ABCMdb

ABCA1 p.Asn1800His

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Publications

PMID: 22923419 [PubMed] Reddy MV et al: "Exome sequencing identifies 2 rare variants for low high-density lipoprotein cholesterol in an extended family."

No. Sentence Comment

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

PMID: 21420943 [PubMed] Daniil G et al: "Characterization of antioxidant/anti-inflammatory properties and apoA-I-containing subpopulations of HDL from family subjects with monogenic low HDL disorders."

No. Sentence Comment

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

PMID: 21575609 [PubMed] Sorrenson B et al: "An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations."

No. Sentence Comment

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

PMID: 21130455 [PubMed] Karuna R et al: "Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism."

No. Sentence Comment

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

PMID: 20800056 [PubMed] Berge KE et al: "Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol."

No. Sentence Comment

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

PMID: 20880529 [PubMed] Candini C et al: "Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol."

No. Sentence Comment

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

PMID: 19596329 [PubMed] Frikke-Schmidt R et al: "Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population."

No. Sentence Comment

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

PMID: 18974039 [PubMed] Juan T et al: "Identification of three loci affecting HDL-cholesterol levels in a screen for chemically induced recessive mutations in mice."

No. Sentence Comment

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

PMID: 18984885 [PubMed] Brunham LR et al: "ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease."

No. Sentence Comment

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

PMID: 18706283 [PubMed] Iatan I et al: "Effect of ABCA1 mutations on risk for myocardial infarction."

No. Sentence Comment

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

PMID: 18523221 [PubMed] Frikke-Schmidt R et al: "Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease."

No. Sentence Comment

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

PMID: 17303779 [PubMed] Kiss RS et al: "Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects."

No. Sentence Comment

49 Eight subjects with sequence variants in ABCA1 had defective cholesterol efflux (measured in repeated assays cholesterol-loaded monocyte-derived macrophage [MDMs]), and these ABCA1 sequence variants were tested in an in vitro expression system for cholesterol efflux activity.38 ABCA1 proteins containing the sequence variants W590L, C1477F, D1706N, S1731C, or N1800H were all found to have significantly impaired cholesterol efflux, whereas the H551D and E1386Q variants had very minor, if any, effects on cholesterol transport (Figure 1A). Login to comment
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

PMID: 16343503 [PubMed] Alrasadi K et al: "Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency."

No. Sentence Comment

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

PMID: 16873719 [PubMed] Singaraja RR et al: "Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro."

No. Sentence Comment

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

PMID: 16704350 [PubMed] Brunham LR et al: "Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis."

No. Sentence Comment

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

PMID: 16429166 [PubMed] Brunham LR et al: "Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene."

No. Sentence Comment

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

PMID: 15019541 [PubMed] Pisciotta L et al: "Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders."

No. Sentence Comment

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

PMID: 14576201 [PubMed] Hong SH et al: "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."

No. Sentence Comment

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

PMID: 12763760 [PubMed] Singaraja RR et al: "Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene."

No. Sentence Comment

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

PMID: 12840658 [PubMed] Miller M et al: "Genetics of HDL regulation in humans."

No. Sentence Comment

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

PMID: 22959828 [PubMed] Fasano T et al: "Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency."

No. Sentence Comment

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

PMID: 23087442 [PubMed] Sorrenson B et al: "Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate."

No. Sentence Comment

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

PMID: 23136402 [PubMed] Bochem AE et al: "ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden."

No. Sentence Comment

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

PMID: 23139370 [PubMed] Schou J et al: "ABC transporter genes and risk of type 2 diabetes: a study of 40,000 individuals from the general population."

No. Sentence Comment

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

PMID: 24385509 [PubMed] Westerterp M et al: "ATP-binding cassette transporters, atherosclerosis, and inflammation."

No. Sentence Comment

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

PMID: 24844148 [PubMed] Koldamova R et al: "ATP-binding cassette transporter A1: from metabolism to neurodegeneration."

No. Sentence Comment

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

PMID: 25972569 [PubMed] Haase CL et al: "HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study."

No. Sentence Comment

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

PMID: 26073400 [PubMed] van Capelleveen JC et al: "Myocardial infarction in a 36-year-old man with combined ABCA1 and APOA-1 deficiency."

No. Sentence Comment

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

PMID: 26109739 [PubMed] Bochem AE et al: "Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins."

No. Sentence Comment

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