ABCMdb

ABCA1 p.Met1091Thr

Predicted by SNAP2:	A: D (71%), C: D (63%), D: D (91%), E: D (85%), F: D (66%), G: D (85%), H: D (85%), I: D (63%), K: D (91%), L: N (87%), N: D (85%), P: D (91%), Q: D (80%), R: D (91%), S: D (80%), T: D (80%), V: D (59%), W: D (66%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Increased risk of coronary artery disease in Cauca... Biochim Biophys Acta. 2012 Mar;1821(3):416-24. doi: 10.1016/j.bbalip.2011.08.006. Epub 2011 Aug 19. Tietjen I, Hovingh GK, Singaraja R, Radomski C, McEwen J, Chan E, Mattice M, Legendre A, Kastelein JJ, Hayden MR
Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT.
Biochim Biophys Acta. 2012 Mar;1821(3):416-24. doi: 10.1016/j.bbalip.2011.08.006. Epub 2011 Aug 19., [PMID:21875686]

Abstract [show]
Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc <10th percentile but no other major lipid abnormalities, including 89 with >/=1 first-degree relative with low HDLc (familial probands) and 89 where familial status of low HDLc is uncertain (unknown probands). Mutations were most frequent in LCAT (15.7%), followed by ABCA1 (9.0%) and APOA1 (4.5%), and were found in 42.7% of familial but only 14.6% of unknown probands (p=2.44 *10(-5)). Interestingly, only 16 of 24 (66.7%) mutations assessed in families conferred an average HDLc <10th percentile. Furthermore, only mutation carriers with HDLc <5th percentile had elevated risk of CAD (odds ratio (OR)=2.26 for 34 ABCA1 mutation carriers vs. 149 total first-degree relative controls, p=0.05; OR=2.50 for 26 APOA1 mutation carriers, p=0.04; OR=3.44 for 38 LCAT mutation carriers, p=1.1 *10(-3)). These observations show that mutations in ABCA1, APOA1, and LCAT are sufficient to explain >40% of familial hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

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117 COOHA B T929I H2N R587W B A M1091T C1477R K776N N935S S1181F IVS24+1 G>C V2244I R282X D571G M640L S930F M968T R1615WIVS16-5 CA>del ABCA1 Transmembrane domain ATP-binding domain Q597R A) AA 1 AA 267 K130del L202P 74 90 98 112 122 145 167 189 211 215 233 253 APOA1 Negative charge domain Alpha-helix E222K E134DT37M 140 178 206 41127 104 121 165 200 229 360 391 Y135N V246F 127 206 369 401 Catalytic triad R322C L338H V371MV52M Y107X A117T T147I V333M Phe Leu Asp His AA 1 AA 440 R159Q I202T LCAT Alpha helixBeta sheet B) 419I.Tietjenetal./BiochimicaetBiophysicaActa1821(2012)416-424 3.4. Login to comment
169 Effects of some ABCA1 mutations described here are also consistent with previous in vitro cellular efflux studies; for example, the highly expressive ABCA1 mutations R587W, Q597R, N935S, and M1091T cause ~10-25% of wild-type efflux in vitro, while the less expressive mutations K776N and T929I cause 62 and 80% efflux, respectively [35-37]. Login to comment

[hide] A functional ABCA1 gene variant is associated with... Hum Mol Genet. 2010 Jul 15;19(14):2877-85. Epub 2010 Apr 23. Acuna-Alonzo V, Flores-Dorantes T, Kruit JK, Villarreal-Molina T, Arellano-Campos O, Hunemeier T, Moreno-Estrada A, Ortiz-Lopez MG, Villamil-Ramirez H, Leon-Mimila P, Villalobos-Comparan M, Jacobo-Albavera L, Ramirez-Jimenez S, Sikora M, Zhang LH, Pape TD, Granados-Silvestre Mde A, Montufar-Robles I, Tito-Alvarez AM, Zurita-Salinas C, Bustos-Arriaga J, Cedillo-Barron L, Gomez-Trejo C, Barquera-Lozano R, Vieira-Filho JP, Granados J, Romero-Hidalgo S, Huertas-Vazquez A, Gonzalez-Martin A, Gorostiza A, Bonatto
A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.
Hum Mol Genet. 2010 Jul 15;19(14):2877-85. Epub 2010 Apr 23., [PMID:20418488]

