ABCMdb

ABCA1 p.His551Asp

Predicted by SNAP2:	A: D (63%), C: D (66%), D: D (59%), E: D (75%), F: D (71%), G: D (66%), I: N (61%), K: N (57%), L: D (66%), M: D (66%), N: N (66%), P: D (80%), Q: N (66%), R: D (75%), S: D (63%), T: D (63%), V: D (59%), W: D (80%), Y: N (57%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Genetic etiology of isolated low HDL syndrome: inc... Arterioscler Thromb Vasc Biol. 2007 May;27(5):1139-45. Epub 2007 Feb 15. Kiss RS, Kavaslar N, Okuhira K, Freeman MW, Walter S, Milne RW, McPherson R, Marcel YL
Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects.
Arterioscler Thromb Vasc Biol. 2007 May;27(5):1139-45. Epub 2007 Feb 15., [PMID:17303779]

Abstract [show]
OBJECTIVE: We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects. METHODS AND RESULTS: We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL. CONCLUSIONS: Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.

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No. Sentence Comment
45 Previous studies demonstrated the importance of the C-terminal region for the functional activity of PLTP and the arginine at position 459 is within the C-terminus.31 PLTP expression in COS7 cells showed that PLTP mutants S107Y and R459Q had normal and 33% decrease in specific activity relative to wild-type protein, respectively (115.3Ϯ11.2, 66.7Ϯ6.0 of wild-type activity). Login to comment
47 In ABCA1, a total of 19 nonsynonymous coding sequence variants; some of these we reported previously.22 Of these, 9 sequence variants were common polymorphisms (ie, reported in the literature as common or of similar prevalence in control subjects): P85L, P85A, R219K, V399A, V771M, V825I, I883M, E1172D, R1587K.14,32-35 Another 5 sequence variants, identified here, were previously reported to be disease causing: W590L (reported as W590S)14; C1477F (reported as C1477R)13; S1731C (only found in French-Canadian populations)36; N1800H32; and 1851X.37 Five sequence variants were novel: K199F, H551D, R965C, E1386Q, and D1706N. Login to comment
49 Eight subjects with sequence variants in ABCA1 had defective cholesterol efflux (measured in repeated assays cholesterol-loaded monocyte-derived macrophage [MDMs]), and these ABCA1 sequence variants were tested in an in vitro expression system for cholesterol efflux activity.38 ABCA1 proteins containing the sequence variants W590L, C1477F, D1706N, S1731C, or N1800H were all found to have significantly impaired cholesterol efflux, whereas the H551D and E1386Q variants had very minor, if any, effects on cholesterol transport (Figure 1A). Login to comment
50 The H551D variant had close to normal efflux capacity but reduced cell surface presentation (Figure 1B), thereby affecting activity. Login to comment
75 All mutants were found to have significantly impaired cholesterol efflux, with the exception of E1386Q and H551D. Login to comment
80 The H551D mutant had significantly decreased cell surface presentation. Login to comment
88 of Subjects Functional Mutations (All Heterozygous) Percentage of Total Population ApoA-I 2 33X, ⌬K182 2 ABCA1 7 H551D, W590L, C1477F, D1706N, S1731C, N1800H, 1851X 6 LCAT 4 W61X, G104S, N131D, S208T 3 PLTP 1 R459Q 1 Unknown 88 Total no. Login to comment
103 As a positive control, we recruited first-degree relatives of a group B subject possessing a novel ABCA1 mutation, H551D. Login to comment
141 Future studies will focus on the HDL 0.68 mM <5th% Efflux 0.31% HDL 1.25 mM 40th% Efflux 0.53% HDL 0.90 mM <5th% Efflux 0.28% HDL 0.85 mM <5th% Efflux 0.29% HDL 1.54 mM 70th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.33% HDL 1.38 mM 50th% Efflux 0.56% HDL 0.90 mM 20th% Efflux 0.41% HDL 0.75 mM <5th% Efflux 0.21% HDL 0.91 mM 20th% Efflux 0.46% HDL 0.62 mM <5th% Efflux 0.35% HDL 1.40 mM 80th% Efflux 0.45% HDL 1.60 mM 90th% Efflux 0.58% HDL 0.72 mM <5th% Efflux 0.29% HDL 1.70 mM 75th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.20% HDL 0.69 mM <5th% Efflux 0.38% HDL 0.78 mM <5th% Efflux 0.30% HDL 1.62 mM 75th% Efflux 0.55% Heritability of efflux defects Group B: H551D mut. Login to comment
145 The proband and 2 children in the family depicted in the top left pedigree are carriers of a H551D mutation in ABCA1, demonstrating cosegregation of this mutation with a cholesterol efflux defect and low HDL. Login to comment
42 In ABCA1, a total of 19 nonsynonymous coding sequence variants; some of these we reported previously.22 Of these, 9 sequence variants were common polymorphisms (ie, reported in the literature as common or of similar prevalence in control subjects): P85L, P85A, R219K, V399A, V771M, V825I, I883M, E1172D, R1587K.14,32-35 Another 5 sequence variants, identified here, were previously reported to be disease causing: W590L (reported as W590S)14; C1477F (reported as C1477R)13; S1731C (only found in French-Canadian populations)36; N1800H32; and 1851X.37 Five sequence variants were novel: K199F, H551D, R965C, E1386Q, and D1706N. Login to comment
44 Eight subjects with sequence variants in ABCA1 had defective cholesterol efflux (measured in repeated assays cholesterol-loaded monocyte-derived macrophage [MDMs]), and these ABCA1 sequence variants were tested in an in vitro expression system for cholesterol efflux activity.38 ABCA1 proteins containing the sequence variants W590L, C1477F, D1706N, S1731C, or N1800H were all found to have significantly impaired cholesterol efflux, whereas the H551D and E1386Q variants had very minor, if any, effects on cholesterol transport (Figure 1A). Login to comment
70 All mutants were found to have significantly impaired cholesterol efflux, with the exception of E1386Q and H551D. Login to comment
83 of Subjects Functional Mutations (All Heterozygous) Percentage of Total Population ApoA-I 2 33X, èc;K182 2 ABCA1 7 H551D, W590L, C1477F, D1706N, S1731C, N1800H, 1851X 6 LCAT 4 W61X, G104S, N131D, S208T 3 PLTP 1 R459Q 1 Unknown 88 Total no. Login to comment
98 As a positive control, we recruited first-degree relatives of a group B subject possessing a novel ABCA1 mutation, H551D. Login to comment
136 Future studies will focus on the HDL 0.68 mM <5th% Efflux 0.31% HDL 1.25 mM 40th% Efflux 0.53% HDL 0.90 mM <5th% Efflux 0.28% HDL 0.85 mM <5th% Efflux 0.29% HDL 1.54 mM 70th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.33% HDL 1.38 mM 50th% Efflux 0.56% HDL 0.90 mM 20th% Efflux 0.41% HDL 0.75 mM <5th% Efflux 0.21% HDL 0.91 mM 20th% Efflux 0.46% HDL 0.62 mM <5th% Efflux 0.35% HDL 1.40 mM 80th% Efflux 0.45% HDL 1.60 mM 90th% Efflux 0.58% HDL 0.72 mM <5th% Efflux 0.29% HDL 1.70 mM 75th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.20% HDL 0.69 mM <5th% Efflux 0.38% HDL 0.78 mM <5th% Efflux 0.30% HDL 1.62 mM 75th% Efflux 0.55% Heritability of efflux defects Group B: H551D mut. Login to comment
140 The proband and 2 children in the family depicted in the top left pedigree are carriers of a H551D mutation in ABCA1, demonstrating cosegregation of this mutation with a cholesterol efflux defect and low HDL. Login to comment

