ABCMdb

ABCA1 p.Arg1925Gln

Predicted by SNAP2:	A: N (57%), C: N (53%), D: D (66%), E: D (59%), F: D (85%), G: D (53%), H: N (78%), I: N (66%), K: N (93%), L: N (61%), M: D (53%), N: D (85%), P: D (63%), Q: D (80%), S: N (72%), T: N (72%), V: N (61%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, S: N, T: D, V: D, W: D, Y: D,

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[hide] Ubiquitin-mediated proteasomal degradation of ABC ... J Pharm Sci. 2011 Sep;100(9):3602-19. doi: 10.1002/jps.22615. Epub 2011 May 12. Nakagawa H, Toyoda Y, Wakabayashi-Nakao K, Tamaki H, Osumi M, Ishikawa T
Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts.
J Pharm Sci. 2011 Sep;100(9):3602-19. doi: 10.1002/jps.22615. Epub 2011 May 12., [PMID:21567408]

Abstract [show]
The interindividual variation in the rate of drug metabolism and disposition has been known for many years. Pharmacogenomics dealing with heredity and response to drugs is a part of science that attempts to explain variability of drug responses and to search for the genetic basis of such variations or differences. Genetic polymorphisms of drug metabolizing enzymes and drug transporters have been found to play a significant role in the patients' responses to medication. Accumulating evidence demonstrates that certain nonsynonymous polymorphisms have great impacts on the protein stability and degradation, as well as the function of drug metabolizing enzymes and transporters. The aim of this review article is to address a new aspect of protein quality control in the endoplasmic reticulum and to present examples regarding the impact of nonsynonymous single-nucleotide polymorphisms on the protein stability of thiopurine S-methyltransferase as well as ATP-binding cassette (ABC) transporters including ABCC4, cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), ABCC11, and ABCG2. Furthermore, we will discuss the molecular mechanisms underlying posttranslational modifications (intramolecular and intermolecular disulfide bond formation and N-linked glycosylation) and ubiquitin-mediated proteasomal degradation of ABCG2, one of the major drug transporter proteins in humans.

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No. Sentence Comment
155 Effect of Mutations and Nonsynonymous SNPs on Protein Trafficking, Maturation, or ERAD of ABC Transporters Protein AA Mutation/SNP Effect on Protein Reference ABCA1 W590S Mutation Functional defect 115 R587W Mutation Impaired glycol processing 115 Q597R Mutation Impaired glycol processing, ERAD 115,116 Y1532C Mutation Altered protein trafficking 117 R1925Q Mutation Altered protein trafficking 118 ABCA3 R43L Mutation Altered protein trafficking 119 L101P Mutation Altered protein trafficking 119 R280C Mutation Altered protein trafficking 119 ABCA4 L541P Mutation Mislocalization 120 R602W Mutation Mislocalization 120 A1038V Mutation Mislocalization 120 C1490Y Mutation Mislocalization 120 ABCB1a G268V Mutation ERAD 121 G341C Mutation ERAD 121 I1196S Mutation Reduced glycosylation 122 ABCB4 I541F Mutation Accumulation in ER 123 ABCB11a E135K Mutation Reduced level of mature protein 124 L198P Mutation Reduced level of mature protein 124 E297G Mutation Reduced level of mature protein 124 L413W Mutation Reduced level of mature protein 124 R432T Mutation Reduced level of mature protein 124 D482G Mutation Immature protein in ER 124,125 N490D Mutation Reduced level of mature protein 124 A570T Mutation Reduced level of mature protein 124 T655I Mutation Reduced level of mature protein 124 Y818F SNP Moderate reduction of protein 124 G982R Mutation Retention in ER 125 R1153C Mutation ERAD 125 R1286Q Mutation Retention in ER 125 ABCC2a R768W Mutation Impaired protein trafficking 126 I1173F Mutation Impaired protein maturation 127 R1392 Mutation Impaired protein maturation 128 M1393 Mutation Impaired protein maturation 129 ABCC4a E757K SNP Altered protein trafficking 23 ABCC7 F508 Mutation Misfolding, ERAD 36-39,130 G85E Mutation Impaired protein maturation 130-132 G91R Mutation Impaired protein maturation 130-132 N1303K Mutation Impaired protein maturation 130-132 ABCC8 WT Wild type Ubiquitin-proteasome degradation 133 A116P Mutation Ubiquitin-proteasome degradation 133 V187D Mutation Ubiquitin-proteasome degradation 133 F1388 Mutation Impaired protein trafficking 134 L1544P Mutation Impaired protein trafficking 135,136 ABCC11a G180R SNP Ubiquitin-proteasome degradation 50 27 Mutation Ubiquitin-proteasome degradation 50 ABCG2a V12M SNP Altered protein localization 96 Q141K SNP Ubiquitin-proteasome degradation 102 F208S SNP Ubiquitin-proteasome degradation 78,99 S441N SNP Ubiquitin-proteasome degradation 78,99 Mutations of ABCA1, ABCA3, ABCA4, ABCB4, ABCB11, ABCC2, ABCC7 (CFTR), and ABCC8 are associated with Tangier disease, fatal surfactant deficiency, Stargardt disease, progressive familial intrahepatic cholestasis type 3 (PFIC-3), progressive familial intrahepatic cholestasis type 2 (PFIC-2), Dubin-Johnson syndrome, cystic fibrosis, and familial hyperinsulinism, respectively. Login to comment