Abstract [show]
It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

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99 (A) Polyclonal stable cell lines expressing the ABCA1 wild-type (WT), variant R230C and mutant M1091T (known defective in lipid efflux) were generated, and efflux activity for cholesterol was performed as described in Materials and Methods. Login to comment
103 (B) The expression of WT, variant R230C and mutant M1091T ABCA1 protein in Flp-In cells was assessed by western immunoblotting. Login to comment
151 The M1091T ABCA1 mutation previously identified in Tangier patients was used as control (32). Login to comment
101 (A) Polyclonal stable cell lines expressing the ABCA1 wild-type (WT), variant R230C and mutant M1091T (known defective in lipid efflux) were generated, and efflux activity for cholesterol was performed as described in Materials and Methods. Login to comment
105 (B) The expression of WT, variant R230C and mutant M1091T ABCA1 protein in Flp-In cells was assessed by western immunoblotting. Login to comment
153 The M1091T ABCA1 mutation previously identified in Tangier patients was used as control (32). Login to comment

[hide] Carriers of loss-of-function mutations in ABCA1 di... Diabetes Care. 2010 Apr;33(4):869-74. Epub 2010 Jan 12. Vergeer M, Brunham LR, Koetsveld J, Kruit JK, Verchere CB, Kastelein JJ, Hayden MR, Stroes ES
Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction.
Diabetes Care. 2010 Apr;33(4):869-74. Epub 2010 Jan 12., [PMID:20067955]

Abstract [show]
OBJECTIVE: Abnormal cellular cholesterol handling in islets may contribute to beta-cell dysfunction in type 2 diabetes. beta-Cell deficiency for the ATP binding cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol, leads to altered intracellular cholesterol homeostasis and impaired insulin secretion in mice. We aimed to assess the impact of ABCA1 dysfunction on glucose homeostasis in humans. RESEARCH DESIGN AND METHODS: In heterozygous carriers of disruptive mutations in ABCA1 and family-based noncarriers of similar age, sex, and BMI, we performed oral glucose tolerance tests (OGTTs) (n = 15 vs. 14) and hyperglycemic clamps (n = 8 vs. 8). RESULTS: HDL cholesterol levels in carriers were less than half those in noncarriers, but LDL cholesterol levels did not differ. Although fasting plasma glucose was similar between groups, glucose curves after an OGTT were mildly higher in carriers than in noncarriers. During hyperglycemic clamps, carriers demonstrated lower first-phase insulin secretion than noncarriers but no difference in insulin sensitivity. The disposition index (a measure of beta-cell function adjusted for insulin sensitivity) of the carriers was significantly reduced in ABCA1 heterozygotes. CONCLUSIONS: Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance. Our data provide evidence that ABCA1 is important for normal beta-cell function in humans.

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46 Subjects included in the present study were heterozygous carriers of the following extremely rare ABCA1 mutations: C1477R, M1091T, and R587W (4,7-10) and L996P and Q978X (C. Candini et al., manuscript in preparation). Login to comment
48 C1477R has been reported in nine heterozygous individuals, M1091T in four individuals, and R587W in seven individuals (11). Login to comment
93 Carriers were recruited from five different families (four C1477R carriers, three M1091T carriers, three R587W carriers, four L996P carriers, and one Q978X carrier); family control subjects were siblings, cousins, or partners of a carrier. Login to comment
103 This group consisted of four C1477R carriers, two M1091T carriers, one L996P carrier, one Q978X carrier, and eight control subjects. Login to comment
47 Subjects included in the present study were heterozygous carriers of the following extremely rare ABCA1 mutations: C1477R, M1091T, and R587W (4,7-10) and L996P and Q978X (C. Candini et al., manuscript in preparation). Login to comment
49 C1477R has been reported in nine heterozygous individuals, M1091T in four individuals, and R587W in seven individuals (11). Login to comment
95 Carriers were recruited from five different families (four C1477R carriers, three M1091T carriers, three R587W carriers, four L996P carriers, and one Q978X carrier); family control subjects were siblings, cousins, or partners of a carrier. Login to comment
105 This group consisted of four C1477R carriers, two M1091T carriers, one L996P carrier, one Q978X carrier, and eight control subjects. Login to comment

[hide] Adenosine-triphosphate-binding cassette transporte... Trends Cardiovasc Med. 2010 Feb;20(2):41-9. Kang MH, Singaraja R, Hayden MR
Adenosine-triphosphate-binding cassette transporter-1 trafficking and function.
Trends Cardiovasc Med. 2010 Feb;20(2):41-9., [PMID:20656214]

Abstract [show]
Mutations in the adenosine-triphosphate-binding cassette transporter-1 (ABCA1) lead to Tangier disease, a genetic disorder characterized by an almost complete absence of plasma high-density lipoprotein cholesterol. Although the importance of ABCA1 localization to its cholesterol efflux function has been extensively characterized, the cellular itinerary of ABCA1 leading to the plasma membrane is not fully elucidated. This review will summarize the current knowledge of ABCA1 trafficking and its relationship to function. Understanding these crucial processes provides potential novel therapeutic targets to regulate high-density lipoprotein biogenesis through influencing pathways of ABCA1 trafficking.

