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The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Abstract

Tangier 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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Figure 1: Pedigrees of TD kindreds.
Figure 2: Sequence analysis of the ABC1 region containing the G1764del frameshift mutation in pedigree TD1.
Figure 3: Predicted topology and mutations of ABC1.
Figure 4: Southern-blot analysis in pedigree TD2.
Figure 5: Sequence analysis of the N-terminal ABC1 Walker A region in kindreds TD3, TD4 and TD5.

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Acknowledgements

We thank U. Stöckl for molecular biological assistance; R. Glätzl, S. Potra and D. Hant for technical help; G. Chimini for helpful discussions and providing Abc1-null mice; and D. Bowyer for critical reading of the manuscript. This work has been supported by a grant from Bayer AG Pharma-Research.

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Correspondence to Gerd Schmitz.

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Bodzioch, M., Orsó, E., Klucken, J. et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22, 347–351 (1999). https://doi.org/10.1038/11914

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