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Journal of Lipid Research, Vol. 43, 1939-1949, November 2002
Copyright © 2002 by Lipid Research, Inc.

Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol

Cheryl L. Wellington^*, Yu-Zhou Yang, Stephen Zhou, Susanne M. Clee^*, Bing Tan, Kenichi Hirano^**, Karin Zwarts^*, Anita Kwok^*, Allison Gelfer^*, Michel Marcil, Scott Newman, Kirsten Roomp, Roshni Singaraja^*, Jennifer Collins, Lin-Hua Zhang^*, Albert K. Groen, Kees Hovingh, Alison Brownlie, Sherrie Tafuri, Jacques Genest, Jr., John J. P. Kastelein and Michael R. Hayden^1,*,

^* Centre for Molecular Medicine and Therapeutics, Childrens' and Women's Hospital, University of British Columbia, 980 West 28th Avenue, Vancouver, British Columbia, Canada
Xenon Genetics, Inc., Vancouver, British Columbia, Canada
Pfizer Global Research, Ann Arbor, MI
^** Graduate School of Medicine, Osaka University, Osaka, Japan
Cardiovascular Genetics Laboratory, University Health Centre, Montreal, Quebec, Canada
Academic Medical Centre, Amsterdam, The Netherlands

¹ To whom correspondence should be addressed. e-mail: mrh{at}cmmt.ubc.ca

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.

Abbreviations: apoA-I, apolipoprotein A-I; apoA-II, apolipoprotein A-II; BMI, body mass index; 9-cis-RA, 9-cis-retinoic acid; FCS, fetal calf serum; FHA, hypoalphalipoproteinemia; GAPDH, glyceraldehyde phosphate dehydrogenase; 22-R-OH-Chol, 22-R-hydroxycholesterol; TD, Tangier Disease

Supplementary key words high density lipoprotein cholesterol • cholesterol efflux • pharmacogenomics

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