title: Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds.
abstract: Tangier disease (TD) is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of high density lipoprotein (HDL) cholesterol and, in some cases, peripheral neuropathy and premature coronary heart disease (CHD). Homozygotes are further characterized by cholesteryl ester deposition in various tissues throughout the body, most notably in those of the reticuloendothelial system. Several studies have demonstrated that the excess lipid deposition in TD is due to defective apolipoprotein-mediated efflux of cellular cholesterol and phospholipids. Although much progress has been made in our understanding of the metabolic basis of TD, the precise molecular defect had remained elusive until very recently. By positional cloning methods, we: 1) confirm the assignment of TD to chromosome 9q31, 2) provide evidence that human ATP-binding cassette-1 (hABC-1) maps to a 250 kb region on 9q31, and 3) describe novel deletion, insertion, and missense mutations in the gene encoding hABC-1 in four unrelated TD kindreds. These results establish a causal role for mutations in hABC-1 in TD and indicate that this transporter has a critical function in the regulation of intracellular lipid trafficking that dramatically affects plasma HDL cholesterol levels.
authors.affiliation: Lipid Metabolism Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University and Department of Medicine, New England Medical Center, Boston, MA 02111, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Brousseau
authors.forename: E J
authors.initials: EJ
authors.lastname: Schaefer
authors.forename: J
authors.initials: J
authors.lastname: Dupuis
authors.forename: B
authors.initials: B
authors.lastname: Eustace
authors.forename: P
authors.initials: P
authors.lastname: Van Eerdewegh
authors.forename: A L
authors.initials: AL
authors.lastname: Goldkamp
authors.forename: L M
authors.initials: LM
authors.lastname: Thurston
authors.forename: M G
authors.initials: MG
authors.lastname: FitzGerald
authors.forename: D
authors.initials: D
authors.lastname: Yasek-McKenna
authors.forename: G
authors.initials: G
authors.lastname: O'Neill
authors.forename: G P
authors.initials: GP
authors.lastname: Eberhart
authors.forename: B
authors.initials: B
authors.lastname: Weiffenbach
authors.forename: J M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: M W
authors.initials: MW
authors.lastname: Freeman
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
authors.forename: J Z
authors.initials: JZ
authors.lastname: Gu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001483:Base Sequence; D002899:Chromosomes, Human, Pair 9; D017931:DNA Primers; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D013631:Tangier Disease / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers