ABCA1 p.Leu1379Phe
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PMID: 19765707
[PubMed]
Cameron J et al: "Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C."
No.
Sentence
Comment
122
Singaraja et al. [22] also showed C1477R-ABCA1 to be present at the cell surface to a similar degree as WT-ABCA1.
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ABCA1 p.Leu1379Phe 19765707:122:42
status: NEW124 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.
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ABCA1 p.Leu1379Phe 19765707:124:42
status: NEW
PMID: 20656214
[PubMed]
Kang MH et al: "Adenosine-triphosphate-binding cassette transporter-1 trafficking and function."
No.
Sentence
Comment
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.
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ABCA1 p.Leu1379Phe 20656214:135:573
status: NEW136 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.
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ABCA1 p.Leu1379Phe 20656214:136:573
status: NEW
PMID: 17412755
[PubMed]
Kyriakou T et al: "Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients."
No.
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Comment
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).
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ABCA1 p.Leu1379Phe 17412755:67:283
status: NEW146 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).
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ABCA1 p.Leu1379Phe 17412755:146:122
status: NEW172 K.O. refers to an ABCA1 (V1704D and L1379F) mutant which had previously been shown to result in complete loss of ABCA1 function (24).
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ABCA1 p.Leu1379Phe 17412755:172:36
status: NEW69 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).
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ABCA1 p.Leu1379Phe 17412755:69:283
status: NEW145 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).
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ABCA1 p.Leu1379Phe 17412755:145:122
status: NEW171 K.O. refers to an ABCA1 (V1704D and L1379F) mutant which had previously been shown to result in complete loss of ABCA1 function (24).
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ABCA1 p.Leu1379Phe 17412755:171:36
status: NEW
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.
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ABCA1 p.Leu1379Phe 16429166:48:779
status: NEWX
ABCA1 p.Leu1379Phe 16429166:48:919
status: NEW
PMID: 15158913
[PubMed]
Albrecht C et al: "Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency."
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Comment
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.
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ABCA1 p.Leu1379Phe 15158913:3:187
status: NEW6 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.
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ABCA1 p.Leu1379Phe 15158913:6:173
status: NEW23 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).
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ABCA1 p.Leu1379Phe 15158913:23:193
status: NEW116 In the proband, the paternal allele (clear box) carried the L1379F variant of ABCA1, and the maternal allele (shaded box) carried the V1704D variant.
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ABCA1 p.Leu1379Phe 15158913:116:60
status: NEW150 In comparison, the allele frequency of the R219K polymorphism was 0.22 (K allele), similar to that found in other European populations [31].
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ABCA1 p.Leu1379Phe 15158913:150:42
status: NEW151 The proband`s father was heterozygous for L1379F, and her mother and sister for the V1704D variant (Fig. 1).
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ABCA1 p.Leu1379Phe 15158913:151:42
status: NEW153 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.
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ABCA1 p.Leu1379Phe 15158913:153:51
status: NEW157 (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.
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ABCA1 p.Leu1379Phe 15158913:157:120
status: NEW159 (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.
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ABCA1 p.Leu1379Phe 15158913:159:62
status: NEW161 A large extent of co-localisation was found for both mutants, suggesting retention of L1379F and V1704D in the ER.
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ABCA1 p.Leu1379Phe 15158913:161:86
status: NEW175 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.
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ABCA1 p.Leu1379Phe 15158913:175:220
status: NEW206 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.
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ABCA1 p.Leu1379Phe 15158913:206:20
status: NEW213 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].
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ABCA1 p.Leu1379Phe 15158913:213:35
status: NEW115 In the proband, the paternal allele (clear box) carried the L1379F variant of ABCA1, and the maternal allele (shaded box) carried the V1704D variant.
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ABCA1 p.Leu1379Phe 15158913:115:60
status: NEW152 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.
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ABCA1 p.Leu1379Phe 15158913:152:51
status: NEW156 (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.
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ABCA1 p.Leu1379Phe 15158913:156:120
status: NEW158 (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.
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ABCA1 p.Leu1379Phe 15158913:158:62
status: NEW160 A large extent of co-localisation was found for both mutants, suggesting retention of L1379F and V1704D in the ER.
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ABCA1 p.Leu1379Phe 15158913:160:86
status: NEW174 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.
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ABCA1 p.Leu1379Phe 15158913:174:220
status: NEW205 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.
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ABCA1 p.Leu1379Phe 15158913:205:20
status: NEW212 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].
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ABCA1 p.Leu1379Phe 15158913:212:35
status: NEW
No.
Sentence
Comment
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.
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ABCA1 p.Leu1379Phe 26546829:1056:167
status: NEW