title: Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol.
abstract: Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5-10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele. These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Childrens' and Women's Hospital, University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Yu-Zhou
authors.initials: YZ
authors.lastname: Yang
authors.forename: Stephen
authors.initials: S
authors.lastname: Zhou
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.forename: Bing
authors.initials: B
authors.lastname: Tan
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Karin
authors.initials: K
authors.lastname: Zwarts
authors.forename: Anita
authors.initials: A
authors.lastname: Kwok
authors.forename: Allison
authors.initials: A
authors.lastname: Gelfer
authors.forename: Michel
authors.initials: M
authors.lastname: Marcil
authors.forename: Scott
authors.initials: S
authors.lastname: Newman
authors.forename: Kirsten
authors.initials: K
authors.lastname: Roomp
authors.forename: Roshni
authors.initials: R
authors.lastname: Singaraja
authors.forename: Jennifer
authors.initials: J
authors.lastname: Collins
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Kees
authors.initials: K
authors.lastname: Hovingh
authors.forename: Alison
authors.initials: A
authors.lastname: Brownlie
authors.forename: Sherrie
authors.initials: S
authors.lastname: Tafuri
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D000077556:Alitretinoin; D000483:Alleles; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D005347:Fibroblasts; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000032:analysis; D008264:Macrophages; D051379:Mice; D009154:Mutation / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D006888:Hydroxycholesterols; D008075:Lipoproteins, HDL; C003585:22-hydroxycholesterol; D000077556:Alitretinoin; D014212:Tretinoin