ABCA1 p.Ala594Thr
| Predicted by SNAP2: | C: N (53%), D: D (80%), E: D (71%), F: D (66%), G: D (59%), H: D (71%), I: N (82%), K: D (80%), L: N (72%), M: N (61%), N: D (66%), P: D (63%), Q: D (66%), R: D (80%), S: N (87%), T: N (82%), V: N (97%), W: D (71%), Y: D (66%), |
| Predicted by PROVEAN: | C: N, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: D, |
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[hide] Functional rescue of mutant ABCA1 proteins by sodi... J Lipid Res. 2013 Jan;54(1):55-62. doi: 10.1194/jlr.M027193. Epub 2012 Oct 20. Sorrenson B, Suetani RJ, Williams MJ, Bickley VM, George PM, Jones GT, McCormick SP
Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate.
J Lipid Res. 2013 Jan;54(1):55-62. doi: 10.1194/jlr.M027193. Epub 2012 Oct 20., [PMID:23087442]
Abstract [show]
Mutations in the ATP-binding cassette transporter A1 (ABCA1) are a major cause of decreased HDL cholesterol (HDL-C), which infers an increased risk of cardiovascular disease (CVD). Many ABCA1 mutants show impaired localization to the plasma membrane. The aim of this study was to investigate whether the chemical chaperone, sodium 4-phenylbutyrate (4-PBA) could improve cellular localization and function of ABCA1 mutants. Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA. Treatment restored localization to the plasma membrane and increased cholesterol efflux function for the majority of mutants. Treatment with 4-PBA also increased ABCA1 protein expression in all transfected cell lines. In fibroblast cells obtained from low HDL-C subjects expressing two of the ABCA1 mutants (p.R1068H and p.N1800H), 4-PBA increased cholesterol efflux without any increase in ABCA1 expression. Our study is the first to investigate the effect of the chemical chaperone, 4-PBA on ABCA1 and shows that it is capable of restoring plasma membrane localization and enhancing the cholesterol efflux function of mutant ABCA1s both in vitro and ex vivo. These results suggest 4-PBA may warrant further investigation as a potential therapy for increasing cholesterol efflux and HDL-C levels.
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No. Sentence Comment
16 Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA.
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ABCA1 p.Ala594Thr 23087442:16:32
status: NEW54 We identified a further three novel mutations, p.A594T, p.Y1767D, and p.Q2239N, and these were also included in this study. We hypothesized that efflux function would be improved for mutants that are dysfunctional as a result of protein mislocation.
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ABCA1 p.Ala594Thr 23087442:54:49
status: NEW73 Both media were RESULTS ABCA1 mutants with impaired localization have reduced cholesterol efflux function We identified three novel ABCA1 variants, p.A594T, p.Y1767D, and p.Q2239N, in heterozygote form in three individuals with HDL-C levels of 0.61, 0.17, and 0.37 mmol/L, respectively.
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ABCA1 p.Ala594Thr 23087442:73:153
status: NEW77 Investigation of the six uncharacterized mutations in transfected HEK293 cells showed the p.A594T, p.I659V, p.Y1767D, p.R2004K, and p.A2028V mutants to have various degrees of mislocalization (Fig. 2A).
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ABCA1 p.Ala594Thr 23087442:77:92
status: NEW112 Treatment with 4-PBA induced a significant increase in colocalization for the p.A594T, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, and p.R2004K mutants. Treatment with 4-PBA did not affect the colocalization of the wild-type ABCA1-GFP protein (supplementary Fig. II).
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ABCA1 p.Ala594Thr 23087442:112:80
status: NEW196 This is in contrast with our results where the majority of the mutants showed significant improvements in function, including the p.A594T mutant, which is of a similar location to p.Q597R.
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ABCA1 p.Ala594Thr 23087442:196:132
status: NEW