ABCA1 p.Asn1611Asp
| Predicted by SNAP2: | A: D (80%), C: D (85%), D: D (85%), E: D (91%), F: D (91%), G: D (80%), H: D (85%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), P: D (91%), Q: D (80%), R: D (91%), S: D (80%), T: D (80%), V: D (91%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Accurate prediction of the functional significance... PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30. Brunham LR, Singaraja RR, Pape TD, Kejariwal A, Thomas PD, Hayden MR
Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.
PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30., [PMID:16429166]
Abstract [show]
The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation.
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48 This SNP has been reported to be associated with decreased HDL cholesterol and increased severity of atherosclerosis in Table 1. subPSEC Scores and Probability of Functional Impairment (Pdeleterious) for ABCA1 Mutations and SNPs Mutations SNPs Variant SubPSEC Pdeleterious Variant subPSEC Pdeleterious P85L À4.62 0.83 R219K À0.57 0.08 H160F À2.79 0.45 V399A À2.26 0.32 R230C À4.27 0.78 V771M À2.86 0.46 A255T À1.81 0.23 T774P À1.99 0.27 E284K À2.34 0.34 K776N À3.53 0.63 Y482C À4.21 0.77 V825I À1.06 0.13 R587W À6.04 0.95 I883M À1.38 0.17 W590S À5.19 0.9 E1172D À1.96 0.26 W590L À4.48 0.82 R1587K À0.58 0.08 Q597R À7.15 0.98 S1731C À4.21 0.77 T929I À4.29 0.78 N935H À8.54 1 N935S À7.53 0.99 A937V À6.6 0.97 A1046D 0;7.52 0.99 M1091T À3.56 0.64 D1099Y À6.09 0.96 D1289N À2.48 0.37 L1379F À3.81 0.69 C1477R À5.44 0.92 S1506L À5.17 0.9 N1611D À5.69 0.94 R1680W À6.02 0.95 V1704D À3.21 0.55 N1800H À4.23 0.77 R1901S À5.06 0.89 F2009S À2.73 0.43 R2081W À8.08 0.99 P2150L À2.88 0.47 Q2196H À2.74 0.43 DOI: 10.1371/journal.pgen.0010083.t001 PLoS Genetics | www.plosgenetics.org December 2005 | Volume 1 | Issue 6 | e83 0740 Accurate Prediction of ABCA1 Variants Synopsis A major goal of human genetics research is to understand how genetic variation leads to differences in the function of genes.
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ABCA1 p.Asn1611Asp 16429166:48:832
status: NEWX
ABCA1 p.Asn1611Asp 16429166:48:987
status: NEW[hide] Efflux and atherosclerosis: the clinical and bioch... Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32. Epub 2003 May 22. Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR
Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene.
Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32. Epub 2003 May 22., [PMID:12763760]
Abstract [show]
Approximately 50 mutations and many single nucleotide polymorphisms have been described in the ABCA1 gene, with mutations leading to Tangier disease and familial hypoalphalipoproteinemia. Homozygotes and heterozygotes for mutations in ABCA1 display a wide range of phenotypes. Identification of ABCA1 as the molecular defect in these diseases has allowed for ascertainment based on genetic status and determination of genotype-phenotype correlations and has permitted us to identify mutations conferring a range of severity of cellular, biochemical, and clinical phenotypes. In this study we review how genetic variation at the ABCA1 locus affects its role in the maintenance of lipid homeostasis and the natural progression of atherosclerosis.
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83 TABLE 2. Conservation of Amino Acid Residues Mutated in Humans Mutation H. sapiens M. musculus G. gallus D. melanogaster C. elegans P85L P P P ⅐ ⅐ ⅐ P R230C R R R P G A255T A A S ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ R587W R R R ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ W590S W W W R Q Q597R Q Q Q Q Q ⌬L693 L L L L L T929I T T T T T N935S/H N N N N N A937V A A A A A A1046D A A A A A M1091T M M M M M D1099Y D D D D D D1289L/N D D D D D C1477R C C C ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ S1506L S S S ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ N1611D N N N N S R1680W R R R R R N1800H N N N A W F2009S F F F I M R2081W R R R R R P2150L P P P R N ⌬E1893 E E E D S ⌬D1894 D D D D D Twenty-three of 24 (95.83%) amino acids affected by mutations are conserved with G. gallus, reflecting the functional importance of these residues.
