ABCMdb

ABCA1 p.Arg587Trp

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PMID: 21567408 [PubMed] Nakagawa H et al: "Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts."

No. Sentence Comment

155 Effect of Mutations and Nonsynonymous SNPs on Protein Trafficking, Maturation, or ERAD of ABC Transporters Protein AA Mutation/SNP Effect on Protein Reference ABCA1 W590S Mutation Functional defect 115 R587W Mutation Impaired glycol processing 115 Q597R Mutation Impaired glycol processing, ERAD 115,116 Y1532C Mutation Altered protein trafficking 117 R1925Q Mutation Altered protein trafficking 118 ABCA3 R43L Mutation Altered protein trafficking 119 L101P Mutation Altered protein trafficking 119 R280C Mutation Altered protein trafficking 119 ABCA4 L541P Mutation Mislocalization 120 R602W Mutation Mislocalization 120 A1038V Mutation Mislocalization 120 C1490Y Mutation Mislocalization 120 ABCB1a G268V Mutation ERAD 121 G341C Mutation ERAD 121 I1196S Mutation Reduced glycosylation 122 ABCB4 I541F Mutation Accumulation in ER 123 ABCB11a E135K Mutation Reduced level of mature protein 124 L198P Mutation Reduced level of mature protein 124 E297G Mutation Reduced level of mature protein 124 L413W Mutation Reduced level of mature protein 124 R432T Mutation Reduced level of mature protein 124 D482G Mutation Immature protein in ER 124,125 N490D Mutation Reduced level of mature protein 124 A570T Mutation Reduced level of mature protein 124 T655I Mutation Reduced level of mature protein 124 Y818F SNP Moderate reduction of protein 124 G982R Mutation Retention in ER 125 R1153C Mutation ERAD 125 R1286Q Mutation Retention in ER 125 ABCC2a R768W Mutation Impaired protein trafficking 126 I1173F Mutation Impaired protein maturation 127 R1392 Mutation Impaired protein maturation 128 M1393 Mutation Impaired protein maturation 129 ABCC4a E757K SNP Altered protein trafficking 23 ABCC7 F508 Mutation Misfolding, ERAD 36-39,130 G85E Mutation Impaired protein maturation 130-132 G91R Mutation Impaired protein maturation 130-132 N1303K Mutation Impaired protein maturation 130-132 ABCC8 WT Wild type Ubiquitin-proteasome degradation 133 A116P Mutation Ubiquitin-proteasome degradation 133 V187D Mutation Ubiquitin-proteasome degradation 133 F1388 Mutation Impaired protein trafficking 134 L1544P Mutation Impaired protein trafficking 135,136 ABCC11a G180R SNP Ubiquitin-proteasome degradation 50 27 Mutation Ubiquitin-proteasome degradation 50 ABCG2a V12M SNP Altered protein localization 96 Q141K SNP Ubiquitin-proteasome degradation 102 F208S SNP Ubiquitin-proteasome degradation 78,99 S441N SNP Ubiquitin-proteasome degradation 78,99 Mutations of ABCA1, ABCA3, ABCA4, ABCB4, ABCB11, ABCC2, ABCC7 (CFTR), and ABCC8 are associated with Tangier disease, fatal surfactant deficiency, Stargardt disease, progressive familial intrahepatic cholestasis type 3 (PFIC-3), progressive familial intrahepatic cholestasis type 2 (PFIC-2), Dubin-Johnson syndrome, cystic fibrosis, and familial hyperinsulinism, respectively. Login to comment

PMID: 21875686 [PubMed] Tietjen I et al: "Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT."

No. Sentence Comment

117 COOHA B T929I H2N R587W B A M1091T C1477R K776N N935S S1181F IVS24+1 G>C V2244I R282X D571G M640L S930F M968T R1615WIVS16-5 CA>del ABCA1 Transmembrane domain ATP-binding domain Q597R A) AA 1 AA 267 K130del L202P 74 90 98 112 122 145 167 189 211 215 233 253 APOA1 Negative charge domain Alpha-helix E222K E134DT37M 140 178 206 41127 104 121 165 200 229 360 391 Y135N V246F 127 206 369 401 Catalytic triad R322C L338H V371MV52M Y107X A117T T147I V333M Phe Leu Asp His AA 1 AA 440 R159Q I202T LCAT Alpha helixBeta sheet B) 419I.Tietjenetal./BiochimicaetBiophysicaActa1821(2012)416-424 3.4. Login to comment
169 Effects of some ABCA1 mutations described here are also consistent with previous in vitro cellular efflux studies; for example, the highly expressive ABCA1 mutations R587W, Q597R, N935S, and M1091T cause ~10-25% of wild-type efflux in vitro, while the less expressive mutations K776N and T929I cause 62 and 80% efflux, respectively [35-37]. Login to comment

PMID: 20067955 [PubMed] Vergeer M et al: "Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction."

No. Sentence Comment

46 Subjects included in the present study were heterozygous carriers of the following extremely rare ABCA1 mutations: C1477R, M1091T, and R587W (4,7-10) and L996P and Q978X (C. Candini et al., manuscript in preparation). Login to comment
48 C1477R has been reported in nine heterozygous individuals, M1091T in four individuals, and R587W in seven individuals (11). Login to comment
93 Carriers were recruited from five different families (four C1477R carriers, three M1091T carriers, three R587W carriers, four L996P carriers, and one Q978X carrier); family control subjects were siblings, cousins, or partners of a carrier. Login to comment
47 Subjects included in the present study were heterozygous carriers of the following extremely rare ABCA1 mutations: C1477R, M1091T, and R587W (4,7-10) and L996P and Q978X (C. Candini et al., manuscript in preparation). Login to comment
49 C1477R has been reported in nine heterozygous individuals, M1091T in four individuals, and R587W in seven individuals (11). Login to comment
95 Carriers were recruited from five different families (four C1477R carriers, three M1091T carriers, three R587W carriers, four L996P carriers, and one Q978X carrier); family control subjects were siblings, cousins, or partners of a carrier. Login to comment

PMID: 20656214 [PubMed] Kang MH et al: "Adenosine-triphosphate-binding cassette transporter-1 trafficking and function."

