ABCMdb

ABCA1 p.Glu89Lys

Predicted by SNAP2:	A: D (59%), C: D (53%), D: D (63%), F: D (63%), G: D (75%), H: D (63%), I: D (59%), K: D (71%), L: D (63%), M: D (59%), N: D (59%), P: D (80%), Q: D (59%), R: D (71%), S: D (66%), T: D (53%), V: D (59%), W: D (71%), Y: D (63%),
Predicted by PROVEAN:	A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] ABCA1 is essential for efficient basolateral chole... J Biol Chem. 2003 Apr 11;278(15):13356-66. Epub 2003 Jan 27. Mulligan JD, Flowers MT, Tebon A, Bitgood JJ, Wellington C, Hayden MR, Attie AD
ABCA1 is essential for efficient basolateral cholesterol efflux during the absorption of dietary cholesterol in chickens.
J Biol Chem. 2003 Apr 11;278(15):13356-66. Epub 2003 Jan 27., [PMID:12551945]

Abstract [show]
The ATP-binding cassette transporter A1 (ABCA1) participates in the efflux of cholesterol from cells. It remains unclear whether ABCA1 functions to efflux cholesterol across the basolateral or apical membrane of the intestine. We used a chicken model of ABCA1 dysfunction, the Wisconsin hypoalpha mutant (WHAM) chicken, to address this issue. After an oral gavage of radioactive cholesterol, the percentage appearing in the bloodstream was reduced by 79% in the WHAM chicken along with a 97% reduction in the amount of tracer in high density lipoprotein. In contrast, the percentage of radioactive cholesterol absorbed from the lumen into the intestine was not affected by the ABCA1 mutation. Liver X receptor (LXR) agonists have been inferred to decrease cholesterol absorption through activation of ABCA1 expression. However, the LXR agonist T0901317 decreased cholesterol absorption equally in both wild type and WHAM chickens, indicating that the effect of LXR activation on cholesterol absorption is independent of ABCA1. The ABCA1 mutation resulted in accumulation of radioactive cholesterol ester in the intestine and the liver of the WHAM chicken (5.0- and 4.4-fold, respectively), whereas biliary lipid concentrations were unaltered by the WHAM mutation. In summary, ABCA1 regulates the efflux of cholesterol from the basolateral but not apical membrane in the intestine and the liver.

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42 The WHAM chicken ABCA1 gene has a G265A substitution that results in a glutamic acid to lysine substitution at amino acid 89 of the ABCA1 protein (E89K) (37). Login to comment
48 In vitro studies showed that the E89K mutation results in intracellular accumulation of ABCA1, decreasing plasma membrane ABCA1 expression by 80-90% of wild type ABCA1 (determined by cell surface biotinylation) and resulting in a complete loss of function assayed by both annexin-V and apoAI binding (37). Login to comment
313 The mechanism for the effect of ABCA1 dysfunction on triglyceride synthesis is unknown but may be caused by instability of SREBP-1c and lipogenic enzymes in the endoplasmic reticulum membrane, possibly due to the intracellular accumulation of the E89K ABCA1 variant (37). Login to comment
314 The mechanism for the effect of ABCA1 dysfunction on triglyceride synthesis is unknown but may be caused by instability of SREBP-1c and lipogenic enzymes in the endoplasmic reticulum membrane, possibly due to the intracellular accumulation of the E89K ABCA1 variant (37). Login to comment

[hide] Identification and functional analysis of a natura... J Lipid Res. 2002 Oct;43(10):1610-7. Attie AD, Hamon Y, Brooks-Wilson AR, Gray-Keller MP, MacDonald ML, Rigot V, Tebon A, Zhang LH, Mulligan JD, Singaraja RR, Bitgood JJ, Cook ME, Kastelein JJ, Chimini G, Hayden MR
Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken.
J Lipid Res. 2002 Oct;43(10):1610-7., [PMID:12364545]

Abstract [show]
The Wisconsin hypoalpha mutant (WHAM) chicken has a >90% reduction in plasma HDL due to hypercatabolism by the kidney of lipid-poor apoA-I. The WHAM chickens have a recessive white skin phenotype caused by a single-gene mutation that maps to the chicken Z-chromosome. This corresponds to human 9q31.1, a chromosomal segment that contains the ATP-binding cassette protein-1 (ABCA1) gene, which is mutated in Tangier Disease and familial hypoalphalipoproteinemia. Complete sequencing of the WHAM ABCA1 cDNA identified a missense mutation near the N-terminus of the protein (E89K). The substitution of this evolutionary conserved glutamate residue for lysine in the mouse ABCA1 transporter leads to complete loss of function, resulting principally from defective intracellular trafficking and very little ABCA1 reaching the plasma membrane. The WHAM chicken is a naturally occurring animal model for Tangier Disease.

