ABCA1 p.Arg1851Gln
| Predicted by SNAP2: | A: D (66%), C: D (59%), D: D (80%), E: D (63%), F: D (71%), G: D (71%), H: N (53%), I: D (71%), K: N (97%), L: D (71%), M: D (63%), N: D (63%), P: D (80%), Q: D (63%), S: D (66%), T: D (59%), V: D (71%), W: D (63%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Do mutations causing low HDL-C promote increased c... Clin Chim Acta. 2007 Feb;377(1-2):273-5. Epub 2006 Oct 7. Miller M, Rhyne J, Hong SH, Friel G, Dolinar C, Riley W
Do mutations causing low HDL-C promote increased carotid intima-media thickness?
Clin Chim Acta. 2007 Feb;377(1-2):273-5. Epub 2006 Oct 7., [PMID:17113061]
Abstract [show]
BACKGROUND: Although observational data support an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD), genetic HDL deficiency states often do not correlate with premature CHD. METHODS: Carotid intima-media thickness (cIMT) measurements were obtained in cases comprising 10 different mutations in LCAT, ABCA1 and APOA1 to further evaluate the relationship between low HDL resulting from genetic variation and early atherosclerosis. RESULTS: In a 1:2 case-control study of sex and age-related (+/-5 y) subjects (n=114), cIMT was nearly identical between cases (0.66+/-0.17 cm) and controls (0.65+/-0.18 cm) despite significantly lower HDL cholesterol (0.67 vs. 1.58 mmol/l) and apolipoprotein A-I levels (96.7 vs. 151.4 mg/dl) (P<0.05) CONCLUSIONS: Genetic variants identified in the present study may be insufficient to promote early carotid atherosclerosis.
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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].
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ABCA1 p.Arg1851Gln 17113061:11:138
status: NEW29 All mutations were heterozygous and 3 subjects were genetic compounds (e.g., IVS46: del T-39…-46/R1851Q and 238X/T321M).
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ABCA1 p.Arg1851Gln 17113061:29:103
status: NEW46 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.
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ABCA1 p.Arg1851Gln 17113061:46:218
status: NEW47 Table 3 Gene mutations, cIMT, onset of CHD and risk factors in 7 caseswith low HDL-C Gene Mutation cIMT Age onset (y) CHD risk factors ABCA1P85L 0.64 48 Smoker, HTN, HTG ABCA1 IVS46: del T-39…-46/ 0.59 44 FCHL R1851Q APOAI L159P 0.71 41 Smoker, FCHL APOAI L159P 0.82 35 FCHL LCAT c-deletion (codon 168) 1.37 76 Smoker, HTN, HTG LCAT P260X 0.59 57 Smoker, FCHL LCAT I178T 0.69 39 FCHL Mean 0.77±0.28 60.9±18.9 Abbreviations: FCHL, familial combined hyperlipidemia; HTN, hypertension; HTG, hypertriglyceridemia.
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ABCA1 p.Arg1851Gln 17113061:47:216
status: NEW[hide] Novel polypyrimidine variation (IVS46: del T -39..... Circ Res. 2003 Nov 14;93(10):1006-12. Epub 2003 Oct 23. Hong SH, Rhyne J, Miller M
Novel polypyrimidine variation (IVS46: del T -39...-46) in ABCA1 causes exon skipping and contributes to HDL cholesterol deficiency in a family with premature coronary disease.
Circ Res. 2003 Nov 14;93(10):1006-12. Epub 2003 Oct 23., [PMID:14576201]
Abstract [show]
Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.
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No. Sentence Comment
9 The first mutation was a G5947A substitution (R1851Q).
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ABCA1 p.Arg1851Gln 14576201:9:46
status: NEW15 Compound heterozygotes (nϭ4) exhibited the lowest HDL-C (11Ϯ5 mg/dL) and ApoA-I (35Ϯ15 mg/dL) compared with wild-type (nϭ25) (HDL-C 51Ϯ14 mg/dL; ApoA-I 133Ϯ21 mg/dL) (PϽ0.0005) or subjects affected with either R1851Q (nϭ6) (HDL-C 36Ϯ8; ApoA-I 117Ϯ19) or IVS46: del T -39. .