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40 The importance of ABCA1 localization to the PM is observed in several mutations underlying TD (R587W, Q597R, ΔL693, M1091T), where mislocalization of ABCA1 away from the cell surface leads to a significant reduction in cholesterol efflux function (Singaraja et al. 2006). Login to comment

[hide] Palmitoylation of ATP-binding cassette transporter... Circ Res. 2009 Jul 17;105(2):138-47. Epub 2009 Jun 25. Singaraja RR, Kang MH, Vaid K, Sanders SS, Vilas GL, Arstikaitis P, Coutinho J, Drisdel RC, El-Husseini Ael D, Green WN, Berthiaume L, Hayden MR
Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function.
Circ Res. 2009 Jul 17;105(2):138-47. Epub 2009 Jun 25., [PMID:19556522]

Abstract [show]
ATP-binding cassette transporter (ABC)A1 lipidates apolipoprotein A-I both directly at the plasma membrane and also uses lipids from the late endosomal or lysosomal compartment in the internal lipidation of apolipoprotein A-I. However, how ABCA1 targeting to these specific membranes is regulated remains unknown. Palmitoylation is a dynamically regulated lipid modification that targets many proteins to specific membrane domains. We hypothesized that palmitoylation may also regulate ABCA1 transport and function. Indeed, ABCA1 is robustly palmitoylated at cysteines 3, -23, -1110, and -1111. Abrogation of palmitoylation of ABCA1 by mutation of the cysteines results in a reduction of ABCA1 localization at the plasma membranes and a reduction in the ability of ABCA1 to efflux lipids to apolipoprotein A-I. ABCA1 is palmitoylated by the palmitoyl transferase DHHC8, and increasing DHHC8 protein results in increased ABCA1-mediated lipid efflux. Thus, palmitoylation regulates ABCA1 localization at the plasma membrane, and regulates its lipid efflux ability.

