Abstract
A low level of high density lipoprotein (HDL) cholesterol is a strong predictor of ischaemic heart disease (IHD) and myocardial infarction1,2,3. 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 America4. Apart from low HDL-cholesterol levels and an increased incidence of atherosclerosis5, 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 tonsils4,6. 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, 8, 9, 10), TD shows a defect in cell signalling and the mobilization of cellular lipids11,12,13,14. 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.
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Acknowledgements
We thank all patients and their family members for their cooperation. This project was sponsored in part by a grant from Interdisziplinäres Klinisches Forschungszentrum der Universität Münster to H.F. (project grant A5). We thank M. Farrall, for critical reading of our manuscript.
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Rust, S., Walter, M., Funke, H. et al. Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategy. Nat Genet 20, 96–98 (1998). https://doi.org/10.1038/1770
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DOI: https://doi.org/10.1038/1770
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