Homozygous familial hypobetalipoproteinemia - Increased LDL catabolism in hypobetalipoproteinemia due to a truncated apolipoprotein B species, Apo B-87(Padova)
Homozygous familial hypobetalipoproteinemia - Increased LDL catabolism in hypobetalipoproteinemia due to a truncated apolipoprotein B species, Apo B-87(Padova)
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DOI：
10.1161/01.atv.16.9.1189
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发表时间：
1996-09-01
影响因子：
8.7
通讯作者：
Baggio, G
中科院分区：
文献类型：
--
作者：
Gabelli, C;Bilato, C;Baggio, G
干扰载脂蛋白（apo） B分子全长翻译的载脂蛋白（apo） B基因突变与家族性低脂蛋白血症（FHBL）有关，FHBL是一种以血浆载脂蛋白（apoB）和低密度脂蛋白胆固醇降低为特征的疾病。在本报告中，我们描述了一个携带独特的截短apoB形式apoB-87（Padova）的FHBL亲缘。对扩增的基因组DNA进行序列分析，发现在核苷酸12032处存在单个G缺失，该缺失移位了翻译阅读框并导致氨基酸3978处终止。研究了2个纯合子和7个杂合子亲缘关系。虽然纯合子个体只有微量的低密度脂蛋白，但他们几乎没有纯合子FHBL受试者的典型症状。我们在一名纯合子患者和两名正常对照中研究了放射性标记正常apoB-100 LDL和apoB-87 LDL的体内转换。ApoB-87 LDL在所有三名受试者中表现出相似的代谢，其分数分解代谢率是正常LDL的两倍多。与正常apoB-100相比，apoB-87进入LDL室的率也明显降低。在体外，这些颗粒抑制正常人培养成纤维细胞对正常apoB-100 LDL的摄取和降解能力增加2.5倍，与体内apoB-87 LDL分解代谢的增加相平行。这些结果表明，apoB-87 LDL与LDL受体的相互作用能力增强；载脂蛋白b分解代谢增加导致低脂蛋白血症，并可能解释在两个纯合子个体中该疾病的轻度表达。
Mutations on the apolipoprotein (apo) B gene that interfere with the full-length translation of the apoB molecule are associated with familial hypobetalipoproteinemia (FHBL), a disease characterized by the reduction of plasma apoB and LDL cholesterol. In this report, we describe an FHBL kindred carrying a unique truncated apoB form, apoB-87(Padova). Sequence analysis of amplified genomic DNA identified a single G deletion at nucleotide 12 032, which shifts the translation reading frame and causes a termination at amino acid 3978. Two homozygous subjects and seven heterozygous relatives were studied. Although homozygous individuals had only trace amounts of LDL, they were virtually free from the symptoms typical of homozygous FHBL subjects. We investigated the in vivo turnover of radiolabeled normal apoB-100 LDL and apoB-87 LDL in one homozygous patient and two normal control subjects. ApoB-87 LDL showed a similar metabolism in all three subjects, with a fractional catabolic rate more than double that of normal LDL. The rate of entry of apoB-87 in the LDL compartment was also markedly decreased compared with normal apoB-100. The increased in vivo catabolism of apoB-87 LDL was paralleled in vitro by a 2.5-fold increased ability of these particles to inhibit the uptake and degradation of normal apoB-100 LDL by normal human cultured fibroblasts. These results indicate that apoB-87 LDL has an enhanced ability to interact with the LDL receptor; the increased apoB catabolism contributes to the hypobetalipoproteinemia and may explain the mild expression of the disease in the two homozygous individuals.