ABCMdb

ABCA1 p.Leu1379Phe

Predicted by SNAP2:	A: D (66%), C: N (57%), D: D (85%), E: D (80%), F: D (63%), G: D (80%), H: D (80%), I: D (53%), K: D (85%), M: N (61%), N: D (80%), P: D (80%), Q: D (71%), R: D (80%), S: D (75%), T: D (71%), V: D (53%), W: D (80%), Y: D (75%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Tangier disease caused by compound heterozygosity ... Atherosclerosis. 2010 Mar;209(1):163-6. Epub 2009 Aug 29. Cameron J, Ranheim T, Halvorsen B, Kulseth MA, Leren TP, Berge KE
Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C.
Atherosclerosis. 2010 Mar;209(1):163-6. Epub 2009 Aug 29., [PMID:19765707]

Abstract [show]
BACKGROUND: Inherited low levels of high density lipoprotein (HDL) cholesterol may be due to mutations in the genes encoding the ATP-binding cassette transporter A1 (ABCA1), apolipoprotein (apo) A-I or lecithin:cholesterol acyltransferase (LCAT). METHODS: The ABCA1, apoA-I and LCAT genes of a 40-year-old male subject with serum HDL cholesterol of 0.06mmol/l were subjected to DNA sequencing. The proband's family was examined for co-segregation between mutations and levels of HDL cholesterol. Cholesterol efflux in fibroblasts from the proband and a normocholesterolemic subject was compared. The effects of an ABCA1 mutation on cholesterol efflux and membrane localization of ABCA1 were studied in transfected HEK293 and HeLa cells, respectively. RESULTS: The proband was a compound heterozygote for ABCA1 mutations R282X (c.844 C>T) and Y1532C (c.4595 A>G). Relatives who were heterozygous for one of these mutations, had about half-normal HDL cholesterol levels. Cholesterol efflux was reduced in fibroblasts from the proband, as was cholesterol efflux from HEK293 cells transfected with an human (h) ABCA1 expression plasmid harboring the Y1532C mutation. Confocal microscopy of HeLa cells transfected with the Y1532C-hABCA1 plasmid revealed that the Y1532C mutation inhibits ABCA1 from reaching the cellular membrane. CONCLUSION: Compound heterozygosity for the nonsense mutation R282X and the missense mutation Y1532C in the ABCA1 gene causes Tangier disease. R282X has a detrimental effect on the function of ABCA1 since a premature stop codon is introduced. Mutation Y1532C disrupts the normal function of ABCA1 as determined by in vitro analyses.

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122 Singaraja et al. [22] also showed C1477R-ABCA1 to be present at the cell surface to a similar degree as WT-ABCA1. Login to comment
124 Albrecht et al. [23] showed that mutation L1379F, which is also predicted to be in the 4th extracellular loop, was present at reduced levels at the cell surface. 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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135 Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 45TCM Vol. 20, No. 2, Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment
136 Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment

[hide] Functional polymorphism in ABCA1 influences age of... Hum Mol Genet. 2007 Jun 15;16(12):1412-22. Epub 2007 Apr 5. Kyriakou T, Pontefract DE, Viturro E, Hodgkinson CP, Laxton RC, Bogari N, Cooper G, Davies M, Giblett J, Day IN, Simpson IA, Albrecht C, Ye S
Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients.
Hum Mol Genet. 2007 Jun 15;16(12):1412-22. Epub 2007 Apr 5., [PMID:17412755]

Abstract [show]
ATP-binding-cassette-transporter-A1 (ABCA1) plays a pivotal role in intracellular cholesterol removal, exerting a protective effect against atherosclerosis. ABCA1 gene severe mutations underlie Tangier disease, a rare Mendelian disorder that can lead to premature coronary artery disease (CAD), with age of CAD onset being two decades earlier in mutant homozygotes and one decade earlier in heterozygotes than in mutation non-carriers. It is unknown whether common polymorphisms in ABCA1 could influence age of symptom onset of CAD in the general population. We examined common promoter and non-synonymous coding polymorphisms in relation to age of symptom onset in a group of CAD patients (n = 1164), and also carried out in vitro assays to test effects of the promoter variations on ABCA1 promoter transcriptional activity and effects of the coding variations on ABCA1 function in mediating cellular cholesterol efflux. Age of symptom onset was found to be associated with the promoter - 407G > C polymorphism, being 2.82 years higher in C allele homozygotes than in G allele homozygotes and intermediate in heterozygotes (61.54, 59.79 and 58.72 years, respectively; P = 0.002). In agreement, patients carrying ABCA1 haplotypes containing the -407C allele had higher age of symptom onset. Patients of the G/G or G/C genotype of the -407G > C polymorphism had significant coronary artery stenosis (>75%) at a younger age than those of the C/C genotype (P = 0.003). Reporter gene assays showed that ABCA1 haplotypes bearing the -407C allele had higher promoter activity than haplotypes with the -407G allele. Functional analyses of the coding polymorphisms showed an effect of the V825I substitution on ABCA1 function, with the 825I variant having higher activity in mediating cholesterol efflux than the wild-type (825V). A trend towards higher symptom onset age in 825I allele carriers was observed. The data indicate an influence of common ABCA1 functional polymorphisms on age of symptom onset in CAD patients.

