ABCMdb

ABCA1 p.Asn1800His

Predicted by SNAP2:	A: D (63%), C: D (66%), D: D (80%), E: D (80%), F: D (71%), G: D (66%), H: D (66%), I: D (71%), K: D (80%), L: D (71%), M: D (66%), P: D (80%), Q: D (75%), R: D (85%), S: N (66%), T: D (66%), V: D (75%), W: D (71%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Exome sequencing identifies 2 rare variants for lo... Circ Cardiovasc Genet. 2012 Oct 1;5(5):538-46. doi: 10.1161/CIRCGENETICS.112.963264. Epub 2012 Aug 25. Reddy MV, Iatan I, Weissglas-Volkov D, Nikkola E, Haas BE, Ruel MJ, Sinsheimer JS, Genest J, Pajukanta P
Exome sequencing identifies 2 rare variants for low high-density lipoprotein cholesterol in an extended family.
Circ Cardiovasc Genet. 2012 Oct 1;5(5):538-46. doi: 10.1161/CIRCGENETICS.112.963264. Epub 2012 Aug 25., [PMID:22923419]

Abstract [show]
Background- Exome sequencing is a recently implemented method to discover rare mutations for Mendelian disorders. Less is known about its feasibility to identify genes for complex traits. We used exome sequencing to search for rare variants responsible for a complex trait, low levels of serum high-density lipoprotein cholesterol (HDL-C). Methods and Results- We conducted exome sequencing in a large French-Canadian family with 75 subjects available for study, of which 27 had HDL-C values less than the fifth age-sex-specific population percentile. We captured approximately 50 Mb of exonic and transcribed sequences of 3 closely related family members with HDL-C levels less than the fifth age-sex percentile and sequenced the captured DNA. Approximately 82 000 variants were detected in each individual, of which 41 rare nonsynonymous variants were shared by the sequenced affected individuals after filtering steps. Two rare nonsynonymous variants in the ATP-binding cassette, subfamily A (ABC1), member 1 (ABCA1), and lipoprotein lipase genes predicted to be damaging were investigated for cosegregation with the low HDL-C trait in the entire extended family. The carriers of either variant had low HDL-C levels, and the individuals carrying both variants had the lowest HDL-C values. Interestingly, the ABCA1 variant exhibited a sex effect which was first functionally identified, and, subsequently, statistically demonstrated using additional French-Canadian families with ABCA1 mutations. Conclusions- This complex combination of 2 rare variants causing low HDL-C in the extended family would not have been identified using traditional linkage analysis, emphasizing the need for exome sequencing of complex lipid traits in unexplained familial cases.

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38 Genotype by sex interaction We included the extended family together with 10 additional families with previously identified mutations in ABCA16-8 in a gene-sex interaction analysis, comprising 200 individuals and 9 different mutations in ABCA1 (DelED1893, G616V, K776N, N1800H, Q2210H, R1851X, R2084X, R909X and S1731C). Login to comment
41 Genotype by Sex Interaction We included the extended family together with 10 additional families with previously identified mutations in ABCA16 -8 in a gene-sex interaction analysis, comprising 200 individuals and 9 different mutations in ABCA1 (DelED1893, G616V, K776N, N1800H, Q2210H, R1851X, R2084X, R909X, and S1731C). Login to comment
158 Figure 3 shows the age-sex specific population HDL-C percentiles by ABCA1 genotypes and sex in 200 French-Canadian family members from 11 French-Canadian families with different ABCA1 mutations (DelED1893, G616V, K776N, N1800H, Q2210H, R1851X, R2084X, R909X, and S1731C). Login to comment

[hide] Characterization of antioxidant/anti-inflammatory ... Clin Chim Acta. 2011 Jun 11;412(13-14):1213-20. Epub 2011 Mar 21. Daniil G, Phedonos AA, Holleboom AG, Motazacker MM, Argyri L, Kuivenhoven JA, Chroni A
Characterization of antioxidant/anti-inflammatory properties and apoA-I-containing subpopulations of HDL from family subjects with monogenic low HDL disorders.
Clin Chim Acta. 2011 Jun 11;412(13-14):1213-20. Epub 2011 Mar 21., [PMID:21420943]

Abstract [show]
BACKGROUND: Genetic factors regulate both high-density lipoprotein (HDL) levels and functionality, thus affecting HDL antiatherogenic properties. We characterized the HDL antioxidant/anti-inflammatory properties and apoA-I-containing subpopulations in families with monogenic low HDL disorders. METHODS: Subjects with mutations in apolipoprotein A-I (apoA-I), ATP-binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT) and family controls were studied. HDL antioxidant/anti-inflammatory properties were assayed by an in vitro fluorometric method and HDL-associated paraoxonase-1 (PON1), platelet activating factor-acetylhydrolase (PAF-AH), LCAT, malondialdehyde (MDA), PAF and serum amyloid A (SAA) were measured. ApoA-I-containing HDL subpopulations were analyzed by two-dimensional non-denaturing gel electrophoresis. RESULTS: ApoA-I heterozygotes and subjects with partial or complete ABCA1 or LCAT deficiency had HDL with reduced antioxidant/anti-inflammatory properties and increased MDA levels. HDL-PON1 activity was reduced in apoA-I heterozygotes and in subjects with complete ABCA1 deficiency. HDL-PAF-AH activity was reduced in subjects with partial or complete ABCA1 deficiency or complete LCAT deficiency. HDL-LCAT activity was reduced in all LCAT mutation carriers. HDL-PAF levels were increased in apoA-I heterozygotes. HDL-SAA levels were increased in subjects with complete ABCA1 deficiency. ApoA-I, ABCA1 and LCAT heterozygotes were depleted of the large alpha1 HDL subpopulation. Subjects with complete LCAT deficiency showed mostly the small alpha4 HDL subpopulation and subjects with complete ABCA1 deficiency the alpha4 and prebeta HDL subpopulations. CONCLUSIONS: This study shows that mutations in apoA-I, ABCA1 and LCAT have direct effect on the antioxidant/anti-inflammatory properties of HDL. Furthermore, our study shows the effect of specific mutations on the apoA-I-containing HDL subpopulation profiles.

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56 Subjects We examined serum obtained from 3 heterozygotes for the apoA-I (NM_000039) mutation p.L202P (n=3; mutation was previously denoted as L178P [14]), 6 heterozygotes for ABCA1 (NM_005502) mutations(p.C1477R,n=3;p.L1056P,n=3),2compoundheterozygotes for ABCA1 mutations (p.C1477R/IVS25+1GNC; p.Q1038X/p.N1800H), 1 homozygote for the ABCA1 mutation p.L1056P, 12 heterozygotes for LCAT (NM_000229) mutations (p.P34Q, n=1; p.Y107X, n=1; p.T147I, n=4; p.N155D, n=2; p.I202T, n=1; p.R322C, n=2, p.V333M, n=1), 3 compound heterozygotes for the LCAT mutation p.T147I/IVS4-22TNC and 1 homozygote for the LCAT mutation p.N155D. Login to comment
150 Male/female TC HDL-c apoA-I apoA-II LDL-c apoB TG apoA-I mutation carriers Unaffected (n=3) 1/2 179±27 45±3 163±13 30±1 131±22 97±15 97±25 Heterozygotes (n=3) 1/2 141±12* 20±14* 87±38* 19±6* 113±5 85±6 97±45 ABCA1 mutation carriers Unaffected (n=8) 4/4 171±56 57±15 160±29 30±4 111±23 84±12 85±20 Heterozygotes (n=6) 3/3 179±64 37±7** 124±12** 28±2 129±35 98±22 90±44 Compound heterozygote 1c (n=1) 1/0 54 6 4 2 44 75 138 Compound heterozygote 2d (n=1) 0/1 220 3 7 ndb 173 192 387 Homozygote (n=1) 0/1 63 0.8 nd nd 61 81 87 LCAT mutation carriers Unaffected (n=7) 5/2 199±32 49±13 166±19 31±2 134±28 100±20 123±58 Heterozygotes (n=12) 8/4 166±47 32±11** 122±27*** 26±5* 122±38 97±28 115±49 Compound heterozygotes (n=3) 0/3 140±24* 5±1*** 48±8*** 3.8±0.3*** 118±17 102±27 244±103* Homozygote (n=1) 1/0 107 3 58 4 77 118 279 a Values presented as mean±SD (mg/dl); b nd, not detectable; c ABCA1[p.C1477R/IVS25+1GNC]; d ABCA1[p.Q1038X/ p.N1800H]. Login to comment
163 A previous study has shown that heterozygotes for ABCA1 mutation p.C1477R, but not for ABCA1 mutation p.L1056P, have increased CAD compared to unaffected family members [24,25]. Login to comment
166 Compound heterozygotes for ABCA1 mutations * * 0 10000 20000 30000 40000 50000 60000 70000 L1056P L1056P C1477R C1477R ** ** C1477R/ IVS25+1G>C Q1038X/ N1800H C1477R/ IVS25+1G>C Q1038X/ N1800H 0.0 2.5 5.0 7.5 10.0 SAA/HDL-c(RLU) ** 0 10 20 30 40 *** 0 1 2 3 PAF-AHactivity (nmolCE/h) A B C D * ** HDL C HDL Het HDL Com HDL Hom HDL C HDL Het HDL Com HDL Hom HDL C HDL Het HDL Com HDL Hom DCF LDL HDL C HDL HetHDL C +LDL HDL Het + LDL HDL Com HDL Com +LDL Fluoresence(AU) MDA/HDL-c(RLU) Fig. 2. Login to comment
177 A compound heterozygote for ABCA1 mutations p.Q1038X/ p.N1800H did not present with CAD [25]. Login to comment
187 Loss of large α1 subpopulation and decrease in α2 apoA-I-containingHDL subpopulations has also been reported for other heterozygotes for ABCA1 gene defects (from two kindreds carrying ABCA1 mutation p.N1800H or variant aa217 to stop), while homozygotes (Tangier disease patients) were reported to only have pre-β1 apoA-I-containing HDL subpopulations [32]. Login to comment
147 Male/female TC HDL-c apoA-I apoA-II LDL-c apoB TG apoA-I mutation carriers Unaffected (n=3) 1/2 179&#b1;27 45&#b1;3 163&#b1;13 30&#b1;1 131&#b1;22 97&#b1;15 97&#b1;25 Heterozygotes (n=3) 1/2 141&#b1;12* 20&#b1;14* 87&#b1;38* 19&#b1;6* 113&#b1;5 85&#b1;6 97&#b1;45 ABCA1 mutation carriers Unaffected (n=8) 4/4 171&#b1;56 57&#b1;15 160&#b1;29 30&#b1;4 111&#b1;23 84&#b1;12 85&#b1;20 Heterozygotes (n=6) 3/3 179&#b1;64 37&#b1;7** 124&#b1;12** 28&#b1;2 129&#b1;35 98&#b1;22 90&#b1;44 Compound heterozygote 1c (n=1) 1/0 54 6 4 2 44 75 138 Compound heterozygote 2d (n=1) 0/1 220 3 7 ndb 173 192 387 Homozygote (n=1) 0/1 63 0.8 nd nd 61 81 87 LCAT mutation carriers Unaffected (n=7) 5/2 199&#b1;32 49&#b1;13 166&#b1;19 31&#b1;2 134&#b1;28 100&#b1;20 123&#b1;58 Heterozygotes (n=12) 8/4 166&#b1;47 32&#b1;11** 122&#b1;27*** 26&#b1;5* 122&#b1;38 97&#b1;28 115&#b1;49 Compound heterozygotes (n=3) 0/3 140&#b1;24* 5&#b1;1*** 48&#b1;8*** 3.8&#b1;0.3*** 118&#b1;17 102&#b1;27 244&#b1;103* Homozygote (n=1) 1/0 107 3 58 4 77 118 279 a Values presented as mean&#b1;SD (mg/dl); b nd, not detectable; c ABCA1[p.C1477R/IVS25+1GNC]; d ABCA1[p.Q1038X/ p.N1800H]. Login to comment
174 A compound heterozygote for ABCA1 mutations p.Q1038X/ p.N1800H did not present with CAD [25]. Login to comment
184 Loss of large b1;1 subpopulation and decrease in b1;2 apoA-I-containingHDL subpopulations has also been reported for other heterozygotes for ABCA1 gene defects (from two kindreds carrying ABCA1 mutation p.N1800H or variant aa217 to stop), while homozygotes (Tangier disease patients) were reported to only have pre-b2;1 apoA-I-containing HDL subpopulations [32]. Login to comment

[hide] An ABCA1 truncation shows no dominant negative eff... Biochem Biophys Res Commun. 2011 Jun 10;409(3):400-5. Epub 2011 May 7. Sorrenson B, Suetani RJ, Bickley VM, George PM, Williams MJ, Scott RS, McCormick SP
An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations.
Biochem Biophys Res Commun. 2011 Jun 10;409(3):400-5. Epub 2011 May 7., [PMID:21575609]

Abstract [show]
The ATP binding cassette transporter (ABCA1) A1 is a key determinant of circulating high density lipoprotein cholesterol (HDL-C) levels. Mutations in ABCA1 are a major genetic contributor to low HDL-C levels within the general population. Following the finding of three different ABCA1 mutations, p.C978fsX988, p.T1512M and p.N1800H in a subject with hypoalphalipoproteinemia, we aimed to establish whether the p.C978fsX988 truncation exerted a dominant negative effect on the full-length ABCA1 alleles within family members as has been reported for other ABCA1 truncations. Characterisation of the p.C978fsX988 mutant in transfected HEK 293 cells showed it to be expressed as a GFP fusion protein but lacking in cholesterol efflux function. This was in keeping with results from cholesterol efflux assays in the fibroblasts of p.C978fsX988 carriers which also showed impaired efflux. Allele- specific quantification of p.C978fsX988 mRNA and analysis of ABCA1 protein levels in the fibroblasts of p.C978fsX988 heterozygotes showed negligible levels of mRNA and protein expression. There was no evidence of a dominant negative effect on wildtype or p.N1800H protein levels. We conclude that in the case of the p.C978fsX988 truncated mutant a lack of expression precludes it from having a dominant negative effect.

