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Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

Abstract

Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).

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Figure 1: Genetic analysis of two families with TD.
Figure 2: A genetic and physical map of 9q31 spanning 35 cM.
Figure 3: Mutation detection in TD1.
Figure 4: Mutation detection in TD2.
Figure 5: Genetic analysis in FHA.
Figure 6: Genetic analysis and mutation detection in FHA.
Figure 7: Reduction in ABC1 transcript levels is associated with decreased cholesterol efflux.
Figure 8: Predicted topology and mutations of ABC1 in Tangier disease and FHA.

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Acknowledgements

We thank C. Du Souich for ascertaining family members with FHA; L. Levesques for help in designing the antisense experiments; B. Boucher for technical support; and C. Visser for administrative assistance, and the members of our laboratories, especially M. Fujiwara, for their useful comments. This is NRC publication No. 42299. This work was supported in part by grants from MRC Canada to M.R.H. and J.G. Jr; an operating grant from the Heart and Stroke Foundation of Canada to J.G. Jr and M.R.H.; and a grant from the Canadian Networks of Centres of Excellence (NCE-Genetics) to M.R.H. The research of K.M., B.K. and B.F.F.O. is also supported in part by NCE Genetics. H.O.F.M. was supported by a grant from the Dutch Heart Foundation. M.R.H. is an established investigator of the B.C. Children's Hospital and MRC-PMAC Senior Scientist.

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Correspondence to Michael R. Hayden.

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Brooks-Wilson, A., Marcil, M., Clee, S. et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22, 336–345 (1999). https://doi.org/10.1038/11905

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