ABCMdb

ABCA1 p.Tyr1532Cys

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Publications

PMID: 21567408 [PubMed] Nakagawa H et al: "Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts."

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

PMID: 19765707 [PubMed] Cameron J et al: "Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C."

No. Sentence Comment

0 Atherosclerosis 209 (2010) -166 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C Jamie Camerona , Trine Ranheima , Bente Halvorsenb,c , Mari Ann Kulsetha , Trond P. Lerena , Knut Erik Bergea,* a Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet, Oslo University Hospital, NO-0027 Oslo, Norway b Research Institute of Internal Medicine, Rikshospitalet, Oslo University Hospital, Norway c University of Oslo, Norway a r t i c l e i n f o Article history: Received 10 July 2009 Received in revised form 18 August 2009 Accepted 19 August 2009 Available online 29 August 2009 Keywords: ABCA1 gene Cholesterol efflux HDL cholesterol Mutation Tangier disease a b s t r a c t 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). Login to comment
5 Results: The proband was a compound heterozygote for ABCA1 mutations R282X (c.844 C>T) and Y1532C (c.4595 A>G). Login to comment
7 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. Login to comment
8 Confocal microscopy of HeLa cells transfected with the Y1532C-hABCA1 plasmid revealed that the Y1532C mutation inhibits ABCA1 from reaching the cellular membrane. Login to comment
9 Conclusion: Compound heterozygosity for the nonsense mutation R282X and the missense mutation Y1532C in the ABCA1 gene causes Tangier disease. Login to comment
11 Mutation Y1532C disrupts the normal function of ABCA1 as determined by in vitro analyses. Login to comment
66 However, DNA sequencing of the ABCA1 gene suggested that the proband was a compound heterozygote for the nonsense mutation R282X (c.844 C>T) in exon 9 and the missense mutation Y1532C (c.4595 A>G) in exon 34. Login to comment
67 R282X has previously been reported by Altilia et al. [19] as a cause of defective function of ABCA1, while Y1532C is a novel mutation. Login to comment
69 With respect to the genotypes, the proband`s mother and brother were both heterozygous for mutation R282X, while his father and daughter were heterozygous for mutation Y1532C. Login to comment
84 Together with the finding that none of 100 healthy unrelated individuals with levels of total serum cholesterol ≤6.5 mmol/l, HDL cholesterol between 1.2 and 1.8 mmol/l and triglycerides ≤3.0 mmol/l were found to be heterozygous for R282X or Y1532C in the ABCA1 gene, our findings suggest that the proband had Tangier disease. Login to comment
90 R282X introduces a premature stop codon in the predicted large 1st extracellular loop of ABCA1. Login to comment
91 mRNA analyses of fibroblasts failed to detect a transcript from the allele harboring mutation R282X, which the authors attributed to nonsense-mediated mRNA Fig. 3. Login to comment
92 Reduced cholesterol efflux from HEK293 cells transfected with Y1532C-hABCA1-FLAG plasmid. Login to comment
93 HEK293 cells were transiently transfected with plasmids encoding WT-hABCA1-FLAG, Y1532C-hABCA1-FLAG or an empty plasmid. Login to comment
95 The differences in cholesterol efflux between HEK293 cells transfected with the WT-hABCA1-FLAG plasmid and the Y1532C hABCA1-FLAG plasmid or an empty plasmid were significant different (p < 0.05 (*)). Login to comment
99 However, some uncertainty may exist regarding the pathogenicity of the Y1532C mutation even though it was predicted to be probably damaging by the use of the web-based software package PolyPhen (http://genetics.bwh.harvard.edu/pph). Login to comment
101 To establish whether the Y1532C mutation affected the function of ABCA1, we set out to perform a series of in vitro experiments. Login to comment