No. Sentence Comment

40 The importance of ABCA1 localization to the PM is observed in several mutations underlying TD (R587W, Q597R, ΔL693, M1091T), where mislocalization of ABCA1 away from the cell surface leads to a significant reduction in cholesterol efflux function (Singaraja et al. 2006). Login to comment
127 A number of clinically relevant mutations of ABCA1 (R587W, Q597R, ΔL693, N935H) acquire only the core and not the complex oligosaccharide chain and fail to exit the ER (Singaraja et al. 2006). Login to comment
128 A number of clinically relevant mutations of ABCA1 (R587W, Q597R, ƊL693, N935H) acquire only the core and not the complex oligosaccharide chain and fail to exit the ER (Singaraja et al. 2006). Login to comment

PMID: 19019193 [PubMed] Pisciotta L et al: "Severe HDL deficiency due to novel defects in the ABCA1 transporter."

No. Sentence Comment

16 The fourth patient, with preclinical atherosclerosis, was a compound heterozygote for two missense mutations (p.R587W/p.W1699C). Login to comment
17 ABCA1-mediated cholesterol efflux was abolished in fibroblasts from patients with p.A1046D and del p.D1567_K1591 mutants and in fibroblasts homozygous for p.R587W. Login to comment
98 p.D1567_K1591); M3 (p.I74YFsX76); M4 (p.W1699C); M5 (p.R587W); ND, not determined. Login to comment
147 The proband was found to be a compound heterozygote for the following mutations of the ABCA1 gene: (i) a C>T transition in exon 14 (c.1759 C>T, p.R587W), inherited from the mother; (ii) a G>T transversion in exon 37 (c.5097 G>T, p.W1699C), inherited from the father (Fig. S3). Login to comment
150 The sister of the proband`s mother (subject I.4) and her children (subjects II.4, II.6 and II.7) were carriers of the p.R587W mutation. Login to comment
157 The cholesterol efflux in fibroblasts of these probands was similar to that observed in fibroblasts of another patient with severe HDL deficiency (homozygous for the p.R587W mutation) we had previously identified [24] (Fig. 3). Login to comment
158 Enrichment of cholesterol in fibroblast plasma membrane We also measured the increase in cholesterol content in the fibroblast plasma membrane from the probands of families 1 and 2 and from the patient homozygous for p.R587W mutation, induced by the stimulation of ABCA1 expression with 9-cis-retinoic acid and 22-hydroxycholesterol. Login to comment
161 In the probands` fibroblasts and in the fibroblasts of the patient homozygous for the ABCA1 p.R587W mutation, the increase in membrane cholesterol varied considerably. Login to comment
162 In the p.A1046D (family 1) and homozygous p.R587W cells this increase was significant, although much lower than that of control cells, whilst in c.4773 + 1g>a mutant cells (family 2) no increase in membrane cholesterol was observed. Login to comment
168 Figure 5 also shows (lane 3) that the ABCA1 protein in fibroblasts from the previously reported patient [24] homozygous for p.R587W (the missense mutation found in the compound heterozygote of family 4) is clearly detect- Fig. 3 3 H-cholesterol efflux to Apo A-I in skin fibroblasts under basal conditions and following stimulation of ABCA1 gene expression with 22-hydroxycholesterol and 9-cis-retinoic acid (22OH / cRA). Login to comment
169 Ctrl, control cells; p.R587W, fibroblasts from a homozygous patient reported previously [24]; p.A1046D, fibroblasts from the proband of family 1; del p.D1567_K1591, fibroblasts of the proband of family 2. able, even though its content appears to be lower than that seen in control fibroblasts. Login to comment
181 Ctrl, control cells; p.R587W, fibroblasts from a homozygous patient reported previously [24]; p.A1046D, fibroblasts from the proband of family 1; del p.D1567_K1591, fibroblasts of the proband of family 2. Login to comment
215 The proband of family 4 was a compound heterozygote carrying two missense mutations (p.R587W and p.W1699C). Login to comment
216 The p.R587W mutation was first reported by Lawn et al. [33] in a compound heterozygote with HDL deficiency, in whom the second allele failed to produce detectable mRNA. Login to comment
218 Previous in vitro experiments in transfected cells expressing the p.R587W mutant (designed to define the alteration in the ABCA1 pathway) were somewhat inconsistent. Login to comment
219 Fitzgerald et al. [27] showed that the p.R587W mutant reached the cell surface just like its wild type counterpart, but showed a 50% reduction in the cross-linking efficiency to Apo A-I. Login to comment
220 Singaraja et al. [32] showed that the p.R587W mutation prevents the migration of the protein to the plasma membrane, causing a 75% decrease in ABCA1-mediated cholesterol efflux. Login to comment
221 In our patient homozygous for the p.R587W mutation [24] the ABCA1 protein content was lower than that observed in control fibroblasts (Fig. 5, lane 3), possibly suggesting an increased rate of intracellular degradation (an event expected if the mutant protein is retained, at least in part, in the endoplasmic reticulum) [32]. Login to comment

PMID: 18776170 [PubMed] Vaughan AM et al: "ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation."

No. Sentence Comment

49 the first extracellular loop (V399A, R587W, W590S, and Q597R), two were in the second extracellular loop (C1477R and I1517R), and one was in the Walker A motif of the first nucleotide binding domain (A937V, NBD1) (Fig. 1). Login to comment
96 Fitzgerald et al. (24) reported similar cell surface localizations for mutants R587W, W590S, Q597R, and C1477R. Login to comment
97 In contrast, Singaraja et al. (14) and Tanaka et al. (25) reported that ABCA1 with the R587W or Q597R mutations had impaired translocation to the plasma membrane in transfected cells. Login to comment
95 Fitzgerald et al. (24) reported similar cell surface localizations for mutants R587W, W590S, Q597R, and C1477R. Login to comment

PMID: 18782226 [PubMed] Tanaka AR et al: "Formation of cholesterol-enriched structures by aberrant intracellular accumulation of ATP-binding cassette transporter A1."

No. Sentence Comment

14 Previously, we have reported that the defect in HDL assembly in two point mutants of ABCA1 (R587W, Q597R) responsible for familial HDL deficiency is due to the impaired localization to the plasma membrane (Tanaka et al. 2003). Login to comment

PMID: 18625867 [PubMed] Theaudin M et al: "Lewis-Sumner syndrome and Tangier disease."

