AN INHERITED POLYMORPHISM IN THE HUMAN APOLIPOPROTEIN A-I GENE LOCUS RELATED TO THE DEVELOPMENT OF ATHEROSCLEROSIS
AN INHERITED POLYMORPHISM IN THE HUMAN APOLIPOPROTEIN A-I GENE LOCUS RELATED TO THE DEVELOPMENT OF ATHEROSCLEROSIS
复制标题
DOI：
10.1038/301718a0
复制
发表时间：
1983-01-01
期刊：
影响因子：
64.8
通讯作者：
BRESLOW, JL
中科院分区：
文献类型：
--
作者：
KARATHANASIS, SK;NORUM, RA;BRESLOW, JL
流行病学研究已确定低密度脂蛋白 (LDL)1-3 升高和高密度脂蛋白 (HDL) 胆固醇水平降低 3,4 是冠状动脉疾病的危险因素。 HDL 的主要蛋白质成分是脱辅基蛋白 A-I (apo A-I)，这是一种具有已知一级氨基酸序列的 243 个氨基酸的多肽5。这种脱辅基蛋白作为血浆卵磷脂胆固醇酰基转移酶 (LCAT) 的辅助因子，负责血浆中大多数胆固醇酯的形成，并且还促进胆固醇从细胞中流出 6,7。 apo A-I 的初级翻译产物包含前片段和前片段8，并且apo A-I 的翻译后加工可能参与功能性血浆apo A-I 同蛋白9,10 的形成。 apo A-I 加工缺陷可能是丹吉尔病的根本问题11，尽管 apo A-I 合成正常，但患者的血浆 HDL 和 apo A-I 水平较低12,13。据报道，患者患有与丹吉尔病不同的病症，其中载脂蛋白 A-I 的严重缺乏或缺失与极低的 HDL 水平和严重的冠状动脉疾病相关 14,15。我们现在已经检查了两名此类患者及其一级亲属的 apo A-I 基因。据报道，这些患者患有皮肤和肌腱黄瘤、角膜混浊和严重的过早冠状动脉粥样硬化，这些症状与 HDL 水平极低和两种脱辅基蛋白（载脂蛋白 A-I 和载脂蛋白 C-III15）缺乏有关。我们证明，两个先证者都是 apo A-I 基因位点缺陷的纯合子。
Epidemiological studies have identified elevated low density lipoprotein (LDL)1–3and diminished high density lipoprotein (HDL) cholesterol levels3,4as risk factors for coronary artery disease. The major protein component of HDL is apoprotein A-I (apo A-I), a polypeptide of 243 amino acids of known primary amino acid sequence5. This apoprotein serves as a cofactor for the plasma lecithin-cholesterol acyltransferase (LCAT) enzyme responsible for the formation of most cholesteryl esters in plasma, and also promotes cholesterol efflux from cells6,7. The primary translation product of apo A-I contains both a pre and a pro segment8, and post-translational processing of apo A-I may be involved in the formation of the functional plasma apo A-I isoproteins9,10. Defective apo A-I processing may be the underlying problem in Tangier disease11, in which patients have low plasma HDL and apo A-I levels despite normal apo A-I synthesis12,13. Patients have been reported with conditions distinct from Tangier disease in whom severe deficiency or absence of apo A-I has been associated with very low HDL levels and severe coronary artery disease14,15. We have now examined the apo A-I gene in two such patients and their first degree relatives. These patients have been reported to have skin and tendon xanthomas, corneal clouding and severe premature coronary atherosclerosis associated with very low HDL levels and deficiencies of two apoproteins, apo A-I and apo C-III15. We show that both probands are homozygous for a defect in the apo A-I gene locus.