Apolipoprotein E variants associated with lipoprotein glomerulopathy

载脂蛋白E是乳糜微粒、极低密度脂蛋白及其残余物的主要蛋白组分。载脂蛋白E是乳糜微粒残基和低密度脂蛋白受体的配体。载脂蛋白E2（Arg 158 Cys）的纯合性易导致III型高脂蛋白血症的发生，从而导致过早的冠状动脉和外周动脉粥样硬化。脂蛋白肾小球病（Lipoproteinglomerulopathy，LPG 9）是一种以肾小球内脂蛋白血栓形成和III型高脂蛋白血症为特征的疾病。我们在10例独立的LPG患者中发现了载脂蛋白E变异体，载脂蛋白E（Arg 145 Pro）仙台型，而在100例无关的日本个体中没有发现载脂蛋白E（Arg 145 Pro）仙台型。我们还发现了一个新的apo E基因点突变，apo E（arg 25 Cys）京都在一个LPG患者，先证者是一个30岁的男性患者维持性血液透析，由于脂蛋白肾小球病。血浆载脂蛋白E水平为29.6mg/dl。载脂蛋白E表型（e2/E4）和基因型（e3/E4）在患者中存在差异。通过在大肠杆菌或COS-1细胞中表达突变的和野生型重组apo E cDNA来检查突变的功能后果。重组载脂蛋白E京都显示LDL-受体结合率降低，为正常载脂蛋白E3活性的6-7%。这些数据表明载脂蛋白E基因突变可能导致脂蛋白肾小球病。

Apolipoprotein (apo) E is a major protein constituent of chylomicrons, very low density lipoprotein, and their remnants. Apo E is a ligand for the chylomicron remnant and low density lipoprotein receptors. Homozygosity for apo E2 (Arg158Cys)-predisposes to the development of type III hyperlipoproteinemia which developed premature coronary and peripheral atherosclerosis. Lipoprotein glomerulopathy (LPG9 is a disease characterized by intraglomerular lipoprotein thrombi and type III hyperlipoproteinemia. We identified apo E variant, apo E (Arg145Pro) Sendai in ten independent patients with LPG.A survey of 100 unrelated Japanese individuals did not identify an apo E (Arg145Pro) Sendai. We also found a novel point mutation in apo E gene, apoE (arg25Cys) Kyoto in a patient with LPG.The propositus was a 30-year-old male patient on maintenance hemodialysis due to lipoprotein glomerulopathy. His plasma apo E level was 29.6mg/dl. Disdcrepancy in apo E phenotype (e2/E4) and genotype (e3/E4) was seen in the patient. Functional consequences of the mutation were examined by expressing the mutated and wild-type recombinant apo E cDNAs in E.coli or COS-1 cells. Recombinant apo E Kyoto showed a reduction in LDL-receptor binding renging from 6-7% of activity of normal apo E3. In conclusion.these data suggest that the mutation in the apo E gene may cause lipoprotein glomerulopathy.