title: Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro.
abstract: Mutations in ATP-binding cassette transporter A1 (ABCA1) cause Tangier disease and familial hypoalphalipoproteinemia, resulting in low to absent plasma high-density lipoprotein cholesterol levels. However, wide variations in clinical lipid phenotypes are observed in patients with mutations in ABCA1. We hypothesized that the various lipid phenotypes would be the direct result of discrete and differing effects of the mutations on ABCA1 function. To determine whether there is a correlation between the mutations and the resulting phenotypes, we generated in vitro 15 missense mutations that have been described in patients with Tangier disease and familial hypoalphalipoproteinemia. Using localization of ABCA1, its ability to induce cell surface binding of apolipoprotein A-I, and its ability to elicit efflux of cholesterol and phospholipids to apolipoprotein A-I we determined that the phenotypes of patients correlate with the severity and nature of defects in ABCA1 function.
authors.affiliation: Center for Molecular Medicine and Therapeutics, University of British Columbia and Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Henk
authors.initials: H
authors.lastname: Visscher
authors.forename: Erick R
authors.initials: ER
authors.lastname: James
authors.forename: Angeliki
authors.initials: A
authors.lastname: Chroni
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coutinho
authors.forename: Liam R
authors.initials: LR
authors.lastname: Brunham
authors.forename: Martin H
authors.initials: MH
authors.lastname: Kang
authors.forename: Vassilis I
authors.initials: VI
authors.lastname: Zannis
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chimini
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism; D019921:Biotinylation; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D005434:Flow Cytometry; D014644:Genetic Variation; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D013631:Tangier Disease / Q000201:enzymology / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D002784:Cholesterol; D002794:Choline; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; C421109:multidrug resistance-associated protein 1