ABCA1 p.Lys1587Arg
| Predicted by SNAP2: | A: N (53%), C: D (53%), D: D (80%), E: N (57%), F: D (63%), G: D (75%), H: D (66%), I: D (63%), L: D (59%), M: D (53%), N: D (63%), P: D (53%), Q: N (82%), R: N (78%), S: D (85%), T: N (57%), V: D (63%), W: D (75%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: D, H: N, I: D, L: D, M: D, N: N, P: N, Q: N, R: N, S: N, T: N, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Maternal ABCA1 genotype is associated with severit... Eur J Hum Genet. 2012 Aug 29. doi: 10.1038/ejhg.2012.169. Lanthaler B, Steichen-Gersdorf E, Kollerits B, Zschocke J, Witsch-Baumgartner M
Maternal ABCA1 genotype is associated with severity of Smith-Lemli-Opitz syndrome and with viability of patients homozygous for null mutations.
Eur J Hum Genet. 2012 Aug 29. doi: 10.1038/ejhg.2012.169., [PMID:22929031]
Abstract [show]
The Smith-Lemli-Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the Delta7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC-III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n=21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P=0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P=0.004. Maternal ABCA1 explains 15.4% (R(2)) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from Hardy-Weinberg equilibrium (HWE) was observed (P=0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS.European Journal of Human Genetics advance online publication, 29 August 2012; doi:10.1038/ejhg.2012.169.
Comments [show]
None has been submitted yet.
No. Sentence Comment
40 These positions correspond to amino-acid residues 112 and 158 of the previous nomenclature.31 SNP genotyping for variants in the genes ABCA1 (NP_005493.2: p.Lys1587Arg; minor allele count: A ¼ 0.4113/900), LCAT (NP_001898.1: p.His173Arg), CETP (NP_000069.2: p.Val422Ile), LDLR, ApoC-III, and MTHFR (NP_005948.3: p.Ala222Val) was performed with the ABI SDS 7000 probes and primers that are part of predesigned assays from Applied Biosystems, Carlsbad, CA, USA (TaqMan SNP Genotyping Assays) (Table 1).
X
ABCA1 p.Lys1587Arg 22929031:40:157
status: NEW47 RESULTS Description of SLOS patients The patients in the first study group were diagnosed by quantification of sterols using gas chromatography and mass spectrometry as mentioned.13 Phenoytpe severity was characterised by the scoring system mentioned earlier.2 The number of persons analysed in the association studies varied depending on availability of variables Table 1 Variants used for association study in SLOS patients Gene reference sequence SNP ref. TaqMan SNP genotyping assay Presumed consequence of SNP MTHFR NM_005957.4 p.Ala222Val rs1801133 C_1202883 Induces increased enzyme activity, significantly increased in mothers of children with cleft lip and cleft palate15-17 LCAT NM_001907.2 p.His173Arg rs2301246 C_8731782 Esterification of extracellular cholesterol in HDL leads to decrease of plasma HDL-cholesterol18 ApoC-III NM_000040.1 c.340G4C rs5128 C_8907537 Association with LDL- and HDL-cholesterol and ApoA-I concentrations in cord blood19 ABCA1 NM_005502.3 p.Lys1587Arg rs2230808 C_2741104 Lys1587 is associated with decreased plasma HDL- and LDL-cholesterol mainly in women20-22 CETP NM_000078.2 p.Val422Ile rs5882 C_790057 Influences the CETP expression, Ile422 is associated with low CETP and high HDL-cholesterol14 (concentrations of relevant metabolites cholesterol, 7-dehydrocholesterol, and 8-dehydrocholesterol, genotypes for patients and parents).
X
ABCA1 p.Lys1587Arg 22929031:47:979
status: NEW[hide] A novel intronic polymorphism of ABCA1 gene reveal... Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):1007-13. Chu LW, Li Y, Li Z, Tang AY, Cheung BM, Leung RY, Yik PY, Jin DY, Song YQ
A novel intronic polymorphism of ABCA1 gene reveals risk for sporadic Alzheimer's disease in Chinese.
Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):1007-13., [PMID:17510949]
Abstract [show]
Recent genetic studies have shown that variants of the ATP-binding cassette transporter A1, ABCA1, may be implicated in the pathogenesis of Alzheimer's disease (AD). In this case-control study, a panel of 19 single nucleotide polymorphisms (SNP) (including three amino-acid-coding SNPs used for replication of previous work, and 16 newly selected intronic tag SNPs) was genotyped. Nominally significant single marker P-values were observed in four SNPs, with the highest score of 0.003 for rs2297404 (OR = 1.88, 95%CI 1.23-2.87). In addition, six distinct linkage disequilibrium (LD) blocks were detected. LD block1 harbored three nominally significant SNPs (rs2297404, rs2230808, and rs2020927), and showed a different haplotype structure in the affected and unaffected groups. Of the four haplotypes identified, haplotype2 (CAC) was more prevalent in the disease group (0.323 in AD vs. 0.202 in control); while haplotype1 (TGG) was over-represented in the healthy controls (0.595 in control vs. 0.493 in AD), indicating disease risk conferring possibility of haplotype2. After doubling the sample size, the three nominally significant SNPs were still significantly associated with AD. Although coding SNP (rs2230808) was confirmed to have a significant association with AD, prediction of the effects of an amino acid substitution SNP rs2230808 (R1587K) on the three-dimensional structure and function of the ABCA1 protein using PolyPhen program revealed that it is unlikely to be functionally significant. However, the adjacent rs2297404 in the same LD block is potentially functionally significant because of its position in the immediate vicinity of a splicing branch site. Further functional analysis of this polymorphism should be a high priority.
Comments [show]
None has been submitted yet.
No. Sentence Comment
133 SNP18 (R219K) is in an N-terminal extracellular loop which possibly mediates ABCA1 interaction with ApoAI; while SNP10 (K1587R) is located in the regulatory segment 2 of the protein [Fitzgerald et al., 2002; Frikke-Schmidt et al., 2004].
X
ABCA1 p.Lys1587Arg 17510949:133:120
status: NEW[hide] Variations on a gene: rare and common variants in ... Annu Rev Nutr. 2006;26:105-29. 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., [PMID:16704350]
Abstract [show]
Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.
Comments [show]
None has been submitted yet.
No. Sentence Comment
605 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.
X
ABCA1 p.Lys1587Arg 16704350:605:618
status: NEW[hide] Quantitative assessment of the effect of ABCA1 gen... Mol Biol Rep. 2013 Feb;40(2):779-85. doi: 10.1007/s11033-012-2115-9. Epub 2012 Oct 31. Wang XF, Cao YW, Feng ZZ, Fu D, Ma YS, Zhang F, Jiang XX, Shao YC
Quantitative assessment of the effect of ABCA1 gene polymorphism on the risk of Alzheimer's disease.
Mol Biol Rep. 2013 Feb;40(2):779-85. doi: 10.1007/s11033-012-2115-9. Epub 2012 Oct 31., [PMID:23111454]
Abstract [show]
ATP-binding cassette transporter A1 (ABCA1) is a membrane-associated protein which has attracted considerable attention as a candidate gene for Alzheimer's disease (AD) based on its function as a key factor in lipid metabolism by mediating cellular cholesterol efflux, the rate-limiting step in the production of nascent high-density lipoprotein (HDL) particles. The relationship between ABCA1 common variations (R219 K rs2230806, I883 M rs4149313 and R1587 K rs2230808) and AD has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 12,248 subjects to evaluate the effect of ABCA1 on genetic susceptibility for AD. Overall, the summary OR of AD was 1.01 (95 % CI: 0.93-1.10; P = 0.77), 1.10 (95 % CI: 0.96-1.26; P = 0.16), and 1.08 (95 % CI: 0.96-1.23; P = 0.21) for R219 K, I883 M and R1587 K polymorphism, respectively. No significant results were observed in dominant and recessive when compared with wild genotype for these polymorphisms. In the stratified analyses by ethnicity and sample size, no evidence of any gene-disease association was obtained. In conclusion, the present meta-analysis does not support the notion that common SNPs on ABCA1 is a major genetic risk factor for AD.
