ABCMdb

ABCA1 p.Asp1099Tyr

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Publications

PMID: 20188211 [PubMed] Koldamova R et al: "The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration."

No. Sentence Comment

95 The second example is a compound heterozygous mutation (D1099Y and F2009S) identified in a subject with severe HDL cholesterol deficiency [16]. Login to comment

PMID: 17113061 [PubMed] Miller M et al: "Do mutations causing low HDL-C promote increased carotid intima-media thickness?"

No. Sentence Comment

11 Materials and methods We previously identified mutations in LCAT [T321M, C-deletion (codon 168) P260X [7,8], ABCA1 [D1099Y, F2009S, P85L, R1851Q, IVS46: del T-39…-46] [9-11] and APOA1 [L159P] [12]. Login to comment
46 Therefore, while we Table 1 Genetic variants causing low HDL-C Gene Mutation Number Affected Reference LCAT c-deletion (codon 168) 2 [7] T321M 5 [7] P260X 3 [8] I178T 6 [13] ABCA1 D1099Y 5 [9] F2009S 1 [9] P85L 4 [10] R1851Q 6 [11] IVS46: del T-39…-46 6 [11] APOAI L159P 6 [12] Total 41 cases (includes 3 compound heterozygotes) Table 2 Selected demographic factors, risk factor prevalence, medication use and biochemical measurements (mean and SD) and cIMT in genetic variant HDL-C cases and controls Cases (n=41) Controls (n=73) Age (y) 44.8 (20.7) 44.8 (19.1) BMI (kg/m2 ) 28.0 (4.3) 26.4 (4.9) Hypertension (%) 10.8% 15.9% Diabetes mellitus (%) 2.7% 0% Smoking history (%) 24.3% 31.7% Antiplatelet therapy (%) 18.9% 9.7% Lipid lowering therapy (%) 21.6% 12.9% cIMT (mm) 0.66 (0.17) 0.65 (0.18) TC (mmol/l) 4.92 (1.52) 5.03 (1.06) TG (mmol/l) 2.10 (1.72) ⁎ 1.36 (0.90) HDL-C (mmol/l) 0.67 (0.36) ⁎ 1.58 (0.75) LDL-C (mmol/l) 3.28 (1.31) 2.85 (0.91) APOAI (mg/dl) 96.7 (37.9) ⁎ 151.4 (34.9) APOB (mg/dl) 123.6 (44.8) ⁎ 89.9 (26.6) ⁎ Pb0.05 cases vs. controls. 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 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
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: 12009425 [PubMed] Ho Hong S et al: "Novel ABCA1 compound variant associated with HDL cholesterol deficiency."

