ABCMdb

PMID: 16704350

Brunham LR, Singaraja RR, Hayden MR
Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.
Annu Rev Nutr. 2006;26:105-29., [PubMed]

Sentences

No. Mutations Sentence Comment

522 ABCA1 p.Asn1800His ABCA1 p.Lys776Asn A small number of mutations have been reported in more than one unrelated individual, such as N1800H (16, 28, 43), and the K776N variant that was recently reported to occur in a Danish population at a frequency of 0.4% and to be associated with a two- to threefold increased risk for ischemic heart disease (44). Login to comment 523 ABCA1 p.Lys776Asn The K776N variant was initially described as a SNP (27); however, the Danish study reporting that it occurs at a frequency less than 1% and is associated with a strong phenotypic effect would suggest that this is a relatively "common" ABCA1 mutation, at least in the Danish population, influencing atherosclerosis susceptibility. Login to comment 550 ABCA1 p.Trp590Ser ABCA1 p.Thr929Ile ABCA1 p.Arg1680Trp ABCB1 p.Ala947Val However, a subset of mutations are associated with greater than 50% of control HDL levels, specifically T929I, A947V, R1680W, and W590S. Login to comment 553 ABCA1 p.Thr929Ile Consistent with this concept, cholesterol efflux from fibroblasts of an individual carrying the T929I mutation has been reported to be approximately 75% of control levels (26). Login to comment 554 ABCA1 p.Arg909* ABCA1 p.Met1091Thr ABCA1 p.Arg282* ABCA1 p.Gly1216Val ABCA1 p.Arg2144* Conversely, a small number of mutations are associated with less than 50% of control HDL cholesterol, specifically M1091T, G1216V, and the truncation mutations R2144X, R282X, and R909X. Login to comment 555 ABCA1 p.Trp590Ser ABCA1 p.Gln597Arg ABCA1 p.Cys1477Arg ABCA1 p.Asn1800His ABCA1 p.Arg909* ABCA1 p.Lys776Asn ABCA1 p.Met1091Thr ABCA1 p.Thr929Ile ABCA1 p.Arg587Trp ABCA1 p.Arg587Trp ABCA1 p.Arg282* ABCA1 p.Asn935Ser ABCA1 p.Ala937Val ABCA1 p.Arg1068His ABCA1 p.Gly1216Val ABCA1 p.Arg1680Trp ABCA1 p.Asp1099Tyr ABCA1 p.Phe2009Ser ABCA1 p.Arg2144* ABCA1 p.Ser364Cys ABCA1 p.Pro1065Ser ABCA1 p.Asp1289Asn ABCA1 p.Ala1046Asp ABCA1 p.Pro85Leu ABCA1 p.Arg2081Trp 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 562 ABCA1 p.Arg1068His Support for this concept comes from a recent study showing that HDL cholesterol levels in carriers of the R1068H mutation are significantly influenced by the ABCA1 promoter haplotype associated with the mutation (100). Login to comment 565 ABCA1 p.Arg1925Gln Albrecht et al. (3) reported a case of Scott syndrome, a rare bleeding disorder characterized by defective phosphatidylserine (PS) exposure on the surface of platelets, that was associated with a novel missense mutation in ABCA1, R1925Q (3). Login to comment 605 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Lys1587Arg ABCA1 p.Ser1731Cys ABCA1 p.Arg230Cys ABCA1 p.Val771Met ABCA1 p.Val399Ala ABCA1 p.Val1054Ile ABCA1 p.Leu1648Pro ABCA12 p.Gly969Ala ABCA1 p.Ile1555Thr ABCA1 p.Glu1005Lys ABCA1 p.Met415Leu ABCA1 p.Ile546Val ABCA1 p.Val1096Ile ABCA1 p.Asp831Asn Many of these variants have been studied in relationship to their association with HDL cholesterol levels and atherosclerosis (11, 15, 22, 27, 28, 38, TABLE 4 Nonsynonymous single-nucleotide polymorphisms (SNPs) in ABCA1 SNP id Nucleotidea Amino acidb Observed heterozygosity rs2230806 G969A R219K 0.488 rs9282541 C1001T R230C 0.029 rs9282543 T1509C V399A 0.020 rs4131108 A1556C M415L - rs13306068 A1949G I546V - rs2066718 G2624A V771M 0.074 rs2472458 G2804A D831N - rs4149313 A2962G I883M - rs2482437 C3326T E1005K - rs13306072 G3473A V1054I - rs13306073 G3599A V1096I - rs1997618 T4977C I1555T - rs2230808 A5073G K1587R 0.480 rs1883024 T5256C L1648P - - C5505G S1731C - a Nucleotide position is with respect to NM 005502. b Amino acid position is with respect to NP 005493. Login to comment 612 ABCA1 p.Val825Ile ABCA1 p.Val771Met The V825I and V771M SNPs were associated with increased HDL cholesterol in one, but not both, genders. Login to comment 622 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Notably, only two of the 15 common ABCA1 nonsynonymous SNPs, I883M and R219K,arerepresentedintheHapMapdataset,whichisanincompletedataset(the phaseIprojecthavingsetouttoidentify1SNPevery5000basepairs)(7).However, it is apparent from the haplotypes in which I883M and R219K reside that the minor alleles of each of these are unique to one particular, different haplotype, which may explain in part why these two SNPs have been consistently found to be associated with HDL levels and atherosclerosis risk. Login to comment 763 ABCA1 p.Arg219Lys The association of the R219K polymorphism in the ATP-binding cassette transporter 1 (ABCA1) gene with coronary artery disease and hyperlipidemia. Login to comment 946 ABCA1 p.Arg1615Pro R1615P: a novel mutation in ABCA1 associated with low levels of HDL and type II diabetes mellitus. Login to comment 974 ABCA1 p.Arg219Lys R219K polymorphism of the ABCA1 gene and its modulation of the variations in serum high-density lipoprotein cholesterol and triglycerides related to age and adiposity in white versus black young adults. Login to comment