Comments [show]
None has been submitted yet.
No. Sentence Comment
86 The two conservative, non-synonymous coding polymorphisms (K1587R and R219 K) had been extensively investigated because of their potentially, functionally Table 2 Meta-analysis of the ABCA1 polymorphisms on Alzheimer`s disease risk Polymorphism Overall association Sub-group analysis by ethnicity Sub-group analysis by sample size Caucasian Asian C300 \300 R219 K OR(95 % CI) P(Q) OR(95 % CI) P(Q) OR(95 % CI) P(Q) OR(95 % CI) P(Q) OR(95 % CI) P(Q) K allele 1.01 (0.93-1.10) P = 0.05 1.04 (0.96-1.14) P = 0.18 0.86 (0.62-1.18) P = 0.06 1.03 (0.91-1.17) P = 0.05 0.98 (0.85-1.14) P = 0.10 Dominant 1.05 (0.94-1.16) P = 0.14 1.08 (0.98-1.17) P = 0.40 0.86 (0.55-1.35) P = 0.07 1.08 (0.95-1.23) P = 0.19 0.99 (0.83-1.19) P = 0.17 Recessive 0.93 (0.78-1.10) P = 0.22 0.98 (0.81-1.18) P = 0.25 0.74 (0.51-1.07) P = 0.34 0.92 (0.70-1.20) P = 0.09 0.92 (0.72-1.18) P = 0.41 I883 M M allele 1.10 (0.96-1.26) P = 0.36 1.13 (0.97-1.31) P = 0.32 0.95 (0.65-1.39) NA 1.18 (0.90-1.55) P = 0.09 1.07 (0.88-1.30) P = 0.81 Dominant 1.13 (0.95-1.33) P = 0.34 1.14 (0.96-1.36) P = 0.28 0.85 (0.36-1.99) NA 1.19 (0.87-1.64) P = 0.06 1.11 (0.86-1.44) P = 0.90 Recessive 1.13 (0.80-1.58) P = 0.70 1.29 (0.81-2.04) P = 0.68 0.97 (0.59-1.59) NA 1.42 (0.75-2.67) P = 0.55 1.03 (0.69-1.54) P = 0.60 R1587 K K allele 1.08 (0.96-1.23) P = 0.06 1.05 (0.92-1.20) P = 0.09 1.31 (0.98-1.74) P = 0.23 1.01 (0.88-1.16) P = 0.17 1.23 (1.02-1.50) P = 0.19 Dominant 1.11 (0.93-1.33) P = 0.01 1.08 (0.89-1.32) P = 0.008 1.32 (0.91-1.92) P = 0.36 1.01 (0.80-1.27) P = 0.02 1.28 (0.97-1.68) P = 0.14 Recessive 1.15 (0.93-1.43) P = 0.44 1.04 (0.81-1.33) P = 0.73 1.64 (0.91-2.94) P = 0.19 1.00 (0.76-1.32) P = 0.44 1.43 (1.01-2.03) P = 0.61 NA not available Fig. 3 Forest plot from the meta-analysis of Alzheimer`s disease risk and ABCA1 R1587 K polymorphism important location in the gene.
X
ABCA1 p.Lys1587Arg 23111454:86:59
status: NEW87 R219 K is in an N-terminal extracellular loop which possibly mediates ABCA1 interaction with ApoAI; while K1587R is located in the regulatory segment 2 of the protein [27, 28].
X
ABCA1 p.Lys1587Arg 23111454:87:106
status: NEW