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3 Complete sequencing of the WHAM ABCA1 cDNA identified a missense mutation near the N-terminus of the protein (E89K). Login to comment
6 Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken. Login to comment
34 We have cloned and sequenced the chicken ABCA1 gene and show that a single missense mutation (E89K) in the amino terminus of ABCA1 results in altered trafficking of ABCA1 with its retention in the endoplasmic reticulum and loss of function at the plasma membrane. Login to comment
95 The sequences of the normal and mutant chickens ABCA1 CDNAs were identical with the exception of a G to A transition in WHAM DNA at nucleotide 265, corresponding to a glutamic acid to lysine substitution at amino acid 89 (E89K) (Fig. 3B). Login to comment
99 Functional analysis of the E89K mutation in the ABCA1 gene In order to establish the impact of the WHAM mutation on the function of the ABCA1 transporter, we engineered a construct harbouring the E89K mutation on a murine ABCA1/EGFP chimeric backbone. Login to comment
118 B: The WHAM chicken ABCA1 gene has a single amino acid substitution (E89K) relative to normal White Leghorn chicken. Login to comment
126 D: The glutamate residue at the position of the non-conservative E89K substitution is conserved between human (CAA10005), mouse (CAA53530), Takifugu rubripes ("fugu"), and chicken. Login to comment
140 The non-conservative E89K mutation described here makes a strong case that this is indeed the WHAM mutation. Login to comment

[hide] Regulation of intestinal cholesterol absorption. Annu Rev Physiol. 2007;69:221-48. Wang DQ
Regulation of intestinal cholesterol absorption.
Annu Rev Physiol. 2007;69:221-48., [PMID:17002594]

Abstract [show]
The identification of defective structures in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in patients with sitosterolemia suggests that these two proteins are an apical sterol export pump promoting active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. The newly identified Niemann-Pick C1-like 1 (NPC1L1) protein is also expressed at the apical membrane of enterocytes and plays a crucial role in the ezetimibe-sensitive cholesterol absorption pathway. These findings indicate that cholesterol absorption is a multistep process that is regulated by multiple genes at the enterocyte level and that the efficiency of cholesterol absorption may be determined by the net effect between influx and efflux of intraluminal cholesterol molecules crossing the brush border membrane of the enterocyte. Combination therapy using cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) provides a powerful novel strategy for the prevention and treatment of hypercholesterolemia.

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689 Attie AD, Hamon Y, Brooks-Wilson AR, Gray-Keller MP, MacDonald ML, et al. 2002. Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken. Login to comment

[hide] Both hepatic and extrahepatic ABCA1 have discrete ... Circulation. 2006 Sep 19;114(12):1301-9. Epub 2006 Aug 28. Singaraja RR, Van Eck M, Bissada N, Zimetti F, Collins HL, Hildebrand RB, Hayden A, Brunham LR, Kang MH, Fruchart JC, Van Berkel TJ, Parks JS, Staels B, Rothblat GH, Fievet C, Hayden MR
Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo.
Circulation. 2006 Sep 19;114(12):1301-9. Epub 2006 Aug 28., [PMID:16940190]

Abstract [show]
BACKGROUND: Extrahepatic tissues have long been considered critical contributors of cholesterol to nascent HDL particles in the reverse cholesterol transport pathway, in which ABCA1 plays the crucial role. Recent studies, however, including both overexpression and deletion of ABCA1 selectively in the liver, have highlighted the primary role of the liver in the maintenance of HDL levels in vivo. METHODS AND RESULTS: The availability of mice with complete deletion of ABCA1 (total knockout [TKO]) and with liver-specific deletion of ABCA1 (LSKO) has enabled us to dissect the discrete roles of hepatic relative to extrahepatic ABCA1 in HDL biogenesis. Delivery of adenoviral ABCA1 resulted in selective expression of physiological levels of ABCA1 in the livers of both LSKO and TKO mice, resulting in increased HDL cholesterol (HDL-C). Expression of ABCA1 in the liver of LSKO mice resulted in plasma HDL-C levels that were similar to those in wild-type mice and significantly above those seen in similarly treated TKO mice. HDL particles from ABCA1-expressing LSKO mice were larger and contained significantly increased cholesterol compared with TKO mice. Infusion of human apolipoprotein A-I/phospholipid reconstituted HDL particles normalized plasma HDL-C levels in LSKO mice but had no effect on HDL-C levels in TKO mice. CONCLUSIONS: Although hepatic ABCA1 appears crucial for phospholipid transport, extrahepatic tissues play an important role in cholesterol transfer to nascent HDL particles. These data highlight the discrete and specific roles of both liver and extrahepatic ABCA1 in HDL biogenesis in vivo and indicate that ABCA1 shows lipid cargo selectivity depending on its site of expression.