No. Sentence Comment

4 Results: After initially unsuccessful treatment with intravenously administered immunoglobulins, the finding of an abnormal lipid profile led to the diagnosis of Tangier disease due to the R587W mutation in the ad- enotriphosphate-binding cassette transporter-1 gene (ABCA1) (OMIM 9q22-q31). Login to comment
34 A sequencing of the 50 exons of ABCA1 led to the identification of a homozygous substitution in exon 14 (c.1759C→T), R587W, which has already been reported in a family with Tangier disease.5 Both parents of the patient were heterozygous for this mutation. Login to comment
50 The abnormallipoproteinprofileledtothediagnosisofTangier disease and identification of the R587W homozygous mutation in exon 14 of ABCA1. Login to comment
64 The R587W homozygous mutation in exon 14 of ABC1 has been reported in only 1 Italian family.5 The proband had severe premature coronary heart disease and a mild clinical phenotype of Tangier disease without neuropathy andwithanormaltriglyceridelevel.Fromthiscase,Bertolini etal5 suggestthattheR587Wmutationmightaffectthefunc- tion of ABCA1, specifically in the intima of the arterial wall, and have a much lower effect on ABCA1 function in other locations such as the peripheral nerves. Login to comment
33 A sequencing of the 50 exons of ABCA1 led to the identification of a homozygous substitution in exon 14 (c.1759C࢐T), R587W, which has already been reported in a family with Tangier disease.5 Both parents of the patient were heterozygous for this mutation. Login to comment
47 The abnormallipoproteinprofileledtothediagnosisofTangier disease and identification of the R587W homozygous mutation in exon 14 of ABCA1. Login to comment
61 The R587W homozygous mutation in exon 14 of ABC1 has been reported in only 1 Italian family.5 The proband had severe premature coronary heart disease and a mild clinical phenotype of Tangier disease without neuropathy andwithanormaltriglyceridelevel.Fromthiscase,Bertolini etal5 suggestthattheR587Wmutationmightaffectthefunc- tion of ABCA1, specifically in the intima of the arterial wall, and have a much lower effect on ABCA1 function in other locations such as the peripheral nerves. Login to comment

PMID: 17655203 [PubMed] Mukhamedova N et al: "The role of different regions of ATP-binding cassette transporter A1 in cholesterol efflux."

No. Sentence Comment

269 Natural mutations found in the Tangier pedigree, R587W, W590S, Q597R, and S1506L, as well as generated mutant C1477R strongly inhibited cholesterol and phospholipid efflux (28, 35, 36) and, with the exception of W590S, also apoA-I binding (36). Login to comment

PMID: 16873719 [PubMed] Singaraja RR et al: "Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro."

No. Sentence Comment

44 In patients defined by missense mutations on both alleles, 2 clear groups were observed: those showing negligible plasma HDL-C (R587W, N935S, N1800H), and those with HDL-C levels that were Ϸ10% of HDL-C in controls (A255T). Login to comment
46 Indeed, patients heterozygous for the mutations R587W, Q597R, ⌬L693, N935S, A1046D, C1477R, and R2081W had between 47% and 69% of HDL-C levels of controls (Table). Login to comment
48 Six mutants, R587W, Q597R, ⌬L693, N935S, N1800H, and R2081W, showed no localization at the plasma membrane and instead accumulated intracellularly (Figure 2A), indicating that these mutations severely affect ABCA1 function by preventing its migration to the plasma membrane, thus diminishing its ability to efflux lipids and generate HDL. Login to comment
54 Of the mutants not localizing to the plasma membrane, R587W, Q597R, ⌬L693, and N935H are all EndoH sensitive, indicating that they do not exit the ER. Login to comment
58 R587W, Q597R, ⌬L693, S1506L, and R2081W showed significantly reduced cell surface ABCA1 expression, confirming our previous localization data. Login to comment
68 All 6 mutants showing no plasma membrane localization elicited significantly reduced cell surface ApoA-I binding (R587W, 33.0Ϯ8.9%, nϭ3, Pϭ0.006; Q597R, 17.4Ϯ14.0%, nϭ3, Pϭ0.009; ⌬L693, 32.6Ϯ10.6%, nϭ3, Pϭ0.008; N935S, 26.4Ϯ37.5%, nϭ3, Pϭ0.01; N1800H, 36.9Ϯ15.5%, nϭ3, Pϭ0.01; R2081W, 34.6Ϯ16.6%, nϭ3, Pϭ0.02) (Figure 3A), confirming that cell surface localization of ABCA1 is essential to elicit ApoA-I binding. Login to comment
78 Wild-type ABCA1 was localized intracellularly and at the plasma membrane. R587W, Q597R, ⌬L693, N935S, N1800H, and R2081W were only localized intracellularly. Login to comment
81 Wt ABCA1 shows both EndoH resistant and sensitive bands, indicating localization at the ER and plasma membrane. R587W, Q597R, ⌬L693, and N935S show only the lower EndoH sensitive band, indicating ER retention. Login to comment
95 Near-Complete Absence of Plasma HDL-C in Homozygotes for Mutations in ABCA1 Implies the Presence of Null Alleles of ABCA1 Patients homozygous for R587W mutations showed 6.3% of normal HDL-C levels, those with N935S showed 2.62%, and those with N1800H showed 3.4% of normal plasma HDL-C levels. Login to comment
158 P2150L has only been described in patients who also have the R587W variant (M.R.H., unpublished data, 2000). Login to comment
159 In our assays R587W clearly shows biochemical defects, implying that in these patients with R587W/P2150L, the defects in ABCA1 function are more appropriately ascribed to the R587W variant. In addition, TD has been diagnosed in patients homozygous for the R587W mutation,8,27 presumably without P2150L, making it more likely that P2150L is a nonfunctional variant. Login to comment
160 D1289N has been described as a variant in patients that are homozygous for R2081W.11 Biochemical characterization of R2081W results in defects in subcellular localization and lipid efflux, suggesting that D1289N is another variant. In addition, the bioinformatics analyses by PANTHER indicated that these were putative nonfunctional residues. Login to comment

PMID: 16501936 [PubMed] Zannis VI et al: "Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL."

No. Sentence Comment

147 In vitro analysis of the effects on apoA-I/ABCA1 interactions (cross-linking assay) by mutations in ABCA1 that are found in Tangier disease patients and diminish lipid efflux [71] showed that cross-linking was dramatically reduced to 5-10% of the WT control for three mutants (Gln597Arg, Cys1477Arg, and Ser1506Leu), reduced by 50% for the Arg587Trp mutant, and was remarkably increased to 125% of control for the Trp590Ser mutant [71]. Login to comment

PMID: 16704350 [PubMed] Brunham LR et al: "Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis."