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125 As a control, cells expressing the ABCA1 mutant M1091T were used. Login to comment
147 Circulation Research July 17, 2009 at harboring the naturally occurring ABCA1 mutation M1091T that was previously characterized as severe loss-of-function mutation8 was reduced by Ϸ80%. Login to comment
156 The severe loss-of-function patient mutation M1091T, previously shown to be absent from the plasma membrane, was used as a positive control. Login to comment
177 As a control, efflux of lipids was reduced by Ϸ80% in a cell line harboring M1091T, a naturally occurring loss-of-function patient mutation. Login to comment
209 As controls for the efflux assay, we used a cell line harboring M1091T, a naturally occurring patient mutation that was previously characterized as severe loss-of-function mutation8 and showed Ͼ80% reduction in efflux, likely representing the absence of ABCA1 both at the plasma membrane and at intracellular sites of function. Login to comment
120 As a control, cells expressing the ABCA1 mutant M1091T were used. Login to comment
142 Circulation Research July 17, 2009 harboring the naturally occurring ABCA1 mutation M1091T that was previously characterized as severe loss-of-function mutation8 was reduced by b07;80%. Login to comment
151 The severe loss-of-function patient mutation M1091T, previously shown to be absent from the plasma membrane, was used as a positive control. Login to comment
172 As a control, efflux of lipids was reduced by b07;80% in a cell line harboring M1091T, a naturally occurring loss-of-function patient mutation. Login to comment
204 As controls for the efflux assay, we used a cell line harboring M1091T, a naturally occurring patient mutation that was previously characterized as severe loss-of-function mutation8 and showed b0e;80% reduction in efflux, likely representing the absence of ABCA1 both at the plasma membrane and at intracellular sites of function. 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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119 Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Clee et al. [28] / 2000 Within 11 TD families: Del L693, R2144X † , Del E,D1893,94 † , R909X, M1091T † , P2150L † , ivs25+1G→C, Del C6825→2145X, CTC6952- 4TT→2203X, C1477R, Q597R, T929I ABCA1 heterozygous patients had a 40%-45% decrease in HDL-C and a greater than threefold increased risk of CHD versus unaffected individuals. 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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43 In ABCA1 heterozygotes, 3 distinct phenotypic groups emerged, one in which HDL-C levels were Ϸ50% of those of age-and sex-matched controls, one in which HDL-C levels were at least 70% of controls (A255T, W590S, T929I), and one in which HDL-C levels were significantly below the expected 50% of the levels for controls (30.4% of controls) (M1091T) (Table). Login to comment
92 Indeed the loss of function mutations showed an intermediate phenotype compared with the mutants with partial function, and the putative dominant negative mutant M1091T showed the most severe phenotype. Login to comment
97 <50% of Normal HDL-C Levels in ABCA1 Heterozygotes Imply a Dominant-Negative Function for the Mutant Allele Of the ABCA1 heterozygotes described thus far, only 1 missense mutation, M1091T, results in HDL-C levels that are Figure 3. Login to comment
107 A significant reduction in biotinylated M1091T was observed, thus corroborating the intracellular localization and EndoH data (Figure 4C). Login to comment
109 Patients heterozygous for this mutation have only 36% of normal relative efflux levels.4 These findings, along with the Ϸ30% of normal HDL-C levels observed in patients harboring this mutation, led us to hypothesize that M1091T acted in a dominant-negative manner and prevented the functioning of the normal ABCA1 allele. Login to comment
118 A, The M1091T mutant was retained in an intracellular compartment and did not reach the plasma membrane. Login to comment
119 B, Endo H digestion of M1091T showed that it was localized to the ER. Login to comment
120 C, Cell surface biotinylation of M1091T confirmed its lack of localization at the plasma membrane compared with wild-type ABCA1. Login to comment
121 D, The M1091T mutant showed a significant reduction in its ability to induce ApoA-I binding. Login to comment
122 A significant reduction in the ability of M1091T to promote efflux of both phosphocholine (E) and cholesterol efflux (F) to ApoA-I acceptors was observed. Login to comment
164 One mutant, M1091T, when present in heterozygous patients, results in significantly lower than 50% of normal HDL-C and efflux levels. Login to comment
169 Thus M1091T may act in a dominant-negative manner by an as of yet unknown mechanism. Login to comment
166 One mutant, M1091T, when present in heterozygous patients, results in significantly lower than 50% of normal HDL-C and efflux levels. Login to comment
171 Thus M1091T may act in a dominant-negative manner by an as of yet unknown mechanism. 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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554 Conversely, a small number of mutations are associated with less than 50% of control HDL cholesterol, specifically M1091T, G1216V, and the truncation mutations R2144X, R282X, and R909X. Login to comment
555 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 0;4.21 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
61 Of all ABCA1 alleles tested functionally, M1091T displays the greatest reduction in cholesterol efflux (6.9 6 20% of wild-type ABCA1), consistent with previous reports that this is a severe mutation associated with a severe clinical presentation [4,13]. Login to comment
63 To determine whether the severe phenotype conferred by the M1091T mutation is a result of the sensitivity of this site, or rather is specific to the insertion of the threonine residue, we generated and characterized cell lines transfected with plasmids bearing M1091L and M1091V alleles, both predicted to have no impact on ABCA1 function (subPSEC scores À2.65 and À2.71, respectively). Login to comment
64 Interestingly, both of these mutations dramatically impair cholesterol efflux, to a similar extent as the M1091T mutation (Figure 2B). 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
87 (B) Cholesterol efflux was assessed in 293 cells stably transfected with wild-type, M1091T, M1091L, or M1091V ABCA1 alleles. Login to comment
138 The subPSEC score for the naturally occurring M1091T mutation (À3.56) is only marginally predictive of a negative impact on function, but this variant resulted in a severe reduction in ABCA1 function, consistent with the severe phenotype observed in patients harboring this mutation [4,13]. Login to comment
142 Therefore, when calculating amino acid probabilities for position 1091, the subPSEC method includes sequences from only ABCA1 and ABCA4, which represents enough sequence variability to predict that a relatively radical mutation such as M1091T will likely be deleterious but not enough to predict that relatively conservative mutations such as M1091L or M1091V will be deleterious. Login to comment

[hide] Heterozygosity for ABCA1 gene mutations: effects o... Atherosclerosis. 2003 Dec;171(2):311-9. Kuivenhoven JA, Hovingh GK, van Tol A, Jauhiainen M, Ehnholm C, Fruchart JC, Brinton EA, Otvos JD, Smelt AH, Brownlee A, Zwinderman AH, Hayden MR, Kastelein JJ
Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size.
Atherosclerosis. 2003 Dec;171(2):311-9., [PMID:14644402]

Abstract [show]
A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.

