ABCMdb

PMID: 14576201

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., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCA1 p.Arg1851Gln The first mutation was a G5947A substitution (R1851Q). Login to comment 9 ABCA1 p.Arg1851Gln The first mutation was a G5947A substitution (R1851Q). Login to comment 10 ABCA1 p.Arg1851Gln 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 15 ABCA1 p.Arg1851Gln 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 55 ABCA1 p.Arg1851Gln Results The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2). Login to comment 60 ABCA1 p.Arg1851Gln Results The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2). Login to comment 65 ABCA1 p.Arg1851Gln 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 70 ABCA1 p.Arg1851Gln 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 92 ABCA1 p.Arg219Lys Moreover, several noncoding (eg, C-17G) and coding (eg, R219K) single-nucleotide polymorphisms that do not affect levels of HDL-C have coincided with reduced CHD.23,24 In contrast, most but not all studies evaluating ABCA1 variants have demonstrated an association TABLE 1. Login to comment 95 ABCA1 p.Asn1800His ABCA1 p.Arg1851* ABCA1 p.Arg1851Gln ABCA1 p.Arg1851Gly 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 97 ABCA1 p.Arg219Lys Moreover, several noncoding (eg, C-17G) and coding (eg, R219K) single-nucleotide polymorphisms that do not affect levels of HDL-C have coincided with reduced CHD.23,24 In contrast, most but not all studies evaluating ABCA1 variants have demonstrated an association TABLE 1. Login to comment 98 ABCA1 p.Arg1851Gln 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 100 ABCA1 p.Asn1800His ABCA1 p.Arg1851* ABCA1 p.Arg1851Gln ABCA1 p.Arg1851Gly 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 ABCA1 p.Arg1851Gln 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 112 ABCA1 p.Arg1851Gln 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 117 ABCA1 p.Arg1851Gln 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