APOE p.Leu167del mutation in familial hypercholesterolemia
APOE p.Leu167del mutation in familial hypercholesterolemia
复制标题
DOI：
10.1016/j.atherosclerosis.2013.09.007
复制
发表时间：
2013-12-01
期刊：
影响因子：
5.3
通讯作者：
Genest, Jacques
中科院分区：
文献类型：
--
作者：
Awan, Zuhier;Choi, Hong Y.;Genest, Jacques
背景：常染色体显性遗传性高胆固醇血症(ADH)是由低密度脂蛋白受体(LDLR)及其配体载脂蛋白B(APOB)或枯草杆菌蛋白转换酶9(PCSK9)基因突变引起的。然而，DNA测序在相当数量的病例中没有发现这些基因的突变，这表明ADH有多种遗传病因。方法：通过临床检查、生化分析、候选基因方法和下一代外显子组测序相结合的方法，我们调查了一名意大利血统先证者ADH表型的遗传基础。他有肌腱黄瘤、黄瘤，总胆固醇和低密度脂蛋白水平升高，分别为11.2和9.69 mmoL/L，而正常高密度脂蛋白和甘油三酯水平分别为1.62和1.13 mmoL/L。高效液相色谱脂蛋白图谱显示低密度脂蛋白选择性升高。DNA测序未发现LDLR、PCSK9、LDLRAP1和APOB基因突变。然后，我们对该家族的三个个体进行了外显子组测序。先前发现的被称为apoE Leu167del的载脂蛋白E突变(apoE，染色体19：45412053-55)的关联性最强的证据被发现，这是一种框内三个碱基对缺失。计算生物学证实了这种突变的有害性质。Leu167del突变可能会改变载脂蛋白E受体结合区内α-螺旋附近的蛋白质结构。结论：本报告证实了先前的报道，即载脂蛋白E基因突变可引起ADH，并代表第4个基因座。ADH的标准筛查应包括APOE基因。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
Background: Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the low density lipoprotein receptor (LDLR), its ligand apoB (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Yet DNA sequencing does not identify mutations in these genes in a significant number of cases, suggesting that ADH has multiple genetic etiologies.Methods: Through a combination of clinical examination, biochemical analysis, candidate gene approach and next-generation exome sequencing we investigated the genetic basis of an ADH phenotype in a proband of an Italian origin.Results: The proband presented with an acute myocardial infarction at age 43. He had tendinous xanthomas, xanthelasmas and elevated levels of total and LDL cholesterol, at 11.2 and 9.69 mmol/L, respectively, with normal levels of HDL cholesterol and triglycerides at 1.62 and 1.13 mmol/L, respectively. HPLC lipoprotein profile showed selective increase in LDL-C. DNA sequencing did not identify any mutation in the LDLR, PCSK9, LDLRAP1 and APOB gene. We then performed exome sequencing on three individuals from the family. The strongest evidence of association was found for the previously identified apolipoprotein E mutation (APOE, chromosome 19:45412053-55) known as APOE Leu167del, an in-frame three base-pair deletion. Computational biology confirmed the deleterious nature of this mutation. The Leu167del mutation is predicted to alter the protein structure of apoE near the alpha-helix within the receptor binding domain.Conclusions: This report confirms a previous report that ADH can be caused by mutations within the APOE gene and represents the 4th loci causing ADH. Standard screening for ADH should include APOE gene. (C) 2013 Elsevier Ireland Ltd. All rights reserved.