ABCA1 p.Arg2004Lys
| Predicted by SNAP2: | A: D (71%), C: D (75%), D: D (91%), E: D (75%), F: D (85%), G: D (85%), H: D (66%), I: D (80%), K: N (57%), L: D (80%), M: D (75%), N: D (80%), P: D (91%), Q: D (66%), S: D (80%), T: D (80%), V: D (71%), W: D (71%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Novel rare mutations and promoter haplotypes in AB... Clin Genet. 2008 Feb;73(2):179-84. Slatter TL, Jones GT, Williams MJ, van Rij AM, McCormick SP
Novel rare mutations and promoter haplotypes in ABCA1 contribute to low-HDL-C levels.
Clin Genet. 2008 Feb;73(2):179-84., [PMID:18199144]
Abstract [show]
The ATP-binding cassette A1 (ABCA1) protein regulates plasma high-density lipoprotein (HDL) levels. Mutations in ABCA1 can cause HDL deficiency and increase the risk of premature coronary artery disease. Single nucleotide polymorphisms (SNPs) in ABCA1 are associated with variation in plasma HDL levels. We investigated the prevalence of mutations and common SNPs in ABCA1 in 154 low-HDL individuals and 102 high-HDL individuals. Mutations were identified in five of the low-HDL subjects, three having novel variants (I659V, R2004K, and A2028V) and two with a previously identified variant (R1068H). Analysis of four SNPs in the ABCA1 gene promoter (C-564T, G-407C, G-278C, and C-14T) identified the C-14T SNP and the TCCT haplotype to be over-represented in low-HDL individuals. The R1587K SNP was over-represented in low-HDL individuals, and the V825I and I883M SNPs over-represented in high-HDL individuals. We conclude that sequence variation in ABCA1 contributes significantly to variation in HDL levels.
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No. Sentence Comment
7 Mutations were identified in five of the low-HDL subjects, three having novel variants (I659V, R2004K, and A2028V) and two with a previously identified variant (R1068H).
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ABCA1 p.Arg2004Lys 18199144:7:95
status: NEW56 Three were novel mutations (I659V, R2004K and A2028V) only detected in single low-HDL individuals.
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ABCA1 p.Arg2004Lys 18199144:56:35
status: NEW59 The R1068H mutation was predicted to be Ôprobably damaging`, the R2004K mutation Ôpossibly damaging` and the I659V and A2028V mutations Ôbenign`.
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ABCA1 p.Arg2004Lys 18199144:59:70
status: NEW91 Three novel ABCA1 mutations were found in low-HDL individuals I659V, R2004K, and A2028V.
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ABCA1 p.Arg2004Lys 18199144:91:69
status: NEW[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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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.Arg2004Lys 23087442:16:90
status: NEW53 The Pearson`s correlation coefficient between the GFP and AlexaFluor594 of the ABCA1 mutations were previously identified in low HDL-C subjects and included three uncharacterized mutations, p.I659V, p.R2004K, and p.A2028V (18) and three variants, p.R1068H, p.T1512M, and p.N1800H, known to have reduced localization and cholesterol efflux (19, 20).
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ABCA1 p.Arg2004Lys 23087442:53:201
status: NEW76 We first characterized the three novel ABCA1 mutants and three previously identified but uncharacterized mutants (p.I659V, p.R2004K, and p.A2028V) in HEK293 cells, which lack the endogenous ABCA1 protein (see supplementary Fig. I).
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ABCA1 p.Arg2004Lys 23087442:76:125
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.Arg2004Lys 23087442:77:120
status: NEW79 Areas of mislocalized ABCA1-GFP are indicated by arrows in Fig. 2A with the p.Y1767D and R2004K mutants being the most affected.
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ABCA1 p.Arg2004Lys 23087442:79:89
status: NEW109 Upon 4-PBA treatment, efflux function was significantly increased relative to the untreated level for the p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, and p.A2028V mutants (Fig. 3B).
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ABCA1 p.Arg2004Lys 23087442:109:148
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.Arg2004Lys 23087442:112:133
status: NEW