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2 Following the finding of three different ABCA1 mutations, p.C978fsX988, p.T1512M and p.N1800H in a subject with hypoalphalipoproteinemia, we aimed to establish whether the p.C978fsX988 truncation exerted a dominant negative effect on the full-length ABCA1 alleles within family members as has been reported for other ABCA1 truncations. Login to comment
6 There was no evidence of a dominant negative effect on wildtype or p.N1800H protein levels. Login to comment
17 The majority of the 154 mutations identified in ABCA1 (see http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ABCA1) are missense mutations associated with isolated cases of Tangier disease or FHA, with some exceptions such as the common p.N1800H mutation [6]. Login to comment
29 In this study, we characterised a pedigree with three different ABCA1 mutations; p.N1800H, p.C978fsX988 and p.T1512M. Login to comment
30 The p.N1800H is a common ABCA1 mutation known to impair function [1,6,11,12]. Login to comment
31 The p.C978fsX988 and p.T1512M mutations were recently reported but were not characterised with respect to segregation, expression or function in the case of the p.C978fsX988 mutation [13]. Login to comment
33 This situation gave us the unique opportunity to test the effect of a short ABCA1 truncation on the expression and function of both the wildtype and the p.N1800H ABCA1 alleles. Login to comment
72 The T1512 primer was used to amplify the wildtype and p.N1800H alleles and the M1512 primer to amplify the p.C978fsX988/p.T1512M allele. Login to comment
84 Sequencing showed the proband (I:1) was heterozygote for three mutations; p.C978fsX988 (c.2934delT), p.T1512M (c.4535C > T) and p.N1800H (c.5398A > C). Login to comment
87 The daughter (II:2) was heterozygous for the N1800H mutation and the son (II:1) heterozygous for the p.C978fsX988 and p.T1512M mutations making it apparent that the p.C978fsX988 and p.T1512M mutations were on the same allele. Login to comment
101 No significant difference in stimulated mRNA levels was seen between wildtype and the two p.N1800H heterozygotes (I:2 and II:2). Login to comment
103 Allele-specific quantification of p.C978fsX988 mRNA in the two heterozygotes (Fig. 4B) showed it to be present at negligible levels compared to their p.N1800H (subject I:1) or wildtype allele (subject II:1). Login to comment
104 The level of p.N1800H and wildtype mRNA in these two subjects was approximately 50% that of the combined p.N1800H and wildtype mRNA levels in p.N1800H heterozygotes (I:2 and II:2). Login to comment
106 Protein levels in the subjects heterozygous for the p.N1800H allele were not significantly different to wildtype. Login to comment
108 Discussion In this study we describe and characterise a FHA pedigree harbouring three different ABCA1 mutations; p.C978fsX988, p.T 1512M and p.N1800H [12,13]. Login to comment
109 The proband, a compound heterozygote for the p.C978fsX988, p.T1512M and p.N1800H mutations, exhibited a low HDL-C level (0.23 mmol/L) but showed no signs of Tangier disease. Login to comment
110 Segregation of alleles within the family showed the p.C978fsX988 and p.T1512M mutations to be on the same allele making the p.T1512M mutation effectively redundant. Login to comment
111 As few studies have characterised the effect of truncated ABCA1 alleles [9,10,17], this family gave us a unique opportunity to test the effect of a short truncated allele on both the full-length wildtype and p.N1800H alleles. Login to comment
113 With respect to function, efflux studies in fibroblasts from all family members showed both the p.N1800H and p.C978fsX988 mutants to have impaired function as heterozygote carriers had significantly reduced cholesterol efflux compared to wildtype. Login to comment
115 The level of stimulated efflux correlated with the HDL-C levels seen in the individuals apart from the two p.N1800H heterozygotes, I:2 and II:2, who had similar efflux levels but different HDL-C levels (0.87 versus 1.33 mmol/L) respectively. Login to comment
117 Prior studies of the p.N1800H mutant in isolation have shown it to impair efflux capacity [6,11]. Login to comment
121 The p.C978fsX988/ p.T1512M and p.N1800H alleles are represented by grey and black shading respectively. Login to comment
144 Treatment of fibroblasts from both p.C978fsX988 carriers with cycloheximide caused an increase in mRNA levels that was not apparent in a p.N1800H heterozygote, providing evidence for nonsense-mediated decay of the p.C978fsX988 transcript. Login to comment
147 Protein analysis of fibroblasts showed p.C978fsX988 heterozygotes had ABCA1 protein levels 50% that of the p.N1800H heterozygotes, precluding a dominant negative effect for the p.C978fsX988 truncation. Login to comment
34 This situation gave us the unique opportunity to test the effect of a short ABCA1 truncation on the expression and function of both the wildtype and the p.N1800H ABCA1 alleles. Login to comment
73 The T1512 primer was used to amplify the wild-type and p.N1800H alleles and the M1512 primer to amplify the p.C978fsX988/p.T1512M allele. Login to comment
85 Sequencing showed the proband (I:1) was heterozygote for three mutations; p.C978fsX988 (c.2934delT), p.T1512M (c.4535C > T) and p.N1800H (c.5398A > C). Login to comment
88 The daughter (II:2) was heterozygous for the N1800H mutation and the son (II:1) heterozygous for the p.C978fsX988 and p.T1512M mutations making it apparent that the p.C978fsX988 and p.T1512M mutations were on the same allele. Login to comment
102 No significant difference in stimulated mRNA levels was seen between wildtype and the two p.N1800H heterozygotes (I:2 and II:2). Login to comment
105 The level of p.N1800H and wildtype mRNA in these two subjects was approximately 50% that of the combined p.N1800H and wildtype mRNA levels in p.N1800H heterozygotes (I:2 and II:2). Login to comment
107 Protein levels in the subjects heterozygous for the p.N1800H allele were not significantly different to wildtype. Login to comment
112 As few studies have characterised the effect of truncated ABCA1 alleles [9,10,17], this family gave us a unique opportunity to test the effect of a short truncated allele on both the full-length wildtype and p.N1800H alleles. Login to comment
114 With respect to function, efflux studies in fibroblasts from all family members showed both the p.N1800H and p.C978fsX988 mutants to have impaired function as heterozygote carriers had significantly reduced cholesterol efflux compared to wildtype. Login to comment
116 The level of stimulated efflux correlated with the HDL-C levels seen in the individuals apart from the two p.N1800H heterozygotes, I:2 and II:2, who had similar efflux levels but different HDL-C levels (0.87 versus 1.33 mmol/L) respectively. Login to comment
118 Prior studies of the p.N1800H mutant in isolation have shown it to impair efflux capacity [6,11]. Login to comment
122 The p.C978fsX988/ p.T1512M and p.N1800H alleles are represented by grey and black shading respectively. Login to comment
145 Treatment of fibroblasts from both p.C978fsX988 carriers with cycloheximide caused an increase in mRNA levels that was not apparent in a p.N1800H heterozygote, providing evidence for nonsense-mediated decay of the p.C978fsX988 transcript. Login to comment
148 Protein analysis of fibroblasts showed p.C978fsX988 heterozygotes had ABCA1 protein levels 50% that of the p.N1800H heterozygotes, precluding a dominant negative effect for the p.C978fsX988 truncation. Login to comment

[hide] Plasma levels of 27-hydroxycholesterol in humans a... Atherosclerosis. 2011 Feb;214(2):448-55. Epub 2010 Nov 3. Karuna R, Holleboom AG, Motazacker MM, Kuivenhoven JA, Frikke-Schmidt R, Tybjaerg-Hansen A, Georgopoulos S, van Eck M, van Berkel TJ, von Eckardstein A, Rentsch KM
Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism.
Atherosclerosis. 2011 Feb;214(2):448-55. Epub 2010 Nov 3., [PMID:21130455]

Abstract [show]
Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations in the genes for apolipoprotein A-I, ATP binding cassette transporter (ABC) A1 and lecithin:cholesterol acylstransferase (LCAT) were associated with reduced concentrations of both HDL-cholesterol and HDL-27OHC whereas mutations in the genes for cholesterylester transfer protein (CETP), scavenger receptor type BI and hepatic lipase were associated with elevated HDL concentrations of either sterol. Compared to family controls and relative to the concentrations of total 27OHC and cholesterol, lower 27OHC-ester but normal cholesterylester levels were found in HDL of heterozygous LCAT mutation carriers and nonHDL of heterozygous CETP mutation carriers. In family controls, LCAT activity and CETP mass were more strongly correlated with 27OHC-ester than cholesterylester concentrations in HDL and nonHDL, respectively. These findings suggest that the formation and transfer of 27OHC-esters are more sensitive to reduced activities of LCAT and CETP, respectively, than the formation and transfer of cholesterylesters. 27OHC plasma levels were also decreased in apoA-I-, ABCA1- or LCAT-knockout mice but increased in SR-BI-knockout mice. Transplantation of ABCA1- and/or ABCG1-deficient bone marrow into LDL receptor deficient mice decreased plasma levels of 27OHC. In conclusion, mutations or absence of HDL genes lead to distinct alterations in the quantity, esterification or lipoprotein distribution of 27OHC. These findings argue against the earlier suggestion that 27OHC-metabolism in plasma occurs independently of HDL.

