The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease
The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease
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DOI：
10.1038/11914
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发表时间：
1999-08-01
期刊：
影响因子：
30.8
通讯作者：
Schmitz, G
中科院分区：
文献类型：
--
作者：
Bodzioch, M;Orsó, E;Schmitz, G
丹吉尔病（TD）是一种常染色体隐性遗传的脂质代谢疾病（1）。其特征是缺乏血浆高密度脂蛋白（HDL）和胆固醇酯沉积在网状内皮系统中，伴有脾肿大和扁桃体和淋巴结肿大（.）(2)虽然低HDL胆固醇与冠状动脉疾病风险增加有关，但这种情况在TD家系中并不一致。TD患者的代谢研究显示，HDL及其前体快速分解（2）。与正常单核吞噬细胞（MNP）相反，TD个体的MNP降解不寻常溶酶体中的内化HDL，表明细胞脂质代谢缺陷（3，4）。HDL介导的胆固醇流出和细胞内脂质运输和周转在TD成纤维细胞中是异常的（5-7），其具有降低的体外生长速率。TD基因座已定位于染色体9 q31（参考文献9）。在这里，我们提出证据表明TD是由ABC 1突变引起的，ABC 1编码ATP结合盒（ABC）转运蛋白家族的一个成员，位于染色体9 q22 -31（参考文献10）。我们分析了5种TD激酶，并鉴定了7种不同的突变，包括3种预期会损害基因产物功能的突变。ABC 1作为TD位点的鉴定对于理解细胞HDL代谢和胆固醇逆向转运及其与早发性心血管疾病的关联具有意义。
Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism(1). It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes(.)(2) Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors(2). In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism(3,4). HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts(5-7), which have a reduced in vitro growth rates. The TD locus has been mapped to chromosome 9q31 (ref. 9). Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31 (ref. 10), We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.