[hide] Accurate prediction of the functional significance... PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30. Brunham LR, Singaraja RR, Pape TD, Kejariwal A, Thomas PD, Hayden MR
Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.
PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30., [PMID:16429166]

Abstract [show]
The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation.

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No. Sentence Comment
110 DOI: 10.1371/journal.pgen.0010083.g003 Table 3. subPSEC Scores for ABCA1 Variants Described in a Cohort of Individuals with Low HDL Cholesterol from the General Population Variant subPSEC Score Macrophage Efflux PolyPhen D1706N À6.57 0.38a Possibly damaging C1477F À5.55 0.34a Probably damaging W590S À5.19 - Probably damaging H551D À4.99 0.32a Probably damaging P85L À4.62 0.8 Probably damaging W590L À4.48 0.31a Probably damaging N1800H À4.23 0.27a Possibly damaging R965C À4.22 0.59 Probably damaging S1731C À4.21 0.28a Possibly damaging A1670T À4.2 - Possibly damaging K401Q À4.2 - Benign T459P À4.11 0.28a Possibly damaging R638Q À4.08 - Possibly damaging L1026P À3.86 0.25a Benign T2073A À3.84 0.28a Possibly damaging E815G À3.53 - Probably damaging R1615Q À3.45 - Possibly damaging S1181F À3.44 - Possibly damaging R306H À3.31 - Benign E1386Q À2.44 0.51 Benign S1376G À2.19 - Benign R1341T À2.09 - Possibly damaging D2243E À1.6 - Benign P248A À0.18 - Benign a Efflux value is 2 SDs or more below control levels of 0.52 6 0.07. Login to comment