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A more recent version of this article appeared on November 1, 2002

Papers In Press, published online ahead of print August 16, 2002
J. Lipid Res., doi:10.1194/jlr.M200277-JLR200
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Submitted on July 18, 2002
Revised on August 16, 2002
Accepted on July 31, 2002

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

University of British Columbia, Vancouver, British Columbia V6z 4H4

Corresponding Author: mrh{at}cmmt.ubc.ca

Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol 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 apoA-I levels in heterozygotes compared to 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 and 22-R-hydroxycholesterol 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.


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