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63 Mutated gene Number of defective alleles Mutationa Age (year) Cholesterol (mM) HDL-cholesterol (mM) NonHDL-cholesterol (mM) Triglyceride (mM) Number of smokers Dutch APOA1 0 27 ± 14 4.59 ± 0.68 1.16 ± 0.06 3.43 ± 0.63 1.09 ± 0.29 0 1 p.L202P (c.605T > C) 26 ± 17 3.61 ± 0.31 0.51 ± 0.35 3.10 ± 0.06 1.09 ± 0.51 0 ABCA1 0 44 ± 20 4.39 ± 0.89 1.47 ± 0.39 2.92 ± 0.62 0.95 ± 0.22 1 1 p.L1056P (c.3167T > C) or p.C1477R (c.4429T > C) 57 ± 11 4.47 ± 1.08 0.94 ± 0.17 3.53 ± 0.96 1.01 ± 0.05 0 2 p.L1056P (c.3167T > C, homozygote) or p.Q1038X (c.3112C > T) + p.N1800H (c.5398A > C) or p.C1477R (c.4429T > C) + IVS25 + 1G > C 53 ± 10 2.89 ± 2.39 NDb NDb 2.29 ± 1.80 0 LCAT 0 49 ± 9 4.96 ± 0.86 1.33 ± 0.38 3.62 ± 0.97 1.29 ± 0.66 0 1 p.T147I (c.440C > T), p.R322C (c.964C > T), p.N155D (c.463A > G), p.P34Q (c.101C > A), p.Y107X (c.321C > A), p.I202T (c.605T > C) or p.V333M (c.997G > A) 43 ± 13 4.27 ± 1.21 0.81 ± 0.28 3.45 ± 1.08 1.30 ± 0.55 1 2 p.T147I (c.440C > T) + V333M 69 ± 4 3.26 ± 0.19 NDb NDb 2.11 ± 0.49 0 SR-BI 0 54 ± 19 4.77 ± 0.89 1.17 ± 0.33 3.60 ± 0.79 1.21 ± 0.64 0 1 p.P297S (c.889C > T) 45 ± 22 4.46 ± 1.21 1.73 ± 0.56 2.73 ± 0.81 0.97 ± 0.28 1 CETP 0 36 ± 16 4.14 ± 0.51 1.30 ± 0.21 2.85 ± 0.48 0.87 ± 0.40 1 1 IVS7 + 1 (G > T) 39 ± 18 4.20 ± 0.51 1.56 ± 0.29 2.64 ± 0.77 0.76 ± 0.32 1 HL (LIPC) 0 45 ± 19 5.23 ± 0.99 1.61 ± 0.54 3.62 ± 0.90 1.45 ± 1.05 3 1 p.S289F (c.866C > T) 45 ± 15 4.92 ± 1.21 2.00 ± 0.68 2.92 ± 0.86 1.14 ± 0.43 1 Danish Controls 0 50 ± 9 5.84 ± 1.24 1.54 ± 0.24 4.30 ± 1.23 1.34 ± 0.62 1 APOA1 1 p.L168R (c.503T > G) 63 ± 4 4.70 ± 0.28 0.85 ± 0.07 3.85 ± 0.35 1.27 ± 0.70 0 CETP 1 p.S349Y (c.1046C > A) 59 ± 4 6.85 ± 2.05 3.05 ± 1.77 3.80 ± 0.28 0.86 ± 0.23 1 Values represent mean ± SD. Login to comment
62 Mutated gene Number of defective alleles Mutationa Age (year) Cholesterol (mM) HDL-cholesterol (mM) NonHDL-cholesterol (mM) Triglyceride (mM) Number of smokers Dutch APOA1 0 27 &#b1; 14 4.59 &#b1; 0.68 1.16 &#b1; 0.06 3.43 &#b1; 0.63 1.09 &#b1; 0.29 0 1 p.L202P (c.605T > C) 26 &#b1; 17 3.61 &#b1; 0.31 0.51 &#b1; 0.35 3.10 &#b1; 0.06 1.09 &#b1; 0.51 0 ABCA1 0 44 &#b1; 20 4.39 &#b1; 0.89 1.47 &#b1; 0.39 2.92 &#b1; 0.62 0.95 &#b1; 0.22 1 1 p.L1056P (c.3167T > C) or p.C1477R (c.4429T > C) 57 &#b1; 11 4.47 &#b1; 1.08 0.94 &#b1; 0.17 3.53 &#b1; 0.96 1.01 &#b1; 0.05 0 2 p.L1056P (c.3167T > C, homozygote) or p.Q1038X (c.3112C > T) + p.N1800H (c.5398A > C) or p.C1477R (c.4429T > C) + IVS25 + 1G > C 53 &#b1; 10 2.89 &#b1; 2.39 NDb NDb 2.29 &#b1; 1.80 0 LCAT 0 49 &#b1; 9 4.96 &#b1; 0.86 1.33 &#b1; 0.38 3.62 &#b1; 0.97 1.29 &#b1; 0.66 0 1 p.T147I (c.440C > T), p.R322C (c.964C > T), p.N155D (c.463A > G), p.P34Q (c.101C > A), p.Y107X (c.321C > A), p.I202T (c.605T > C) or p.V333M (c.997G > A) 43 &#b1; 13 4.27 &#b1; 1.21 0.81 &#b1; 0.28 3.45 &#b1; 1.08 1.30 &#b1; 0.55 1 2 p.T147I (c.440C > T) + V333M 69 &#b1; 4 3.26 &#b1; 0.19 NDb NDb 2.11 &#b1; 0.49 0 SR-BI 0 54 &#b1; 19 4.77 &#b1; 0.89 1.17 &#b1; 0.33 3.60 &#b1; 0.79 1.21 &#b1; 0.64 0 1 p.P297S (c.889C > T) 45 &#b1; 22 4.46 &#b1; 1.21 1.73 &#b1; 0.56 2.73 &#b1; 0.81 0.97 &#b1; 0.28 1 CETP 0 36 &#b1; 16 4.14 &#b1; 0.51 1.30 &#b1; 0.21 2.85 &#b1; 0.48 0.87 &#b1; 0.40 1 1 IVS7 + 1 (G > T) 39 &#b1; 18 4.20 &#b1; 0.51 1.56 &#b1; 0.29 2.64 &#b1; 0.77 0.76 &#b1; 0.32 1 HL (LIPC) 0 45 &#b1; 19 5.23 &#b1; 0.99 1.61 &#b1; 0.54 3.62 &#b1; 0.90 1.45 &#b1; 1.05 3 1 p.S289F (c.866C > T) 45 &#b1; 15 4.92 &#b1; 1.21 2.00 &#b1; 0.68 2.92 &#b1; 0.86 1.14 &#b1; 0.43 1 Danish Controls 0 50 &#b1; 9 5.84 &#b1; 1.24 1.54 &#b1; 0.24 4.30 &#b1; 1.23 1.34 &#b1; 0.62 1 APOA1 1 p.L168R (c.503T > G) 63 &#b1; 4 4.70 &#b1; 0.28 0.85 &#b1; 0.07 3.85 &#b1; 0.35 1.27 &#b1; 0.70 0 CETP 1 p.S349Y (c.1046C > A) 59 &#b1; 4 6.85 &#b1; 2.05 3.05 &#b1; 1.77 3.80 &#b1; 0.28 0.86 &#b1; 0.23 1 Values represent mean &#b1; SD. Login to comment

[hide] Mutations in APOA-I and ABCA1 in Norwegians with l... Clin Chim Acta. 2010 Dec 14;411(23-24):2019-23. Epub 2010 Aug 25. Berge KE, Leren TP
Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol.
Clin Chim Acta. 2010 Dec 14;411(23-24):2019-23. Epub 2010 Aug 25., [PMID:20800056]

Abstract [show]
BACKGROUND: Epidemiological studies have shown that low levels of plasma high density lipoprotein (HDL) cholesterol are associated with increased risk of ischemic heart disease (IHD), but it appears that genetic forms of low HDL cholesterol levels, as opposed to lifestyle-induced low levels of HDL cholesterol, do not result in increased risk of IHD. Therefore, the etiology of reduced levels of plasma HDL cholesterol may represent a factor that should be considered in risk stratification with respect to primary prevention. Genes encoding proteins involved in HDL metabolism, such as the ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein (apo) A-I genes, are candidate genes for harboring mutations that lead to low HDL cholesterol levels. METHODS: The ABCA1 and apoA-I genes in 56 Norwegian patients, with a mean HDL cholesterol level of 0.53 (+/-0.15) mmol/l, were subjected to DNA sequencing. RESULTS: Several mutations were identified in the ABCA1 gene, and two mutations were identified in the apoA-I gene. A total of 18 patients (32%) were carriers of mutations considered to be pathogenic. Their mean HDL cholesterol level was 0.45 (+/-0.15) mmol/l compared to 0.57 (+/-0.14) mmol/l in noncarriers (p<0.005). CONCLUSION: Mutations in the genes encoding ABCA1 and apoA-I are common in Norwegians, with a markedly decreased HDL cholesterol level.

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59 of patients (het/hom)a Mutation Nucleotide Exon/Intron (i) PolyPhen prediction (score) SNP rs ID, ref.# ABCA1 Missense 8/3 R219K c.656, GNA 7 Benign (0.489) rs2230806 0/1 R282Q c.845, GNA 9 Benign (0.592) Novel 1/0 V399A c.1196, TNC 11 Benign (0.040) rs9282543 1/0 M636V c.1906, ANG 15 Benign (0.418) Novel 3/0 V771M c.2311, GNA 16 Benign (0.931) rs2066718 2/0 V825I c.2473, GNA 17 Benign (0.440) rs2066715 3/1 I883M c.2649, ANG 18 Benign (0.147) rs2066714 1/0 C887F c.2660, GNT 19 Benign (0.888) Novel 3/0 E1172D c.3516, GNC 24 Benign (0.546) rs33918808 1/0 G1216V c.3647, GNT 25 Prob damb (2.154) Ref. [18] 1/0 L1244Q c.3731, TNA 25 Prob dam (2.269) Novel 1/0 C1477F c.4430, TNA 31 Prob dam (3.688) Ref. [17] 14/1 R1587K c.4760, ANT 35 Benign (0.284) rs2230808 1/0 V1674I c.5020, GNA 37 Benign (0.821) Novel 1/0 R1680Q c.5039, GNA 37 Poss damc (1.926) Ref. [17] 1/0 N1800H c.5398, ANC 40 Poss dam (1.845) Ref. [19] Nonsense/splice 1/0 IVS4+1, GNA c.302+1, GNA i4 - 1/0 C1429X c.4287, CNA 31 - 1/0 IVS32+1, GNA c.4559+1, GNA i32 - APOA-I 7/0 R160L c.551, GNT 4 Prob dam (2.491) Ref. [21] 1/0 del182K del c.616-618 AAG 4 - Novel a Het: heterozygote, hom: homozygote. Login to comment
74 Three patients were heterozygous for ABCA1 mutations G1216V, C1477F, and N1800H that have been reported to be associated with low HDL cholesterol levels [17-19]. Login to comment
88 HDL cholesterol levels in individuals carrying a pathogenic mutation in the ABCA1 or apoA-I genes Both the two identified apoA-I mutations and the following ABCA1 mutations were considered pathogenic: the nonsense mutation (C1429X); the two splice-site mutations (IVS4 +1, G NA and IVS32+1, GNA ); novel mutations R282Q, M636V, C887F, L1244Q, and V1674I; and mutations previously reported to be associated with low HDL cholesterol levels (G1216V, C1477F and N1800H). Login to comment
116 This has been shown for mutations G1216V, C1477F, and N1800H [11,17], thereby explaining the mechanism for the low HDL cholesterol levels in carriers of these mutations. Login to comment

[hide] Identification and characterization of novel loss ... Atherosclerosis. 2010 Dec;213(2):492-8. Epub 2010 Aug 26. Candini C, Schimmel AW, Peter J, Bochem AE, Holleboom AG, Vergeer M, Dullaart RP, Dallinga-Thie GM, Hovingh GK, Khoo KL, Fasano T, Bocchi L, Calandra S, Kuivenhoven JA, Motazacker MM
Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.
Atherosclerosis. 2010 Dec;213(2):492-8. Epub 2010 Aug 26., [PMID:20880529]

Abstract [show]
OBJECTIVES: The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations. METHODS: The coding regions and exon-intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A-I as acceptor) after transient expression of ABCA1 variants in BHK cells. RESULTS: Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity. CONCLUSION: This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.

