Rust S, Walter M, Funke H, von Eckardstein A, Cullen P, Kroes H Y, Hordijk R, Geisel J, Kastelein J, Molhuizen H O, Schreiner M, Mischke A, Hahmann H W, Assmann G
Institute of Arteriosclerosis Research, University of Münster, Germany.
Nat Genet. 1998 Sep;20(1):96-8. doi: 10.1038/1770.
A low level of high density lipoprotein (HDL) cholesterol is a strong predictor of ischaemic heart disease (IHD) and myocardial infarction. One cause of low HDL-cholesterol is Tangier disease (TD), an autosomal codominant inherited condition first described in 1961 in two siblings on Tangier Island in the United States of America. Apart from low HDL-cholesterol levels and an increased incidence of atherosclerosis, TD is characterized by reduced total cholesterol, raised triglycerides, peripheral neuropathy and accumulation of cholesteryl esters in macrophages, which causes enlargement of the liver, spleen and tonsils. In contrast to two other monogenic HDL deficiencies in which defects in the plasma proteins apoA-I and LCAT interfere primarily with the formation of HDL (refs 7-10), TD shows a defect in cell signalling and the mobilization of cellular lipids. The genetic defect in TD is unknown, and identification of the Tangier gene will contribute to the understanding of this intracellular pathway and of HDL metabolism and its link with IHD. We report here the localization of the genetic defect in TD to chromosome 9q31, using a genome-wide graphical linkage exclusion strategy in one pedigree, complemented by classical lod score calculations at this region in a total of three pedigrees (combined lod 10.05 at D9S1784). We also provide evidence that TD may be due to a loss-of-function defect.
高密度脂蛋白（HDL）胆固醇水平较低是缺血性心脏病（IHD）和心肌梗死的有力预测指标。HDL胆固醇水平低的一个原因是丹吉尔病（TD），这是一种常染色体共显性遗传疾病，1961年在美国丹吉尔岛的两名兄弟姐妹中首次被描述。除了HDL胆固醇水平低和动脉粥样硬化发病率增加外，TD的特征还包括总胆固醇降低、甘油三酯升高、周围神经病变以及巨噬细胞中胆固醇酯的积累，这会导致肝脏、脾脏和扁桃体肿大。与另外两种单基因HDL缺乏症不同，在这两种疾病中，血浆蛋白载脂蛋白A-I和卵磷脂胆固醇酰基转移酶（LCAT）的缺陷主要干扰HDL的形成（参考文献7 - 10），TD表现为细胞信号传导和细胞脂质动员方面的缺陷。TD的基因缺陷尚不清楚，确定丹吉尔基因将有助于理解这一细胞内途径以及HDL代谢及其与IHD的联系。我们在此报告，通过在一个家系中使用全基因组图形连锁排除策略，并在总共三个家系的该区域进行经典的对数优势计分计算（在D9S1784处联合对数优势分数为10.05），将TD的基因缺陷定位到9号染色体q31区域。我们还提供了证据表明TD可能是由于功能丧失缺陷所致。
