title: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.
abstract: Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. 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 nodes. 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 precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. 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. 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.
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bodzioch
authors.forename: E
authors.initials: E
authors.lastname: Orsó
authors.forename: J
authors.initials: J
authors.lastname: Klucken
authors.forename: T
authors.initials: T
authors.lastname: Langmann
authors.forename: A
authors.initials: A
authors.lastname: Böttcher
authors.forename: W
authors.initials: W
authors.lastname: Diederich
authors.forename: W
authors.initials: W
authors.lastname: Drobnik
authors.forename: S
authors.initials: S
authors.lastname: Barlage
authors.forename: C
authors.initials: C
authors.lastname: Büchler
authors.forename: M
authors.initials: M
authors.lastname: Porsch-Ozcürümez
authors.forename: W E
authors.initials: WE
authors.lastname: Kaminski
authors.forename: H W
authors.initials: HW
authors.lastname: Hahmann
authors.forename: K
authors.initials: K
authors.lastname: Oette
authors.forename: G
authors.initials: G
authors.lastname: Rothe
authors.forename: C
authors.initials: C
authors.lastname: Aslanidis
authors.forename: K J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: G
authors.initials: G
authors.lastname: Schmitz
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002675:Child, Preschool; D008076:Cholesterol, HDL / Q000172:deficiency / Q000378:metabolism; D002899:Chromosomes, Human, Pair 9; D005260:Female; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D013631:Tangier Disease / Q000235:genetics*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D006023:Glycoproteins