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49 In family 2, two sisters with near complete HDL deficiency (HDL-cholesterol levels of 0.06 and 0.1 mmol/l, respectively) were found to only be heterozygous for a missense mutation (T3212C) resulting in M1091T. Login to comment
185 The material and method section describes that we have excluded two female heterozygotes of family 2 who presented with a remarkable HDL-deficiency (0.1 and 0.06 mmol/l, respectively) but were only found to be heterozygous for the M1091T defect. Login to comment
186 Heterozygosity for the same mutation surprisingly only resulted in half normal HDL-cholesterol in two of their sisters indicating that dominant-negative effects of M1091T are unlikely as was recently described for ABCA1 truncation mutations [38]. 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
124 This could be caused by dominant-negative effects of ABCA1, as previously shown for truncation mutations.69 Patients harboring the mutation M1091T show HDL-C levels that are 30% of age-and sex-matched controls.70 This finding suggests that ABCA1 acts as a dimer or as part of a complex in the exertion of its function. Login to comment
136 Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon -1095A/G Promoter ⅐ ⅐ ⅐ -477C/T Promoter ⅐ ⅐ ⅐ -419A/C Promoter ⅐ ⅐ ⅐ -320G/C Promoter ⅐ ⅐ ⅐ -191G/C Promoter ⅐ ⅐ ⅐ C69T 5ЈUTR 1 C117G 5ЈUTR 1 InsG319 5ЈUTR 2 G378C 5ЈUTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. 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
116 This could be caused by dominant-negative effects of ABCA1, as previously shown for truncation mutations.69 Patients harboring the mutation M1091T show HDL-C levels that are 30% of age-and sex-matched controls.70 This finding suggests that ABCA1 acts as a dimer or as part of a complex in the exertion of its function. Login to comment
128 Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon afa;1095A/G Promoter ዼ ዼ ዼ afa;477C/T Promoter ዼ ዼ ዼ afa;419A/C Promoter ዼ ዼ ዼ afa;320G/C Promoter ዼ ዼ ዼ afa;191G/C Promoter ዼ ዼ ዼ C69T 5b18;UTR 1 C117G 5b18;UTR 1 InsG319 5b18;UTR 2 G378C 5b18;UTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 Singaraja et al Clinical and Biochemical Impact of ABCA1 Variants markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. 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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66 TD 1591 T/C 11 V399A extracellular [68] TD 1979 (110bpAlu Ins) 12 truncated truncation [60] TD/FHA 2154 C/T 14 R587W extracellular [67,69] TD 2164 G/C 14 W590S extracellular [61] TD 2185 A/G 14 Q597R extracellular [59,67] TD 2219 G/del 14 truncated, 635X truncated [60,61] FHA 2472-2474 3bp del 15 Del L693 TM domain #3 [59] phosphorylation 2706 G/A 16 V771M extracellular [68] 2715 A/C 16 T774P extracellular [68] 2723 G/C 16 K776N extracellular [68] 2868 G/A 17 V825I TM domain #6 [67,68] TD/FHA 3044 A/G 18 I883M cytoplasmic [68] phosphorylat site FHA 3120 C/T 19 R909X truncation [63,71] TD 3181 C/T 19 T929I cytoplasmic [62] TD 3199 A/G 19 N935S Walker A [61] TD 3205 C/T 19 A937V Walker A [61] TD 3532 C/A 22 A1046D cytoplasmic, Walker A/B [70] FHA 3667 T/C 23 M1091T cytoplasmic [63] 3690 G/T 23 D1099Y cytoplasmic [9] TD 3738 2bp del 23 1145X truncation [66] FHA 3911 G/C 24 E1172D linker/cytoplasmic [68] FHA 4242 4bp del 27 1297X truncated [64] TD 4260 G/A 27 D1289N linker cytoplasm [64,65] TD 4824 T/C 31 C1477R extracellular [59] TD 4912 C/T 32 S1506L extracellular loop #2 [71] TD 5025 ins A 34 A1544S?1552X truncation [70] 5059 T/C 34 I1555T extracellular loop #2 [67] 5155 G/A 35 R1587K extracellular loop #2 [68] FHA 5226 A/G 36 N1611D extracellular loop #2 [75..] 5338 T/C 36 L1648P extracellular loop #2 [67] TD 5443 C/T 37 R1680W cytoplasmic [74.] Login to comment

[hide] The role of the ABCA1 transporter and cholesterol ... J Lipid Res. 2003 Jun;44(6):1251-5. Epub 2003 Apr 16. Hovingh GK, Van Wijland MJ, Brownlie A, Bisoendial RJ, Hayden MR, Kastelein JJ, Groen AK
The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia.
J Lipid Res. 2003 Jun;44(6):1251-5. Epub 2003 Apr 16., [PMID:12700344]

Abstract [show]
Defects in the gene encoding for the ATP binding cassette (ABC) transporter A1 (ABCA1) were shown to be one of the genetic causes for familial hypoalphalipoproteinemia (FHA). We investigated the role of ABCA1-mediated cholesterol efflux in Dutch subjects suffering from FHA. Eighty-eight subjects (mean HDL cholesterol levels 0.63 +/- 0.21 mmol/l) were enrolled. Fibroblasts were cultured and loaded with [3H]cholesterol. ABCA1 and non-ABCA1-mediated efflux was studied by using apolipoprotein A-I (apoA-I), HDL, and methyl-beta-cyclodextrin as acceptors. Efflux to apoA-I was decreased in four patients (4/88, 4.5%), and in all cases, a mutation in the ABCA1 gene was found. In the remaining 84 subjects, no correlation between efflux and apoA-I or HDL cholesterol was found. Efflux to both HDL and cyclodextrin, in contrast, did correlate with HDL cholesterol plasma levels (r = 0.34, P = 0.01; and r = 0.27, P = 0.008, respectively). The prevalence of defects in ABCA1-dependent cholesterol efflux in Dutch FHA patients is low. The significant correlation between plasma HDL cholesterol levels and methyl-beta-cyclodextrin-mediated efflux in the FHA patients with normal ABCA1 function suggests that non-ABCA1-mediated efflux might also be important for plasma HDL cholesterol levels in these individuals.