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76 Patients (gender, age) Amino acida (nucleotidea ) change TC TG LDL-c HDL-c Clinical manifestations of TD CVD Other relevant clinical data Homozygotes Patient 1 (female, 42) p.L1056P (c.3167T > C) 2.4 0.9 1.99 <0.10 Absent CAD Thrombocytopenia Patient 2 (male, 40) p.Wl747X (c.5240G > A) 1.76 1.93 0.52 0.1-0.3 Neuropathy, splenomegaly, thrombocytopenia Mild stenosis (20-30%) of coronary arteries None Patient 3 (male, 55) p.F593L (c.1779C > G) 4.4 1.4 3.6 <0.10 Absent CAD None p.E1253K (c.3757G > A) Compound heterozygotes Patient 4 (female, 63) p.Q1038X (c.3112C > T) 6.68 2.72 5.4 <0.10 Absent None None p.N1800H (c.5398A > C) [32] Patient 5 (female, 28) p.T1512M (c.4535C > T) 4.42 1.83 3.46 0.1 Absent None None p.N1800H (c.5398A > C) [32] p.C978fsX988 (c.2934delT) Patient 6 (female, 17) p.D575G (c.1724A > G) 4.96 2.84 4.35 <0.10 Absent None DM1 p.C1941R(c.5821T > C) Heterozygotes Patient 7 (male, 42) p.S100C (c.299C > G) 8.5 8.7 4.3 0.3 N.A. None None Patient 8 (male, 58) p.E1172D (c.3516G > C) [33] 6.4 2.7 4.1 0.9 N.A. None None Patient 9 (male, 35) p.S1181F (c.3542C > T) [17] 2.9 0.31 1.88 0.88 N.A. None None Patient 10 (male, 48) p.C1477R (c.4429T > C) [13] 2.01 1.4 0.92 0.46 N.A. CAD None Patient 11 (male, 68) p.V1858A (c.5573T > C) 4.9 3.78 2.41 0.75 N.A. CAD None Patient 12 (female, 36) p.N1800H (c.5398A > C) [32] 4.6 1.2 4 <0.10 N.A. None DM2, obesity Patient 13 (male, 67) p.R282X (c.844C > T) [34] 3.2 1.21 2.14 0.51 N.A. None DM2 Patient 14 (female, 42) p.W424X (c.1272G > A) 2.07 1.04 1.39 0.21 N.A. None None Patient 15 (female, 52) N.A. - (IVS11 - 1G > A) 5.51 3.51 3.28 0.56 N.A. None Hypothyroidism, hypertension Patient 16 (female, 54) N.A. - (IVS48 + 2T > C) 3.29 1.92 1.94 0.49 N.A. None DM2, hypertension a Nomenclature based on guidelines of Human Genome Variation Society. Login to comment
89 In ABCA1, we identified 14 novel and 5 known genetic variations in 16 subjects including one frameshift (p.C978fsX988), 2 splice-site (IVS11-1G > C and IVS48 + 2T > C), 4 nonsense (p.R282X, p.W424X, p.Q1038X, p.Wl747X) and 12 missense variations (p.S100C, p.D575G, p.F593L, p.L1056P, p.E1172D, p.S1181F, p.E1253K, p.C1477R, p.T1512M, p.N1800H, p.V1858A, p.C1941R). Login to comment

[hide] Genetic variation in the ABCA1 gene, HDL cholester... Atherosclerosis. 2010 Feb;208(2):305-16. Epub 2009 Jun 11. Frikke-Schmidt R
Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population.
Atherosclerosis. 2010 Feb;208(2):305-16. Epub 2009 Jun 11., [PMID:19596329]

Abstract [show]
Epidemiological studies consistently demonstrate a strong inverse association between low levels of high-density lipoprotein (HDL) cholesterol and increased risk of ischemic heart disease (IHD). This review focuses on whether both rare and common genetic variation in ABCA1 contributes to plasma levels of HDL cholesterol and to risk of IHD in the general population, and further seeks to understand whether low levels of HDL cholesterol per se are causally related to IHD. Studies of the ABCA1 gene demonstrate a general strategy for detecting functional genetic variants, and show that both common and rare ABCA1 variants contribute to levels of HDL cholesterol and risk of IHD in the general population. The association between ABCA1 variants and risk of IHD appears, however, to be independent of plasma levels of HDL cholesterol. With the recent identification of the largest number of individuals heterozygous for loss-of-function mutations in ABCA1 worldwide, population studies suggests that genetically low HDL cholesterol per se does not predict an increased risk of IHD, and thus questions the causality of isolated low levels of HDL cholesterol for the development of IHD.

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2337 4.2. Frequency of mutations in the general population Four of seven non-synonymous mutations (P1065C, G1216V, N1800H, R2144X), ranging in frequency from 0.1 to two per 1000, were associated with low levels of HDL cholesterol in the general population. Login to comment
2340 These mutations were considered to be private mutations occurring only in individual families [30], until two studies of two different general population samples detected the well known Tangier disease mutation, N1800H [67], in three unrelated white individuals with low HDL cholesterol (below the 1st percentile) from the CCHS and in one white individual with low HDL cholesterol (below the 5th percentile) from the Dallas Heart Study [57,58]. Login to comment
2342 Genotyping revealed 28 het- erozygous carriers of P1065S, G1216V, N1800H, and R2144X in the CCHS (n = 9022), and 76 heterozygous carriers of G1216V, N1800H, and R2144 in the Copenhagen General Population Study (CGPS) (n = 31,241) [66]. Login to comment
2343 By large-scale genotyping, and confirmed by in vitro cellular cholesterol efflux assays, Frikke-Schmidt et al. showed that the P1065S, G1216V, and N1800H were indeed loss-of-function mutations causing low HDL cholesterol levels in the general population. Login to comment
2344 The N1800H mutation accounted for the majority of HDL lowering mutations, 22 of 28 carriers in the CCHS, and 70 of 76 carriers in the CGPS [66]. Login to comment
2488 Left panel: Median decrease in HDL cholesterol levels for ABCA1 heterozygotes in the general population for all mutations (top), and for N1800H alone (bottom). Login to comment
2487 Left panel: Median decrease in HDL cholesterol levels for ABCA1 heterozygotes in the general population for all mutations (top), and for N1800H alone (bottom). Login to comment

[hide] Identification of three loci affecting HDL-cholest... J Lipid Res. 2009 Mar;50(3):534-45. Epub 2008 Oct 29. Juan T, Veniant MM, Helmering J, Babij P, Baker DM, Damore MA, Bass MB, Gyuris T, Chhoa M, Li CM, Ebeling C, Amato J, Carlson GA, Lloyd DJ
Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice.
J Lipid Res. 2009 Mar;50(3):534-45. Epub 2008 Oct 29., [PMID:18974039]

Abstract [show]
We conducted a genome-wide screen using the mutagen N-ethyl-N-nitrosourea to identify recessive mutations in genes that lead to altered lipid traits in mice. We screened 7,546 G3 mice that were of mixed C57BL/6J (B6) x C3.SW-H2(b)/SnJ (C3) genomes and identified three pedigrees with differences in plasma HDL-cholesterol. Genome scan analyses mapped three distinct loci to chromosomes 3, 4, and 7. An S1748L missense mutation was identified in ABCA1 in one pedigree with undetectable levels of HDL-cholesterol and resulted in reduced protein levels. This phenotype was completely penetrant, semi-dominant, and cosegregated with high plasma triglycerides. Mice in a second pedigree had very high levels of plasma total cholesterol and HDL-cholesterol (up to 800 mg/dl total cholesterol). Despite a high degree of phenotype lability and reduced penetrance, an I68N missense mutation was identified in the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha). Finally, a second high HDL-cholesterol pedigree of mice, again with a highly labile phenotype and reduced penetrance, was mapped to a 7 Mb locus on chromosome 3. These results illustrate the use of a hybrid background for simultaneous screening and mapping of mutagenized pedigrees of mice and identification of three novel alleles of HDL-cholesterol phenotypes.

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246 The S1748L mutation is predicted to be located in a transmembrane domain between the V1704D and N1800H missense mutations identified in patients with Tangier disease (39). Login to comment
247 Although 44 missense mutations have been identified in ABCA1, only 2 (W840R and V1704D) are expected to lie in the transmembrane domain. Login to comment

[hide] ABCA1 gene mutations, HDL cholesterol levels, and ... JAMA. 2008 Nov 5;300(17):1997-8; author reply 1998. Brunham LR, Kastelein JJ, Hayden MR
ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease.
JAMA. 2008 Nov 5;300(17):1997-8; author reply 1998., [PMID:18984885]

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24 The N1800H mutation, although known to impair ABCA1-mediated cholesterol efflux,1,2 was associated with only a 28% reduction in HDL levels in this cohort.1 Complete loss-of-function mutations in ABCA1 tend to be associated with a 50% reduction in HDL levels, corresponding to a complete loss of function of one ABCA1 allele.3 The mild nature of these variants is again indicated by the modest impairment in efflux, especially for the rare variants, reported as 74% to 79% of normal.1 Such a small reduction in function is of questionable significance given the relatively large variability of this assay. Login to comment
27 The N1800H mutation, although known to impair ABCA1-mediated cholesterol efflux,1,2 was associated with only a 28% reduction in HDL levels in this cohort.1 Complete loss-of-function mutations in ABCA1 tend to be associated with a 50% reduction in HDL levels, corresponding to a complete loss of function of one ABCA1 allele.3 The mild nature of these variants is again indicated by the modest impairment in efflux, especially for the rare variants, reported as 74% to 79% of normal.1 Such a small reduction in function is of questionable significance given the relatively large variability of this assay. Login to comment

[hide] Effect of ABCA1 mutations on risk for myocardial i... Curr Atheroscler Rep. 2008 Oct;10(5):413-26. Iatan I, Alrasadi K, Ruel I, Alwaili K, Genest J
Effect of ABCA1 mutations on risk for myocardial infarction.
Curr Atheroscler Rep. 2008 Oct;10(5):413-26., [PMID:18706283]

Abstract [show]
The adenosine triphosphate-binding cassette A1 (ABCA1) gene codes for a cellular phospholipid and cholesterol transporter that mediates the initial and essential step in high-density lipoprotein (HDL) biogenesis: the formation of nascent HDL particles. Mutations at the ABCA1 gene locus cause severe familial HDL deficiency and, in the homozygous form, cause Tangier disease. Several studies have investigated the influence of ABCA1 variation on lipid metabolism and coronary heart disease, but they have resulted in controversial and inconsistent results. Genetic variability at the ABCA1 gene has also been associated with increased risk of myocardial infarction. In one study, this association was independent of HDL cholesterol levels, raising the possibility that the measurement of HDL cholesterol levels may not provide adequate information on the functional roles of HDL particles. Nevertheless, genomic screening for complex diseases, such as coronary heart disease, and HDL deficiency in particular, may not add additional information to that gained from conventional global cardiovascular risk stratification.

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87 One mutation (ABCA1 N1800H) was found in both Canadian and Dallas low-HDL-C groups. Login to comment

[hide] Association of loss-of-function mutations in the A... JAMA. 2008 Jun 4;299(21):2524-32. Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, Grande P, Tybjaerg-Hansen A
Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.
JAMA. 2008 Jun 4;299(21):2524-32., [PMID:18523221]

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CONTEXT: Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. OBJECTIVE: To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD). DESIGN, SETTING, AND PARTICIPANTS: Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31,241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16,623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. MAIN OUTCOME MEASURES: Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. RESULTS: Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41,961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62). CONCLUSION: Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.