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67 As expected, compared with the rate of cholesterol efflux in cells transfected with the plasmid expressing the wild-type ABCA1, the rates of cholesterol efflux were significantly lower in untransfected cells and in cells transfected with the plasmid expressing the ABCA1 (V1704D and L1379F) mutant which had previously been shown to result in complete loss of ABCA1 function (24) (P , 0.001; Fig. 4). Login to comment
146 Cultured COS-7 cells were transfected with each of the above plasmids or a plasmid expressing an ABCA1 mutant (V1704D and L1379F) described in Albrecht et al. (24). Login to comment
172 K.O. refers to an ABCA1 (V1704D and L1379F) mutant which had previously been shown to result in complete loss of ABCA1 function (24). Login to comment
69 As expected, compared with the rate of cholesterol efflux in cells transfected with the plasmid expressing the wild-type ABCA1, the rates of cholesterol efflux were significantly lower in untransfected cells and in cells transfected with the plasmid expressing the ABCA1 (V1704D and L1379F) mutant which had previously been shown to result in complete loss of ABCA1 function (24) (P , 0.001; Fig. 4). Login to comment
145 Cultured COS-7 cells were transfected with each of the above plasmids or a plasmid expressing an ABCA1 mutant (V1704D and L1379F) described in Albrecht et al. (24). Login to comment
171 K.O. refers to an ABCA1 (V1704D and L1379F) mutant which had previously been shown to result in complete loss of ABCA1 function (24). Login to comment

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

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

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48 This SNP has been reported to be associated with decreased HDL cholesterol and increased severity of atherosclerosis in Table 1. subPSEC Scores and Probability of Functional Impairment (Pdeleterious) for ABCA1 Mutations and SNPs Mutations SNPs Variant SubPSEC Pdeleterious Variant subPSEC Pdeleterious P85L À4.62 0.83 R219K À0.57 0.08 H160F À2.79 0.45 V399A À2.26 0.32 R230C À4.27 0.78 V771M À2.86 0.46 A255T À1.81 0.23 T774P À1.99 0.27 E284K À2.34 0.34 K776N À3.53 0.63 Y482C À4.21 0.77 V825I À1.06 0.13 R587W À6.04 0.95 I883M À1.38 0.17 W590S À5.19 0.9 E1172D À1.96 0.26 W590L À4.48 0.82 R1587K À0.58 0.08 Q597R À7.15 0.98 S1731C À4.21 0.77 T929I À4.29 0.78 N935H À8.54 1 N935S À7.53 0.99 A937V À6.6 0.97 A1046D À7.52 0.99 M1091T À3.56 0.64 D1099Y À6.09 0.96 D1289N À2.48 0.37 L1379F À3.81 0.69 C1477R À5.44 0.92 S1506L À5.17 0.9 N1611D À5.69 0.94 R1680W À6.02 0.95 V1704D À3.21 0.55 N1800H À4.23 0.77 R1901S À5.06 0.89 F2009S À2.73 0.43 R2081W À8.08 0.99 P2150L À2.88 0.47 Q2196H À2.74 0.43 DOI: 10.1371/journal.pgen.0010083.t001 PLoS Genetics | www.plosgenetics.org December 2005 | Volume 1 | Issue 6 | e83 0740 Accurate Prediction of ABCA1 Variants Synopsis A major goal of human genetics research is to understand how genetic variation leads to differences in the function of genes. Login to comment

[hide] Two novel missense mutations in ABCA1 result in al... Biochim Biophys Acta. 2004 May 24;1689(1):47-57. Albrecht C, Baynes K, Sardini A, Schepelmann S, Eden ER, Davies SW, Higgins CF, Feher MD, Owen JS, Soutar AK
Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency.
Biochim Biophys Acta. 2004 May 24;1689(1):47-57., [PMID:15158913]

