ABCMdb

PMID: 12763760

Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR
Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene.
Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32. Epub 2003 May 22., [PubMed]

Sentences

No. Mutations Sentence Comment

68 ABCA1 p.Trp590Ser ABCA1 p.Gln597Arg ABCA1 p.Gln597Arg ABCA1 p.Gln597Arg ABCA1 p.Arg587Trp ABCA1 p.Arg587Trp ABCA1 p.Arg587Trp Additional insights into how the mutations R587W, W590S, and Q597R that occur in the extracellular loops affect ABCA1 function have recently been described.58-60 Two studies have reported that ABCA1 containing the point mutation Q597R, which occurs in the first extracellular loop, does not localize to the plasma membrane.59,60 However, other studies have reported that this mutant is expressed at the plasma membrane but at reduced levels relative to wild-type ABCA1.58,44 R587W, another missense mutation in the first extracellular loop, also prevents the trafficking of ABCA1 to the plasma membrane, although results with this mutant have been variable.58-60 Both the R587W and Q597R mutants are resistant to PNGase digestion, indicating that they are not glycosylated, suggesting that ABCA1 harboring these mutations does not traverse the medial and trans Golgi network. Login to comment 70 ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 harboring the W590S mutation does reach the cell surface, and cross-linking studies reported normal interaction of the W590S mutant with ApoA-I despite defective efflux, suggesting that interaction with ApoA-I may not be sufficient for lipid efflux.58 ABCA1 that does not reach the plasma membrane cannot induce the binding of ApoA-I. Login to comment 71 ABCA1 p.Gln597Arg This is indeed the case with mutant Q597R,58,60 which shows no ApoA-I binding. Login to comment 72 ABCA1 p.Cys1477Arg ABCA1 p.Ser1506Leu However, failure of binding may also occur because of disruption of residues crucial for this function. Indeed, the variants C1477R and S1506L, which are both localized in the second large extracellular loop, are normally translocated to the plasma membrane but show no ApoA-I binding, indicating that specific amino acids in the large extracellular loops are Figure 4. Login to comment 75 ABCA1 p.Trp590Ser ABCA1 p.Gln597Arg ABCA1 p.Cys1477Arg ABCA1 p.Asn1800His ABCA1 p.Met1091Thr ABCA1 p.Thr929Ile ABCA1 p.Arg587Trp ABCA1 p.Asn935Ser ABCA1 p.Arg230Cys ABCA1 p.Ala937Val ABCA1 p.Arg1680Trp ABCA1 p.Asp1099Tyr ABCA1 p.Phe2009Ser ABCA1 p.Ser1506Leu ABCA1 p.Ala255Thr ABCA1 p.Ala1046Asp ABCA1 p.Pro2150Leu ABCA1 p.Pro85Leu ABCA1 p.Arg2081Trp ABCA1 p.Asp1289Leu ABCA1 p.Asn1611Asp 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 76 ABCA1 p.Trp590Ser ABCA1 p.Gln597Arg ABCA1 p.Gln597Arg ABCA1 p.Gln597Arg ABCA1 p.Arg587Trp ABCA1 p.Arg587Trp ABCA1 p.Arg587Trp Additional insights into how the mutations R587W, W590S, and Q597R that occur in the extracellular loops affect ABCA1 function have recently been described.58-60 Two studies have reported that ABCA1 containing the point mutation Q597R, which occurs in the first extracellular loop, does not localize to the plasma membrane.59,60 However, other studies have reported that this mutant is expressed at the plasma membrane but at reduced levels relative to wild-type ABCA1.58,44 R587W, another missense mutation in the first extracellular loop, also prevents the trafficking of ABCA1 to the plasma membrane, although results with this mutant have been variable.58-60 Both the R587W and Q597R mutants are resistant to PNGase digestion, indicating that they are not glycosylated, suggesting that ABCA1 harboring these mutations does not traverse the medial and trans Golgi network. Login to comment 78 ABCA1 