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12 Results Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (PϽ.001). Login to comment
26 The 9022 individuals were genotyped for all non-synonymous mutations (S364C, T774P, K776N, P1065S, G1216V, N1800H, R2144X [http://www.hgmd.cf.ac.uk/ac /index.php; http://www.mutdb.org]), which were previously identified by resequencing the promoter, coding region,andconsensussplicesitesofABCA1 in 190 individuals of Danish ancestry with high and low HDL cholesterol levels.13 All end points and data collection were recorded in the follow-up period of January 1, 1976, through July 9, 2007. Login to comment
39 Participants in the CIHDS were genotyped for the 4 mutations (P1065S, G1216V, N1800H, R2144X) associated with reduced HDL cholesterol levels in the CCHS and the CGPS. Login to comment
48 HeLa cells were transfected (ExGen 500 in vitro transfection reagent, Fermentas Inc, Hanover, Maryland) with plasmids expressing the ABCA1 mutations (P1065S, G1216V, N1800H) created by site-directed mutagenesis (Quick- Change II XL Site-Directed Mutagenesis Kit, Stratagene Inc, La Jolla, California);R2144Xhaspreviouslybeenshown to cause reduced cholesterol efflux.7 Sequences of all plasmids were confirmed by direct sequencing (Applied Biosys- temsInc),andtransfectionefficiencywas examined by flow cytometry of transfected HeLa cells. Login to comment
60 On a continuous scale, a 17-mg/dL (to convert to mmol/L, multiply by 0.0259) lower HDL cholesterol level associated with a multifactorially adjusted HR for IHD of 1.70 (95% CI, 1.57-1.85), similar to that reported in other studies.1 ABCA1 Mutation Heterozygotes and Plasma HDL Cholesterol Four of 7 mutations (P1065S, G1216V, N1800H, R2144X) were associated with Figure 1. Login to comment
69 Number of Participants Heterozygous for Missense or Nonsense Mutations in ABCA1 in the Studied Populations Mutation CCHS (n = 9022) CGPS (n = 31 241) CIHDS (n = 2498) P1065S 1 0 0 G1216V 3 3 1 N1800H 22 70 3 R2144X 2 3 1 Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study. Login to comment
72 The overall heterozygote frequency in the general population was approximately 3:1000 in both the CCHS and the CGPS, the majority carrying the N1800H mutation. Login to comment
74 Unadjusted plasma levels of HDL cholesterol were reduced by, respectively, 17 mg/dL in heterozygotes overall and 16 mg/dL in N1800H heterozygotes alone (PϽ.001); the corresponding reductions for apolipoprotein A-I were 40 mg/dL and 34 mg/dL (to convert to g/L, multiply by 0.01) (PϽ.001). Login to comment
78 ABCA1 Mutations and Cellular Cholesterol Efflux in Vitro In agreement with the observed lower plasma HDL cholesterol levels associated with these mutations in vivo, 4 mutations were associated with impaired cholesterol efflux in vitro: 79% (95% CI, 56%-103%) for P1065S, 74% (95% CI, 54%-95%) for G1216V, 49% (95% CI, 37%-60%) for N1800H, and 48%7 for R2144X compared with 100% in wild-type (P=.04 for all). Login to comment
81 Characteristics of Individuals Heterozygous for Missense or Nonsense Mutations in ABCA1 and Cardiovascular Risk Factors Among 9022 Participants in the Copenhagen City Heart Studya Characteristic Noncarriers (n = 8994) Heterozygotes N1800H (n = 22) Rare Mutations (n = 6)b All Mutations (n = 28)c Age, median (IQR), y 60 (48-70) 64 (58-78)d 61 (54-74) 64 (57-77)d Sex, No. Login to comment
89 cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment
98 When restricting the analyses to N1800H heterozygotes, the corresponding values were an HR of 0.50 (95% CI, 0.16-1.56), an OR of 0.87 (95% CI, 0.36-2.10), and an OR of 0.51 (95% CI, 0.15-1.80). Login to comment
100 When restricting the analyses to N1800H heterozygotes (n=95), the equivalent OR was 0.77 (95% CI, 0.41-1.45); with 80% statistical power to exclude an OR of 1.85 or more. Login to comment
111 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen City Heart Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 220 140 160 120 180 200 100 80 60 0 20 40 60 80 100 Women Age, y Age, y Age, y 200 160 140 180 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I Mutation P1065S G1216V N1800H R2144X 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th mg/dLmg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (N=9022). Login to comment
117 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen General Population Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 240 140 160 120 180 200 220 100 80 0 20 40 60 80 100 Women Age, y 240 160 140 180 200 220 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th G1216V N1800H R2144X Mutation Age, y Age, y mg/dLmg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (n=31 241). Login to comment
137 1741 2427 2498 6666 HR (95% CI) OR (95% CI) Age-and sex-adjusted All mutations 0.65 (0.27-1.56) 0.96 (0.41-2.26) 0.73 (0.29-1.86) 0.84 (0.48-1.45) N1800H 0.47 (0.15-1.46) 1.04 (0.44-2.47) 0.46 (0.14-1.51) 0.69 (0.37-1.29) Multifactorially adjustedb All mutations 0.67 (0.28-1.61) 0.82 (0.34-1.96) 0.86 (0.32-2.32) 0.93 (0.53-1.62) N1800H 0.50 (0.16-1.56) 0.87 (0.36-2.10) 0.51 (0.15-1.80) 0.77 (0.41-1.45) Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study; HR, hazard ratio; OR, odds ratio. Login to comment
25 The 9022 individuals were genotyped for all nonsynonymous mutations (S364C, T774P, K776N, P1065S, G1216V, N1800H, R2144X [http://www.hgmd.cf.ac.uk/ac /index.php; http://www.mutdb.org]), which were previously identified by resequencing the promoter, coding region,andconsensussplicesitesofABCA1 in 190 individuals of Danish ancestry with high and low HDL cholesterol levels.13 All end points and data collection were recorded in the follow-up period of January 1, 1976, through July 9, 2007. Login to comment
38 Participants in the CIHDS were genotyped for the 4 mutations (P1065S, G1216V, N1800H, R2144X) associated with reduced HDL cholesterol levels in the CCHS and the CGPS. Login to comment
47 When restricting the analyses to N1800H heterozygotes, the corresponding values were an HR of 0.50 (95% CI, 0.16-1.56), an OR of 0.87 (95% CI, 0.36-2.10), and an OR of 0.51 (95% CI, 0.15-1.80). Login to comment
52 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen City Heart Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 220 140 160 120 180 200 100 80 60 0 20 40 60 80 100 Women Age, y Age, y Age, y 200 160 140 180 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I Mutation P1065S G1216V N1800H R2144X 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th mg/dL mg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (N=9022). Login to comment
56 The overall heterozygote frequency in the general population was approximately 3:1000 in both the CCHS and the CGPS, the majority carrying the N1800H mutation. Login to comment
58 Unadjusted plasma levels of HDL cholesterol were reduced by, respectively, 17 mg/dL in heterozygotes overall and 16 mg/dL in N1800H heterozygotes alone (Pb0d;.001); the corresponding reductions for apolipoprotein A-I were 40 mg/dL and 34 mg/dL (to convert to g/L, multiply by 0.01) (Pb0d;.001). Login to comment
62 ABCA1 Mutations and Cellular Cholesterol Efflux in Vitro In agreement with the observed lower plasma HDL cholesterol levels associated with these mutations in vivo, 4 mutations were associated with impaired cholesterol efflux in vitro: 79% (95% CI, 56%-103%) for P1065S, 74% (95% CI, 54%-95%) for G1216V, 49% (95% CI, 37%-60%) for N1800H, and 48%7 for R2144X compared with 100% in wild-type (P=.04 for all). Login to comment
65 Characteristics of Individuals Heterozygous for Missense or Nonsense Mutations in ABCA1 and Cardiovascular Risk Factors Among 9022 Participants in the Copenhagen City Heart Studya Characteristic Noncarriers (n = 8994) Heterozygotes N1800H (n = 22) Rare Mutations (n = 6)b All Mutations (n = 28)c Age, median (IQR), y 60 (48-70) 64 (58-78)d 61 (54-74) 64 (57-77)d Sex, No. Login to comment
73 cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment
84 When restricting the analyses to N1800H heterozygotes, the corresponding values were an HR of 0.50 (95% CI, 0.16-1.56), an OR of 0.87 (95% CI, 0.36-2.10), and an OR of 0.51 (95% CI, 0.15-1.80). Login to comment
85 When the number of IHD events/cases and controls from all 3 studies were combined to achieve the maximal statistical power (n=41 961; n=6666 cases; 109 heterozygotes), the corresponding OR for IHD inheterozygotesvsnoncarrierswas0.93 (95% CI, 0.53-1.62); with 80% statistical power to exclude an OR of 1.77 or more. When restricting the analyses to N1800H heterozygotes (n=95), the equivalent OR was 0.77 (95% CI, 0.41-1.45); with 80% statistical power to exclude an OR of 1.85 or more. COMMENT The principal finding of this study is that heterozygosity for loss-of-function mutations in ABCA1 associated with substantial, lifelong lowering of plasma levels of HDL cholesterol, but not with corresponding higher levels of plasma triglycerides or atherogenic remnant lipoproteins, did not predict an increased risk of IHD. Login to comment
120 1741 2427 2498 6666 HR (95% CI) OR (95% CI) Age-and sex-adjusted All mutations 0.65 (0.27-1.56) 0.96 (0.41-2.26) 0.73 (0.29-1.86) 0.84 (0.48-1.45) N1800H 0.47 (0.15-1.46) 1.04 (0.44-2.47) 0.46 (0.14-1.51) 0.69 (0.37-1.29) Multifactorially adjustedb All mutations 0.67 (0.28-1.61) 0.82 (0.34-1.96) 0.86 (0.32-2.32) 0.93 (0.53-1.62) N1800H 0.50 (0.16-1.56) 0.87 (0.36-2.10) 0.51 (0.15-1.80) 0.77 (0.41-1.45) Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study; HR, hazard ratio; OR, odds ratio. Login to comment

[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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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
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
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
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

[hide] Functional mutations of the ABCA1 gene in subjects... Atherosclerosis. 2006 Oct;188(2):281-91. Epub 2005 Dec 15. Alrasadi K, Ruel IL, Marcil M, Genest J
Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency.
Atherosclerosis. 2006 Oct;188(2):281-91. Epub 2005 Dec 15., [PMID:16343503]

Abstract [show]
Mutations in the ABCA1 gene cause defective cellular lipid efflux and severe familial HDL deficiency. We examined the prevalence of mutations at the ABCA1 gene in 58 unrelated probands of French-Canadian descent with HDL deficiency (HDL-C<5th percentile). A defective cellular cholesterol or phospholipid efflux (<75% and <70% of normal controls, respectively) was identified in 14/58 (24%) of subjects. Using direct sequencing of the ABCA1 gene, we found mutations in 12/58 ( approximately 20%) of subjects. Four probands were previously identified with diverse ABCA1 gene defects. However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Three probands had the S1731C mutation, while two others had the R1851X and K776N documented mutations, respectively. Taken together, these data suggest that approximately 20% of French-Canadian patients with severe HDL deficiency are associated with a defective ABCA1. Interestingly, in two families studied, mutations in the ABCA1 gene did not segregate with the lipid efflux defect, suggesting that other proteins are involved in the ABCA1-mediated cellular lipid efflux.

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5 However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Login to comment
86 Table 2 Mutations of the ABCA1 gene in French-Canadian probands with HDL deficiency and defective cellular lipid efflux Probandsa Gene region Nucleotide change Amino acid change Predicted effect by Polyphenb Reference ABE Exon 48 C6370T R2084X Truncated protein [8,9] MGA Exon 14 del 2017-2019 del L693 Probably damaging [8,9] ALA Exon 41 del 5618-5623 del ED1893,4 Probably damaging [8,9] RLA Exon 18 C2665T R909X Truncated protein [8,9] RDU Exon 41 C5864T R1851X Truncated protein [4] SBO Exon 40 A5711C N1800H Possibly damaging [27] Exon 49 G6943C Q2210H Probably damaging - RPH Exon 14 G2160T G616V Probably damaging - GOB Exon 41 del 5833 fs F1840L, L1869X Truncated protein - LNO Exon 38 C5505G S1731C Possibly damaging [4] VDU Exon 38 C5505G S1731C Possibly damaging [4] RRI Exon 38 C5505G S1731C Possibly damaging [4] PCH Exon 16 G2641C K776N Possibly damaging [5] GCH - - - - - LBO - - - - - a Probands refer to subjects ID # 301 in the pedigrees. b Polyphen computer software (http://www.bork.embl-heidelberg.de/polphen/). Login to comment
111 In another proband, SBO, we identified heteroallelic mutations N1800H (previously reported in Tangier disease [27]) and a novel mutation, Q2210H, which is predicted to be probably damaging to the protein by the computer program Polyphen. Login to comment
140 Single amino acid substitutions were identified in the six remaining subjects, with one proband heteroallelic for the N1800H and Q2210H mutation (a novel mutation, predicted to be probably damaging to the protein). Login to comment
142 In fact, the N1800H mutation in the ABCA1 gene has been previously reported in a case of Tangier disease [27] in a patient homozygous for this mutation. Login to comment

[hide] Specific mutations in ABCA1 have discrete effects ... Circ Res. 2006 Aug 18;99(4):389-97. Epub 2006 Jul 27. Singaraja RR, Visscher H, James ER, Chroni A, Coutinho JM, Brunham LR, Kang MH, Zannis VI, Chimini G, Hayden MR
Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro.
Circ Res. 2006 Aug 18;99(4):389-97. Epub 2006 Jul 27., [PMID:16873719]

Abstract [show]
Mutations in ATP-binding cassette transporter A1 (ABCA1) cause Tangier disease and familial hypoalphalipoproteinemia, resulting in low to absent plasma high-density lipoprotein cholesterol levels. However, wide variations in clinical lipid phenotypes are observed in patients with mutations in ABCA1. We hypothesized that the various lipid phenotypes would be the direct result of discrete and differing effects of the mutations on ABCA1 function. To determine whether there is a correlation between the mutations and the resulting phenotypes, we generated in vitro 15 missense mutations that have been described in patients with Tangier disease and familial hypoalphalipoproteinemia. Using localization of ABCA1, its ability to induce cell surface binding of apolipoprotein A-I, and its ability to elicit efflux of cholesterol and phospholipids to apolipoprotein A-I we determined that the phenotypes of patients correlate with the severity and nature of defects in ABCA1 function.