No. Sentence Comment

555 Since a complete loss of function allele would be expected to result in a 50% reduction in HDL levels, a greater than 50% reduction in HDL is most likely explained by a dominant negative allele, in which TABLE 3 Patient phenotypes associated with heterozygous ABCA1 mutations Mutation HDL (mmol/L) HDL (% of control) Number of patients M1091T 0.48 ± 0.5 30 ± 30 4 G1216V 0.50 40 1 R2144X 0.56 ± 0.2 41 ± 18 12 R282X 0.52 41 1 R909X 0.59 ± 0.3 42 ± 19 5 K776N 0.55 ± 0.1 47 ± 5 2 R587W 0.61 ± 0.1 47 ± 8 7 S364C 0.60 48 1 P1065S 0.80 51 1 c-ter deletion 0.75 53 1 N1800H - 56.5 33 P85L 0.72 ± 0.4 57 ± 33 5 Del693L 0.79 ± 0.2 57 ± 15 8 D1289N 0.80 ± 0.1 59 ± 12 4 R2081W 0.80 ± 0.1 59 ± 12 4 2203X 0.80 ± 0.2 59 ± 20 4 DelED1893,4 0.77 ± 0.2 59 ± 18 8 2145X 0.82 ± 0.1 59 ± 9 4 A1046D 0.70 ± 0.1 60 ± 8 2 Q597R 0.82 ± 0.1 60 ± 5 5 C1477R 0.82 ± 0.2 61 ± 15 9 IVS25 + 1G > C 0.78 ± 0.1 62 ± 12 4 D1099Y 0.83 ± 0.3 63 ± 21 5 1552X 1.00 64 1 F2009S 0.82 ± 0.2 64 ± 19 6 R587W 0.86 ± 0.1 65 ± 17 2 R1068H 0.90 ± 0.3 67 ± 26 9 N935S 1.00 ± 0.3 74 ± 16 7 T929I 1.01 ± 0.2 76 ± 7 8 1284X 1.11 ± 0.2 83 ± 14 5 A937V 1.15 ± 0.6 85 ± 28 2 R1680W 1.22 ± 0.2 87 ± 17 3 635X 1.24 ± 0.5 90 ± 32 7 W590S 1.32 ± 0.6 103 ± 46 15 the mutant protein actually interferes with the activity of the remaining wild-type protein. Login to comment

PMID: 16429166 [PubMed] Brunham LR et al: "Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene."

No. Sentence Comment

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 À;3.53 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 À7.52 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. Login to comment
75 Cholesterol Efflux Values for 293 Cells Transfected with ABCA1 Variants and subPSEC and PolyPhen Predictions of the Functional Impact of these Variants Variant Variant Type subPSEC Cholesterol Efflux PolyPhen R2081W Mutation À8.08 21.1 6 21%* Probably damaging N935S Mutation À7.53 29.3 6 13%* Benign A1046D Mutation À7.52 16.8 6 7%* Possibly damaging Q597R Mutation À7.15 17.7 6 14%* Probably damaging R587W Mutation À6.04 31.7 6 33%* Probably damaging C1477R Mutation À5.44 20.5 6 10%* Probably damaging W590S Mutation À5.19 47.1 6 13%* Probably damaging S1506L Mutation À5.17 17.8 6 15%* Probably damaging T929I Mutation À4.29 69.9 6 11%* Possibly damaging N1800H Mutation À4.23 31.3 6 16%* Possibly damaging S1731C SNP À4.21 12.3 6 10%* Possibly damaging M1091T Mutation À3.56 6.9 6 20%* Probably damaging P2150L Mutation À2.88 88.4 6 21% Probably damaging V771M SNP À2.86 145.4 6 33% Benign D1289N Mutation À2.48 137.7 6 86% Benign I883M SNP À1.38 69.1 6 16%* Benign R219K SNP À0.57 103.7 6 21.05 Benign Wild-type - 0.0 100% - *p , 0.01 compared to wild-type ABCA1. Login to comment

PMID: 16183915 [PubMed] Oram JF et al: "ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease."

No. Sentence Comment

412 Some studies have suggested that ABCA1 proteins with substitution mutations Q597R and R587W in the first extracellular loop do not localize to the plasma membrane (232, 263), but other studies have contradicted these findings (73, 150). Login to comment
411 Some studies have suggested that ABCA1 proteins with substitution mutations Q597R and R587W in the first extracellular loop do not localize to the plasma membrane (232, 263), but other studies have contradicted these findings (73, 150). Login to comment

PMID: 16158173 [PubMed] Takahashi K et al: "ABC proteins: key molecules for lipid homeostasis."

No. Sentence Comment

90 Many mutations in patients with TD and FHA have been identified in ECD1 of ABCA1, and three mutations (R587W, W590S, Q597R) cluster amino acids 587 to 59746,48,72 (see Fig. 2). Login to comment
91 When these three TD mutations were introduced into ECD1 of ABCA1-GFP and the mutants were transiently or stably expressed in HEK293, R587W and Q597R appeared to be distributed mainly in the ER and not the plasma membrane. Login to comment

PMID: 16116948 [PubMed] Li Y et al: "Effects of oxidized low density lipoprotein on the expression and function of ABCA1 in macrophages."

No. Sentence Comment

102 The gene examination of Tangier patients showed that the gene mutation of R587W and Q597R could result in the localized dysfunction of ABCA1, accumulation of cholesterol in macrophages, and the occurrence of AS. Login to comment

PMID: 15019541 [PubMed] Pisciotta L et al: "Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders."

No. Sentence Comment

204 The E284K and the Y482C are located in the first extracellular loop of ABCA1, where they may interfere with the binding to Apo A-I and/or the membrane release of phospholipids, as it has been demonstrated for other mutations (R587W and Q597R) located in the same extracellular domain [40,41]. Login to comment
203 The E284K and the Y482C are located in the first extracellular loop of ABCA1, where they may interfere with the binding to Apo A-I and/or the membrane release of phospholipids, as it has been demonstrated for other mutations (R587W and Q597R) located in the same extracellular domain [40,41]. Login to comment

PMID: 14592415 [PubMed] Ikeda Y et al: "Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release."

No. Sentence Comment

15 In fact, the three different mutants in ECD1 associated with TD, R587W, W590S, and Q597R, all had reduced apoA-I-mediated lipid release and subsequent HDL assembly when expressed in HEK293 [12-14]. Login to comment

PMID: 12763760 [PubMed] Singaraja RR et al: "Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene."