p.Trp590Ser ABCA1 p.Trp590Ser ABCA1 harboring the W590S mutation does reach the cell surface, and cross-linking studies reported normal interaction of the W590S mutant with ApoA-I despite defective efflux, suggesting that interaction with ApoA-I may not be sufficient for lipid efflux.58 ABCA1 that does not reach the plasma membrane cannot induce the binding of ApoA-I. Login to comment 79 ABCA1 p.Gln597Arg This is indeed the case with mutant Q597R,58,60 which shows no ApoA-I binding. Login to comment 80 ABCA1 p.Cys1477Arg ABCA1 p.Ser1506Leu However, failure of binding may also occur because of disruption of residues crucial for this function. Indeed, the variants C1477R and S1506L, which are both localized in the second large extracellular loop, are normally translocated to the plasma membrane but show no ApoA-I binding, indicating that specific amino acids in the large extracellular loops are Figure 4. Login to comment 83 ABCA1 p.Trp590Ser ABCA1 p.Gln597Arg ABCA1 p.Cys1477Arg ABCA1 p.Asn1800His ABCA1 p.Met1091Thr ABCA1 p.Thr929Ile ABCA1 p.Arg587Trp ABCA1 p.Asn935Ser ABCA1 p.Arg230Cys ABCA1 p.Ala937Val ABCA1 p.Arg1680Trp ABCA1 p.Asp1099Tyr ABCA1 p.Phe2009Ser ABCA1 p.Ser1506Leu ABCA1 p.Ala255Thr ABCA1 p.Ala1046Asp ABCA1 p.Pro2150Leu ABCA1 p.Pro85Leu ABCA1 p.Arg2081Trp ABCA1 p.Asp1289Leu ABCA1 p.Asn1611Asp 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 105 ABCA1 p.Asn1800His ABCA1 p.Asn935Ser This could result from 2 null alleles for ABCA1 preventing export of the protein to the plasma membrane or from ABCA1 at the plasma membrane harboring mutations in residues crucial for its function. Indeed, patients harboring the mutations 635X, N935S, N1800H, 1851X, and 2203X and the large C-terminal deletion all have below 1% of HDL-C levels of age-and sex-matched controls from the Lipid Research Clinic population. Login to comment 106 ABCA1 p.Arg1680Trp ABCA1 p.Ala255Thr Patients homozygous for the mutations A255T and R1680W show HDL-C levels that are greater than 10% of age-and sex-matched population controls. Login to comment 113 ABCA1 p.Asn1800His ABCA1 p.Asn935Ser This could result from 2 null alleles for ABCA1 preventing export of the protein to the plasma membrane or from ABCA1 at the plasma membrane harboring mutations in residues crucial for its function. Indeed, patients harboring the mutations 635X, N935S, N1800H, 1851X, and 2203X and the large C-terminal deletion all have below 1% of HDL-C levels of age-and sex-matched controls from the Lipid Research Clinic population. Login to comment 114 ABCA1 p.Trp590Ser ABCA1 p.Thr929Ile ABCA1 p.Ala937Val ABCA1 p.Arg1680Trp ABCA1 p.Arg1680Trp ABCA1 p.Ala255Thr ABCA1 p.Ala255Thr Patients homozygous for the mutations A255T and R1680W show HDL-C levels that are greater than 10% of age-and sex-matched population controls. Login to comment 116 ABCA1 p.Met1091Thr This could be caused by dominant-negative effects of ABCA1, as previously shown for truncation mutations.69 Patients harboring the mutation M1091T show HDL-C levels that are 30% of age-and sex-matched controls.70 This finding suggests that ABCA1 acts as a dimer or as part of a complex in the exertion of its function. Login to comment 122 ABCA1 p.Trp590Ser ABCA1 p.Thr929Ile ABCA1 p.Ala937Val ABCA1 p.Arg1680Trp ABCA1 p.Ala255Thr This is indeed the case in heterozygous patients harboring mutations A255T, W590S, T929I, R1680W, and A937V, who all show HDL-C levelsϾ75% of normal age-and sex-matched controls. Login to comment 124 ABCA1 p.Met1091Thr This could be caused by dominant-negative effects of ABCA1, as previously shown for truncation mutations.69 Patients harboring the mutation M1091T show HDL-C levels that are 30% of age-and sex-matched controls.70 This finding