ABCMdb

ABCA1 p.Arg1851Gln

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Publications

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
29 All mutations were heterozygous and 3 subjects were genetic compounds (e.g., IVS46: del T-39…-46/R1851Q and 238X/T321M). 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
47 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. Login to comment

PMID: 14576201 [PubMed] Hong SH et al: "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."

No. Sentence Comment

9 The first mutation was a G5947A substitution (R1851Q). Login to comment
15 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. . Login to comment
60 Results The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2). Login to comment
70 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. . Login to comment
100 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. Login to comment
103 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. . Login to comment
117 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. Login to comment
4 The first mutation was a G5947A substitution (R1851Q). Login to comment
10 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. . Login to comment
55 Results The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2). Login to comment
65 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. . Login to comment
95 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. Login to comment
98 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. . Login to comment
112 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. Login to comment