No. Sentence Comment

3 One mutation was a G3295T substitution with conversion of asparagine to tyrosine (D1099Y) in ABCA1. Login to comment
43 Pedigree of the kindred showing HDL segregation of D1099Y and F2009S mutations. Login to comment
44 Horizontal line symbols indicates heterozygote carrier status for the D1099Y mutation. Login to comment
45 The heterozygous subjects for F2009S mutation are indicated by vertical line symbols. Login to comment
68 Results and discussion The first mutation was heterozygous for a G3295T substitution that changes asparagine to tyrosine (D1099Y). Login to comment
73 The proband had a compound mutation for D1099Y and F2009S (Fig. 1, arrow). Login to comment
76 Significant differences between (+) and ( À ) subjects of D1099Y mutation were noted for HDL cholesterol [(+), 27.3 F 14.6 vs. ( À ), 47.0 F 12.9 mg/dl; P < 0.001] and apoA-I [(+), 83.0 F 40.8 vs. ( À ), 125.4 F 23.7 mg/dl; P < 0.001] levels. Login to comment
77 The F2009S mutation was also associated with low HDL cholesterol [(+), 17.0 F 18.4 vs. ( À ), 40.6 F 13.9 mg/dl; P < 0.05] and apoA-I [(+), 54.0 F 65.1 vs. ( À ) 114.0 F 28.4 mg/dl; P < 0.05] levels. Login to comment
79 The amino acids at the D1099Y and F2009S mutation sites are conserved between human and mouse, indicating a potentially important biological function. Login to comment
80 The D1099Y Table 2 Positions of ABCA1 exons and sequences of oligonucleotide primers Exon Sequence Annealing Tm (jC) 5 5V-CACTTGGCAGTCACTTCTGT-3V 56 5V-ACGGATGCAGAGAAGGTT-3V 6 5V-TCCTGATATGGCGATGCTCC-3V 56 5V-TGAGGAAGCTGGAGGCATCA-3V 9 5V-CGCCAGCTGTTCAGCATGAG-3V 55 5V-CATCTTCCTCAGTGCCATTG-3V 12 5V-GGATGGCTTAGATTGGACAG-3V 55 5V-CATGAAGCGAGATATGGTCC-3V 17 5V-CAGAGCCTGCTGTCTCCTGT-3V 55 5V-AGACAGCCTCAATGTACCAG-3V 21 5V-CAGGCTGACTGTCGAAGA-3V 55 5V-CCTGACAGCTGGCTTGTT-3V 23 5V-GGCCGCACCATTATTCTCTCT-3V 55 5V-CAGCTCACCTTTTTCAGGTA-3V 25 5V-TGTCTCTGCTATCTCCAACC-3V 55 5V-GTCGTCTCTGAGATGCCATA-3V 27 5V-TCCTTGTGCCTTCAGATGGT-3V 55 5V-GGATCAGCAGCATCATCTTC-3V 28 5V-TGGCTTCTTGCAGAATCC-3V 54 5V-GACTCCGTCTGGCAATTA-3V 29 5V-AGATTGTCTTGCCAGCTGTG-3V 55 5V-CTGTTCGTTGTACATCCAGG-3V 36 5V-CTGGCATGCAATCAGCTCTT-3V 55 5V-ACCTCTGAGAGCTGCTGCTT-3V 37 5V-TTCTCTCCAGGATGACCACA-3V 55 5V-AGAGAGCCAGTAGATGACAG-3V 39 5V-TTGTGTCTCAACAGGTGGTC-3V 55 5V-ACATTGTCGGTGAACAGCTC-3V Exons of the ABCA1 gene are designated by the nomenclature of Santamarina-Fojo et al. [17]. Login to comment
89 While five additional members of this kindred are heterozygous for the D1099Y allele, they are relatively or considerably younger and have not yet manifested CVD. Login to comment
90 One carrier member for F2009Y heterozygous mutation also had no cardiovascular symptom and is younger. Login to comment
69 Results and discussion The first mutation was heterozygous for a G3295T substitution that changes asparagine to tyrosine (D1099Y). Login to comment
74 The proband had a compound mutation for D1099Y and F2009S (Fig. 1, arrow). Login to comment
81 The D1099Y Table 2 Positions of ABCA1 exons and sequences of oligonucleotide primers Exon Sequence Annealing Tm (jC) 5 5V-CACTTGGCAGTCACTTCTGT-3V 56 5V-ACGGATGCAGAGAAGGTT-3V 6 5V-TCCTGATATGGCGATGCTCC-3V 56 5V-TGAGGAAGCTGGAGGCATCA-3V 9 5V-CGCCAGCTGTTCAGCATGAG-3V 55 5V-CATCTTCCTCAGTGCCATTG-3V 12 5V-GGATGGCTTAGATTGGACAG-3V 55 5V-CATGAAGCGAGATATGGTCC-3V 17 5V-CAGAGCCTGCTGTCTCCTGT-3V 55 5V-AGACAGCCTCAATGTACCAG-3V 21 5V-CAGGCTGACTGTCGAAGA-3V 55 5V-CCTGACAGCTGGCTTGTT-3V 23 5V-GGCCGCACCATTATTCTCTCT-3V 55 5V-CAGCTCACCTTTTTCAGGTA-3V 25 5V-TGTCTCTGCTATCTCCAACC-3V 55 5V-GTCGTCTCTGAGATGCCATA-3V 27 5V-TCCTTGTGCCTTCAGATGGT-3V 55 5V-GGATCAGCAGCATCATCTTC-3V 28 5V-TGGCTTCTTGCAGAATCC-3V 54 5V-GACTCCGTCTGGCAATTA-3V 29 5V-AGATTGTCTTGCCAGCTGTG-3V 55 5V-CTGTTCGTTGTACATCCAGG-3V 36 5V-CTGGCATGCAATCAGCTCTT-3V 55 5V-ACCTCTGAGAGCTGCTGCTT-3V 37 5V-TTCTCTCCAGGATGACCACA-3V 55 5V-AGAGAGCCAGTAGATGACAG-3V 39 5V-TTGTGTCTCAACAGGTGGTC-3V 55 5V-ACATTGTCGGTGAACAGCTC-3V Exons of the ABCA1 gene are designated by the nomenclature of Santamarina-Fojo et al. [17]. Login to comment

PMID: 20799350 [PubMed] Kelly L et al: "Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains."

