Nature Genetics
20, 96 - 98 (1998)
doi:10.1038/1770
Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategyStephan Rust1, Michael Walter1, 2, Harald Funke1, 2, Arnold von Eckardstein1, 2, Paul Cullen1, 2, Hester Y. Kroes3, Roel Hordijk3, Jürgen Geisel4, John Kastelein5, Henri O.F. Molhuizen5, Michaela Schreiner2, Anja Mischke1, Harry W. Hahmann6
& Gerd Assmann1, 21
Institute of Arteriosclerosis Research, University of Münster, Domagkstrasse 3, D-48149 Münster, Germany. 2
Institute of Clinical Chemistry and Laboratory Medicine, University of Münster, Albert-Schweitzer Strasse 33, D-48149 Münster, Germany. 3
Department of Medical Genetics, University of Groningen, Antonius Deusinglaan 4, 9713 AW Groningen, The Netherlands. 4
Klinisch-Chemisches Zentrallabor, Universitätskliniken des Saarlandes, D-66421 Homburg/Saar, Germany. 5
Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 6
Klinik Schwabenland, D-88316 Isny-Neutrauchburg, Germany.
Correspondence should be addressed to Stephan Rust Rusts@uni-muenster.deA 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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