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ABCA1 p.Asn1611Asp 12763760:83:629
status: NEW75 TABLE 2. Conservation of Amino Acid Residues Mutated in Humans Mutation H. sapiens M. musculus G. gallus D. melanogaster C. elegans P85L P P P ዼ ዼ ዼ P R230C R R R P G A255T A A S ዼ ዼ ዼ ዼ ዼ ዼ R587W R R R ዼ ዼ ዼ ዼ ዼ ዼ W590S W W W R Q Q597R Q Q Q Q Q èc;L693 L L L L L T929I T T T T T N935S/H N N N N N A937V A A A A A A1046D A A A A A M1091T M M M M M D1099Y D D D D D D1289L/N D D D D D C1477R C C C ዼ ዼ ዼ ዼ ዼ ዼ S1506L S S S ዼ ዼ ዼ ዼ ዼ ዼ N1611D N N N N S R1680W R R R R R N1800H N N N A W F2009S F F F I M R2081W R R R R R P2150L P P P R N èc;E1893 E E E D S èc;D1894 D D D D D Twenty-three of 24 (95.83%) amino acids affected by mutations are conserved with G. gallus, reflecting the functional importance of these residues.
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ABCA1 p.Asn1611Asp 12763760:75:601
status: NEW[hide] Genetics of HDL regulation in humans. Curr Opin Lipidol. 2003 Jun;14(3):273-9. Miller M, Rhyne J, Hamlette S, Birnbaum J, Rodriguez A
Genetics of HDL regulation in humans.
Curr Opin Lipidol. 2003 Jun;14(3):273-9., [PMID:12840658]
Abstract [show]
PURPOSE OF REVIEW: To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states. RECENT FINDINGS: The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future. SUMMARY: Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.
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66 TD 1591 T/C 11 V399A extracellular [68] TD 1979 (110bpAlu Ins) 12 truncated truncation [60] TD/FHA 2154 C/T 14 R587W extracellular [67,69] TD 2164 G/C 14 W590S extracellular [61] TD 2185 A/G 14 Q597R extracellular [59,67] TD 2219 G/del 14 truncated, 635X truncated [60,61] FHA 2472-2474 3bp del 15 Del L693 TM domain #3 [59] phosphorylation 2706 G/A 16 V771M extracellular [68] 2715 A/C 16 T774P extracellular [68] 2723 G/C 16 K776N extracellular [68] 2868 G/A 17 V825I TM domain #6 [67,68] TD/FHA 3044 A/G 18 I883M cytoplasmic [68] phosphorylat site FHA 3120 C/T 19 R909X truncation [63,71] TD 3181 C/T 19 T929I cytoplasmic [62] TD 3199 A/G 19 N935S Walker A [61] TD 3205 C/T 19 A937V Walker A [61] TD 3532 C/A 22 A1046D cytoplasmic, Walker A/B [70] FHA 3667 T/C 23 M1091T cytoplasmic [63] 3690 G/T 23 D1099Y cytoplasmic [9] TD 3738 2bp del 23 1145X truncation [66] FHA 3911 G/C 24 E1172D linker/cytoplasmic [68] FHA 4242 4bp del 27 1297X truncated [64] TD 4260 G/A 27 D1289N linker cytoplasm [64,65] TD 4824 T/C 31 C1477R extracellular [59] TD 4912 C/T 32 S1506L extracellular loop #2 [71] TD 5025 ins A 34 A1544S?1552X truncation [70] 5059 T/C 34 I1555T extracellular loop #2 [67] 5155 G/A 35 R1587K extracellular loop #2 [68] FHA 5226 A/G 36 N1611D extracellular loop #2 [75..] 5338 T/C 36 L1648P extracellular loop #2 [67] TD 5443 C/T 37 R1680W cytoplasmic [74.]
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ABCA1 p.Asn1611Asp 12840658:66:1246
status: NEW[hide] Truncation mutations in ABCA1 suppress normal upre... J Lipid Res. 2002 Nov;43(11):1939-49. Wellington CL, Yang YZ, Zhou S, Clee SM, Tan B, Hirano K, Zwarts K, Kwok A, Gelfer A, Marcil M, Newman S, Roomp K, Singaraja R, Collins J, Zhang LH, Groen AK, Hovingh K, Brownlie A, Tafuri S, Genest J Jr, Kastelein JJ, Hayden MR
Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol.
J Lipid Res. 2002 Nov;43(11):1939-49., [PMID:12401893]
Abstract [show]
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. 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.
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164 Finally, cells were cotransfected with Xpress-tagged wild-type and FLAG-tagged missense ABCA1 (N1611D).