[hide] Genotypic variation in ATP-binding cassette transp... Transl Res. 2007 Apr;149(4):205-10. Mantaring M, Rhyne J, Ho Hong S, Miller M
Genotypic variation in ATP-binding cassette transporter-1 (ABCA1) as contributors to the high and low high-density lipoprotein-cholesterol (HDL-C) phenotype.
Transl Res. 2007 Apr;149(4):205-10., [PMID:17383594]

Abstract [show]
The ATP-binding cassette transporter-1 (ABCA1) mediates cholesterol efflux and genotypic variation in ABCA1 and may impact reverse cholesterol transport and influence cardiovascular disease (CVD) risk. However, although mutations in ABCA1 have generally been identified with low HDL-C, few have undertaken a comparative evaluation between high and low high-density lipoprotein-cholesterol (HDL-C). Therefore, to evaluate for potential gain-of-function polymorphisms/mutations in ABCA1, 56 consecutive subjects were screened presenting with high (60-99 mg/dL [1.6-2.6 mmol/L]) or very high HDL-C (>100 mg/dL [2.6 mmol/L]) and were compared with subjects with average or low HDL-C (n = 68). Carrier frequencies of common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K were also assessed. All 50 exons and exon-intron boundaries of ABCA1 were screened using single-stranded conformation polymorphism (SSCP). DNA samples with SSCP-shifts or differing band patterns were sequenced. For the 6 common polymorphisms, genotyping was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Overall, 5 novel nonsynonymous mutations were identified, all of which were associated with low HDL-C. Of the 6 common ABCA1 polymorphisms, very high HDL-C was associated with a higher genotype frequency for R219K (P(trend) = 0.04) and higher genotype and allelic frequency for E1172D (P(trend) = 0.0004, P(trend) = 0.0002, respectively) compared with lower HDL-C. These data reaffirm that rare mutations in ABCA1 are associated with low HDL-C. However, at least 1 ABCA1 polymorphism (eg, E1172D) may contribute to the high HDL-C phenotype.