suggests that ABCA1 acts as a dimer or as part of a complex in the exertion of its function. Login to comment 128 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Cys1477Arg ABCA1 p.Ser1731Cys ABCA1 p.Lys776Asn ABCA1 p.Val825Ile ABCA1 p.Met1091Thr ABCA1 p.Thr929Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val399Ala ABCA1 p.Thr774Pro ABCA1 p.Pro2150Leu Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon afa;1095A/G Promoter ዼ ዼ ዼ afa;477C/T Promoter ዼ ዼ ዼ afa;419A/C Promoter ዼ ዼ ዼ afa;320G/C Promoter ዼ ዼ ዼ afa;191G/C Promoter ዼ ዼ ዼ C69T 5b18;UTR 1 C117G 5b18;UTR 1 InsG319 5b18;UTR 2 G378C 5b18;UTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 Singaraja et al Clinical and Biochemical Impact of ABCA1 Variants markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. Login to comment 136 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Cys1477Arg ABCA1 p.Ser1731Cys ABCA1 p.Lys776Asn ABCA1 p.Val825Ile ABCA1 p.Met1091Thr ABCA1 p.Thr929Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val399Ala ABCA1 p.Thr774Pro ABCA1 p.Pro2150Leu Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon -1095A/G Promoter ⅐ ⅐ ⅐ -477C/T Promoter ⅐ ⅐ ⅐ -419A/C Promoter ⅐ ⅐ ⅐ -320G/C Promoter ⅐ ⅐ ⅐ -191G/C Promoter ⅐ ⅐ ⅐ C69T 5ЈUTR 1 C117G 5ЈUTR 1 InsG319 5ЈUTR 2 G378C 5ЈUTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. Login to comment 139 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Glu1172Asp The R219K, V771M, and I883M variants have been recognized as putative antiatherogenic polymorphisms, associated with increased HDL-C and decreased triglyceride levels (K219 and M883) and increased HDL-C and ApoA-I (M771).41,75,82 The E1172D, R1587K cSNPs have been reported to be associated with decreased HDL-C.75 Five promoter SNPs are associated with increased severity of atherosclerosis, including the afa;191C/afa;320C/afa;477T hap- lotype76,78 as well as the G-191C and A-1096G SNPs. Login to comment 140 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Ser1731Cys ABCA1 p.Lys776Asn ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val399Ala ABCA1 p.Thr774Pro In TABLE 4. Conservation of Amino Acids Polymorphic in Humans cSNP H. sapiens M. musculus G. gallus D. melanogaster C. elegans R219K R R K ዼ ዼ ዼ L V399A V V V A I V771M V V V L Y T774P T S S S G K776N K K K K R V825I V V A M L I883M I V P R A E1172D E E E ዼ ዼ ዼ ዼ ዼ ዼ R1587K R K K E V S1731C S S S T H Five of 10 (50%) amino acids at which cSNPs occur are conserved with G. gallus, indicating a relatively less crucial functional role of these residues compared with those at which mutations occur (Figure 2). Login to comment 145 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Glu1172Asp The V825I, I883M, and E1172D SNPs have also been associated with increased clinical events and severity of atherosclerosis.75,77 The R219K Variant The R219K SNP has been most studied and highlights many of the difficulties associated with the study of SNPs in general. Login to comment 147 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Glu1172Asp The R219K, V771M, and I883M variants have been recognized as putative antiatherogenic polymorphisms, associated with increased HDL-C and decreased triglyceride levels (K219 and M883) and increased HDL-C and ApoA-I (M771).41,75,82 The E1172D, R1587K cSNPs have been reported to be associated with decreased HDL-C.75 Five promoter SNPs are associated with increased severity of atherosclerosis, including the -191C/-320C/-477T hap- lotype76,78 as well as the G-191C and A-1096G SNPs. Login to comment 148 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Ser1731Cys ABCA1 p.Lys776Asn ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val399Ala ABCA1 p.Thr774Pro