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ABCA1 p.Asn1611Asp 12401893:164:95
status: NEW196 Cos-7 cells were transfected singly with vector (mock), Xpress-tagged wild-type human ABCA1 cDNA (WT/Xpress), or cotransfected with FLAG-tagged wild-type ABCA1 (WT/Xpress ϩ WT/FLAG), FLAG-tagged ABCA1 containing the N1611D mutation (WT/Xpress ϩ N1611D/FLAG), or with FLAG-tagged ABCA1 containing the R1851X mutation (WT/Xpress ϩ R1851X/FLAG).
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ABCA1 p.Asn1611Asp 12401893:196:222
status: NEWX
ABCA1 p.Asn1611Asp 12401893:196:257
status: NEW165 Finally, cells were cotransfected with Xpress-tagged wild-type and FLAG-tagged missense ABCA1 (N1611D).
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ABCA1 p.Asn1611Asp 12401893:165:95
status: NEW197 Cos-7 cells were transfected singly with vector (mock), Xpress-tagged wild-type human ABCA1 cDNA (WT/Xpress), or cotransfected with FLAG-tagged wild-type ABCA1 (WT/Xpress WT/FLAG), FLAG-tagged ABCA1 containing the N1611D mutation (WT/Xpress N1611D/FLAG), or with FLAG-tagged ABCA1 containing the R1851X mutation (WT/Xpress R1851X/FLAG).
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ABCA1 p.Asn1611Asp 12401893:197:216
status: NEWX
ABCA1 p.Asn1611Asp 12401893:197:245
status: NEW[hide] Expression and functional analyses of novel mutati... Biochem Biophys Res Commun. 2002 Jan 18;290(2):713-21. Nishida Y, Hirano K, Tsukamoto K, Nagano M, Ikegami C, Roomp K, Ishihara M, Sakane N, Zhang Z, Tsujii Ki K, Matsuyama A, Ohama T, Matsuura F, Ishigami M, Sakai N, Hiraoka H, Hattori H, Wellington C, Yoshida Y, Misugi S, Hayden MR, Egashira T, Yamashita S, Matsuzawa Y
Expression and functional analyses of novel mutations of ATP-binding cassette transporter-1 in Japanese patients with high-density lipoprotein deficiency.
Biochem Biophys Res Commun. 2002 Jan 18;290(2):713-21., [PMID:11785958]
Abstract [show]
ATP-binding cassette transporter-1 (ABCA1) gene is mutated in patients with familial high-density lipoprotein deficiency (FHD). In order to know the molecular basis for FHD, we characterized three different ABCA1 mutations associated with FHD (G1158A/A255T, C5946T/R1851X, and A5226G/N1611D) with respect to their expression in the passaged fibroblasts from the patients and in the cells transfected with the mutated cDNAs. Fibroblasts from the all patients showed markedly decreased cholesterol efflux to apolipoprotein (apo)-Al. In the fibroblasts homozygous for G1158A/A255T, the immunoreactive mass of ABCA1 could not be detected, even when stimulated by 9-cis-retinoic acid and 22-R-hydroxycholesterol. In the fibroblasts homozygous for C5946T/R1851X, ABCA1 mRNA was comparable. Because the mutant ABCA1 protein (R1851X) was predicted to lack the epitope for the antibody used, we transfected FLAG-tagged truncated mutant (R1851X/ABCA1-FLAG) cDNA into Cos-7 cells, showing that the mutant protein expression was markedly reduced. The expression of N1611D ABCA1 protein was comparable in both fibroblasts and overexpressing cells, although cholesterol efflux from the cells was markedly reduced. These data indicated that, in the three patients investigated, the abnormalities and dysfunction of ABCA1 occurred at the different levels, providing important information about the expression, regulation, and function of ABCA1.
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1 In order to know the molecular basis for FHD, we characterized three different ABCA1 mutations associated with FHD (G1158A/ A255T, C5946T/R1851X, and A5226G/N1611D) with respect to their expression in the passaged fibroblasts from the patients and in the cells transfected with the mutated cDNAs.
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ABCA1 p.Asn1611Asp 11785958:1:157
status: NEW5 The expression of N1611D ABCA1 protein was comparable in both fibroblasts and overexpressing cells, although cholesterol efflux from the cells was markedly reduced.