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62 According to the third National Health and Nutrition Examination Survey (NHANES III) (n ϭ 17,000), the prevalence of HDL-C Ͼ 100 mg/dL (0.85%) is similar to that of very low HDL-C (eg, Ͻ20 mg/dL).20 Complete screening of ABCA1 disclosed 5 mutations (E868K, Q1279K, G1421X, R1925Q, and Y2178H) that, to the authors` knowledge,3,4 have not been previously reported. Login to comment
68 Novel ABCA1 mutations and associated clinical characteristics Mutation Gender YOB HDL-C† CVD Risk factors E868K Male* 1936 37 ϩ Diabetes Q1279K Male 1949 37 ϩ MetS G1421X Female 1942 32 ϩ Diabetes/Smoker R1925Q Male* 1931 23 ϩ MetS Y2178H Male 1955 36 ϩ Smoker Abbreviations: MetS, metabolic syndrome; YOB, year of birth. Login to comment
61 According to the third National Health and Nutrition Examination Survey (NHANES III) (n afd; 17,000), the prevalence of HDL-C b0e; 100 mg/dL (0.85%) is similar to that of very low HDL-C (eg, b0d;20 mg/dL).20 Complete screening of ABCA1 disclosed 5 mutations (E868K, Q1279K, G1421X, R1925Q, and Y2178H) that, to the authors` knowledge,3,4 have not been previously reported. 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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565 Albrecht et al. (3) reported a case of Scott syndrome, a rare bleeding disorder characterized by defective phosphatidylserine (PS) exposure on the surface of platelets, that was associated with a novel missense mutation in ABCA1, R1925Q (3). Login to comment

[hide] A novel missense mutation in ABCA1 results in alte... Blood. 2005 Jul 15;106(2):542-9. Epub 2005 Mar 24. Albrecht C, McVey JH, Elliott JI, Sardini A, Kasza I, Mumford AD, Naoumova RP, Tuddenham EG, Szabo K, Higgins CF
A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome.
Blood. 2005 Jul 15;106(2):542-9. Epub 2005 Mar 24., [PMID:15790791]

Abstract [show]
Scott syndrome (SS) is a bleeding disorder characterized by a failure to expose phosphatidylserine (PS) to the outer leaflet of the platelet plasma membrane. Because the adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) is implicated in the exofacial translocation of PS, we assessed its role in the pathophysiology of a patient with SS. Substantially reduced levels of ABCA1 mRNA were found in the patient's leukocytes, compared with controls. The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R1925Q), absent from unaffected family members and controls. Both mutant and wild-type alleles were reduced in mRNA expression, and no causative mutation for this phenomenon was identified in the ABCA1 gene or its proximal promoter, suggesting a putative second mutation in a trans-acting regulatory gene may also be involved in the disorder in this patient. In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Overexpression of wild-type ABCA1 in SS lymphocytes complemented the Ca2+-dependent PS exposure at the cell surface. These data identify a mutation in ABCA1 that contributes to the defective PS translocation phenotype in our patient with SS.