In TABLE 4. Conservation of Amino Acids Polymorphic in Humans cSNP H. sapiens M. musculus G. gallus D. melanogaster C. elegans R219K R R K ⅐ ⅐ ⅐ L V399A V V V A I V771M V V V L Y T774P T S S S G K776N K K K K R V825I V V A M L I883M I V P R A E1172D E E E ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ R1587K R K K E V S1731C S S S T H Five of 10 (50%) amino acids at which cSNPs occur are conserved with G. gallus, indicating a relatively less crucial functional role of these residues compared with those at which mutations occur (Figure 2). Login to comment 152 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Lys776Asn ABCA1 p.Val771Met Clee et al75 reported significant LD between the R219K and the V771M, K776N, I883M, and R1587K cSNPs but found that after carriers of these variants were excluded, R219K remained significantly associated with degree of atherosclerosis and triglyceride levels. Login to comment 153 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Glu1172Asp The V825I, I883M, and E1172D SNPs have also been associated with increased clinical events and severity of atherosclerosis.75,77 The R219K Variant The R219K SNP has been most studied and highlights many of the difficulties associated with the study of SNPs in general. Login to comment 154 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met Functional Effects of cSNPs and Regulatory SNPs in the ABCA1 Gene Nucleotide Amino Acid/Position Lipids CAD/Atherosclerosis Antiatherogenic SNPs C-17G Promoter No change 2 InsG319 5b18;UTR No change 2 G1051A R219K 2 TG, 1 HDL, 1 ApoA-1, 1 ApoB, 1 LDL 2 A3044G I883M 2 TG, 1 HDL 1 Proatherogenic SNPs afa;191C/afa;320C/afa;477T haplotype Promoter No change 1 G-191C Promoter No change 1 A-1095G Promoter No change 1 C117G 5b18;UTR 1 TG No change G2706A V771M No change 1 G2868A V825I No change 1 G3911C E1172D 2 HDL, 2 ApoB 1 G5155A R1587K 2 HDL No change Associations with lipid levels and CAD are shown by arrows to represent the direction of association. Login to comment 160 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Lys776Asn ABCA1 p.Val771Met Clee et al75 reported significant LD between the R219K and the V771M, K776N, I883M, and R1587K cSNPs but found that after carriers of these variants were excluded, R219K remained significantly associated with degree of atherosclerosis and triglyceride levels. Login to comment 162 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met Functional Effects of cSNPs and Regulatory SNPs in the ABCA1 Gene Nucleotide Amino Acid/Position Lipids CAD/Atherosclerosis Antiatherogenic SNPs C-17G Promoter No change 2 InsG319 5ЈUTR No change 2 G1051A R219K 2 TG, 1 HDL, 1 ApoA-1, 1 ApoB, 1 LDL 2 A3044G I883M 2 TG, 1 HDL 1 Proatherogenic SNPs -191C/-320C/-477T haplotype Promoter No change 1 G-191C Promoter No change 1 A-1095G Promoter No change 1 C117G 5ЈUTR 1 TG No change G2706A V771M No change 1 G2868A V825I No change 1 G3911C E1172D 2 HDL, 2 ApoB 1 G5155A R1587K 2 HDL No change Associations with lipid levels and CAD are shown by arrows to represent the direction of association. Login to comment 163 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met The noncoding SNPs G-191C, C-69T, C-17G, and InsG319 and the cSNPs R219K, V771M, and V825I have all been found to be associated with differences in severity of atherosclerosis but not with changes in HDL-C levels in at least 1 study. Login to comment 171 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met The noncoding SNPs G-191C, C-69T, C-17G, and InsG319 and the cSNPs R219K, V771M, and V825I have all been found to be associated with differences in severity of atherosclerosis but not with changes in HDL-C levels in at least 1 study. Login to comment