发生Thr3 83 →Ile(T383I)杂合错义突变 ,因此该患儿LDL R基因第 4、9外显子各存在一个杂合突变 ,上述突变尚未在FH突变数据库见到。未检测出患儿及其父母ApoB10 0 Q35 0 0R突变。结论 此患儿为LDL R基因存在C12 2Y、T383I复合纯合突变并分别来自其父母 ;以上两位点突变可引起FH ;是FH患者LDL R基因的一种新突变类型。

Objective To screen the point mutation of low density lipoprotein receptor (LDL R) gene in Chinese familial hypercholesterolemia(FH) patients, explore the relationship between the genotype and the phenotype, and discuss the molecular pathologic mechanism Methods A patient with the clinical phenotype of homozygous FH as well as his parents have been investigated for mutations of promoter and all eighteen exons of LDL R gene Screening was carried out by using Touch down PCR and agarose gel electrophoresis, combined with DNA sequence analysis Then the result were compared with that in FH database(www.ucl.uk/fh) In addition, we screened the apolipoprotein B gene (ApoB) for known mutations (R3500Q) that cause familial defective apo B 100(FDB) by PCR RFLP Results Two novel hyterozygote mutations in exon 4 and 9 of the LDL R were identified in the proband (C122Y and T383I) and her parents respectively Both of the mutations have not been published in FH mutant database No mutations R3500Q of ApoB 100 were observed Conclusion The presence of two novel mutations at C112Y and T383I in LDL R gene may be the cause of FH Perhaps it is a particular pathogeneticgenotype in Chinese people