No. Sentence Comment

76 Additional insights into how the mutations R587W, W590S, and Q597R that occur in the extracellular loops affect ABCA1 function have recently been described.58-60 Two studies have reported that ABCA1 containing the point mutation Q597R, which occurs in the first extracellular loop, does not localize to the plasma membrane.59,60 However, other studies have reported that this mutant is expressed at the plasma membrane but at reduced levels relative to wild-type ABCA1.58,44 R587W, another missense mutation in the first extracellular loop, also prevents the trafficking of ABCA1 to the plasma membrane, although results with this mutant have been variable.58-60 Both the R587W and Q597R mutants are resistant to PNGase digestion, indicating that they are not glycosylated, suggesting that ABCA1 harboring these mutations does not traverse the medial and trans Golgi network. Login to comment
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. Login to comment
68 Additional insights into how the mutations R587W, W590S, and Q597R that occur in the extracellular loops affect ABCA1 function have recently been described.58-60 Two studies have reported that ABCA1 containing the point mutation Q597R, which occurs in the first extracellular loop, does not localize to the plasma membrane.59,60 However, other studies have reported that this mutant is expressed at the plasma membrane but at reduced levels relative to wild-type ABCA1.58,44 R587W, another missense mutation in the first extracellular loop, also prevents the trafficking of ABCA1 to the plasma membrane, although results with this mutant have been variable.58-60 Both the R587W and Q597R mutants are resistant to PNGase digestion, indicating that they are not glycosylated, suggesting that ABCA1 harboring these mutations does not traverse the medial and trans Golgi network. Login to comment
75 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. Login to comment

PMID: 12840658 [PubMed] Miller M et al: "Genetics of HDL regulation in humans."

No. Sentence Comment

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.] Login to comment

PMID: 12642355 [PubMed] Marcil M et al: "Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency."

No. Sentence Comment

85 Molecular Characterization of ABCA1 Gene in Study Subjects Cell Lines HDL-C, mmol/L Nucleotide Change Predicted Protein Alteration TD CTL-1 0.10 Exon 30 T4369C; exon 24 splice site G3C C1477R; part of the transcript deleted TD CTL-2 0.15 Exon 13 A1730G Q597R FHD-1 0.40 Exon 14 ⌬2017-9 ⌬L693 FHD-2 0.18 Exon 48 C6370T R2144X FHD-3 0.39 Exon 41 ⌬5618-23 ⌬ED1893,4 FHD-4 0.18 Exon 18 C2665T R909X FHD-5 0.10 Exon 23 T3667C M1091T FHD-6 0.57 Exon 49 C6844T P2150L, R587W TD-1 0.03 Exon 48 ⌬C6370; ND 2145X TD-2 0.07 ND ND TD-3 0.03 ND 2203X TD-4 0.09 Exon 19 C3181T; ND T929I; ND CTL indicates control. Login to comment
79 Molecular Characterization of ABCA1 Gene in Study Subjects Cell Lines HDL-C, mmol/L Nucleotide Change Predicted Protein Alteration TD CTL-1 0.10 Exon 30 T4369C; exon 24 splice site G3C C1477R; part of the transcript deleted TD CTL-2 0.15 Exon 13 A1730G Q597R FHD-1 0.40 Exon 14 èc;2017-9 èc;L693 FHD-2 0.18 Exon 48 C6370T R2144X FHD-3 0.39 Exon 41 èc;5618-23 èc;ED1893,4 FHD-4 0.18 Exon 18 C2665T R909X FHD-5 0.10 Exon 23 T3667C M1091T FHD-6 0.57 Exon 49 C6844T P2150L, R587W TD-1 0.03 Exon 48 èc;C6370; ND 2145X TD-2 0.07 ND ND TD-3 0.03 ND 2203X TD-4 0.09 Exon 19 C3181T; ND T929I; ND CTL indicates control. Login to comment

PMID: 12509412 [PubMed] Tanaka AR et al: "Effects of mutations of ABCA1 in the first extracellular domain on subcellular trafficking and ATP binding/hydrolysis."