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81 The two compound heterozygous patients have been described previously [one of the compound heterozygous carriers suffered from a missense mutation (T to C at position 4,369) resulting in a C1477R, and a defect (IVS24 ϩ 1G to C) that caused differential splicing, whereas the other was shown to carry a missense mutation (C to T at position 3,181 resulting in T929I) and a de novo nonsense mutation] (16). Login to comment
82 A missense mutation (T3212C) resulting in M1091T, and a C to T nucleotide substitution at position 6,844 resulting in P2150L were the defects in the two heterozygous carriers. Login to comment

[hide] Cellular phospholipid and cholesterol efflux in hi... Circulation. 2003 Mar 18;107(10):1366-71. Marcil M, Bissonnette R, Vincent J, Krimbou L, Genest J
Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency.
Circulation. 2003 Mar 18;107(10):1366-71., [PMID:12642355]

Abstract [show]
BACKGROUND: Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C). METHODS AND RESULTS: We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C <5th percentile) in 64 subjects (12 women and 52 men). Apolipoprotein AI-mediated cellular cholesterol and phospholipid efflux were measured in fibroblasts from HypoA subjects, 9 controls, 2 patients with Tangier disease, and 5 patients with hyperalphalipoproteinemia. A phospholipid efflux defect was defined as <70% of controls. Mean HDL-C was 0.49+/-0.21 mmol/L. Cholesterol and phospholipid efflux correlated strongly (r=0.72, P<0.001). Phospholipid efflux and HDL-C (r=0.64, P<0.001) correlated in HypoA subjects. However, phospholipid or cholesterol efflux was no longer a determinant of HDL-C levels at higher levels (> approximately 1.0 mmol/L) of HDL-C. In HypoA subjects, 4 cases of Tangier disease and 6 of familial HDL deficiency (heterozygous Tangier disease) were identified (10 of 64; 16%). In the remaining 54 subjects, mean lipid efflux was not significantly different from controls and subjects with hyperalphalipoproteinemia. A phospholipid efflux defect was identified in 7 additional HypoA subjects, and a cholesterol efflux defect was detected in 11 subjects. In 2 of these subjects, the ABCA1 gene was ruled out as the cause of the efflux defect, while in 3, the low HDL-C trait segregated with the ABCA1 gene locus. CONCLUSIONS: Lipidation of lipid-poor apolipoprotein AI may not be a major determinant of cholesterol accumulation within more mature HDL particles and increasing cholesterol or phospholipid efflux beyond normal levels may not lead to increase in plasma HDL-C levels. ABCA1 is essential in the initial steps of HDL formation but other plasma events are major modulators of HDL-C levels.

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85 Molecular Characterization of ABCA1 Gene in Study Subjects Cell Lines HDL-C, mmol/L Nucleotide Change Predicted Protein Alteration TD CTL-1 0.10 Exon 30 T4369C; exon 24 splice site G3C C1477R; part of the transcript deleted TD CTL-2 0.15 Exon 13 A1730G Q597R FHD-1 0.40 Exon 14 ⌬2017-9 ⌬L693 FHD-2 0.18 Exon 48 C6370T R2144X FHD-3 0.39 Exon 41 ⌬5618-23 ⌬ED1893,4 FHD-4 0.18 Exon 18 C2665T R909X FHD-5 0.10 Exon 23 T3667C M1091T FHD-6 0.57 Exon 49 C6844T P2150L, R587W TD-1 0.03 Exon 48 ⌬C6370; ND 2145X TD-2 0.07 ND ND TD-3 0.03 ND 2203X TD-4 0.09 Exon 19 C3181T; ND T929I; ND CTL indicates control. Login to comment
79 Molecular Characterization of ABCA1 Gene in Study Subjects Cell Lines HDL-C, mmol/L Nucleotide Change Predicted Protein Alteration TD CTL-1 0.10 Exon 30 T4369C; exon 24 splice site G3C C1477R; part of the transcript deleted TD CTL-2 0.15 Exon 13 A1730G Q597R FHD-1 0.40 Exon 14 èc;2017-9 èc;L693 FHD-2 0.18 Exon 48 C6370T R2144X FHD-3 0.39 Exon 41 èc;5618-23 èc;ED1893,4 FHD-4 0.18 Exon 18 C2665T R909X FHD-5 0.10 Exon 23 T3667C M1091T FHD-6 0.57 Exon 49 C6844T P2150L, R587W TD-1 0.03 Exon 48 èc;C6370; ND 2145X TD-2 0.07 ND ND TD-3 0.03 ND 2203X TD-4 0.09 Exon 19 C3181T; ND T929I; ND CTL indicates control. Login to comment

