ABCMdb

ABCA1 p.Asp1289Asn

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Publications

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

No. Sentence Comment

135 Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 45TCM Vol. 20, No. 2, Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment
136 Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. 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

49 In contrast, C1477R, D1289N, and P2150L showed similar distribution to wild-type ABCA1, indicating that these mutants cause defects despite their normal localization at the plasma membrane. Login to comment
55 R2081W, along with the mutants localizing to the plasma membrane by fluorescence, D1289N, C1477R, and P2150L, showed both EndoH resistant and sensitive bands, indicating that they are distributed at the ER and at the Golgi, thus confirming the GFP localization data. Login to comment
59 By contrast, D1289N, C1477R, and P2150L were at the plasma membrane in similar quantities as wild-type ABCA1(Figure 2C), also confirming our previous localization data. Login to comment
69 Of the 3 mutants that showed normal plasma membrane localization, D1289N and P2150L showed ApoA-I binding similar to wild-type (D1289N, 100.5Ϯ26.3%, nϭ3; P2150L, 80.0Ϯ10.8%, nϭ2). Login to comment
84 D1289N, C1477R, and P2150L showed normal ABCA1 localization at the membrane. Login to comment
89 However, D1289N and P2150L showed normal cholesterol efflux and close to normal phosphocholine efflux. Login to comment
156 Both P2150L and D1289N are functionally undistinguishable from wild-type ABCA1. 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
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

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

45 À3), R219K, V771M, I883M, D1289N, and P2150L, four had cholesterol efflux values that were not statistically different from wild-type ABCA1. Login to comment
46 This included two variants, D1289N and P2150L, that have been previously reported to be disease-causing mutations [4,8,9], as well as two cSNPs, R219K and V771M. Login to 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
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
106 Both the D1289N and P2150L mutations are reported as pathogenic and causative of disease in the TD patients in which they were identified [4,8,9]. Login to comment
114 The TD patient described with the D1289N variant was also homozygous for a second mutation, R2081W [9], and our results strongly suggest that it is this second mutation, and not D1289N, that causes the phenotype observed in that patient. Login to comment
119 Our efflux data showing that the D1289N and P2150L mutations are functionally neutral confirm the prediction that the conservation of these residues among ABCA1 proteins is not due to functional constraint, but rather reflects their recent common ancestry. 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