No. Sentence Comment

1 The three different mutants in the first extracellular domain of human ABCA1 associated with Tangier disease, R587W, W590S, and Q597R, were examined for their subcellular localization and function by using ABCA1-GFP fusion protein stably expressed in HEK293 cells. Login to comment
5 R587W and Q597R were associated with impaired processing of oligosaccharide from high mannose type to complex type and failed to be localized to the PM, whereas W590S did not show such dysfunctions. Login to comment
8 These results suggest that the defect of HDL assembly in R587W and Q597R is due to the impaired localization to the PM, whereas W590S has a functional defect other than the initial ATP binding and hydrolysis. Login to comment
20 Three TD mutants (R587W, W590S, Q597R), clustered in ECD1, were examined in the present report. Login to comment
24 On the other hand, the two mutants R587W and Q597R were only partially or scarcely localized to the PM, whereas W590S * This work was supported by Grant-in-aid for Scientific Research 10217205 on Priority Areas "ABC Proteins" from the Ministry of Education, Science, Sports, and Culture of Japan and by the Nakajima Foundation. Login to comment
44 DNA Construction-DNA fragments (XhoI-BclI) containing each missense TD mutation (R587W, W590S, or Q597R) were generated using the polymerase chain reaction method with R587W (XhoI) primer (5Ј-GTCCTCGAGCTGACCCCTTTGAGGACATGTGGTACGTC-3Ј), W590S (XhoI) primer (5Ј-GTCCTCGAGCTGACCCCTTTGAGGACAT- GCGGTACGTCTCGGGGGGCTTC-3Ј), or Q597 (XhoI) primer (5Ј-GT- CCTCGAGCTGACCCCTTTGAGGACATGCGGTACGTCTGGGGGGG- CTTCGCCTACTTGCGGGATGTGGTG-3Ј), where the mutated nucleotide is underlined, and BclI primer (5Ј-CGATGCCCTTGATGATCACA- GCCACTGAG-3Ј). Login to comment
47 In brief, 10 ␮g of membrane proteins from HEK293 cells stably expressing the wild-type, R587W, W590S, or Q597R ABCA1-GFP were treated with 500 units of Endo H or 0.3 units of PNGaseF for 1 h at 37 °C. Login to comment
64 Effects of ECD1 Mutations on Subcellular Localization of ABCA1-GFP-Many mutations in patients with TD and FHA have been identified in ECD1 of ABCA1, and three mutations (R587W, W590S, Q597R) cluster in the vicinity between amino acids 587 and 597 (20)(Fig. 2A). Login to comment
68 Confocal microscopic examination revealed that R587W and Q597R appeared to be localized mainly in the ER and not to the PM (Fig. 2B). Login to comment
70 Immunostaining with the antibody against ECD1 confirmed the proper orientation of W590S (Fig. 2C). Login to comment
71 Glycosylation of ABCA1-GFP-Glycosylation of the wild-type ABCA1-GFP and its mutants R587W, W590S, and Q597R was examined by the treatment with PNGaseF and Endo H (Fig. 3A). Login to comment
74 ABCA1 with TD mutations, R587W and Q597R ABCA1-GFP, was sensitive to Endo H to produce the deglycosylated form of ABCA1-GFP, whereas the wild-type ABCA1-GFP was little digested by Endo H. Login to comment
75 These results indicated that R587W and Q597R ABCA1-GFP did not contain complex oligosaccharides and supported the confocal microscopy observation, which suggested the localization of these two TD mutants in the ER or the cis-Golgi complex. Login to comment
84 The R587W mutation resulted in the apoA-I-mediated release of cholesterol and choline-phospholipids to 24 and 23% of the wild-type ABCA1-GFP, respectively. Login to comment
102 A, a putative secondary structure of ABCA1 and localization of Tangier Disease mutations R587W, W590S, and Q597R in ECD1. Login to comment
103 B, GFP fluorescence of HEK293 cells stably expressing the wild-type (WT) ABCA1-GFP and three TD mutants R587W, W590S, and Q597R ABCA1-GFP. Login to comment
107 The wild-type (WT), R587W, W590S, and Q597R ABCA1-GFP were treated with none (-), Endo H (H), or PNGaseF (F) and separated with 7% SDS-PAGE. Login to comment
111 Cholesterol (A) and choline-phospholipid (B) content in the medium in a 6-well plate containing HEK293 cells stably expressing the wild-type (WT), R587W (RW), W590S (WS), and Q597R (QR) ABCA1-GFP were measured after a 24-h incubation in the presence (black bars) or absence (white bars) of 10 ␮g/ml apoA-I. The relative amount of cholesterol (C) and choline-phospholipid (D) in the medium in a 6-well plate containing HEK293 cells transiently expressing the wild-type (WT), R587W (RW), W590S (WS), and Q597R (QR) ABCA1-GFP was measured after a 24-h incubation in the presence of 10 ␮g/ml apoA-I. The expression levels of mutants were normalized with the GFP fluorescence of cells. Login to comment
119 ABCA1-GFP with a R587W or Q597R mutation appeared to be impaired with intracellular trafficking and predominantly localized in the ER. Login to comment
122 R587W and Q597 ABCA1-GFP contained high mannose oligosaccharides, indicating that they do not reach the trans-Golgi complex. Login to comment
125 R587W and Q597R ABCA1-GFP appeared to be retained in the ER. Login to comment
127 This region (R587 to Q597) in ECD1 would be critical for proper folding of ABCA1 and would probably affect the intracellular translocation process, whereas the W590S mutation does not. Login to comment
128 Fitzgerald et al. (17) reported that R587W or Q597R mutation did not affect the PM localization but disrupted the direct interaction with ApoA-I. This supports a major conformational alteration of ECD1 by these mutations. Login to comment
154 Interestingly, clinical manifestations of these mutations are apparently different (20): R587W is associated with coronary heart disease, whereas W590S is associated with splenomegaly. Login to comment
155 In this study, we demonstrated that the defect of HDL assembly in R587W and Q597R is due to the impaired localization of ABCA1 to the PM. Login to comment
67 Confocal microscopic examination revealed that R587W and Q597R appeared to be localized mainly in the ER and not to the PM (Fig. 2B). Login to comment
73 ABCA1 with TD mutations, R587W and Q597R ABCA1-GFP, was sensitive to Endo H to produce the deglycosylated form of ABCA1-GFP, whereas the wild-type ABCA1-GFP was little digested by Endo H. Login to comment
83 The R587W mutation resulted in the apoA-I-mediated release of cholesterol and choline-phospholipids to 24 and 23% of the wild-type ABCA1-GFP, respectively. Login to comment
101 A, a putative secondary structure of ABCA1 and localization of Tangier Disease mutations R587W, W590S, and Q597R in ECD1. Login to comment
106 The wild-type (WT), R587W, W590S, and Q597R ABCA1-GFP were treated with none (afa;), Endo H (H), or PNGaseF (F) and separated with 7% SDS-PAGE. Login to comment
110 Cholesterol (A) and choline-phospholipid (B) content in the medium in a 6-well plate containing HEK293 cells stably expressing the wild-type (WT), R587W (RW), W590S (WS), and Q597R (QR) ABCA1-GFP were measured after a 24-h incubation in the presence (black bars) or absence (white bars) of 10 òe;g/ml apoA-I. The relative amount of cholesterol (C) and choline-phospholipid (D) in the medium in a 6-well plate containing HEK293 cells transiently expressing the wild-type (WT), R587W (RW), W590S (WS), and Q597R (QR) ABCA1-GFP was measured after a 24-h incubation in the presence of 10 òe;g/ml apoA-I. The expression levels of mutants were normalized with the GFP fluorescence of cells. Login to comment
118 ABCA1-GFP with a R587W or Q597R mutation appeared to be impaired with intracellular trafficking and predominantly localized in the ER. Login to comment
121 R587W and Q597 ABCA1-GFP contained high mannose oligosaccharides, indicating that they do not reach the trans-Golgi complex. Login to comment
124 R587W and Q597R ABCA1-GFP appeared to be retained in the ER. Login to comment
153 Interestingly, clinical manifestations of these mutations are apparently different (20): R587W is associated with coronary heart disease, whereas W590S is associated with splenomegaly. Login to comment

PMID: 12576507 [PubMed] Altilia S et al: "Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2 +5G>C mutation in ABCA1 gene."

No. Sentence Comment

158 The cholesterol efflux in proband`s fibroblasts was similar to that observed in another patient with TD (homozygous for R587W in ABCA1 gene) we have previously reported (13) (Fig. 2). Login to comment
179 Skin fibroblasts from a control subject, proband I.1 of Family 1 (IVS2 ϩ5GϾC/ R282X), and another TD patient (homozygous for R587W) reported previously (13) were labeled with [3H]cholesterol and then incubated in the presence or in the absence of 22-hydroxycholesterol and 9-cis- retinoic acid (22ch/RA). Login to comment
157 The cholesterol efflux in proband`s fibroblasts was similar to that observed in another patient with TD (homozygous for R587W in ABCA1 gene) we have previously reported (13) (Fig. 2). Login to comment
178 Skin fibroblasts from a control subject, proband I.1 of Family 1 (IVS2 5GC/ R282X), and another TD patient (homozygous for R587W) reported previously (13) were labeled with [3H]cholesterol and then incubated in the presence or in the absence of 22-hydroxycholesterol and 9-cis-retinoic acid (22ch/RA). Login to comment

PMID: 12454269 [PubMed] Rigot V et al: "Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids."

