Abstract
Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island1. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease1 (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals1. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families2. We report here refining of our previous linkage of the TD gene3 to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.
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Acknowledgements
We thank E. Jung, A. Wittelmann and A. Mischke for technical assistance; G. Chimini for the mouse Abc1 probe; M. Jaye and G. Searfoss for the THP-1 cell libraries and advice on the protein structure predictions; I. Arnould, C. Prades, C. Lemoine, L. Naudin and C. Lafargues for critical contributions; W. Riesen for referring the Swiss patient with TD; and P. Cullen for critical revision of the manuscript. The work was supported by grants no. A5 and B7 to G.A., S.R. and H.F. from the Interdisziplinäres Zentrum für Klinische Forschung, University of Münster, and a grant from the Thyssen Foundation (S.R. and G.A.).
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Rust, S., Rosier, M., Funke, H. et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22, 352–355 (1999). https://doi.org/10.1038/11921
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DOI: https://doi.org/10.1038/11921
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