103 Studies of mutation Y1532C in the ABCA1 gene 3.2.1. Login to comment
104 Cholesterol efflux in HEK293 cells To further elucidate the role of mutation Y1532C on ABCA1-mediated cholesterol efflux, an ABCA1-containing plasmid harboring this mutation (Y1532C-hABCA1-FLAG) was transiently transfected into HEK293 cells. Login to comment
107 The apoA-I induced cholesterol efflux in HEK293 cells transfected with the Y1532C-hABCA1-FLAG Fig. 4. Login to comment
108 Y1532C-hABCA1-FLAG is predominantly located intracellularly. Login to comment
109 Confocal microscopy of permeabilized HeLa cells transiently transfected with WT-hABCA1-FLAG or Y1532C-hABCA1-FLAG plasmids. Login to comment
113 Thus, mutation Y1532C causes reduced cholesterol efflux. Login to comment
116 To study whether the mutant Y1532C-ABCA1 is inserted into the cell membrane, HeLa cells were transiently transfected with WT-hABCA1-FLAG or Y1532C-hABCA1-FLAG plasmids. Login to comment
117 HeLa cells transfected with WT-hABCA1-FLAG showed a membrane-associated localization of ABCA1, while cells transfected with Y1532C-hABCA1-FLAG predominantly showed an intracellular localization of ABCA1 (Fig. 4). Login to comment
118 Thus, the failure of Y1532C-ABCA1 to promote cholesterol efflux appears to be caused by disrupted transport of the mutant protein to the cell surface. 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
126 In conclusion, we have identified the first patient with Tangier disease of Norwegian origin, due to compound heterozygosity for the previously described ABCA1 mutation R282X [19], and the novel ABCA1 mutation Y1532C. Login to comment
64 However, DNA sequencing of the ABCA1 gene suggested that the proband was a compound heterozygote for the nonsense mutation R282X (c.844 C>T) in exon 9 and the missense mutation Y1532C (c.4595 A>G) in exon 34. Login to comment
65 R282X has previously been reported by Altilia et al. [19] as a cause of defective function of ABCA1, while Y1532C is a novel mutation. Login to comment
82 Together with the finding that none of 100 healthy unrelated individuals with levels of total serum cholesterol ࣘ6.5 mmol/l, HDL cholesterol between 1.2 and 1.8 mmol/l and triglycerides ࣘ3.0 mmol/l were found to be heterozygous for R282X or Y1532C in the ABCA1 gene, our findings suggest that the proband had Tangier disease. Login to comment
97 However, some uncertainty may exist regarding the pathogenicity of the Y1532C mutation even though it was predicted to be probably damaging by the use of the web-based software package PolyPhen (http://genetics.bwh.harvard.edu/pph). Login to comment
102 Cholesterol efflux in HEK293 cells To further elucidate the role of mutation Y1532C on ABCA1-mediated cholesterol efflux, an ABCA1-containing plasmid harboring this mutation (Y1532C-hABCA1-FLAG) was transiently transfected into HEK293 cells. Login to comment
105 The apoA-I induced cholesterol efflux in HEK293 cells transfected with the Y1532C-hABCA1-FLAG Fig. 4. Login to comment
106 Y1532C-hABCA1-FLAG is predominantly located intracellularly. Login to comment
111 Thus, mutation Y1532C causes reduced cholesterol efflux. Login to comment
114 To study whether the mutant Y1532C-ABCA1 is inserted into the cell membrane, HeLa cells were transiently transfected with WT-hABCA1-FLAG or Y1532C-hABCA1-FLAG plasmids. Login to comment
115 HeLa cells transfected with WT-hABCA1-FLAG showed a membrane-associated localization of ABCA1, while cells transfected with Y1532C-hABCA1-FLAG predominantly showed an intracellular localization of ABCA1 (Fig. 4). Login to comment

PMID: 26546829 [PubMed] Ramasamy I et al: "Update on the molecular biology of dyslipidemias."

No. Sentence Comment

1064 All three mutations p.A1046D, p. Y1532C and p. W1699C were reported to be deleterious in functional studies (473). Login to comment