No. Sentence Comment

140 Three point mutations in the region 580-600 had been reported in Tangier pedigrees (namely R587W, W590S, and Q597R). Login to comment
148 This was virtually complete in the case of W590S, Q597R, and ⌬L693, and reduced to one fourth for R587W and C1477R (Table 3). Login to comment
170 The last category is illustrated by R587W and W590S Tangier transporters, which are correctly targeted to the plasma membrane, but show a marked functional dissociation. Login to comment
171 Indeed, these variants, while eliciting an apoA-I binding indistinguishable from wild-type ABCA1 (79% Ϯ 5, n ϭ 7, P Ͼ 0.05 and 126% Ϯ 18, n ϭ 6, P Ͼ 0.05 of wild type, respectively) fail to drive both flipping of PS (annexin V binding ϭ 39% Ϯ 11of wild type for R587W, n ϭ 5, P Ͻ 0.05 and 30% Ϯ 9 for W590S, n ϭ 7, P Ͻ 0.01) and membrane release of PL (27% Ϯ 16, n ϭ 3, P Ͻ 0.05 and 16% Ϯ 3, n ϭ 2, P Ͻ 0.01 of wild type, respectively, Table 3), thus indicating that apoA-I binding per se is insufficient for the generation of PL effluxes, which also requires PS flipping. Login to comment
205 Morphological and functional evaluation of Tangier- associated ABCA1 variants Identity SL AnnV St ApoA-I St PL Efflux St % % % R587W PM 39 Ϯ 11(5) a 79 Ϯ 5 (7) a 27 Ϯ 16 (3) a W590S PM 30 Ϯ 9 (7) b 126 Ϯ 18 (6) ns 16 Ϯ 3 (2) b Q597R ER, PM 24 Ϯ 9 (4) b 15 Ϯ 8 (4) c 8 Ϯ 7 (2) b ⌬L693 ER 26 Ϯ 11 (5) a 12 Ϯ 6 (4) c nd C1477R PM 53 Ϯ 12 (9) ns 33 Ϯ 9 (6) b 12 Ϯ 2 (2) b HA819/1466 PM 54 Ϯ 12 (6) ns 49 Ϯ 7 (6) a 108 Ϯ 28 (4) b HA819/C1477R PM 57 Ϯ 15 (4) ns 68 Ϯ 6 (4) a 142 Ϯ 24 (2) b SL, subcellular localization as detected by confocal imaging and confirmed by surface biotynilation; AnnV and ApoA-I, binding of annexin V or apoA-I in cells successfully transfected with the test construct (GFP positive); St, statistical significance. Login to comment
139 We deliberately excluded mutations in the nucleotide binding folds, i.e., those expected to impair function by interference with the ATPase activity, and conversely selected the mutations located in the extracellular region defined by the topological model proposed in Fig. 4A. Three point mutations in the region 580-600 had been reported in Tangier pedigrees (namely R587W, W590S, and Q597R). Login to comment
147 This was virtually complete in the case of W590S, Q597R, and L693, and reduced to one fourth for R587W and C1477R (Table 3). Login to comment
169 The last category is illustrated by R587W and W590S Tangier transporters, which are correctly targeted to the plasma membrane, but show a marked functional dissociation. Login to comment
204 Morphological and functional evaluation of Tangier-associated ABCA1 variants Identity SL AnnV St ApoA-I St PL Efflux St % % % R587W PM 39 11(5) a 79 5 (7) a 27 16 (3) a W590S PM 30 9 (7) b 126 18 (6) ns 16 3 (2) b Q597R ER, PM 24 9 (4) b 15 8 (4) c 8 7 (2) b L693 ER 26 11 (5) a 12 6 (4) c nd C1477R PM 53 12 (9) ns 33 9 (6) b 12 2 (2) b HA819/1466 PM 54 12 (6) ns 49 7 (6) a 108 28 (4) b HA819/C1477R PM 57 15 (4) ns 68 6 (4) a 142 24 (2) b SL, subcellular localization as detected by confocal imaging and confirmed by surface biotynilation; AnnV and ApoA-I, binding of annexin V or apoA-I in cells successfully transfected with the test construct (GFP positive); St, statistical significance. Login to comment

PMID: 12084722 [PubMed] Fitzgerald ML et al: "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I."

No. Sentence Comment

39 DNA Constructs-Five missense mutants of ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) were generated using overlap polymerase chain reaction methods, as described previously (17). Login to comment
70 Missense Mutations in Two Putative Extracellular Loops of ABCA1 Ablate Efflux Activity-Five missense mutations (R587W, W590S, Q597R, C1477R, and S1506L) were introduced into a wild type ABCA1 cDNA using PCR mutagenesis techniques. Login to comment
71 Three of these mutations (R587W, W590S, and Q597R) fall in a tight cluster within the large N-terminal loop at a point near the putative second transmembrane domain shown in Fig. 3. Login to comment
116 The cells were transfected with either empty vector (mock), wild type ABCA1 (WT), or ABCA1 constructs carrying the indicated point mutations (R587W, W590S, Q597R, C1477R, and S1506L). Login to comment
119 Absolute apoA-I and medium efflux values, respectively, are as follows: mock, 1.59 Ϯ 0.04% versus 1.21 Ϯ 0.39%; WT, 3.92 Ϯ 0.13% versus 1.9 Ϯ 0.08%; R587W, 1.78 Ϯ 0.11% versus 1.61 Ϯ 0.24%; W590S, 1.92 Ϯ 0.24% versus 1.63 Ϯ 0.08%; Q597R, 1.5 Ϯ 0.14% versus 1.49 Ϯ 0.03%; C1477R, 1.67 Ϯ 0.18% versus 1.52 Ϯ 0.15%; and S1506L, 1.66 Ϯ 0.28% versus 1.6 Ϯ 0.13%. Login to comment
199 The R587W mutant showed an intermediate phenotype, with cross-linking efficiency reduced ϳ50%. Login to comment
202 DISCUSSION In this study, we have established that several naturally occurring missense mutations in ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) located in the two largest loop domains of the protein (comprising amino acids ϳ44-640 and ϳ1371-1649, respectively) are, in fact, loss-of-function mutations. Login to comment
212 Although three of the mutations (Q597R, C1477R, and S1506L) showed no appreciable cross-linking to apoA-I, the R587W mutant had an intermediate activity, and the W590S mutant retained full, if not enhanced, cross-linking to the apoprotein. Login to comment
37 DNA Constructs-Five missense mutants of ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) were generated using overlap polymerase chain reaction methods, as described previously (17). Login to comment
67 Missense Mutations in Two Putative Extracellular Loops of ABCA1 Ablate Efflux Activity-Five missense mutations (R587W, W590S, Q597R, C1477R, and S1506L) were introduced into a wild type ABCA1 cDNA using PCR mutagenesis techniques. Login to comment
68 Three of these mutations (R587W, W590S, and Q597R) fall in a tight cluster within the large N-terminal loop at a point near the putative second transmembrane domain shown in Fig. 3. Login to comment
112 The cells were transfected with either empty vector (mock), wild type ABCA1 (WT), or ABCA1 constructs carrying the indicated point mutations (R587W, W590S, Q597R, C1477R, and S1506L). Login to comment
115 Absolute apoA-I and medium efflux values, respectively, are as follows: mock, 1.59 afe; 0.04% versus 1.21 afe; 0.39%; WT, 3.92 afe; 0.13% versus 1.9 afe; 0.08%; R587W, 1.78 afe; 0.11% versus 1.61 afe; 0.24%; W590S, 1.92 afe; 0.24% versus 1.63 afe; 0.08%; Q597R, 1.5 afe; 0.14% versus 1.49 afe; 0.03%; C1477R, 1.67 afe; 0.18% versus 1.52 afe; 0.15%; and S1506L, 1.66 afe; 0.28% versus 1.6 afe; 0.13%. Login to comment
191 The R587W mutant showed an intermediate phenotype, with cross-linking efficiency reduced b03;50%. Login to comment
194 DISCUSSION In this study, we have established that several naturally occurring missense mutations in ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) located in the two largest loop domains of the protein (comprising amino acids b03;44-640 and b03;1371-1649, respectively) are, in fact, loss-of-function mutations. Login to comment
204 Although three of the mutations (Q597R, C1477R, and S1506L) showed no appreciable cross-linking to apoA-I, the R587W mutant had an intermediate activity, and the W590S mutant retained full, if not enhanced, cross-linking to the apoprotein. Login to comment

