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Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

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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Figure 1: YACs were selected from a public YAC contig (Whitehead Institute, GDB) to cover the candidate region and were obtained from the German human genome project.
Figure 2: Disruption of ABC1 by a single nucleotide deletion.
Figure 3: Insertion of a 110-bp Alu-Sq fragment into exon 12 of ABC1 in place of a 14-bp DNA fragment.
Figure 4: Schematic representation of the predicted structure of the ABC1 protein (as an output of "Sosui" transmembrane prediction program at http://www.tuat.ac.jp/~mitaku/ adv_sosui/submit.html).

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References

  1. Assmann, G., von Eckardstein, A. & Brewer, H.B. Familial high density lipoprotein deficiency: Tangier disease. in The Metabolic and Molecular Basis of Inherited Disease (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2053–2072 (McGraw-Hill, New York, 1995).

    Google Scholar 

  2. Ferrans, V.J. & Fredrickson, D.S. The pathology of Tangier disease. A light and electron microscopic study. Am. J. Pathol. 78, 101–158 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Rust, S. et al. Assignment of Tangier disease to chromosome 9q31 by a graphical linkage exclusion strategy. Nature Genet. 20, 96–98 (1998).

    Article  CAS  Google Scholar 

  4. Langmann, T. et al. Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages. Biochem. Biophys. Res. Commun. 257, 29– 33 (1999).

    Article  CAS  Google Scholar 

  5. Luciani, M.F., Denizot, F., Savary, S., Mattei, M.G. & Chimini, G. Cloning of 2 novel ABC transporters mapping on human chromosome 9. Genomics 21, 150– 159 (1994).

    Article  CAS  Google Scholar 

  6. Strautnieks, S.S. et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genet. 20, 233–238 (1998).

    Article  CAS  Google Scholar 

  7. Wada, M. et al. Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II Dubin-Johnson syndrome. Hum. Mol. Genet. 7, 203–207 (1998).

    Article  CAS  Google Scholar 

  8. Luciani, M.F. & Chimini, G. The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J. 15, 226– 235 (1996).

    Article  CAS  Google Scholar 

  9. Thomas, P.M. et al. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268 , 426–429 (1995).

    Article  CAS  Google Scholar 

  10. Mosser, J. et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361, 726–730 (1993).

    Article  CAS  Google Scholar 

  11. Gartner, J., Moser, H. & Valle, D. Mutations in the 70k peroxisomal membrane-protein gene in Zellweger syndrome. Nature Genet. 1, 16–23 (1992).

    Article  CAS  Google Scholar 

  12. Riordan, J.R. et al. Identification of the cystic-fibrosis gene—cloning and characterization of complementary-DNA. Science 245, 1066–1072 (1989).

    Article  CAS  Google Scholar 

  13. Devree, J.M.L. et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc. Natl Acad. Sci. USA 95, 282–287 (1998).

    Article  CAS  Google Scholar 

  14. Allikmets, R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genet. 17, 122 (1997).

    CAS  PubMed  Google Scholar 

  15. Becq, F. et al. ABC1, an ATP binding cassette transporter required for phagocytosis of apoptotic cells, generates a regulated anion flux after expression in Xenopus laevis oocytes. J. Biol. Chem. 272, 2695 –2699 (1997).

    Article  CAS  Google Scholar 

  16. Walter, M., Gerdes, U., Seedorf, U. & Assmann, G. The high density lipoprotein- and apolipoprotein A-I-induced mobilization of cellular cholesterol is impaired in fibroblasts from Tangier disease subjects. Biochem. Biophys. Res. Commun. 205, 850–856 (1994).

    Article  CAS  Google Scholar 

  17. Marcil, M. et al. Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency. Arterioscler. Thromb. Vasc. Biol. 19, 159–169 (1999).

    Article  CAS  Google Scholar 

  18. Stangl, H., Cao, G.Q., Wyne, K.L. & Hobbs, H.H. Scavenger receptor, class B, type I-dependent stimulation of cholesterol esterification by high density lipoproteins, low density lipoproteins, and nonlipoprotein cholesterol. J. Biol. Chem. 273, 31002– 31008 (1998).

    Article  CAS  Google Scholar 

  19. Babitt, J. et al. Murine SR-BI, a high density lipoprotein receptor that mediates selective lipid uptake, is N-glycosylated and fatty acylated and colocalizes with plasma membrane caveolae. J. Biol. Chem. 272, 13242–13249 (1997).

    Article  CAS  Google Scholar 

  20. Bojanovski, D. et al. In vivo metabolism of proapolipoprotein A-I in Tangier disease. J. Clin. Invest. 80, 1742– 1747 (1987).

    Article  CAS  Google Scholar 

  21. Miyake, M. et al. YAC and cosmid contigs encompassing the Fukuyama-type congenital muscular dystrophy (FMCD) candidate region on 9q31. Genomics 40, 284–293 (1997).

    Article  CAS  Google Scholar 

  22. Kobayashi, K. et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394, 388–392 (1998).

    Article  CAS  Google Scholar 

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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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