Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.
Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.
复制标题
低密度脂蛋白受体的遗传学。
DOI：
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发表时间：
1978
影响因子：
15.9
通讯作者：
Goldstein
中科院分区：
文献类型：
--
作者：
D. Bilheimer;Y.;K.;Ho;Michael;S.;BROwN;G. Richard;WI.;Anderson;Joseph;L.;Goldstein
使用循环单核细胞作为现成的组织，并使用125- i标记的低密度脂蛋白（LDL）的高亲和力降解率作为细胞表面LDL受体活性的指标，我们测量了53个人细胞中的受体活性。本组包括32名健康受试者，15名杂合型家族性高胆固醇血症患者，6名非家族性高胆固醇血症的高脂血症患者。7名健康受试者和10名杂合子是一个大家族的成员，突变的家族性高胆固醇血症基因遗传了5代。在两组条件下测定血单核细胞LDL受体活性。首先，在没有脂蛋白的情况下，纯化淋巴细胞培养3天，以诱导高水平的LDL受体活性，测量125I-LDL降解。用125I-LDL孵育细胞的相衬自显影图和用铁蛋白标记的LDL孵育细胞的电镜图证实了淋巴细胞上LDL受体的存在。其次，在混合单核细胞（85-90%淋巴细胞和5-15%单核细胞）从血液中分离后立即测量125I-LDL降解。这个实验代表了一种评估细胞在循环中实际表达的受体数量的尝试。在两组条件下，来自家族性高胆固醇血症杂合子的细胞平均表达的LDL受体数量约为正常数量的一半。目前的研究结果与以下结论一致：家族性高胆固醇血症的杂合子在LDL受体位点只有一个功能性等位基因，因此LDL受体的缺乏产生了杂合子家族性高胆固醇血症的临床综合征。
Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. The current findings are consistent with the conclusion that heterozygotes with familial hypercholesterolemia possess only one functional allele at the LDL receptor locus and that the consequent deficiency of LDL receptors produces the clinical syndrome of heterozygous familial hypercholesterolemia.