PMID: 11257260 [PubMed] Bertolini S et al: "A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier disease."

No. Sentence Comment

142 Thus the correct location of the mutation reported in our paper is in exon 14 (instead of 13) and the amino acid substitution is R587W (instead of R527W). Login to comment
141 Thus the correct location of the mutation reported in our paper is in exon 14 (instead of 13) and the amino acid substitution is R587W (instead of R527W). Login to comment

PMID: 16959783 [PubMed] Matsumura Y et al: "Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency."

No. Sentence Comment

219 For example, R587W and Q597R mutations of ABCA1, which are found in Tangier disease patients with high density lipoprotein deficiency, appear to be impaired in intracellular trafficking and localized predominantly to the ER (36). Login to comment
218 For example, R587W and Q597R mutations of ABCA1, which are found in Tangier disease patients with high density lipoprotein deficiency, appear to be impaired in intracellular trafficking and localized predominantly to the ER (36). Login to comment

PMID: 16103129 [PubMed] Wiszniewski W et al: "ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies."

No. Sentence Comment

156 Similar misfolding effects were observed for the analogous R587W mutation found in ABCA1 in patients with Tangier disease. Login to comment
157 Experiments in which COS7 cells were transfected with a mutant ABCA1 construct, R587W, demonstrated the retention of the misfolded protein in the ER (39). Login to comment

PMID: 23136402 [PubMed] Bochem AE et al: "ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden."

No. Sentence Comment

69 Subjects were carriers of the following mutations: c.6401+2T.C, p.Ser930Phe, p.Ser824Leu, p.Arg587Trp, p.Thr929Ile, p.Asn935Ser, c.3535+1G.C, p.Asp571Gly, p.Asn1800his, p.Leu1056Pro, p.Gln1038Ter, c.1195-1G.C, p.Arg579Gln, and p.Phe1760Valfs*21. Login to comment
78 Five of these mutations have already been shown to have a significant impact on ABCA1 function (p.Asn1800his,27 p.Thr929Ile,27 p.Arg587Trp,28,29 p.Leu1056Pro,21 and p.Phe1760Valfs*21.30 ). Login to comment

PMID: 23288845 [PubMed] Karunakaran D et al: "Protein kinase C controls vesicular transport and secretion of apolipoprotein E from primary human macrophages."

No. Sentence Comment

131 HMDMs were isolated from three separate Tangier disease subjects, who have documented extremely low HDL cholesterol, with homozygous and compound heterozygous mutations in the ABCA1 gene (Patient 1, homozygous for c.4121Cb0e;T (R1270X) in exon 27 (27, 62); Patients 2 and 3, c.1759Cb0e;T (p.Arg587Trp) in exon 14 and c.4957_4961del (p.Val1653CysfsX48) in exon 37 (63)). Login to comment

PMID: 23559627 [PubMed] Wang S et al: "ABCA1 mediates unfolding of apolipoprotein AI N terminus on the cell surface before lipidation and release of nascent high-density lipoprotein."

No. Sentence Comment

114 Fitzgerald et al17 examined 5 Tangier disease mutations that mapped to the 2 large extracellular domains, and reported that only the W590S mutation in the first extracellular domain was still competent to mediate apoAI cross-linking, whereas other mutations in the first (R587W and Q597R) and second (C1477R and S1506L) extracellular domains could not mediate apoAI cross-linking. Login to comment
115 Although the flag-tagged R587W and Q597R variants were reported to be expressed on the plasma membrane in transfected cells,17 2 other independent groups reported that these 2 variants have impaired processing and decreased cell surface expression5,8,18 ; but all agree that the W590S is expressed on the plasma membrane similarly to the WT isoform and can mediate apoAI binding. Login to comment

PMID: 24456889 [PubMed] Colin S et al: "HDL does not influence the polarization of human monocytes toward an alternative phenotype."

No. Sentence Comment

39 We included 6 subjects who carried heterozygous mutations in ABCA1: p.Arg587Trp, p.Val618Asp, p.Ser140Ter, p.Pro85Leu, p.Cys1941Arg/c.6402 + 2TNG, 3 subjects with a homozygous mutation in LCAT: p.Thr147Leu/p.Val333Met, p.Thr147Leu and 3 subjects with a heterozygous mutation in LCAT: p.Pro34Gln [19,20]. Login to comment

PMID: 26109739 [PubMed] Bochem AE et al: "Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins."

No. Sentence Comment

28 Homozygous and compoundheterozygoussubjectshadTangierDisease.Subjects were carriers of the following mutations: p.Leu1056Pro, c.3535+1G>C, c.6401+2T>C, p.Asn1800his, p.Ser930Phe, p.Phe1760Valfs*21, p.Ser824Leu, p.Gln1038Ter, p.Thr929Ile, p.Arg587Trp, p.Asn935Ser, and p.Arg579Gln. Login to comment