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ABCA1 p.Arg1851Gln 14576201:15:252
status: NEW60 Results The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2).
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ABCA1 p.Arg1851Gln 14576201:60:104
status: NEW70 Compound heterozygotes (nϭ4) exhibited the lowest HDL-C (11Ϯ5 mg/dL) and ApoA-I (35Ϯ15 mg/dL) compared with wild-type (nϭ25) (HDL-C 51Ϯ14 mg/dL; ApoA-I 133Ϯ21 mg/ dL) (PϽ0.0005) or subjects affected with either R1851Q (nϭ6) (HDL-C 36Ϯ8; ApoA-I 117Ϯ19) or IVS46: del T -39. .
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ABCA1 p.Arg1851Gln 14576201:70:253
status: NEW100 between premature CHD and either increased carotid intimal-medial thickness or reduced ABCA1-mediated cholesterol efflux.25-27 The premature CHD identified in the proband extends previous observational data in normolipidemic indi- viduals1-3 and may not only reflect alterations in RCT but other recently identified antiatherogenic effects potentially subserved by HDL including reduced ischemic-reperfusion injury28 and improved vascular function.29 To date, only a small proportion of ABCA1 variants have been characterized in pivotal regions (eg, extracellular loop, transmembrane domain, nucleotide binding folds, C-terminus) that when altered, result in marked reduction in ABCA1 activity and/or function.6,7 The G5947A/ R1851Q mutation occurs within the extracellular loop proximal to the final transmembrane spanner and bears regional similarity to the C5946T/R1851X variant recently reported in a compound heterozygote with TD.30 Variants located within the extracellular loop (between amino acids 1370 to 1650) have been shown to adversely affect the interaction of ABCA1 and ApoA-I resulting in reduced cholesterol efflux.31 Whether distal variants (eg, N1800H, R1851G) exhibit similar interactions with ApoA-I has not been studied, but the marked reductions in HDL-C that have been observed in affected subjects suggest that binding may be similarly disrupted.
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ABCA1 p.Arg1851Gln 14576201:100:726
status: NEW103 Although the functional implications of previously identified ABCA1 variants affecting the C-terminus have not been studied, disruption of this segment as previously identified in other ABC transporters, most notably CFTR, leads to reduced stability of the translated protein.32 Not surprisingly, the 4 subjects who were compound heterozygotes (CH) (R1851Q/IVS46: del T -39. .
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ABCA1 p.Arg1851Gln 14576201:103:350
status: NEW117 Levels of Plasma Lipids, Lipoproteins, and Apolipoproteins in Subjects With or Without R1851Q and IVS46: del T -39⅐ ⅐ ⅐-46 Sex Age TC TG HDL-C LDL-C ApoA-I ApoB Mutation M F Wild-type (nϭ25) 11 14 42Ϯ20 195Ϯ43 125Ϯ75 51Ϯ14 119Ϯ39 133Ϯ21 99Ϯ34 R1581Q (nϭ6) 2 4 39Ϯ23 213Ϯ94 165Ϯ56 36Ϯ7.5* 145Ϯ91 117Ϯ19 92Ϯ15 del T -39⅐ ⅐ ⅐-46 (nϭ5) 4 1 62Ϯ27 209Ϯ41 219Ϯ140* 31Ϯ9.0† 134Ϯ38 115Ϯ28 130Ϯ18¶ CH (nϭ4) 3 1 48Ϯ7 145Ϯ23*§ 151Ϯ69 11Ϯ4.9‡§ʈ 104Ϯ18 35Ϯ15.3‡§ʈ 116Ϯ24 TC indicates total cholesterol; TG, triglycerides; and CH, compound heterozygotes.
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ABCA1 p.Arg1851Gln 14576201:117:87
status: NEW4 The first mutation was a G5947A substitution (R1851Q).