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193 Attie AD, Hamon Y, Brooks-Wilson AR, Gray-Keller MP, MacDonald ML, Rigot V, Tebon A, Zhang LH, Mulligan JD, Singaraja RR, Bitgood JJ, Cook ME, Kastelein JJ, Chimini G, Hayden MR. Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken. Login to comment

[hide] Genetic evidence for role of carotenoids in age-re... Invest Ophthalmol Vis Sci. 2014 Jan 29;55(1):587-99. doi: 10.1167/iovs.13-13216. Meyers KJ, Mares JA, Igo RP Jr, Truitt B, Liu Z, Millen AE, Klein M, Johnson EJ, Engelman CD, Karki CK, Blodi B, Gehrs K, Tinker L, Wallace R, Robinson J, LeBlanc ES, Sarto G, Bernstein PS, SanGiovanni JP, Iyengar SK
Genetic evidence for role of carotenoids in age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS).
Invest Ophthalmol Vis Sci. 2014 Jan 29;55(1):587-99. doi: 10.1167/iovs.13-13216., [PMID:24346170]

Abstract [show]
PURPOSE: We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS). METHODS: Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0-4.9). CONCLUSIONS: Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.

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381 Attie AD, Hamon Y, Brooks-Wilson AR, et al. Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken. Login to comment

[hide] Effect of compounds affecting ABCA1 expression and... Lipids. 2014 Dec;49(12):1233-43. doi: 10.1007/s11745-014-3958-8. Epub 2014 Oct 10. Niesor EJ, Chaput E, Mary JL, Staempfli A, Topp A, Stauffer A, Wang H, Durrwell A
Effect of compounds affecting ABCA1 expression and CETP activity on the HDL pathway involved in intestinal absorption of lutein and zeaxanthin.
Lipids. 2014 Dec;49(12):1233-43. doi: 10.1007/s11745-014-3958-8. Epub 2014 Oct 10., [PMID:25300953]

Abstract [show]
The antioxidant xanthophylls lutein and zeaxanthin are absorbed from the diet in a process involving lipoprotein formation. Selective mechanisms exist for their intestinal uptake and tissue-selective distribution, but these are poorly understood. We investigated the role of high-density lipoprotein (HDL), apolipoprotein (apo) A1 and ATP-binding cassette transporter (ABC) A1 in intestinal uptake of lutein in a human polarized intestinal cell culture and a hamster model. Animals received dietary lutein and zeaxanthin and either a liver X receptor (LXR) agonist or statin, which up- or down-regulate intestinal ABCA1 expression, respectively. The role of HDL was studied following treatment with the cholesteryl ester transfer protein (CETP) modulator dalcetrapib or the CETP inhibitor anacetrapib. In vitro, intestinal ABCA1 at the basolateral surface of enterocytes transferred lutein and zeaxanthin to apoA1, not to mature HDL. In hamsters, plasma lutein and zeaxanthin levels were markedly increased with the LXR agonist and decreased with simvastatin. Dalcetrapib, but not anacetrapib, increased plasma and liver lutein and zeaxanthin levels. ABCA1 expression and apoA1 acceptor activity are important initial steps in intestinal uptake and maintenance of lutein and zeaxanthin levels by an HDL-dependent pathway. Their absorption may be improved by physiological and pharmacological interventions affecting HDL metabolism.

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17 In the Wisconsin HypoAlpha Mutant chicken, a single E89K loss of function mutation in the ATP-binding cassette transporter (ABC) A1 gene [12] results in a [95 % decrease in HDL cholesterol (HDL-C) [13], and dietary supplementation with lutein is poorly effective in raising plasma, tissue, and retinal lutein [14]. Login to comment

[hide] Will Lipidation of ApoA1 through Interaction with ... Biology (Basel). 2015 Jan 6;4(1):17-38. doi: 10.3390/biology4010017. Niesor EJ
Will Lipidation of ApoA1 through Interaction with ABCA1 at the Intestinal Level Affect the Protective Functions of HDL?
Biology (Basel). 2015 Jan 6;4(1):17-38. doi: 10.3390/biology4010017., [PMID:25569858]

Abstract [show]
The relationship between levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) risk is well recognized; however, in recent years, large-scale phase III studies with HDL-C-raising or -mimicking agents have failed to demonstrate a clinical benefit on CV outcomes associated with raising HDL-C, casting doubt on the "HDL hypothesis." This article reviews potential reasons for the observed negative findings with these pharmaceutical compounds, focusing on the paucity of translational models and relevant biomarkers related to HDL metabolism that may have confounded understanding of in vivo mechanisms. A unique function of HDL is its ability to interact with the ATP-binding cassette transporter (ABC) A1 via apolipoprotein (Apo) A1. Only recently, studies have shown that this process may be involved in the intestinal uptake of dietary sterols and antioxidants (vitamin E, lutein and zeaxanthin) at the basolateral surface of enterocytes. This parameter should be assessed for HDL-raising drugs in addition to the more documented reverse cholesterol transport (RCT) from peripheral tissues to the liver. Indeed, a single mechanism involving the same interaction between ApoA1 and ABCA1 may encompass two HDL functions previously considered as separate: antioxidant through the intestinal uptake of antioxidants and RCT through cholesterol efflux from loaded cells such as macrophages.

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No. Sentence Comment
341 Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken. Login to comment