Abstract [show]
Extremely low concentrations of high density lipoprotein (HDL)-cholesterol and apolipoprotein (apo) AI are features of Tangier disease caused by autosomal recessive mutations in ATP-binding cassette transporter A1 (ABCA1). Less deleterious, but dominantly inherited mutations cause HDL deficiency. We investigated causes of severe HDL deficiency in a 42-year-old female with progressive coronary disease. ApoAI-mediated efflux of cholesterol from the proband's fibroblasts was less than 10% of normal and nucleotide sequencing revealed inheritance of two novel mutations in ABCAI, V1704D and L1379F. ABCA1 mRNA was approximately 3-fold higher in the proband's cells than in control cells; preincubation with cholesterol increased it 5-fold in control and 8-fold in the proband's cells, but similar amounts of ABCA1 protein were present in control and mutant cells. When transiently transfected into HEK293 cells, confocal microscopy revealed that both mutant proteins were retained in the endoplasmic reticulum, while wild-type ABCA1 was located at the plasma membrane. Severe HDL deficiency in the proband was caused by two novel autosomal recessive mutations in ABCA1, one (V1704D) predicted to lie in a transmembrane segment and the other (L1379F) in a large extracellular loop. Both mutations prevent normal trafficking of ABCA1, thereby explaining their inability to mediate apoA1-dependent lipid efflux.

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3 ApoAI-mediated efflux of cholesterol from the proband`s fibroblasts was less than 10% of normal and nucleotide sequencing revealed inheritance of two novel mutations in ABCAI, V1704D and L1379F. Login to comment
6 Severe HDL deficiency in the proband was caused by two novel autosomal recessive mutations in ABCA1, one (V1704D) predicted to lie in a transmembrane segment and the other (L1379F) in a large extracellular loop. Login to comment
23 In this study, we describe a patient who has inherited two defective alleles of ABCA1 from apparently unaffected parents, each encoding a previously undescribed single amino acid substitution (L1379F and V1704D). Login to comment
116 In the proband, the paternal allele (clear box) carried the L1379F variant of ABCA1, and the maternal allele (shaded box) carried the V1704D variant. Login to comment
150 In comparison, the allele frequency of the R219K polymorphism was 0.22 (K allele), similar to that found in other European populations [31]. Login to comment
151 The proband`s father was heterozygous for L1379F, and her mother and sister for the V1704D variant (Fig. 1). Login to comment
153 Expression of normal and mutant ABCA1 in vitro The L1379F and V1704D mutations were introduced into the full-length cDNA for ABCA1, fused at its carboxy-terminus to eGFP. Login to comment
157 (a) Confocal sections of transiently transfected HEK 293 cells expressing wild-type ABCA1-eGFP (left panel), ABCA1-eGFP L1379F (middle panel) and ABCA1-eGFP V1704D (right panel); eGFP fluorescence is shown in green and DAPI staining of nuclear DNA in blue. Login to comment
159 (b) HEK 293 cells expressing wild-type ABCA1-eGFP, ABCA1-eGFP L1379F and ABCA1-eGFP V1704D were stained for SERCA 2 as an ER marker. Login to comment
161 A large extent of co-localisation was found for both mutants, suggesting retention of L1379F and V1704D in the ER. Login to comment
175 Discussion We describe a patient of English origin with severe HDL deficiency and premature coronary disease who is heterozygous for two rare alleles of ABCA1 that are predicted to cause single amino acid substitutions, L1379F and V1704D. Login to comment
206 The position of the L1379F substitution in ABCA1 is indicated in bold; the residues predicted by Simple Modular Architecture Research Tool (SMART; http://www.smart.embl-heidelberg.de) analysis of the amino acid sequence of ABCA1 to form membrane-spanning segment 7 in ABCA1 and ABCA4 are underlined. Login to comment
213 The other amino acid substitution, L1379F, is predicted to lie in the extracellular loop between transmembrane segments 7 and 8 that may constitute the binding site for apoAI [41]. Login to comment
115 In the proband, the paternal allele (clear box) carried the L1379F variant of ABCA1, and the maternal allele (shaded box) carried the V1704D variant. Login to comment
152 Expression of normal and mutant ABCA1 in vitro The L1379F and V1704D mutations were introduced into the full-length cDNA for ABCA1, fused at its carboxyterminus to eGFP. Login to comment
156 (a) Confocal sections of transiently transfected HEK 293 cells expressing wild-type ABCA1-eGFP (left panel), ABCA1-eGFP L1379F (middle panel) and ABCA1-eGFP V1704D (right panel); eGFP fluorescence is shown in green and DAPI staining of nuclear DNA in blue. Login to comment
158 (b) HEK 293 cells expressing wild-type ABCA1-eGFP, ABCA1-eGFP L1379F and ABCA1-eGFP V1704D were stained for SERCA 2 as an ER marker. Login to comment
160 A large extent of co-localisation was found for both mutants, suggesting retention of L1379F and V1704D in the ER. Login to comment
174 Discussion We describe a patient of English origin with severe HDL deficiency and premature coronary disease who is heterozygous for two rare alleles of ABCA1 that are predicted to cause single amino acid substitutions, L1379F and V1704D. Login to comment
205 The position of the L1379F substitution in ABCA1 is indicated in bold; the residues predicted by Simple Modular Architecture Research Tool (SMART; http://www.smart.embl-heidelberg.de) analysis of the amino acid sequence of ABCA1 to form membrane-spanning segment 7 in ABCA1 and ABCA4 are underlined. Login to comment
212 The other amino acid substitution, L1379F, is predicted to lie in the extracellular loop between transmembrane segments 7 and 8 that may constitute the binding site for apoAI [41]. Login to comment