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ABCA1 p.Arg1851Gln 14576201:4:46
status: NEW10 Compound heterozygotes (nafd;4) exhibited the lowest HDL-C (11afe;5 mg/dL) and ApoA-I (35afe;15 mg/dL) compared with wild-type (nafd;25) (HDL-C 51afe;14 mg/dL; ApoA-I 133afe;21 mg/dL) (Pb0d;0.0005) or subjects affected with either R1851Q (nafd;6) (HDL-C 36afe;8; ApoA-I 117afe;19) or IVS46: del T afa;39. .
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ABCA1 p.Arg1851Gln 14576201:10:252
status: NEW55 Results The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2).
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ABCA1 p.Arg1851Gln 14576201:55:104
status: NEW65 Compound heterozygotes (nafd;4) exhibited the lowest HDL-C (11afe;5 mg/dL) and ApoA-I (35afe;15 mg/dL) compared with wild-type (nafd;25) (HDL-C 51afe;14 mg/dL; ApoA-I 133afe;21 mg/ dL) (Pb0d;0.0005) or subjects affected with either R1851Q (nafd;6) (HDL-C 36afe;8; ApoA-I 117afe;19) or IVS46: del T afa;39. .
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ABCA1 p.Arg1851Gln 14576201:65:253
status: NEW95 Ho Hong et al Exon Skipping in ABCA1 and HDL-C Deficiency between premature CHD and either increased carotid intimal-medial thickness or reduced ABCA1-mediated cholesterol efflux.25-27 The premature CHD identified in the proband extends previous observational data in normolipidemic indi- viduals1-3 and may not only reflect alterations in RCT but other recently identified antiatherogenic effects potentially subserved by HDL including reduced ischemic-reperfusion injury28 and improved vascular function.29 To date, only a small proportion of ABCA1 variants have been characterized in pivotal regions (eg, extracellular loop, transmembrane domain, nucleotide binding folds, C-terminus) that when altered, result in marked reduction in ABCA1 activity and/or function.6,7 The G5947A/ R1851Q mutation occurs within the extracellular loop proximal to the final transmembrane spanner and bears regional similarity to the C5946T/R1851X variant recently reported in a compound heterozygote with TD.30 Variants located within the extracellular loop (between amino acids 1370 to 1650) have been shown to adversely affect the interaction of ABCA1 and ApoA-I resulting in reduced cholesterol efflux.31 Whether distal variants (eg, N1800H, R1851G) exhibit similar interactions with ApoA-I has not been studied, but the marked reductions in HDL-C that have been observed in affected subjects suggest that binding may be similarly disrupted.
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ABCA1 p.Arg1851Gln 14576201:95:786
status: NEW98 Although the functional implications of previously identified ABCA1 variants affecting the C-terminus have not been studied, disruption of this segment as previously identified in other ABC transporters, most notably CFTR, leads to reduced stability of the translated protein.32 Not surprisingly, the 4 subjects who were compound heterozygotes (CH) (R1851Q/IVS46: del T afa;39. .
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ABCA1 p.Arg1851Gln 14576201:98:350
status: NEW112 Levels of Plasma Lipids, Lipoproteins, and Apolipoproteins in Subjects With or Without R1851Q and IVS46: del T d1a;39ዼ ዼ ዼd1a;46 Sex Age TC TG HDL-C LDL-C ApoA-I ApoB Mutation M F Wild-type (nafd;25) 11 14 42afe;20 195afe;43 125afe;75 51afe;14 119afe;39 133afe;21 99afe;34 R1581Q (nafd;6) 2 4 39afe;23 213afe;94 165afe;56 36afe;7.5* 145afe;91 117afe;19 92afe;15 del T afa;39ዼ ዼ ዼafa;46 (nafd;5) 4 1 62afe;27 209afe;41 219afe;140* 31afe;9.0ߤ 134afe;38 115afe;28 130afe;18&#b6; CH (nafd;4) 3 1 48afe;7 145afe;23*&#a7; 151afe;69 11afe;4.9ߥ&#a7;2a8; 104afe;18 35afe;15.3ߥ&#a7;2a8; 116afe;24 TC indicates total cholesterol; TG, triglycerides; and CH, compound heterozygotes.
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ABCA1 p.Arg1851Gln 14576201:112:87
status: NEW