ABCMdb

ABCA1 p.Asn935His

ClinVar:	c.2804A>G , p.Asn935Ser D , Pathogenic c.2803A>C , p.Asn935His D , Pathogenic
Predicted by SNAP2:	A: D (75%), C: D (80%), D: D (85%), E: D (91%), F: D (91%), G: D (85%), H: D (75%), I: D (85%), K: D (85%), L: D (91%), M: D (85%), P: D (85%), Q: D (80%), R: D (91%), S: D (75%), T: D (75%), V: D (85%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Adenosine-triphosphate-binding cassette transporte... Trends Cardiovasc Med. 2010 Feb;20(2):41-9. Kang MH, Singaraja R, Hayden MR
Adenosine-triphosphate-binding cassette transporter-1 trafficking and function.
Trends Cardiovasc Med. 2010 Feb;20(2):41-9., [PMID:20656214]

Abstract [show]
Mutations in the adenosine-triphosphate-binding cassette transporter-1 (ABCA1) lead to Tangier disease, a genetic disorder characterized by an almost complete absence of plasma high-density lipoprotein cholesterol. Although the importance of ABCA1 localization to its cholesterol efflux function has been extensively characterized, the cellular itinerary of ABCA1 leading to the plasma membrane is not fully elucidated. This review will summarize the current knowledge of ABCA1 trafficking and its relationship to function. Understanding these crucial processes provides potential novel therapeutic targets to regulate high-density lipoprotein biogenesis through influencing pathways of ABCA1 trafficking.

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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

[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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29 This patient was heterozygous for an Asn935His mutation; however, the other mutation in the ABCA1 gene has not been identified yet. Case 4 was diagnosed with homozygous TD in 2002. Login to comment
33 This patient was homozygous for a mutation at A3198C (Asn935His)9) . 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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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

[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] Double deletions and missense mutations in the fir... J Hum Genet. 2002;47(6):325-9. Guo Z, Inazu A, Yu W, Suzumura T, Okamoto M, Nohara A, Higashikata T, Sano R, Wakasugi K, Hayakawa T, Yoshida K, Suehiro T, Schmitz G, Mabuchi H
Double deletions and missense mutations in the first nucleotide-binding fold of the ATP-binding cassette transporter A1 ( ABCA1) gene in Japanese patients with Tangier disease.
J Hum Genet. 2002;47(6):325-9., [PMID:12111381]

Abstract [show]
Tangier disease (TD) is a rare autosomal recessive disease characterized by plasma high-density lipoprotein deficiency caused by an ATP-binding cassette transporter A1 ( ABCA1) gene mutation. We describe three different mutations in Japanese patients with TD. The first patient was homozygous for double deletions of 1221 bp between intron 12 and 14 and 19.9 kb between intron 16 and 31. The breakpoint sequence analyses suggest that it is a simultaneous event caused by double-loop formation through multiple Alu. The second patient was homozygous for a novel mutation of A3198C in exon 19, resulting in Asn935His. The third patient was homozygous for A3199G of exon 19 that leads to Asn935Ser, which is the same mutation found in German and Spanish families. Both Asn mutations involved Walker A motif of the first nucleotide-binding fold.

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No. Sentence Comment
4 The second patient was homozygous for a novel mutation of A3198C in exon 19, resulting in Asn935His. Login to comment
52 The A3198C mutation in exon 19 found in case 2 had resulted in a change of Asn935His. Login to comment
64 Case 2, homozygous for the AϾC mutation at 3198 (Asn935His), as shown in the left panel, was detected by PCR-RFLP using NlaIII digestion in the right panel. Login to comment
76 The second patient had a novel mutation of Asn935His. Login to comment