[hide] Update on the molecular biology of dyslipidemias. Clin Chim Acta. 2015 Nov 4. pii: S0009-8981(15)30036-X. doi: 10.1016/j.cca.2015.10.033. Ramasamy I
Update on the molecular biology of dyslipidemias.
Clin Chim Acta. 2015 Nov 4. pii: S0009-8981(15)30036-X. doi: 10.1016/j.cca.2015.10.033., [PMID:26546829]

Abstract [show]
Dyslipidemia is a commonly encountered clinical condition and is an important determinant of cardiovascular disease. Although secondary factors play a role in clinical expression, dyslipidemias have a strong genetic component. Familial hypercholesterolemia is usually due to loss-of-function mutations in LDLR, the gene coding for low density lipoprotein receptor and genes encoding for proteins that interact with the receptor: APOB, PCSK9 and LDLRAP1. Monogenic hypertriglyceridemia is the result of mutations in genes that regulate the metabolism of triglyceride rich lipoproteins (eg LPL, APOC2, APOA5, LMF1, GPIHBP1). Conversely familial hypobetalipoproteinemia is caused by inactivation of the PCSK9 gene which increases the number of LDL receptors and decreases plasma cholesterol. Mutations in the genes APOB, and ANGPTL3 and ANGPTL4 (that encode angiopoietin-like proteins which inhibit lipoprotein lipase activity) can further cause low levels of apoB containing lipoproteins. Abetalipoproteinemia and chylomicron retention disease are due to mutations in the microsomal transfer protein and Sar1b-GTPase genes, which affect the secretion of apoB containing lipoproteins. Dysbetalipoproteinemia stems from dysfunctional apoE and is characterized by the accumulation of remnants of chylomicrons and very low density lipoproteins. ApoE deficiency can cause a similar phenotype or rarely mutations in apoE can be associated with lipoprotein glomerulopathy. Low HDL can result from mutations in a number of genes regulating HDL production or catabolism; apoAI, lecithin: cholesterol acyltransferase and the ATP-binding cassette transporter ABCA1. Patients with cholesteryl ester transfer protein deficiency have markedly increased HDL cholesterol. Both common and rare genetic variants contribute to susceptibility to dyslipidemias. In contrast to rare familial syndromes, in most patients, dyslipidemias have a complex genetic etiology consisting of multiple genetic variants as established by genome wide association studies. Secondary factors, obesity, metabolic syndrome, diabetes, renal disease, estrogen and antipsychotics can increase the likelihood of clinical presentation of an individual with predisposed genetic susceptibility to hyperlipoproteinemia. The genetic profiles studied are far from complete and there is room for further characterization of genes influencing lipid levels. Genetic assessment can help identify patients at risk for developing dyslipidemias and for treatment decisions based on 'risk allele' profiles. This review will present the current information on the genetics and pathophysiology of disorders that cause dyslipidemias.

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1056 Severe HDL deficiency in a patient was caused by two autosomal recessive mutations of ABCA1, one predicted to lie in the transmembrane segment (V1704D) and the other (L1379F) in the extracellular loop. Login to comment