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44 In patients defined by missense mutations on both alleles, 2 clear groups were observed: those showing negligible plasma HDL-C (R587W, N935S, N1800H), and those with HDL-C levels that were Ϸ10% of HDL-C in controls (A255T). Login to comment
48 Six mutants, R587W, Q597R, ⌬L693, N935S, N1800H, and R2081W, showed no localization at the plasma membrane and instead accumulated intracellularly (Figure 2A), indicating that these mutations severely affect ABCA1 function by preventing its migration to the plasma membrane, thus diminishing its ability to efflux lipids and generate HDL. Login to comment
68 All 6 mutants showing no plasma membrane localization elicited significantly reduced cell surface ApoA-I binding (R587W, 33.0Ϯ8.9%, nϭ3, Pϭ0.006; Q597R, 17.4Ϯ14.0%, nϭ3, Pϭ0.009; ⌬L693, 32.6Ϯ10.6%, nϭ3, Pϭ0.008; N935S, 26.4Ϯ37.5%, nϭ3, Pϭ0.01; N1800H, 36.9Ϯ15.5%, nϭ3, Pϭ0.01; R2081W, 34.6Ϯ16.6%, nϭ3, Pϭ0.02) (Figure 3A), confirming that cell surface localization of ABCA1 is essential to elicit ApoA-I binding. Login to comment
78 Wild-type ABCA1 was localized intracellularly and at the plasma membrane. R587W, Q597R, ⌬L693, N935S, N1800H, and R2081W were only localized intracellularly. Login to comment
95 Near-Complete Absence of Plasma HDL-C in Homozygotes for Mutations in ABCA1 Implies the Presence of Null Alleles of ABCA1 Patients homozygous for R587W mutations showed 6.3% of normal HDL-C levels, those with N935S showed 2.62%, and those with N1800H showed 3.4% of normal plasma HDL-C levels. Login to comment

[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.

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522 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
555 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

[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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48 This SNP has been reported to be associated with decreased HDL cholesterol and increased severity of atherosclerosis in Table 1. subPSEC Scores and Probability of Functional Impairment (Pdeleterious) for ABCA1 Mutations and SNPs Mutations SNPs Variant SubPSEC Pdeleterious Variant subPSEC Pdeleterious P85L À4.62 0.83 R219K À0.57 0.08 H160F À2.79 0.45 V399A À2.26 0.32 R230C À4.27 0.78 V771M À2.86 0.46 A255T À1.81 0.23 T774P À1.99 0.27 E284K À2.34 0.34 K776N À3.53 0.63 Y482C À4.21 0.77 V825I À1.06 0.13 R587W À6.04 0.95 I883M À1.38 0.17 W590S À5.19 0.9 E1172D À1.96 0.26 W590L À4.48 0.82 R1587K À0.58 0.08 Q597R À7.15 0.98 S1731C À4.21 0.77 T929I À4.29 0.78 N935H À8.54 1 N935S À7.53 0.99 A937V À6.6 0.97 A1046D À7.52 0.99 M1091T À3.56 0.64 D1099Y À6.09 0.96 D1289N À2.48 0.37 L1379F À3.81 0.69 C1477R À5.44 0.92 S1506L À5.17 0.9 N1611D À5.69 0.94 R1680W À6.02 0.95 V1704D À3.21 0.55 N1800H À4.23 0.77 R1901S À5.06 0.89 F2009S À2.73 0.43 R2081W À8.08 0.99 P2150L À2.88 0.47 Q2196H À2.74 0.43 DOI: 10.1371/journal.pgen.0010083.t001 PLoS Genetics | www.plosgenetics.org December 2005 | Volume 1 | Issue 6 | e83 0740 Accurate Prediction of ABCA1 Variants Synopsis A major goal of human genetics research is to understand how genetic variation leads to differences in the function of genes. Login to comment
75 Cholesterol Efflux Values for 293 Cells Transfected with ABCA1 Variants and subPSEC and PolyPhen Predictions of the Functional Impact of these Variants Variant Variant Type subPSEC Cholesterol Efflux PolyPhen R2081W Mutation À8.08 21.1 6 21%* Probably damaging N935S Mutation À7.53 29.3 6 13%* Benign A1046D Mutation À7.52 16.8 6 7%* Possibly damaging Q597R Mutation À7.15 17.7 6 14%* Probably damaging R587W Mutation À6.04 31.7 6 33%* Probably damaging C1477R Mutation À5.44 20.5 6 10%* Probably damaging W590S Mutation À5.19 47.1 6 13%* Probably damaging S1506L Mutation À5.17 17.8 6 15%* Probably damaging T929I Mutation À4.29 69.9 6 11%* Possibly damaging N1800H Mutation À4.23 31.3 6 16%* Possibly damaging S1731C SNP À4.21 12.3 6 10%* Possibly damaging M1091T Mutation À3.56 6.9 6 20%* Probably damaging P2150L Mutation À2.88 88.4 6 21% Probably damaging V771M SNP À2.86 145.4 6 33% Benign D1289N Mutation À2.48 137.7 6 86% Benign I883M SNP À1.38 69.1 6 16%* Benign R219K SNP À0.57 103.7 6 21.05 Benign Wild-type - 0.0 100% - *p , 0.01 compared to wild-type ABCA1. Login to 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 À;4.48 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

[hide] Familial HDL deficiency due to ABCA1 gene mutation... Atherosclerosis. 2004 Feb;172(2):309-20. Pisciotta L, Hamilton-Craig I, Tarugi P, Bellocchio A, Fasano T, Alessandrini P, Bon GB, Siepi D, Mannarino E, Cattin L, Averna M, Cefalu AB, Cantafora A, Calandra S, Bertolini S
Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders.
Atherosclerosis. 2004 Feb;172(2):309-20., [PMID:15019541]

Abstract [show]
Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with premature coronary artery disease (pCAD), had a combination of genetic defects. Besides being heterozygotes for ABCA1 mutations, two of them were also carriers of the R3500Q substitution in apolipoprotein B and the third was a carrier of N291S substitution in lipoprotein lipase. By extending family studies we identified 17 heterozygotes for ABCA1 mutations. Plasma HDL-C and Apo A-I values in these subjects were 38.3 and 36.9% lower than in unaffected family members and similar to the values found in heterozygotes for Apo A-I gene mutations which prevent Apo A-I synthesis. This survey underlines the allelic heterogeneity of ABCA1 mutations and suggests that: (i) TD subjects, if asymptomatic, may be overlooked and (ii) there may be a selection bias in genotyping towards carriers of ABCA1 mutations who have pCAD possibly related to a combination of genetic and environmental cardiovascular risk factors.

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63 The proband of Family 2 was a carrier of an ABCA1 mutation (N1800H) and a common LPL variant (N291S). Login to comment
65 The Proband of Family 3 was a compound heterozygote for two ABCA1 mutations (Y482C and N1800H); the N1800H mutation was transmitted to her son. Login to comment
125 Transversion c.5398 A > C in exon 40 (N1800H) As this mutation introduces a new Nla III restriction site, a 144 bp PCR fragment encompassing exon 40 was digested with Nla III (Amersham Pharmacia Biotech, Cologno Monzese, Italy). Login to comment
146 3.2.2. DNA sequence analysis The sequence of LCAT and Apo A-I genes did not reveal any mutation in the proband (I.2); the sequence of ABCA1 gene revealed a heterozygous transversion c.5398 A > C (N1800H) in exon 40 (Fig. 3). Login to comment
155 The sequence of ABCA1 gene showed that the proband was a compound heterozygote, as she carried a transition c.1445 A > G (Y482C) in exon 12 (Fig. 3) and a transversion c.5398 A > C (N1800H) in exon 40 (Fig. 3). Login to comment
156 The proband`s son (III.3) inherited the N1800H mutation from his mother. No members of this family carried LPL variants. Login to comment
164 II.2 W/W 43 M 28.0 5.10 3.70 0.96 0.80 104 98 ε3ε4 III.3 M2/W 9 M - 3.00 1.94 0.75 0.70 92 52 ε3ε4 Family 4 II.1 M4/W 62 M 23.3 4.45 2.71 0.72 2.21 102 92 ε3ε3 +++ Family 5 II.1a M5/W 59 M 36.7 7.16 6.02 0.52 1.71 81 133 ε3ε4 +++ III.1a W/W 33 F 21.8 7.52 5.02 1.99 1.13 162 112 ε4ε4 III.2 M5/W 31 F 22.8 4.68 3.28 0.85 1.18 92 82 ε3ε4 III.3 M5/W 31 F 24.4 4.00 2.74 0.90 0.78 97 72 ε3ε4 Family 6 I.2 M6/W 53 F 40.2 4.76 3.00 1.16 1.31 104 81 ε3ε3 II.1 W/W 41 M 27.5 6.54 4.35 1.19 2.20 141 148 ε3ε4 II.2 M6/W 39 M 26.2 3.57 2.44 0.77 0.77 93 71 ε3ε4 II.3 M6/W 37 F 21.3 4.44 2.63 0.76 2.30 85 89 ε3ε4 II.4 M7/W 37 M 18.8 3.67 2.43 1.00 0.50 89 57 ε3ε3 III.1 M6/M7 16 F 25.4 3.33 2.45 0.18 1.55 12 102 ε3ε3 III.2 M7/W 10 F 14.2 2.66 1.34 0.98 0.76 103 38 ε3ε3 W, ABCA1 wild-type allele; M, ABCA1 mutant allele: M1 (E284K); M2 (N1800H); M3 (Y482C); M4 (Q2196H); M5 (R557X); M6 (H160FsX173); M7 (R1901S); ND: not determined. Login to comment
193 One of these mutations (N1800H) had been reported previously [10,38] in a TD patient of Italian origin (case 52 in ref. Login to comment
195 Since we have found N1800H in two unrelated subjects Fig. 4. Login to comment
200 of our series (Families 2 and 3), we are tempted to suggest that N1800H might be a recurrent mutation. Login to comment
236 In the proband of Family 2 and her son the HDL-lowering effect of N291S may have been masked by the more pronounced effect of the ABCA1 mutation (N1800H). Login to comment
194 Since we have found N1800H in two unrelated subjects Fig. 4. Login to comment
199 of our series (Families 2 and 3), we are tempted to suggest that N1800H might be a recurrent mutation. Login to comment
235 In the proband of Family 2 and her son the HDL-lowering effect of N291S may have been masked by the more pronounced effect of the ABCA1 mutation (N1800H). Login to comment

[hide] Novel polypyrimidine variation (IVS46: del T -39..... Circ Res. 2003 Nov 14;93(10):1006-12. Epub 2003 Oct 23. 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., [PMID:14576201]

Abstract [show]
Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q). The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11+/-5 mg/dL) and ApoA-I (35+/-15 mg/dL) compared with wild-type (n=25) (HDL-C 51+/-14 mg/dL; ApoA-I 133+/-21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36+/-8; ApoA-I 117+/-19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.

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100 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
95 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

[hide] Efflux and atherosclerosis: the clinical and bioch... Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):1322-32. Epub 2003 May 22. 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., [PMID:12763760]

Abstract [show]
Approximately 50 mutations and many single nucleotide polymorphisms have been described in the ABCA1 gene, with mutations leading to Tangier disease and familial hypoalphalipoproteinemia. Homozygotes and heterozygotes for mutations in ABCA1 display a wide range of phenotypes. Identification of ABCA1 as the molecular defect in these diseases has allowed for ascertainment based on genetic status and determination of genotype-phenotype correlations and has permitted us to identify mutations conferring a range of severity of cellular, biochemical, and clinical phenotypes. In this study we review how genetic variation at the ABCA1 locus affects its role in the maintenance of lipid homeostasis and the natural progression of atherosclerosis.

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83 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
113 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
75 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
105 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

[hide] Genetics of HDL regulation in humans. Curr Opin Lipidol. 2003 Jun;14(3):273-9. Miller M, Rhyne J, Hamlette S, Birnbaum J, Rodriguez A
Genetics of HDL regulation in humans.
Curr Opin Lipidol. 2003 Jun;14(3):273-9., [PMID:12840658]

Abstract [show]
PURPOSE OF REVIEW: To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states. RECENT FINDINGS: The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future. SUMMARY: Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.

