Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype.
Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype.
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DOI：
10.1172/jci15387
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发表时间：
2002-07
期刊：
影响因子：
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通讯作者：
C. Pullinger;C. Eng;G. Salen;S. Shefer;A. Batta;S. Erickson;A. Verhagen;Christopher R. Rivera;
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文献类型：
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作者：
C. Pullinger;C. Eng;G. Salen;S. Shefer;A. Batta;S. Erickson;A. Verhagen;Christopher R. Rivera;
胆汁酸合成在维持哺乳动物胆固醇稳态中起关键作用。CYP 7A 1基因编码胆固醇7 α-羟化酶，该酶催化胆固醇催化剂和胆汁酸合成的初始步骤。我们在这里报告一个新的代谢紊乱表现为高脂血症引起的纯合性缺失突变的CYP 7A 1。该突变导致移码（L413 fsX 414），导致活性位点和酶功能的丧失。高水平的低密度脂蛋白胆固醇被认为是在三个纯合子受试者。对其中一名受试者的肝活检和粪便进行分析，发现其肝脏胆固醇含量是正常的两倍，胆汁酸排泄率明显不足，并有证据表明替代胆汁酸途径上调。研究的两名男性受试者患有高胆固醇血症和早发性胆结石病，他们的LDL胆固醇水平明显对3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂有抵抗力。1例受试者还患有早发冠状动脉和外周血管疾病。对具有英国和凯尔特背景的亲属的研究表明，突变杂合子的个体也是高脂血症，表明这是一种共显性疾病。
Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7alpha-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.