ABCMdb

ABCA1 p.Ala255Thr

Predicted by SNAP2:	C: N (87%), D: N (82%), E: N (87%), F: N (82%), G: N (93%), H: N (87%), I: N (87%), K: N (87%), L: N (87%), M: N (82%), N: N (87%), P: N (82%), Q: N (93%), R: N (82%), S: N (97%), T: N (97%), V: N (87%), W: D (66%), Y: D (59%),
Predicted by PROVEAN:	C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] A novel missense mutation of ABCA1 in transmembran... Atherosclerosis. 2009 Sep;206(1):216-22. Epub 2009 Feb 25. Maekawa M, Kikuchi J, Kotani K, Nagao K, Odgerel T, Ueda K, Kawano M, Furukawa Y, Sakurabayashi I
A novel missense mutation of ABCA1 in transmembrane alpha-helix in a Japanese patient with Tangier disease.
Atherosclerosis. 2009 Sep;206(1):216-22. Epub 2009 Feb 25., [PMID:19344898]

Abstract [show]
Tangier disease (TD) is a hereditary disorder characterized by the severe deficiency or absence of high-density lipoprotein cholesterol (HDL-C). TD is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, most of which are located in the extracellular loops and nucleotide-binding domains. Here we describe the first case of TD carrying a missense mutation in a transmembrane alpha-helix of ABCA1. A 31-year-old Japanese woman had an extremely low level of HDL-C (1mg/dl) and yellowish tonsillar swelling, leading to the diagnosis of TD. The proband was homozygous for a point mutation of T4978C in exon 37, which results in the substitution of cysteine-1660 to arginine (C1660R) in the 8th transmembrane segment of ABCA1. Her parents, grandmother, and brother were found to be heterozygous for the same mutation. Both peripheral blood leukocytes from the patient and HEK293 cells transfected with T4978C-mutated ABCA1 normally expressed ABCA1 on the plasma membrane and had normal apolipoprotein A-I-binding ability. However, apolipoprotein A-I-mediated efflux of cholesterol and phospholipids was markedly diminished in HEK293 cells transfected with T4978C-mutated ABCA1. These results suggest that this mutant is normally translated and exists as a stable product with normal localization, yet is functionally defective. Cysteine-1660 appears to be a critical residue for cholesterol transport of ABCA1.

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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

[hide] Impaired insulin secretion in four Tangier disease... J Atheroscler Thromb. 2009 Jun;16(3):292-6. Epub 2009 Jun 25. Koseki M, Matsuyama A, Nakatani K, Inagaki M, Nakaoka H, Kawase R, Yuasa-Kawase M, Tsubakio-Yamamoto K, Masuda D, Sandoval JC, Ohama T, Nakagawa-Toyama Y, Matsuura F, Nishida M, Ishigami M, Hirano K, Sakane N, Kumon Y, Suehiro T, Nakamura T, Shimomura I, Yamashita S
Impaired insulin secretion in four Tangier disease patients with ABCA1 mutations.
J Atheroscler Thromb. 2009 Jun;16(3):292-6. Epub 2009 Jun 25., [PMID:19556721]

Abstract [show]
AIM: Tangier disease (TD), caused by deficiency of ATP-binding cassette transporter A1, is characterized by the absence of high density lipoprotein and the accumulation of cholesteryl esters in many tissues. Recently, it has been reported that ABCA1 is expressed in pancreatic beta cells and mice with specific inactivation of ABCA1 in beta cells showed markedly impaired insulin secretion, suggesting that ABCA1 deficiency may be involved in diabetes. The aim of the current study was to confirm these findings by the oral glucose tolerance test (OGTT) in human subjects with ABCA1 deficiency. METHODS AND RESULTS: Four Japanese patients with TD were investigated by OGTT with 75 g glucose. In all TD patients, the plasma glucose concentration after 30 min progressively increased, indicating a type 2 diabetic pattern; however the plasma insulin concentration did not respond well to glucose increase. The calculated insulinogenic index was significantly lower in TD patients than in non-diabetic controls (0.055+/-0.034 vs 0.775+/-0.538, mean+/-SD, p<0.05, respectively). CONCLUSIONS: Although the number of TD patients was very small in the current study, these observations indicated a possible mechanism that glucose-stimulated insulin secretion might be impaired in human TD patients with ABCA1 mutations. Taken together, ABCA1 may be involved in insulin secretion from pancreatic beta-cells.

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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

[hide] Specific mutations in ABCA1 have discrete effects ... Circ Res. 2006 Aug 18;99(4):389-97. Epub 2006 Jul 27. Singaraja RR, Visscher H, James ER, Chroni A, Coutinho JM, Brunham LR, Kang MH, Zannis VI, Chimini G, Hayden MR
Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro.
Circ Res. 2006 Aug 18;99(4):389-97. Epub 2006 Jul 27., [PMID:16873719]

Abstract [show]
Mutations in ATP-binding cassette transporter A1 (ABCA1) cause Tangier disease and familial hypoalphalipoproteinemia, resulting in low to absent plasma high-density lipoprotein cholesterol levels. However, wide variations in clinical lipid phenotypes are observed in patients with mutations in ABCA1. We hypothesized that the various lipid phenotypes would be the direct result of discrete and differing effects of the mutations on ABCA1 function. To determine whether there is a correlation between the mutations and the resulting phenotypes, we generated in vitro 15 missense mutations that have been described in patients with Tangier disease and familial hypoalphalipoproteinemia. Using localization of ABCA1, its ability to induce cell surface binding of apolipoprotein A-I, and its ability to elicit efflux of cholesterol and phospholipids to apolipoprotein A-I we determined that the phenotypes of patients correlate with the severity and nature of defects in ABCA1 function.

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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

[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 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

[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. 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

[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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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

[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. 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