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67 TD 3` deletion (intron 38) truncated truncation [61] 5587 C/G 38 S1731C extracellular [68] TD 5793 A/C 40 N1800H extracellular loop, sm [65] FHA 5946 C/T 41 R1851X truncation [75..] FHA 6068 del 42 del 1893-1894(E,D) cytoplasmic [63] TD 6152 (14bp Ins) (42-43) truncated truncation [67] 6316 A/G 44 K1974R cytoplasmic [67] 6421 T/C 45 F2009S cytoplasmic [9] TD 6636 C/T 47 R2081W cytoplasmic [64] FHA 6825 C/T 49 R2144X cytoplasmic [63] TD 6825 del C 49 2145X truncation [62] FHA 6844 C/T 49 P2150L cytoplasmic [62] 6898 C/T 49 P2168L cytoplasmic [67] TD CTC6952-4TT 49 2203X truncation [62] TD 6968 (4bp Ins) 49 2215X, truncated PDZ binding (cyto) [65] *Location in accordance with Santamaria-Fojo et al. (Proc Natl Acad Sci U S A 2000; 97:7987-7992). Login to comment

[hide] Novel mutations of ABCA1 transporter in patients w... Mol Genet Metab. 2012 Nov;107(3):534-41. doi: 10.1016/j.ymgme.2012.08.005. Epub 2012 Aug 18. Fasano T, Zanoni P, Rabacchi C, Pisciotta L, Favari E, Adorni MP, Deegan PB, Park A, Hlaing T, Feher MD, Jones B, Uzak AS, Kardas F, Dardis A, Sechi A, Bembi B, Minuz P, Bertolini S, Bernini F, Calandra S
Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency.
Mol Genet Metab. 2012 Nov;107(3):534-41. doi: 10.1016/j.ymgme.2012.08.005. Epub 2012 Aug 18., [PMID:22959828]

Abstract [show]
The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia.

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6 Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. Login to comment
176 PolyPhen (PSIC score) SIFT (P score) p.R130K Possibly damaging (1.540) Predicted tolerated p.R1068C Probably damaging (3.143) Predicted not tolerated (0.00) p.D1099Y Probably damaging (3.047) Predicted not tolerated (0.00) p.H1600R Probably damaging (3.197) Predicted not tolerated (0.02) p.N1800H Possibly damaging (1.845) Predicted tolerated termination codon (p.R587Afs*43) and ii) a single nucleotide substitution (c.4799A>G) in exon 36, resulting in a novel missense mutation (p.H1600R) (Table 1). Login to comment
193 3.6. Patient # Mo-6 3.6.1. Analysis of ABCA1 gene This patient was a carrier of two single nucleotide substitutions: i) c.389G>A resulting in the conversion of arginine to lysine (p.R130K) predicted in silico to be benign and ii) c.5398A>C resulting in a previously reported missense mutation (p.N1800H) [8], predicted in silico to be possibly damaging (Table 2). Login to comment
224 3.10. Patient # Ge-10 3.10.1. Analysis of ABCA1 gene This patient was heterozygous for a mutation (c.5398A>C, p.N1800H), previously reported in patients with hypoalphalipoproteinemia [8] and found in another patient with low HDL of our series (patient # Mo-6). Login to comment

[hide] Functional rescue of mutant ABCA1 proteins by sodi... J Lipid Res. 2013 Jan;54(1):55-62. doi: 10.1194/jlr.M027193. Epub 2012 Oct 20. Sorrenson B, Suetani RJ, Williams MJ, Bickley VM, George PM, Jones GT, McCormick SP
Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate.
J Lipid Res. 2013 Jan;54(1):55-62. doi: 10.1194/jlr.M027193. Epub 2012 Oct 20., [PMID:23087442]

Abstract [show]
Mutations in the ATP-binding cassette transporter A1 (ABCA1) are a major cause of decreased HDL cholesterol (HDL-C), which infers an increased risk of cardiovascular disease (CVD). Many ABCA1 mutants show impaired localization to the plasma membrane. The aim of this study was to investigate whether the chemical chaperone, sodium 4-phenylbutyrate (4-PBA) could improve cellular localization and function of ABCA1 mutants. Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA. Treatment restored localization to the plasma membrane and increased cholesterol efflux function for the majority of mutants. Treatment with 4-PBA also increased ABCA1 protein expression in all transfected cell lines. In fibroblast cells obtained from low HDL-C subjects expressing two of the ABCA1 mutants (p.R1068H and p.N1800H), 4-PBA increased cholesterol efflux without any increase in ABCA1 expression. Our study is the first to investigate the effect of the chemical chaperone, 4-PBA on ABCA1 and shows that it is capable of restoring plasma membrane localization and enhancing the cholesterol efflux function of mutant ABCA1s both in vitro and ex vivo. These results suggest 4-PBA may warrant further investigation as a potential therapy for increasing cholesterol efflux and HDL-C levels.

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16 Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA. Login to comment
18 In fibroblast cells obtained from low HDL-C subjects expressing two of the ABCA1 mutants (p.R1068H and p.N1800H), 4-PBA increased cholesterol efflux without any increase in ABCA1 expression. Login to comment
53 The Pearson`s correlation coefficient between the GFP and AlexaFluor594 of the ABCA1 mutations were previously identified in low HDL-C subjects and included three uncharacterized mutations, p.I659V, p.R2004K, and p.A2028V (18) and three variants, p.R1068H, p.T1512M, and p.N1800H, known to have reduced localization and cholesterol efflux (19, 20). Login to comment
74 The individual heterozygote for p.Y1767D was also heterozygote for the p.N1800H ABCA1 mutation. Login to comment
85 4-PBA rescues mutant ABCA1 localization and improves cholesterol efflux function in transfected HEK293 cells 4-PBA treatment was applied to the six uncharacterized ABCA1 mutants as well as to three mutants that we have previously shown to have reduced cholesterol efflux function, p.R1068H (19), p.T1512M (20), and p.N1800H (20, Fig. 1). Login to comment
109 Upon 4-PBA treatment, efflux function was significantly increased relative to the untreated level for the p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, and p.A2028V mutants (Fig. 3B). Login to comment
112 Treatment with 4-PBA induced a significant increase in colocalization for the p.A594T, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, and p.R2004K mutants. Treatment with 4-PBA did not affect the colocalization of the wild-type ABCA1-GFP protein (supplementary Fig. II). Login to comment
121 4-PBA improves mutant ABCA1 efflux function independent of protein level in primary fibroblasts We assessed the effect of 4-PBA treatment in the con- textofthenativeABCA1promoterusingavailablep.R1068H, p.N1800H, and wild-type primary fibroblast cell lines (19, 20). Login to comment
122 Fibroblasts were obtained from two p.R1068H heterozygote carriers (RH1 and RH2), two p.N1800H heterozygote carriers (NH1 and NH2), and two ABCA1 wild-type subjects (WT1 and WT2). Login to comment
124 We had previously determined that subject NH2 was also heterozygous for the p.C978fsX988 mutation, which encodes a truncated protein that is functionally null and in this individual was present on a seperate allele to the p.N1800H mutation (20). Login to comment
125 mislocated mutants, p.Y1767D, and p.N1800H, showed a restored efflux function that was equivalent to wild-type untreated cells. Login to comment
141 In contrast, there was a clear trend for increased efflux in the mutants fibroblast cells with statistically significant increases for the p.R1068H heterozygote RH1 (p < 0.05) and the p.N1800H heterozygote NH2 (p < 0.001). Login to comment
143 It was noted that the increase in cholesterol efflux promoted by 4-PBA in the p.N1800H fibroblasts was not as striking as that seen in HEK293 cells transfected with this mutant where 4-PBA promoted cholesterol efflux back up to untreated wild-type levels. Login to comment
156 Fibroblast cultures established from wild-type (WT1, WT2), p.R1068H carriers (RH1, RH2) and p.N1800H carriers (NH1, NH2) were treated with 10 mM 4-PBA for 24 h. Login to comment
188 For two of the most dramatically affected mutants, p.R1068H and p.N1800H, a functional improvement with 4-PBA treatment was also confirmed ex vivo using primary fibroblast cells. Login to comment
193 The NH2 fibroblasts, which harbor a p.N1800H allele and a null allele, show a significant improvement in function, yet the NH1 fibroblasts, which harbor a p.N1800H allele and a wild-type allele, show no significant functional improvement. Login to comment
201 The authors thank the p.R1068H and p.N1800H family members for their participation in this study. We are grateful to Professor Christiane Albrecht for kindly providing the pCIneo-ABCA1-GFP expression vector. Login to comment

[hide] ABCA1 mutation carriers with low high-density lipo... Eur Heart J. 2013 Jan;34(4):286-91. doi: 10.1093/eurheartj/ehs376. Epub 2012 Nov 7. Bochem AE, van Wijk DF, Holleboom AG, Duivenvoorden R, Motazacker MM, Dallinga-Thie GM, de Groot E, Kastelein JJ, Nederveen AJ, Hovingh GK, Stroes ES
ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.
Eur Heart J. 2013 Jan;34(4):286-91. doi: 10.1093/eurheartj/ehs376. Epub 2012 Nov 7., [PMID:23136402]

Abstract [show]
AIMS: Low HDL-C is a potent risk factor for cardiovascular disease (CVD). Yet, mutations in ABCA1, a major determinant of circulating HDL-C levels, were previously not associated with CVD risk in cohort studies. To study the consequences of low plasma levels of high-density lipoprotein cholesterol (HDL-C) due to ATP-binding cassette transporter A1 (ABCA1) dysfunction for atherosclerotic vascular disease in the carotid arteries. METHODS AND RESULTS: We performed 3.0 Tesla magnetic resonance imaging (MRI) measurements of the carotid arteries in 36 carriers of high impact functional ABCA1 mutations and 36 normolipidemic controls. Carriers presented with 42% lower HDL-C levels (P < 0.001), a larger mean wall area (18.6 +/- 6.0 vs. 15.8 +/- 4.3 mm(2); P = 0.02), a larger mean wall thickness (0.82 +/- 0.21 vs. 0.70 +/- 0.14 mm; P = 0.005), and a higher normalized wall index (0.37 +/- 0.06 vs. 0.33 +/- 0.04; P = 0.005) compared with controls, retaining significance after adjustment for smoking, alcohol consumption, systolic blood pressure, diabetes, body mass index, history of CVD, LDL-C, and statin use (P = 0.002). CONCLUSION: Carriers of loss of function ABCA1 mutations display a larger atherosclerotic burden compared with age and sex-matched controls, implying a higher risk for CVD. Further studies are needed to elucidate the full function of ABCA1 in the protection against atherosclerosis. These data support the development of strategies to up-regulate ABCA1 in patients with established CVD.

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69 Subjects were carriers of the following mutations: c.6401+2T.C, p.Ser930Phe, p.Ser824Leu, p.Arg587Trp, p.Thr929Ile, p.Asn935Ser, c.3535+1G.C, p.Asp571Gly, p.Asn1800his, p.Leu1056Pro, p.Gln1038Ter, c.1195-1G.C, p.Arg579Gln, and p.Phe1760Valfs*21. Login to comment
78 Five of these mutations have already been shown to have a significant impact on ABCA1 function (p.Asn1800his,27 p.Thr929Ile,27 p.Arg587Trp,28,29 p.Leu1056Pro,21 and p.Phe1760Valfs*21.30 ). Login to comment

[hide] ABC transporter genes and risk of type 2 diabetes:... Diabetes Care. 2012 Dec;35(12):2600-6. doi: 10.2337/dc12-0082. Epub 2012 Nov 8. Schou J, Tybjaerg-Hansen A, Moller HJ, Nordestgaard BG, Frikke-Schmidt R
ABC transporter genes and risk of type 2 diabetes: a study of 40,000 individuals from the general population.
Diabetes Care. 2012 Dec;35(12):2600-6. doi: 10.2337/dc12-0082. Epub 2012 Nov 8., [PMID:23139370]

Abstract [show]
OBJECTIVE: Alterations of pancreatic beta-cell cholesterol content may contribute to beta-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATP-binding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1). Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown. RESEARCH DESIGN AND METHODS: We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415). RESULTS: Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively). CONCLUSIONS: Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1.