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ABCA1 p.Asn1611Asp 11785958:5:18
status: NEW59 TABLE 1 Clinical Profiles of Patients with Familial HDL Deficiency Case 1 Case 2 Case 3 ABCA1 substitutions found (nt/aa) G1158A/A255T C5946T/R1851X A5226G/N1611D Age (years)/sex (M, F) 56/M 71/F 53/F Total cholesterol (mmol/L) 0.72 1.47 2.7 HDL-cholesterol (mmol/L) 0.16 0.05 0.11 Triglyceride (mmol/L) 2.6 3.27 1.75 Apo-Al (mg/dL) 3.9 5.0 11.0 Atherosclerosis ϩ ϩ ϩ Typical TD phenotype ϩ ϩ - Cholesterol efflux (% of control) 5.0 2.0 7.0 Note.
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ABCA1 p.Asn1611Asp 11785958:59:156
status: NEW105 R1851X appeared to lack the second nucleotide binding domain.
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ABCA1 p.Asn1611Asp 11785958:105:0
status: NEW106 N1611D appeared to be located in the middle of extracellular loop from codons 1369 to 1654 (Ref.
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ABCA1 p.Asn1611Asp 11785958:106:0
status: NEW112 Case 3 was homozygous for a A to G substitution at nucleotide position 5226, causing a change of amino acid from asparagine (N) to aspartic acid (D) at codon 1611 (N1611D), as shown in Fig. 1C. The codon 1611 appeared to be located around the proximal part of the second transmembrane domain (Fig. 2).
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ABCA1 p.Asn1611Asp 11785958:112:164
status: NEW116 In Cases 2 (Ho/ R1851X) and 3 (Ho/N1611D), the expression of mRNA did not appear to be altered with and without the stimulation (Figs. 3A and 3B).
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ABCA1 p.Asn1611Asp 11785958:116:34
status: NEW119 It was likely that no-trace amount of ABCA1 protein contributed to the FHD phenotype in Case 1 (Ho/A255T).
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ABCA1 p.Asn1611Asp 11785958:119:92
status: NEW121 We could observe the comparable expression of ABCA1 protein in fibroblasts from Case 3 (Ho/ N1611D).
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ABCA1 p.Asn1611Asp 11785958:121:92
status: NEW129 We could detect a significant amount of cholesterol efflux from cells expressing A255T/ABCA1-FLAG.
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ABCA1 p.Asn1611Asp 11785958:129:22
status: NEW131 From cells expressing N1611D/ ABCA1-FLAG, no significant cholesterol efflux could be observed, although we obtained the comparable expression of the mutant protein (Figs. 4A and 4B).
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ABCA1 p.Asn1611Asp 11785958:131:22
status: NEW167 In Case 3, who did not have typical TD phenotype such as orange tonsils and hepatosplenomegaly, we found the other novel substitution (A5226G/N1611D).
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ABCA1 p.Asn1611Asp 11785958:167:142
status: NEW58 TABLE 1 Clinical Profiles of Patients with Familial HDL Deficiency Case 1 Case 2 Case 3 ABCA1 substitutions found (nt/aa) G1158A/A255T C5946T/R1851X A5226G/N1611D Age (years)/sex (M, F) 56/M 71/F 53/F Total cholesterol (mmol/L) 0.72 1.47 2.7 HDL-cholesterol (mmol/L) 0.16 0.05 0.11 Triglyceride (mmol/L) 2.6 3.27 1.75 Apo-Al (mg/dL) 3.9 5.0 11.0 Atherosclerosis af9; af9; af9; Typical TD phenotype af9; af9; afa; Cholesterol efflux (% of control) 5.0 2.0 7.0 Note.
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ABCA1 p.Asn1611Asp 11785958:58:156
status: NEW110 Case 3 was homozygous for a A to G substitution at nucleotide position 5226, causing a change of amino acid from asparagine (N) to aspartic acid (D) at codon 1611 (N1611D), as shown in Fig. 1C. The codon 1611 appeared to be located around the proximal part of the second transmembrane domain (Fig. 2).
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ABCA1 p.Asn1611Asp 11785958:110:164
status: NEW114 In Cases 2 (Ho/ R1851X) and 3 (Ho/N1611D), the expression of mRNA did not appear to be altered with and without the stimulation (Figs. 3A and 3B).
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ABCA1 p.Asn1611Asp 11785958:114:34
status: NEW165 In Case 3, who did not have typical TD phenotype such as orange tonsils and hepatosplenomegaly, we found the other novel substitution (A5226G/N1611D).
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ABCA1 p.Asn1611Asp 11785958:165:142
status: NEW