[hide] Truncation mutations in ABCA1 suppress normal upre... J Lipid Res. 2002 Nov;43(11):1939-49. Wellington CL, Yang YZ, Zhou S, Clee SM, Tan B, Hirano K, Zwarts K, Kwok A, Gelfer A, Marcil M, Newman S, Roomp K, Singaraja R, Collins J, Zhang LH, Groen AK, Hovingh K, Brownlie A, Tafuri S, Genest J Jr, Kastelein JJ, Hayden MR
Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol.
J Lipid Res. 2002 Nov;43(11):1939-49., [PMID:12401893]

Abstract [show]
Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5-10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele. These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations.

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131 Expression data by mutation Family Mutation Proteinc Induced/Uninduced HDL-C Net Effluxd mmol/l % of control FHA1 Del L 693 5.95 (0.82) 0.4 79.47 (22.63) FHA2 R2144X 2.45 (0.19) 0.18 64.01 (11.12) FHA3 Del E,D 1893, 1894 7.82 (1.48) 0.39 60.03 (11.85) FHA4 R909X 2.32 (0.52) 0.18 72.28 (18.01) FHA5 M1091T 6.42 (0.29) 0.1 47.24 (3.79) TD1 ivs2511G-C, C1477R 3.46 (0.50) 0.1 2.73 (1.05) TD1-ha C1477R 10.28 (1.07) 0.9 58.14 (5.49) TD3 GG 5277C - 1636 2.89 (0.59) 0.09 23.3 (1.29) TD3-hb T9291 6.65 (0.10) 1.12 51.8 (1.30) TD4 Del C 6825 - 2145X, unidentified 1.14 (0.13) 0.03 17.22 (0) Control None 11.31 (0.68) 1.63 100.00 (7.09) a TD1-h is the heterozygous parent of the TD1 proband. Login to comment

[hide] Association between increased arterial-wall thickn... Lancet. 2002 Jan 5;359(9300):37-42. van Dam MJ, de Groot E, Clee SM, Hovingh GK, Roelants R, Brooks-Wilson A, Zwinderman AH, Smit AJ, Smelt AH, Groen AK, Hayden MR, Kastelein JJ
Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.
Lancet. 2002 Jan 5;359(9300):37-42., [PMID:11809185]

Abstract [show]
BACKGROUND: Decreased concentrations of HDL cholesterol are associated with increased cardiovascular risk. These concentrations are directly related to cholesterol efflux from cells-the first step and a key process in reverse cholesterol transport. Cholesterol efflux is mediated by the ATP-binding cassette A1 transporter (ABCA1), the rate-limiting step in the production of HDL. We aimed to assess the relation between cholesterol efflux, HDL concentrations, and arterial-wall changes in individuals with impaired ABCA1 function. METHODS: We investigated 30 individuals from families with ABCA1 mutations, and 110 controls matched for age, sex, and ethnic origin. We measured concentrations of HDL cholesterol in plasma and intima-media thickness of the carotid arteries by B-mode ultrasonography in all participants. We also measured cholesterol efflux from skin fibroblasts in nine individuals with ABCA1 mutations and in ten controls. FINDINGS: Individuals with ABCA1 mutations had lower amounts of cholesterol efflux, lower HDL cholesterol concentrations, and greater intima-media thicknesses than controls. An intima-media thickness at the upper limit of normal (0.80 mm) was reached by age 55 years in the ABCA1 heterozygotes, and at age 80 years in unaffected controls (p<0.0001). Additionally, strong positive correlations were seen between HDL cholesterol concentrations and cholesterol efflux (r=0.90, p=0.001), and negative correlations between apolipoprotein-AI-mediated (r=-0.61, p=0.030) and HDL-particle-mediated (r=-0.60, p=0.018) efflux and intima-media thickness in the ABCA1 mutation carriers. INTERPRETATION: These results show a direct relation between ABCA1-mediated cellular cholesterol efflux and arterial-wall thickness, and therefore suggest that increasing efflux could inhibit atherosclerosis progression before the manifestation of symptomatic cardiovascular disease.