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5 Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C.T) (n = 322) and a common variant (ABCG1 g.-530A.G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415). Login to comment
7 Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C.T) nor ABCG1 g.-530A.G were associated with type 2 diabetes (P values .0.57 and .0.30, respectively). Login to comment
17 Finally, we recently reported that two functional variants, ABCA1 N1800H and ABCG1 g.-376C.T, were associated with, respectively, substantial reductions in levels of HDL cholesterol or reduced ABCG1 mRNA expression levels and increased risk of ischemic heart disease and myocardial infarction (12,13)drisk factors and disease entities closely related to diabetes. Login to comment
45 Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C.T), as well as a common variant associated with reduced risk of type 2 diabetes in the CCHS (ABCG1 g.-530A.G), were further genotyped in the CGPS. Login to comment
85 Two loss-of-function mutations, as well as a common variant with effect on risk of type 2 diabetes in the CCHS, were further genotyped in the CGPS and displayed minor allele frequencies similar to those in the CCHS: 0.1, 0.2, and 6.7% for ABCA1 N1800H, ABCG1 g.- 376C.T, and ABCG1 g.-530A.G, respectively. Login to comment
89 After application of a Bonferroni-corrected P value of 0.0002 (0.05/8 biochemical markers multiplied by 27 genetic variants), only one association remained significant: plasma levels of HDL cholesterol were reduced by 0.45 mmol/L in heterozygotes for ABCA1 N1800H compared with noncarriers (P 5 0.0001) (Fig. 1); the corresponding reduction for apoAI was 27.6 mg/dL. Login to comment
97 Neither the two loss-of-function mutations nor the ABCG1 g.- 530A.G associated with type 2 diabetes in the CGPS (ABCA1 N1800H AC vs. AA odds ratio 0.7 [95% CI 0.2-2.8], ABCG1 g.- 376C.T CT vs. CC 1.1 [0.5-2.3], ABCG1 g.-530A.G AG vs. AA 1.1 [0.9-1.3], and GG vs. AA 0.8 [0.3-2.2]) or in CCHS and CGPS combined (N1800H AC vs. AA 0.6 [0.2-1.8], g.-376C.T CT vs. CC 1.0 [0.5-1.8], g.-530A.G AG vs. AA 1.0 [0.8-1.1], and GG vs. AA 1.1 [0.5-2.0]) (Fig. 4). Login to comment
98 Finally, when burden testing of rare variants was performed, neither collapsed genotypes including all rare variants with minor allele frequencies ,1% (CCHS: P = 0.34) nor collapsed genotypes including rare variants that were experimentally verified to be functional (ABCA1 N1800H and ABCG1 g.-376C.T) associated with type 2 diabetes (CCHS and CGPS combined: P = 0.70). Login to comment
102 This is the largest study to date of genetic variation in ABCA1 and ABCG1 and risk of type 2 diabetes and, in particular, is the largest study of loss-of-function mutations, including 94 ABCA1 N1800H heterozygotes and 228 ABCG1 g.-376C.T heterozygotes. Login to comment

[hide] ATP-binding cassette transporters, atherosclerosis... Circ Res. 2014 Jan 3;114(1):157-70. doi: 10.1161/CIRCRESAHA.114.300738. Westerterp M, Bochem AE, Yvan-Charvet L, Murphy AJ, Wang N, Tall AR
ATP-binding cassette transporters, atherosclerosis, and inflammation.
Circ Res. 2014 Jan 3;114(1):157-70. doi: 10.1161/CIRCRESAHA.114.300738., [PMID:24385509]

Abstract [show]
Although recent genome-wide association studies have called into question the causal relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular disease, ongoing research in animals and cells has produced increasing evidence that cholesterol efflux pathways mediated by ATP-binding cassette (ABC) transporters and HDL suppress atherosclerosis. These differing perspectives may be reconciled by a modified HDL theory that emphasizes the antiatherogenic role of cholesterol flux pathways, initiated in cells by ABC transporters. ABCA1 and ABCG1 control the proliferation of hematopoietic stem and multipotential progenitor cells in the bone marrow and hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis in the spleen. Thus, activation of cholesterol efflux pathways by HDL infusions or liver X receptor activation results in suppression of hematopoietic stem and multipotential progenitor cell mobilization and extramedullary hematopoiesis, leading to decreased production of monocytes and neutrophils and suppression of atherosclerosis. In addition, macrophage-specific knockout of transporters has confirmed their role in suppression of inflammatory responses in the arterial wall. Recent studies have also shown that ABCG4, a close relative of ABCG1, controls platelet production, atherosclerosis, and thrombosis. ABCG4 is highly expressed in megakaryocyte progenitors, where it promotes cholesterol efflux to HDL and controls the proliferative responses to thrombopoietin. Reconstituted HDL infusions act in an ABCG4-dependent fashion to limit hypercholesterolemia-driven excessive platelet production, thrombosis, and atherogenesis, as occurs in human myeloproliferative syndromes. Activation of ABC transporter-dependent cholesterol efflux pathways in macrophages, hematopoietic stem and multipotential progenitor cells, or platelet progenitors by reconstituted HDL infusion or liver X receptor activation remain promising approaches to the treatment of human atherothrombotic diseases.

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59 In a Mendelian randomization approach in a prospective cohort comprising ࣈ9000 individuals, heterozygosity for the ABCA1 mutation K776N led to a 2-to-3 times higher risk of ischemic heart disease.105 Furthermore, 5 single-nucleotide polymorphisms (SNPs) inABCA1 (V771M,V825I, I883M, E1172D, R1587K) were shown to predict risk of ischemic heart disease in a cohort of 9259 individuals.106 However, the same group reported more recently that heterozygosity for 4 loss-of-function mutations (P1065S, G1216V, N1800H, R2144X) was not associated with a higher risk of ischemic heart disease in 3 prospective cohorts comprising 56ߙ886 individuals.107 It must be noted, however, that only small decreases in HDL, of ࣈ28% as opposed to ࣈ50% in previously reported ABCA1 heterozygotes, were observed.94,101-103,107 Also, the residual cholesterol efflux was substantial (74%-79% for P1065S and G1216V and 48%-49% for N1800H and R2144X for homozygous mutations compared with controls),107 whereas in patients with TD there was only 20% to 30% residual cholesterol efflux.108 In addition, LDL levels were reduced by ࣈ25%, probably offsetting the effects of reduced HDL on CVD.107 Thus, the conflicting results in these studies could be related to inclusion of relatively mild ABCA1 mutations as well as offsetting effects of reduced LDL cholesterol levels.109 In a meta-analysis of genome-wide association studies, SNPs near the ABCA1 gene have been associated with HDL and total cholesterol levels,110,111 but not with cardiovascular risk.112 Although these studies have the benefit of huge statistical power, some caution is merited in the interpretation of findings. Login to comment

[hide] ATP-binding cassette transporter A1: from metaboli... Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17. Koldamova R, Fitz NF, Lefterov I
ATP-binding cassette transporter A1: from metabolism to neurodegeneration.
Neurobiol Dis. 2014 Dec;72 Pt A:13-21. doi: 10.1016/j.nbd.2014.05.007. Epub 2014 May 17., [PMID:24844148]

Abstract [show]
ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of high density lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimer's disease (AD). A series of reports have revealed a significant impact of ABCA1 on Abeta deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD.

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932 For example, some of the ABCA1 missense mutations (P1065S, G1216V, N1800H, R2144X) cause only a mild decrease of cholesterol efflux which in heterozygous state results in a relatively small reduction of HDL (less than 30% decrease compared to the normal values) explaining the lack of atherosclerosis (Frikke-Schmidt et al., 2008). Login to comment

[hide] HDL Cholesterol and Risk of Type 2 Diabetes: A Men... Diabetes. 2015 Sep;64(9):3328-33. doi: 10.2337/db14-1603. Epub 2015 May 13. Haase CL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R
HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study.
Diabetes. 2015 Sep;64(9):3328-33. doi: 10.2337/db14-1603. Epub 2015 May 13., [PMID:25972569]

Abstract [show]
Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol-related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol-decreasing gene scores and allele numbers associated with up to -13 and -20% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38-1.52) and 1.77 (1.61-1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75-1.09) and 0.93 (0.78-1.11) for HDL cholesterol-decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32-1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.

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36 ATP-binding cassette transporter A1 (ABCA1) N1800H (rs146292819), cholesteryl-ester transfer protein (CETP) 2629C.A (rs1800775) and Taq1bG.A (rs708272), lecithin-cholesterol acyltransferase (LCAT) S208T (rs4986970), hepatic lipase (LIPC) 2480C.T (rs1800588), apolipoprotein A1 (APOA1) S36A (rs199759119), F71Y (rs138407155), K107del (rs number not available), and L144R (rs number not available) were genotyped using an ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Life Technologies, Paisley, U.K.) and TaqMan-based assays. Login to comment

[hide] Myocardial infarction in a 36-year-old man with co... J Clin Lipidol. 2015 May-Jun;9(3):396-9. doi: 10.1016/j.jacl.2015.01.006. Epub 2015 Jan 28. van Capelleveen JC, Kootte RS, Hovingh GK, Bochem AE
Myocardial infarction in a 36-year-old man with combined ABCA1 and APOA-1 deficiency.
J Clin Lipidol. 2015 May-Jun;9(3):396-9. doi: 10.1016/j.jacl.2015.01.006. Epub 2015 Jan 28., [PMID:26073400]

Abstract [show]
In this report, we present a patient who suffered from a myocardial infarction at an extremely young age. The only remarkable finding in the risk factor workup was a near undetectable high-density lipoprotein (HDL)-cholesterol plasma level (0.09 mmol/L). Genetic analysis of key genes involved in HDL metabolism resulted in the discovery of 2 very rare mutations in the ABCA1 and APOA1 genes. We discuss the effects of these mutations on HDL metabolism and reverse cholesterol transport and interpret these findings in relation to the extensive atherosclerosis at a very young age in this patient.

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31 One mutation in the ATP-binding cassette transporter 1 (ABCA1) gene, c.A5398C, p.Asn1800His, and a mutation in the apolipoprotein A1 (APOA1) gene, c.T6051C; p.Leu202Pro. Login to comment
44 The mutation found in the ABCA1 gene (c.A5398C) results in an amino acid change of asparagine to histidine at position 1800 (p.N1800H). Login to comment
48 The role of ABCA1 mutations in CVD risk has recently been quantified in heterozygous carriers of functional ABCA1 mutations (including p.N1800H), who were shown to be characterized by an increased atherosclerotic burden, as assessed by 3-T magnetic resonance imaging of the carotid arteries.9 The additional mutation in the APOA1 gene, c.C605T, results in the change of leucine for proline at position 202 (p.L202P). Login to comment

[hide] Increased Systemic and Plaque Inflammation in ABCA... Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1663-9. doi: 10.1161/ATVBAHA.114.304959. Epub 2015 Feb 19. Bochem AE, van der Valk FM, Tolani S, Stroes ES, Westerterp M, Tall AR
Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins.
Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1663-9. doi: 10.1161/ATVBAHA.114.304959. Epub 2015 Feb 19., [PMID:26109739]

Abstract [show]
OBJECTIVE: We previously demonstrated that subjects with functional ATP-binding cassette (ABC) A1 mutations have increased atherosclerosis, which has been attributed to the role of ABCA1 in reverse cholesterol transport. More recently, a proinflammatory effect of Abca1 deficiency was shown in mice, potentially contributing to atherogenesis. In this study, we investigated whether ABCA1 deficiency was associated with proinflammatory changes in humans. APPROACH AND RESULTS: Thirty-one heterozygous, 5 homozygous ABCA1 mutation carriers, and 21 matched controls were studied. (18)Fluorodeoxyglucose positron emission tomography with computed tomographic scanning was performed in a subset of carriers and controls to assess arterial wall inflammation (target:background ratio). Heterozygous ABCA1 mutation carriers had a 20% higher target:background ratio than in controls (target:background ratio; P=0.008). In carriers using statins (n=7), target:background ratio was 21% reduced than in nonstatin users (n=7; P=0.03). We then measured plasma cytokine levels. Tumor necrosis factor alpha, monocyte chemoattractant protein-1, and interleukin-6 levels were increased in heterozygous and homozygous ABCA1 mutation carriers. We isolated monocytes from carriers and controls and measured inflammatory gene expression. Only TNFalpha mRNA was increased in monocytes from heterozygous ABCA1 mutation carriers. Additional studies in THP-1 macrophages showed that both ABCA1 deficiency and lipoprotein-deficient plasma from ABCA1 mutation carriers increased inflammatory gene expression. CONCLUSIONS: Our data suggest a proinflammatory state in ABCA1 mutation carriers as reflected by an increased positron emission tomography-MRI signal in nonstatin using subjects, and increased circulating cytokines. The increased inflammation in ABCA1 mutation carriers seems to be attenuated by statins.

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28 Homozygous and compoundheterozygoussubjectshadTangierDisease.Subjects were carriers of the following mutations: p.Leu1056Pro, c.3535+1G>C, c.6401+2T>C, p.Asn1800his, p.Ser930Phe, p.Phe1760Valfs*21, p.Ser824Leu, p.Gln1038Ter, p.Thr929Ile, p.Arg587Trp, p.Asn935Ser, and p.Arg579Gln. Login to comment