No. Sentence Comment

50 Disease-associated nsSNPs at Three Structural Hotspots in Human ABC Transporter NBDs Gene Disease Position ARA motif ABCB11 BRIC2 A570T ABCD1 X-ALD A616V CFTR CF A559T ABCC6 PXE R765Q ABCC8 HHF1 R841G ABCC8 HHF1 R1493Q ABCC8 HHF1 R1493W ABCD1 X-ALD R617C ABCD1 X-ALD R617G ABCD1 X-ALD R617H CFTR CF R560K CFTR CF R560S CFTR CF R560T ABCA1 HDLD1 A1046D ABCB4 ICP A546D C-loop 1 motif ABCC8 HHF1 D1471H ABCC8 HHF1 D1471N CFTR CBAVD G544V ABCC8 HHF1 G1478R C-loop2 motif ABCA4 STGD1 H2128R ABCC8 HHF1 K889T ABCD1 X-ALD R660P ABCD1 X-ALD R660W ABCA1 HDLD2 M1091T ABCA4 STGD1 E2131K ABCA12 LI2 E1539K ABCA4 STGD1 and CORD3 E1122K CFTR CF L610S ABCC8 HHF1 L1543P ABCA1 Colorectal cancer sample; somatic mutation A2109T ABCC9 CMD1O A1513T ABCD1 X-ALD H667D CFTR CF A613T ABCA1 HDLD2 D1099Y ABCD1 X-ALD T668I CFTR CF D614G ABCA4 STGD1 R2139W ABCA4 STGD1 R1129C ABCA4 ARMD2, STGD1, and FFM R1129L Disease abbreviations are as follows: BRIC2, benign recurrent intrahepatic cholestasis type 2; X-ALD, X-linked adrenoleukodystrophy; CF, cystic fibrosis; PXE, Pseudoxanthoma elasticum; HHF1, familial hyperinsulinemic hypoglycemia-1; HDLD1, high density lipoprotein deficiency type 1; ICP, intrahepatic cholestasis of pregnancy; CBAVD, congenital bilateral absence of the vas deferens; STGD1, Stargardt disease type 1; HDLD2, high density lipoprotein deficiency type 2; LI2, ichthyosis lamellar type 2; CORD3, cone-rod dystrophy type 3; CMD1O, cardiomyopathy dilated type 1O; ARMD2, age-related macular degeneration type 2; FFM, fundus flavimaculatus. Login to comment

PMID: 22959828 [PubMed] Fasano T et al: "Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency."

No. Sentence Comment

169 Results 3.1. Patient # Mo-1 3.1.1. Analysis of ABCA1 gene The resequencing of the ABCA1 gene showed that this patient was heterozygous for a previously reported mutation (c.3295G>T, p.D1099Y) [19] (Table 1), predicted to be pathogenic by in silico analysis (Table 2). Login to comment
176 PolyPhen (PSIC score) SIFT (P score) p.R130K Possibly damaging (1.540) Predicted tolerated p.R1068C Probably damaging (3.143) Predicted not tolerated (0.00) p.D1099Y Probably damaging (3.047) Predicted not tolerated (0.00) p.H1600R Probably damaging (3.197) Predicted not tolerated (0.02) p.N1800H Possibly damaging (1.845) Predicted tolerated termination codon (p.R587Afs*43) and ii) a single nucleotide substitution (c.4799A>G) in exon 36, resulting in a novel missense mutation (p.H1600R) (Table 1). Login to comment
235 The alternative hypothesis is that the missense mutation (p.D1099Y) found in this patient has a dominant negative effect. Login to comment

PMID: 24844148 [PubMed] Koldamova R et al: "ATP-binding cassette transporter A1: from metabolism to neurodegeneration."

No. Sentence Comment

1001 The second example is a compound heterozygous mutation (D1099Y and F2009S) identified in a subject with severe HDL cholesterol deficiency (Ho Hong et al., 2002). Login to comment

PMID: 26616730 [PubMed] Murano T et al: "Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation."

No. Sentence Comment

125 Remarkably, Asp1099Tyr also disturbs the ABCA1-mediated cholesterol efflux in skin fibroblasts and causes phenotypes of hypo-alphalipoproteinemia, Tangier disease and FHA, in the patients [23,27]. Login to comment