ABCMdb

ABCA1 p.Ala255Thr

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Publications

PMID: 19344898 [PubMed] Maekawa M et al: "A novel missense mutation of ABCA1 in transmembrane alpha-helix in a Japanese patient with Tangier disease."

No. Sentence Comment

152 The loss of lipid efflux without impaired apo A-I binding was also observed in A255T, W590S, and T929I mutations [18]. Login to comment

PMID: 19556721 [PubMed] Koseki M et al: "Impaired insulin secretion in four Tangier disease patients with ABCA1 mutations."

No. Sentence Comment

21 He was found to be homozygous for a mutation at G1158A (Ala255Thr) of the ABCA1 gene7) . Login to comment
36 Clinical characteristics of Japanese patients with Tangier disease and normal subjects Case 1 Case 2 Case 3 Case 4 Normal (n =123) ABCA1 mutations Ala255Thr Arg1851Stop Asn935His/N.D.＊ Asn935His Age (years)/Sex (M/F) BMI (kg/m2 ) Fasting plasma glucose (mg/dL) Fasting plasma insulin (μU/mL) HbA1c (%) Total cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) 54M 24.6 163 4.0 5.8 35 0＊＊ 395 71F - 180 4.0 7.9 59 6.0 162 44M 23.5 180 3.0 - 64 2.5 272 74M 22.4 176 4.26 6.1 69 3.5 42 55.3±6.9 (M94/F29) 23.4±0.8 93.8±6.9 5.1±3.0 4.7±0.3 198.3±31.1 52.2±14.1 127.0±92.1 Coronary artery disease (＋) (＋) Sudden death (＋) 3VD, CABG (-) 3VD: triple vessel disease, CABG: coronary artery bypass graft surgery Data are the means±SD. ＊ N.D.: The other mutation has not been identified so far. ＊＊ Less than sensitivity subjects. 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

43 In ABCA1 heterozygotes, 3 distinct phenotypic groups emerged, one in which HDL-C levels were Ϸ50% of those of age-and sex-matched controls, one in which HDL-C levels were at least 70% of controls (A255T, W590S, T929I), and one in which HDL-C levels were significantly below the expected 50% of the levels for controls (30.4% of controls) (M1091T) (Table). Login to 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
111 Three mutations fit this criteria, with patients harboring A255T showing 76%, W590S showing 83%, and T929I showing 76% of normal HDL-C levels. Login to comment
112 Intracellular Localization All 3 mutants A255T, W590S, and T929I, were localized by immunofluorescence to the plasma membrane and to intracellular regions in a manner indistinguishable from wild-type ABCA1 (Figure 5A). Login to comment
115 ApoA-I Binding All mutants showed normal ApoA-I binding compared with wild-type ABCA1 (A255T, 98.0Ϯ10.2%, nϭ4; W590S, 94.9Ϯ26.7%, nϭ3; T929I, 83.6Ϯ14.5, nϭ3) (Figure 5D). Login to comment
116 Cholesterol and Phosphocholine Efflux All 3 mutants displayed defects in both cholesterol (Figure 5E) and phosphocholine (Figure 5F) efflux (A255T, cholesterol 49.2Ϯ7.7%, nϭ5, Pϭ0.0001, choline 41.5Ϯ22.5%, nϭ8, Pϭ0.0002; W590S, cholesterol 47.1Ϯ13.1%, nϭ5, Pϭ0.0008, choline 44.7Ϯ21.1%, nϭ3, PϽ0.05; and T929I, Figure 4. Login to comment
126 Recent work has shown that W590S associates normally with ApoA-I. However, the ApoA-I released from wild-type ABCA1 was bound to lipids, whereas the ApoA-I released from W590S was lipid-free, indicating a defect in the lipidation of ApoA-I.24 When the ability of the ABCA1 mutants to promote ␣HDL formation was assessed (Figure 5G), wild-type ABCA1 was able to form ␣HDL of 10.4 to 12.2 nM diameter, whereas A255T and W590S formed only lipid-free ApoA-I and T929I formed lipid-free and ApoA-I of 7.1 to Ϸ9-nM diameter. Login to comment
127 Increased Plasma HDL-C Levels (>10th Percentile) in Homozygotes Confirm the Retention of Partial Activity by Mutant Alleles Data generated thus far would predict that mutant alleles that retain partial activity in patients homozygous for mutations in ABCA1 would confer higher plasma HDL-C levels than of those in whom both mutant alleles lack complete function. We had previously hypothesized and confirmed in heterozygous FHA patients that the mutant A255T allele retained partial activity. Login to comment
128 Similarly, patients with TD who were homozygous for A255T show 13.3% of age-and sex-matched control HDL-C levels. Login to comment
132 Heterozygous patients with the mutations A255T, W590S and T929I show Ͼ70% of normal HDL-C levels, and therefore are hypothesized to have mutant alleles that partially retain function. Login to comment
135 C, Cell surface biotinylation revealed normal levels of A255T, W590S, and T929I at the plasma membrane. Login to comment
161 All 3 missense mutations (A255T, W590S, and T929I) that showed residual function were localized to the plasma membrane and induced cell surface ApoA-I binding at levels similar to wild-type ABCA1. Login to comment
163 Previous studies showed that W590S, which has defective lipid efflux, cross-links efficiently to ApoA-I ,and its rate of dissociation from ApoA-I was similar to wild-type ABCA1.24 However, the ApoA-I released from wild-type ABCA1 was bound to lipids, whereas the ApoA-I released from W590S was lipid-free.24 Mutants A255T, W590S, and T929I were normal in their binding to lipid-free ApoA-I. However, A255T and W590S failed completely to lipidate ApoA-I, and T929I produced lipidated species with abnormal size. Login to comment
165 Previous studies showed that W590S, which has defective lipid efflux, cross-links efficiently to ApoA-I ,and its rate of dissociation from ApoA-I was similar to wild-type ABCA1.24 However, the ApoA-I released from wild-type ABCA1 was bound to lipids, whereas the ApoA-I released from W590S was lipid-free.24 Mutants A255T, W590S, and T929I were normal in their binding to lipid-free ApoA-I. However, A255T and W590S failed completely to lipidate ApoA-I, and T929I produced lipidated species with abnormal size. 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 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 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

