Dysbetalipoproteinemia in a kindred with hypobetalipoproteinemia due to mutations in the genes for ApoB (ApoB-70.5) and ApoE (ApoE2).

W A Groenewegen, E S Krul, M R Averna, J Pulai, G Schonfeld
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引用次数: 18

Abstract

We identified the first insertion mutation that specifies an apolipoprotein (apo)B truncation, apoB-70.5, in a father and son with hypobetalipoproteinemia (total and low-density lipoprotein [LDL] cholesterol < 5th percentile, plasma apoB levels approximately one third of normal). The mutation is due to insertion of an adenine (A) into a 7-A repeat between cDNA position 9754 and 9760 of the apoB gene, resulting in a frame shift of 13 new amino acids and a termination codon at amino acid residue 3197. The DNA mutation cosegregated with the apoB truncation and hypobetalipoproteinemia in the kindred. The two apoB-70.5/apoB-100 heterozygotes also are apoE2 homozygotes by genotyping; beta-very-low-density lipoprotein (VLDL) was present, and VLDL cholesterol/triglyceride ratios were increased (0.29) in the plasmas of both. Density gradient ultracentrifugation and gel filtration chromatography profiles showed increased amounts of particles in the VLDL and intermediate-density lipoprotein density and size ranges and relatively smaller peaks of LDL than in controls. Two populations of LDL were present, ApoB-70.5 was primarily associated with LDL particles of higher density and of smaller size than the LDL particles containing apoB-100. ApoB-48-containing particles were present in the VLDL of fasting plasmas of both subjects, and the postprandial levels of chylomicrons and remnants as measured by the vitamin A fat tolerance test were increased. In conclusion, both subjects heterozygous for apoB-70.5 and homozygous for apoE2 showed the classic characteristics of dysbetalipoproteinemia superimposed onto the hypolipoproteinemia state.

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由于ApoB (ApoB-70.5)和ApoE (ApoE2)基因突变导致的低脂蛋白血症亲属的脂蛋白异常血症。
我们在一对患有低脂蛋白血症(总胆固醇和低密度脂蛋白[LDL]胆固醇< 5百分位,血浆载脂蛋白(apoB)水平约为正常水平的三分之一)的父子中发现了第一个指定载脂蛋白(apo)B截断的插入突变,载脂蛋白-70.5。突变是由于在apoB基因的cDNA位置9754和9760之间的7-A重复序列中插入了一个腺嘌呤(A),导致13个新氨基酸的帧移位和氨基酸残基3197的终止密码子。DNA突变与载脂蛋白ob截断和低脂蛋白血症共分离。两个apoB-70.5/apoB-100杂合子也为apoE2纯合子;两者血浆中均存在-极低密度脂蛋白(VLDL),且VLDL胆固醇/甘油三酯比值升高(0.29)。密度梯度超离心和凝胶过滤色谱分析显示,与对照组相比,VLDL和中密度脂蛋白密度和大小范围内的颗粒数量增加,LDL的峰相对较小。LDL存在两个种群,与含有apoB-100的LDL颗粒相比,ApoB-70.5主要与密度更高、尺寸更小的LDL颗粒相关。两组受试者空腹血浆VLDL中均存在含apob -48颗粒,经维生素A脂肪耐量试验测定,餐后乳糜微粒及残体水平升高。综上所述,apoB-70.5杂合和apoE2纯合的受试者都表现出典型的脂蛋白异常血症叠加在低脂蛋白血症状态上的特征。
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