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52 The ABCA1 mutations in NL-014 and NL-016, which have been previously described, consist of 4369T→C (C1477R) and 3212T→C (M1091T), respectively.6,9 Mutation carriers from the two newly discovered families with familial hypoalphalipoproteinaemia NL-020 and NL-016 had a 6844C→T (P2150L) and a 3181C→T (T929I) mutation in the ABCA1 gene respectively. Login to comment

[hide] Functional hot spots in human ATP-binding cassette... Protein Sci. 2010 Nov;19(11):2110-21. Kelly L, Fukushima H, Karchin R, Gow JM, Chinn LW, Pieper U, Segal MR, Kroetz DL, Sali A
Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains.
Protein Sci. 2010 Nov;19(11):2110-21., [PMID:20799350]

Abstract [show]
The human ATP-binding cassette (ABC) transporter superfamily consists of 48 integral membrane proteins that couple the action of ATP binding and hydrolysis to the transport of diverse substrates across cellular membranes. Defects in 18 transporters have been implicated in human disease. In hundreds of cases, disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs). The functional impact of the majority of ABC transporter nsSNPs has yet to be experimentally characterized. Here, we combine experimental mutational studies with sequence and structural analysis to describe the impact of nsSNPs in human ABC transporters. First, the disease associations of 39 nsSNPs in 10 transporters were rationalized by identifying two conserved loops and a small alpha-helical region that may be involved in interdomain communication necessary for transport of substrates. Second, an approach to discriminate between disease-associated and neutral nsSNPs was developed and tailored to this superfamily. Finally, the functional impact of 40 unannotated nsSNPs in seven ABC transporters identified in 247 ethnically diverse individuals studied by the Pharmacogenetics of Membrane Transporters consortium was predicted. Three predictions were experimentally tested using human embryonic kidney epithelial (HEK) 293 cells stably transfected with the reference multidrug resistance transporter 4 and its variants to examine functional differences in transport of the antiviral drug, tenofovir. The experimental results confirmed two predictions. Our analysis provides a structural and evolutionary framework for rationalizing and predicting the functional effects of nsSNPs in this clinically important membrane transporter superfamily.

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50 Disease-associated nsSNPs at Three Structural Hotspots in Human ABC Transporter NBDs Gene Disease Position ARA motif ABCB11 BRIC2 A570T ABCD1 X-ALD A616V CFTR CF A559T ABCC6 PXE R765Q ABCC8 HHF1 R841G ABCC8 HHF1 R1493Q ABCC8 HHF1 R1493W ABCD1 X-ALD R617C ABCD1 X-ALD R617G ABCD1 X-ALD R617H CFTR CF R560K CFTR CF R560S CFTR CF R560T ABCA1 HDLD1 A1046D ABCB4 ICP A546D C-loop 1 motif ABCC8 HHF1 D1471H ABCC8 HHF1 D1471N CFTR CBAVD G544V ABCC8 HHF1 G1478R C-loop2 motif ABCA4 STGD1 H2128R ABCC8 HHF1 K889T ABCD1 X-ALD R660P ABCD1 X-ALD R660W ABCA1 HDLD2 M1091T ABCA4 STGD1 E2131K ABCA12 LI2 E1539K ABCA4 STGD1 and CORD3 E1122K CFTR CF L610S ABCC8 HHF1 L1543P ABCA1 Colorectal cancer sample; somatic mutation A2109T ABCC9 CMD1O A1513T ABCD1 X-ALD H667D CFTR CF A613T ABCA1 HDLD2 D1099Y ABCD1 X-ALD T668I CFTR CF D614G ABCA4 STGD1 R2139W ABCA4 STGD1 R1129C ABCA4 ARMD2, STGD1, and FFM R1129L Disease abbreviations are as follows: BRIC2, benign recurrent intrahepatic cholestasis type 2; X-ALD, X-linked adrenoleukodystrophy; CF, cystic fibrosis; PXE, Pseudoxanthoma elasticum; HHF1, familial hyperinsulinemic hypoglycemia-1; HDLD1, high density lipoprotein deficiency type 1; ICP, intrahepatic cholestasis of pregnancy; CBAVD, congenital bilateral absence of the vas deferens; STGD1, Stargardt disease type 1; HDLD2, high density lipoprotein deficiency type 2; LI2, ichthyosis lamellar type 2; CORD3, cone-rod dystrophy type 3; CMD1O, cardiomyopathy dilated type 1O; ARMD2, age-related macular degeneration type 2; FFM, fundus flavimaculatus. Login to comment

[hide] Subfraction analysis of circulating lipoproteins i... Clin Chim Acta. 2016 Jan 15;452:167-72. doi: 10.1016/j.cca.2015.11.021. Epub 2015 Nov 23. Murano T, Yamaguchi T, Tatsuno I, Suzuki M, Noike H, Takanami T, Yoshida T, Suzuki M, Hashimoto R, Maeno T, Terai K, Tokuyama W, Hiruta N, Schneider WJ, Bujo H
Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation.
Clin Chim Acta. 2016 Jan 15;452:167-72. doi: 10.1016/j.cca.2015.11.021. Epub 2015 Nov 23., [PMID:26616730]

Abstract [show]
Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high-performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL-type particles accumulate over time, would experience an increased propensity for developing atherosclerosis.

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124 The mutations, Pro1065Ser and Met1091Thr, have been shown to disturb the ATP-binding function; these mutations cause FHA [7,19,21, 26]. Login to comment