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| 2代3人同患家族性高胆固醇血症及其低密度脂蛋白受体基因突变分析 |
| 吴弘1△*,谢芳2,3△,郎希龙1△,郭志福1,朱霓1,白元1,陈峰1,潘静薇1,郑兴1,赵仙先1,秦永文1,黄薇2,3 |
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(1.第二军医大学长海医院心血管内科,上海200433
2.上海交通大学附属瑞金医院血液学研究所,上海200025
3.国家人类基因组南方研究中心遗传学部,上海 201203
△共同第一作者
*通信作者) |
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| 摘要: |
| 目的 调查2代3人同患家族性高胆固醇血症(familial hypercholesterolemia, FH)的家系,并检测和分析低密度脂蛋白受体(LDL-R)基因突变,以探讨FH发病的分子机制。方法 对17岁先证者进行体格、心电图、血脂水平、心脏超声、冠状动脉造影检查。根据患者及其家系的血缘关系绘制家系图谱。以PCR法分别扩增家系成员LDL-R基因启动子、18个外显子及侧翼序列,应用直接测序法进行突变检测；并以90名来自患者原籍的正常人群和190个随机人群样本为对照。结果 共检查先证者4代28人。先证者、其胞姐及姨外祖母均为FH黄色瘤患者,3人血浆总胆固醇分别为18.89、15.23、12.89 mmol/L；临床诊断基因型分别为纯合型、杂合型及杂合型。系谱分析该家系遗传方式符合常染色体显性遗传规律。核苷酸序列分析显示3名患者LDL-R基因的10号外显子存在G1448A改变,为W462X终止突变。先证者、其胞姐及姨外祖母的基因型分别是GA、GA、AA；先证者的父亲家系均为GG纯合子。90名来自患者原籍的正常人群和190个随机人群样本该位点测序结果均为GG纯合子。结论 3名患者LDL-R基因均存在G1448A突变,为终止突变,来自母系亲属,此位点的突变很可能是该家系发病的分子基础。 |
| 关键词: 高胆固醇血症Ⅱ型 基因型 低密度脂蛋白受体 突变 |
| DOI：10.3724/SP.J.1008.2012.00445 |
| 投稿时间：2011-08-21修订日期：2012-03-22 |
| 基金项目: |
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| Mutation analysis of low-density lipoprotein receptor gene in3 patients with familial hypercholesterolemia in two generations |
| WU Hong1△*,XIE Fang2,3△,LANG Xi-long1△,GUO Zhi-fu1,ZHU Ni1,BAI Yuan1,CHEN Feng1,PAN Jing-wei1,ZHENG Xing1,ZHAO Xian-xian1,QIN Yong-wen1,HUANG Wei2,3 |
(1. Department of Cardiovasology, Changhai Hospital, Second Military Medical University, Shanghai200433, China
2. Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai200025, China
3. Genetics Division, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China
△Co-first authors.
*Corresponding author.) |
| Abstract: |
| Objective To investigate the mutation of low-density lipoprotein receptor (LDL-R) gene in 3 patients with familial hypercholesterolemia (FH) in two generations, so as to discuss the pathogenesis of FH. Methods A 17-year-old patients was selected to undergo physical examination, lipid level test, electrocardiography, cardiac ultrasound and coronary artery angiography. Pedigree analysis was carried out based on family investigation. The promoter and the 18 exons of the LDL-R gene and the flank sequence were amplified by PCR; DNA sequencing was used to detect point mutation. Ninety normal subjects from the native place of the proband and 190 subjects from random population were taken as controls. Results Totally 28 members of 4 generations were examined. The proband, her elder sister and grandaunt had FH with xanthoma, and their total cholesterol (TC) levels were 18.89 mmol/L, 15.23 mmol/L, and 12.89 mmol/L, respectively. Pedigree analysis showed that the genetic pattern of this family was consistent to autosomal dominant inheritance trait. DNA sequencing demonstrated that a G1448A substitution caused a nonsense mutation TGG to TAG in exon 10 of LDL-R gene, a Trp→462 stop mutation. The mutation of the proband, her older sister and grandaunt were homozygous, heterozygous and heterozygous, respectively. The same mutation was not detected in the family members from the proband’s father and people from control group. Conclusion The proband, her elder sister and grandaunt have the same mutation, the Trp→462 stop mutation in exon 10 of LDL-R gene, which might be the key mutation that causes FH in this pedigree. |
| Key words: hypercholesterolemia type Ⅱ genotype low-density lipoprotein receptor mutation |