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

No. Sentence 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
114 Patients homozygous for the mutations A255T and R1680W show HDL-C levels that are greater than 10% of age-and sex-matched population controls. Login to comment
122 This is indeed the case in heterozygous patients harboring mutations A255T, W590S, T929I, R1680W, and A937V, who all show HDL-C levelsϾ75% of normal age-and sex-matched controls. 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
106 Patients homozygous for the mutations A255T and R1680W show HDL-C levels that are greater than 10% of age-and sex-matched population controls. Login to comment

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

No. Sentence Comment

64 TD 1051 G/A 7 R219K extracellular [67,68] FHA 1083 C/T 7 R230C extracellular [70] FHA 1158 G/A 8 A255T extracellular [75.] Login to comment

PMID: 11785958 [PubMed] Nishida Y et al: "Expression and functional analyses of novel mutations of ATP-binding cassette transporter-1 in Japanese patients with high-density lipoprotein deficiency."

No. Sentence Comment

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. Login to comment
2 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. Login to comment
59 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. Login to comment
103 Recently, the existence of extracellular loop at the amino-terminus, where the A255T may be located, was proposed (Refs. Login to comment
109 We could not find the G1158A/A255T substitution in 48 unrelated Americans or 176 Japanese control subjects (data not shown). Login to comment
115 Fibroblasts from Case 1 (Ho/A255T) had markedly low levels of ABCA1 mRNA in the condition without the stimulation, whereas these levels became comparable after the stimulation. Login to comment
119 It was likely that no-trace amount of ABCA1 protein contributed to the FHD phenotype in Case 1 (Ho/A255T). Login to comment
124 It was noted that we obtained the comparable protein expression of A255T/ABCA1-FLAG cDNA construct, though we could observe no ABCA1 protein in the fibroblasts from Case 1 (Ho/A255T). Login to comment
129 We could detect a significant amount of cholesterol efflux from cells expressing A255T/ABCA1-FLAG. Login to comment
135 In Case 1, we found a novel substitution (G1158A/ A255T). Login to comment
137 Because the recent clinical mutational analyses in patients with TD appeared to show that many potential loss-of-function mutations are located around this lesion (8-11), we had initially speculated that this predicted mutant ABCA1 protein (A255T) could have any dysfunction of this loop. Login to comment
141 The ABCA1 cDNA construct carrying the G1158A/A255T substitution appeared to be functionally normal in the overexpressing cells (Figs. 5A and 5B). Login to comment
58 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. Login to comment
102 Recently, the existence of extracellular loop at the amino-terminus, where the A255T may be located, was proposed (Refs. Login to comment
107 We could not find the G1158A/A255T substitution in 48 unrelated Americans or 176 Japanese control subjects (data not shown). Login to comment
113 Fibroblasts from Case 1 (Ho/A255T) had markedly low levels of ABCA1 mRNA in the condition without the stimulation, whereas these levels became comparable after the stimulation. Login to comment
117 It was likely that no-trace amount of ABCA1 protein contributed to the FHD phenotype in Case 1 (Ho/A255T). Login to comment
122 It was noted that we obtained the comparable protein expression of A255T/ABCA1-FLAG cDNA construct, though we could observe no ABCA1 protein in the fibroblasts from Case 1 (Ho/A255T). Login to comment
127 We could detect a significant amount of cholesterol efflux from cells expressing A255T/ABCA1-FLAG. Login to comment
133 In Case 1, we found a novel substitution (G1158A/ A255T). Login to comment
139 The ABCA1 cDNA construct carrying the G1158A/A255T substitution appeared to be functionally normal in the overexpressing cells (Figs. 5A and 5B). Login to comment