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See detailTruncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol
Wellington, C. L.; Yang, Y. Z.; Zhou, S. et al

in Journal of Lipid Research (2002), 43(11), 1939-1949

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 ... [more ▼]

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. [less ▲]

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See detailABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels
Zwarts, K. Y.; Clee, S. M.; Zwinderman, A. H. et al

in Clinical Genetics (2002), 61(2), 115-125

The authors have previously shown that individuals heterozygous for ABCA1 mutations have decreased high density lipoprotein cholesterol, increased triglycerides and an increased frequency of coronary ... [more ▼]

The authors have previously shown that individuals heterozygous for ABCA1 mutations have decreased high density lipoprotein cholesterol, increased triglycerides and an increased frequency of coronary artery disease (CAD), and that single nucleotide polymorphisms (SNPs) in the coding region of the ABCA1 gene significantly impact plasma lipid levels and the severity of CAD in the general population. They have now identified several SNPs in non-coding regions of ABCA1 which may be important for the appropriate regulation of ABCA1 expression (i.e. in the promoter, intron 1 and the 5′ untranslated region), and have examined the phenotypic effects of these SNPs in the REGRESS population. Out of 12 SNPs, four were associated with a clinical outcome. A threefold increase in coronary events with an increased family history of CAD was evident for the G-191C variant. Similarly, the C69T SNP was associated with a twofold increase in events. In contrast, the C-17G was associated with a decrease in coronary events and the InsG319 was associated with less atherosclerosis. For all these SNPs, the changes in atherosclerosis and CAD occurred without detectable changes in plasma lipid levels. These data suggest that common variation in non-coding regions of ABCA1 may significantly alter the severity of atherosclerosis, without necessarily influencing plasma lipid levels. [less ▲]

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