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4 The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R1925Q), absent from unaffected family members and controls. Login to comment
6 In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Login to comment
115 The R1925Q variant was not found in 164 alleles of a control population of British origin,32 evidenced by WAVE analysis. Login to comment
122 Localization studies To test the impact of the R1925Q mutation on intracellular trafficking of ABCA1, we introduced the c.6064GϾA mutation into a full-length cDNA encoding ABCA1 fused at its carboxyterminus to EGFP, and expressed the fusion protein in HEK 293 Figure 1. Login to comment
149 In contrast, little or no fluorescence was detected on the surface of cells transfected with the ABCA1 R1925Q-EGFP construct (Figure 4A middle and right panels; Figure 4B left panel). Login to comment
158 The mutated residue (ABCA1 R1925Q) is indicated by a rectangle. Login to comment
163 (A) Confocal sections of transiently transfected HEK 293 cells expressing wild-type ABCA1-EGFP (left) and ABCA1 R1925Q-EGFP (middle and right). Login to comment
166 (B) HEK 293 cells expressing wild-type ABCA1-EGFP and ABCA1 R1925Q-EGFP were stained for SERCA 2 (red) as marker for the ER. The same confocal sections are shown for EGFP (green, left column), SERCA 2 (red, middle column) and colocalization of EGFP and SERCA2 in the overlay (yellow, right column). Login to comment
167 Colocalization of ABCA1-SERCA2 was observed in cells transfected with mutant ABCA1, implying retention of R1925Q in the ER. In contrast, wild-type ABCA1-EGFP localized predominantly to the plasma membrane and no colocalization was detected. Login to comment
179 We identified a novel missense mutation in ABCA1 (R1925Q) in the SS patient, which results in severely impaired trafficking and reduced expression of functional ABCA1 protein at the cell surface. Login to comment
3 The SS patient was heterozygous for a novel missense mutation c.6064G>A (ABCA1 R1925Q), absent from unaffected family members and controls. Login to comment
5 In vitro expression studies showed impaired trafficking of ABCA1 R1925Q to the plasma membrane. Login to comment
114 The R1925Q variant was not found in 164 alleles of a control population of British origin,32 evidenced by WAVE analysis. Login to comment
121 Localization studies To test the impact of the R1925Q mutation on intracellular trafficking of ABCA1, we introduced the c.6064Gb0e;A mutation into a full-length cDNA encoding ABCA1 fused at its carboxyterminus to EGFP, and expressed the fusion protein in HEK 293 Figure 1. Login to comment
148 In contrast, little or no fluorescence was detected on the surface of cells transfected with the ABCA1 R1925Q-EGFP construct (Figure 4A middle and right panels; Figure 4B left panel). Login to comment
157 The mutated residue (ABCA1 R1925Q) is indicated by a rectangle. Login to comment
162 (A) Confocal sections of transiently transfected HEK 293 cells expressing wild-type ABCA1-EGFP (left) and ABCA1 R1925Q-EGFP (middle and right). Login to comment
165 (B) HEK 293 cells expressing wild-type ABCA1-EGFP and ABCA1 R1925Q-EGFP were stained for SERCA 2 (red) as marker for the ER. The same confocal sections are shown for EGFP (green, left column), SERCA 2 (red, middle column) and colocalization of EGFP and SERCA2 in the overlay (yellow, right column). Login to comment
177 We identified a novel missense mutation in ABCA1 (R1925Q) in the SS patient, which results in severely impaired trafficking and reduced expression of functional ABCA1 protein at the cell surface. Login to comment

[hide] A novel ABCA1 nonsense mutation, R1270X, in Tangie... Clin Chim Acta. 2009 Nov;409(1-2):136-9. doi: 10.1016/j.cca.2009.08.017. Epub 2009 Aug 31. Hooper AJ, Robertson K, Ng L, Kattampallil JS, Latchem D, Willsher PC, Thom J, Baker RI, Burnett JR
A novel ABCA1 nonsense mutation, R1270X, in Tangier disease associated with an unrecognised bleeding tendency.
Clin Chim Acta. 2009 Nov;409(1-2):136-9. doi: 10.1016/j.cca.2009.08.017. Epub 2009 Aug 31., [PMID:19723515]

Abstract [show]
The ATP binding cassette transporter A1 (ABCA1) is involved in the regulation of lipid trafficking and export of cholesterol from cells to high density lipoprotein (HDL). ABCA1 gene defects cause Tangier disease, an autosomal recessive disorder characterised by the absence of HDL-cholesterol in plasma, abnormal deposition of cholesteryl esters in the reticuloendothelial system, defective platelet dense and lysosomal granule release, and disordered cellular cholesterol efflux. We describe the case of a 62-year-old man with Tangier disease who presented with severe anaemia secondary to a spontaneous splenic haematoma. He underwent elective splenectomy without haemorrhage and his thrombocytopaenia resolved with a platelet count rising from 97 to 560 x 10(9)/L. Macroscopically, the resected spleen was enlarged with evidence of splenic haematoma. Histologic analysis of sections of spleen revealed lipid histiocytosis consistent with the diagnosis of Tangier disease. DNA sequence analysis revealed the subject to be a homozygote for a novel ABCA1 mutation c.4121C>T, which changes arginine 1270 to a stop codon (R1270X). In conclusion, we describe a case of Tangier disease in association with an unrecognised bleeding tendency, in a man homozygous for a novel ABCA1 gene mutation, R1270X.

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71 Of interest, Scott syndrome, an extremely rare bleeding disorder characterised by a failure to expose phosphatidylserine on the surface of platelets, is associated with the ABCA1 missense mutation R1925Q [18]. Login to comment