J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

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
This Article
Right arrow Full Text (Accepted Manuscript)
Right arrow All Versions of this Article:
M200277-JLR200v1
43/11/1939    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wellington, C. L.
Right arrow Articles by Hayden, M. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wellington, C. L.
Right arrow Articles by Hayden, M. R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

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.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Lipid Res.Home page
M. L. E. MacDonald, R. R. Singaraja, N. Bissada, P. Ruddle, R. Watts, J. M. Karasinska, W. T. Gibson, C. Fievet, J. E. Vance, B. Staels, et al.
Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice
J. Lipid Res., January 1, 2008; 49(1): 217 - 229.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
G. H. Tansley, B. L. Burgess, M. T. Bryan, Y. Su, V. Hirsch-Reinshagen, J. Pearce, J. Y. Chan, A. Wilkinson, J. Evans, K. E. Naus, et al.
The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of {beta}-amyloid precursor protein
J. Lipid Res., May 1, 2007; 48(5): 1022 - 1034.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
R. R. Singaraja, H. Visscher, E. R. James, A. Chroni, J. M. Coutinho, L. R. Brunham, M. H. Kang, V. I. Zannis, G. Chimini, and M. R. Hayden
Specific Mutations in ABCA1 Have Discrete Effects on ABCA1 Function and Lipid Phenotypes Both In Vivo and In Vitro
Circ. Res., August 18, 2006; 99(4): 389 - 397.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
V. Hirsch-Reinshagen, S. Zhou, B. L. Burgess, L. Bernier, S. A. McIsaac, J. Y. Chan, G. H. Tansley, J. S. Cohn, M. R. Hayden, and C. L. Wellington
Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain
J. Biol. Chem., September 24, 2004; 279(39): 41197 - 41207.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
D. M. Selva, V. Hirsch-Reinshagen, B. Burgess, S. Zhou, J. Chan, S. McIsaac, M. R. Hayden, G. L. Hammond, A. W. Vogl, and C. L. Wellington
The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility
J. Lipid Res., June 1, 2004; 45(6): 1040 - 1050.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
L. Krimbou, M. Denis, B. Haidar, M. Carrier, M. Marcil, and J. Genest Jr.
Molecular interactions between apoE and ABCA1: impact on apoE lipidation
J. Lipid Res., May 1, 2004; 45(5): 839 - 848.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
C. L. Wellington, L. R. Brunham, S. Zhou, R. R. Singaraja, H. Visscher, A. Gelfer, C. Ross, E. James, G. Liu, M. T. Huber, et al.
Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1
J. Lipid Res., August 1, 2003; 44(8): 1470 - 1480.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
R. R. Singaraja, L. R. Brunham, H. Visscher, J. J.P. Kastelein, and M. R. Hayden
Efflux and Atherosclerosis: The Clinical and Biochemical Impact of Variations in the ABCA1 Gene
Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1322 - 1332.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
G. K. Hovingh, M. J. A. van Wijland, A. Brownlie, R. J. Bisoendial, M. R. Hayden, J. J. P. Kastelein, and A. K. Groen
The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia
J. Lipid Res., June 1, 2003; 44(6): 1251 - 1255.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.