Nature Genetics
22, 347 - 351 (1999)
doi:10.1038/11914
The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier
diseaseMarek Bodzioch1, Evelyn Orsó1, Jochen Klucken1, Thomas Langmann1, Alfred Böttcher1, Wendy Diederich1, Wolfgang Drobnik1, Stefan Barlage1, Christa Büchler1, Mustafa Porsch-Özcürümez1, Wolfgang E. Kaminski1, Harry W. Hahmann2, Kurt Oette3, Gregor Rothe1, Charalampos Aslanidis1, Karl J. Lackner1
& Gerd Schmitz11
Institute for Clinical Chemistry and Laboratory Medicine,
University of Regensburg, D-93042 Regensburg,
Germany. 2
Klinik Schwabenland, Waldburgallee 5
, D-88315 Isny-Neutrauchburg, Germany
. 3
Medical Faculty of the University of Cologne,
D-50924 Koeln, Germany.
Correspondence should be addressed to Gerd Schmitz gerd.schmitz@klinik.uni-regensburg.deTangier disease (TD) is an autosomal recessive disorder of lipid metabolism1. 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 nodes2.
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 precursors2. In contrast to normal mononuclear phagocytes
(MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes,
indicating a defect in cellular lipid metabolism3,
4. HDL-mediated
cholesterol efflux and intracellular lipid trafficking and turnover are abnormal
in TD fibroblasts5,
6,
7, which have a reduced in vitro
growth rate8. 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.
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