家族性高胆固醇血症患者二例的LDLR基因复合杂合新突变分析  

Analysis of compound heterozygous mutation of low-density lipoprotein receptor gene in two patients with familial hypercholesterolemia

作　　者：代艳芳[1] 潘晓冬[1] 孙立元[1] 杨娅[1] 宋砾[1] 蔺洁[1] 王绿娅[1] 

机构地区：[1]首都医科大学附属北京安贞医院北京市心肺血管疾病研究所教育部心血管重塑相关疾病重点实验室,100029

出　　处：《中华检验医学杂志》2011年第5期454-458,共5页Chinese Journal of Laboratory Medicine

基　　金：基金项目：国家自然科学基金资助项目（30771986、30772356）;北京市自然科学基金资助项目（7112012、7092016）

摘　　要：目的探讨2例临床确诊的湖北籍FH患者的LDLR基因突变状况，为FH的基因诊断提供依据。方法收集2例临床确诊的FH患者及其父母血脂检测指标等临床资料，通过PCR扩增LDLR基因的1-18个外显子和内含子区域，再将扩增产物进行正、反双向核苷酸序列分析，并与GenBank中LDLR基因的正常序列对比找出突变后，结合FH先证者的临床表型证实致病突变的类型。结果氧化酶法测定1号、2号FH先证者血浆TC，分别为12．79、11．98mmol／L；经核苷酸序列分析，其ApoB100基因涵盖的3500～3531区域均未见突变；LDLR基因均为复合杂合突变，1号FH先证者LDLR基因第4外显子的665位碱基G〉T为杂合错义突变，且该突变为新的点突变，第9内含子的1358＋32位碱基C〉T突变也为新的点突变，并均由其父母遗传。2号先证者第9外显子1257位碱基C〉A突变导致终止密码子提前出现，但其核苷酸改变与比利时报道的C〉G不同，第13外显子检测到1879位碱基G〉A杂合错义突变，且分别来源于其父母。结论2例FH先证者均存在LDLR基因复合杂合突变，1号FH先证者的第4外显子665位碱基G〉T和第9内含子1358＋32位碱基C〉T、2号FH先证者的第9外显子1257位碱基C〉A突变均为新突变，这可能是导致FH的分子机制。[ Abstract] Objective To determine LDLR gene mutation in 2 clinically diagnosed FH patients from Hubei province and provide basis for gene diagnosis of FH. Methods Clinical data of 2 FH patients and their parents were collected. The promoter region and exon 1 to exon 18 region of LDLR gene were amplified through PCR and the amplified products were analyzed by forward and reverse DNA sequencing. The mutations were identified after comparison with LDLR gene sequence in GenBank. The pathogenic gene mutations were confirmed according to both genotype and phenotype of FH probands. Results The levels of plasma TC of two probands were 12.79 and 11.98 mmol/L, respectively. No gene mutations were detected in region 3 500 to 3 531 of ApoB100. The mutations of LDLR gene were compound heterozygous mutations. The novel mutation 665G 〉 T detected in the exon 4 of No. 1 proband＇s LDLR gene was heterozygous missense mutation. The novel mutation 1 358 ＋32C 〉 T was detected in the exon 9 of No. 1 proband＇s LDLR gene. The mutations 665G 〉 T （paternal origin） and 1 358 ＋ 32C 〉 T （maternal origin） were inherited from the parents. A novel mutation 1 257 C 〉 A was detected in the exon 9 of No. 2 proband＇s LDLR gene, resulting the presence of a premature termination codon, which was different from 1 257 C 〉 G reported in Belgium. Another heterozygous missense mutation 1 879 G 〉 A was detected in exon 13. They were derived from paternal origin and maternal origin, respectively. Conclusions There are three novel gene mutations： 665G 〉T, 1 358 ＋32C 〉 T, 1 257C 〉 A found in two probands with compound heterozygous mutations in LDLR respectively. They maybe play a potential role in FH pathogensis.

关 键 词：高胆固醇血症Ⅱ型 受体 LDL 杂合子 突变 

分 类 号：R589.2[医药卫生—内分泌] R440[医药卫生—内科学]