ABCA1 p.Tyr1532Cys
Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (95%), E: D (91%), F: D (66%), G: D (91%), H: D (85%), I: D (85%), K: D (95%), L: D (85%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), R: D (91%), S: D (91%), T: D (91%), V: D (85%), W: D (91%), |
Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: 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.
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ABCA1 p.Tyr1532Cys 21567408:155:304
status: NEW[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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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).
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ABCA1 p.Tyr1532Cys 19765707:0:228
status: NEW5 Results: The proband was a compound heterozygote for ABCA1 mutations R282X (c.844 C>T) and Y1532C (c.4595 A>G).
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ABCA1 p.Tyr1532Cys 19765707:5:91
status: NEW7 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.
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ABCA1 p.Tyr1532Cys 19765707:7:177
status: NEW8 Confocal microscopy of HeLa cells transfected with the Y1532C-hABCA1 plasmid revealed that the Y1532C mutation inhibits ABCA1 from reaching the cellular membrane.
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ABCA1 p.Tyr1532Cys 19765707:8:55
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:8:95
status: NEW9 Conclusion: Compound heterozygosity for the nonsense mutation R282X and the missense mutation Y1532C in the ABCA1 gene causes Tangier disease.
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ABCA1 p.Tyr1532Cys 19765707:9:94
status: NEW11 Mutation Y1532C disrupts the normal function of ABCA1 as determined by in vitro analyses.
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ABCA1 p.Tyr1532Cys 19765707:11:9
status: NEW66 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.
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ABCA1 p.Tyr1532Cys 19765707:66:177
status: NEW67 R282X has previously been reported by Altilia et al. [19] as a cause of defective function of ABCA1, while Y1532C is a novel mutation.
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ABCA1 p.Tyr1532Cys 19765707:67:107
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:67:168
status: NEW69 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.
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ABCA1 p.Tyr1532Cys 19765707:69:168
status: NEW84 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.
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ABCA1 p.Tyr1532Cys 19765707:84:255
status: NEW90 R282X introduces a premature stop codon in the predicted large 1st extracellular loop of ABCA1.
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ABCA1 p.Tyr1532Cys 19765707:90:62
status: NEW91 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.
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ABCA1 p.Tyr1532Cys 19765707:91:81
status: NEW92 Reduced cholesterol efflux from HEK293 cells transfected with Y1532C-hABCA1-FLAG plasmid.
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ABCA1 p.Tyr1532Cys 19765707:92:62
status: NEW93 HEK293 cells were transiently transfected with plasmids encoding WT-hABCA1-FLAG, Y1532C-hABCA1-FLAG or an empty plasmid.
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ABCA1 p.Tyr1532Cys 19765707:93:81
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:93:111
status: NEW95 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 (*)).
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ABCA1 p.Tyr1532Cys 19765707:95:111
status: NEW99 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).
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ABCA1 p.Tyr1532Cys 19765707:99:25
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:99:71
status: NEW101 To establish whether the Y1532C mutation affected the function of ABCA1, we set out to perform a series of in vitro experiments.
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ABCA1 p.Tyr1532Cys 19765707:101:20
status: NEW103 Studies of mutation Y1532C in the ABCA1 gene 3.2.1.
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ABCA1 p.Tyr1532Cys 19765707:103:20
status: NEW104 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.
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ABCA1 p.Tyr1532Cys 19765707:104:77
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:104:175
status: NEW107 The apoA-I induced cholesterol efflux in HEK293 cells transfected with the Y1532C-hABCA1-FLAG Fig. 4.
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ABCA1 p.Tyr1532Cys 19765707:107:75
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:107:95
status: NEW108 Y1532C-hABCA1-FLAG is predominantly located intracellularly.
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ABCA1 p.Tyr1532Cys 19765707:108:0
status: NEW109 Confocal microscopy of permeabilized HeLa cells transiently transfected with WT-hABCA1-FLAG or Y1532C-hABCA1-FLAG plasmids.
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ABCA1 p.Tyr1532Cys 19765707:109:95
status: NEW113 Thus, mutation Y1532C causes reduced cholesterol efflux.
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ABCA1 p.Tyr1532Cys 19765707:113:15
status: NEW116 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.
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ABCA1 p.Tyr1532Cys 19765707:116:21
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:116:28
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:116:140
status: NEW117 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).
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ABCA1 p.Tyr1532Cys 19765707:117:124
status: NEW118 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.
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ABCA1 p.Tyr1532Cys 19765707:118:21
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.Tyr1532Cys 19765707:124:210
status: NEW126 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.
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ABCA1 p.Tyr1532Cys 19765707:126:210
status: NEW64 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.
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ABCA1 p.Tyr1532Cys 19765707:64:177
status: NEW65 R282X has previously been reported by Altilia et al. [19] as a cause of defective function of ABCA1, while Y1532C is a novel mutation.
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ABCA1 p.Tyr1532Cys 19765707:65:107
status: NEW82 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.
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ABCA1 p.Tyr1532Cys 19765707:82:253
status: NEW97 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).
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ABCA1 p.Tyr1532Cys 19765707:97:71
status: NEW102 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.
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ABCA1 p.Tyr1532Cys 19765707:102:77
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:102:175
status: NEW105 The apoA-I induced cholesterol efflux in HEK293 cells transfected with the Y1532C-hABCA1-FLAG Fig. 4.
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ABCA1 p.Tyr1532Cys 19765707:105:75
status: NEW106 Y1532C-hABCA1-FLAG is predominantly located intracellularly.
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ABCA1 p.Tyr1532Cys 19765707:106:0
status: NEW111 Thus, mutation Y1532C causes reduced cholesterol efflux.
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ABCA1 p.Tyr1532Cys 19765707:111:15
status: NEW114 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.
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ABCA1 p.Tyr1532Cys 19765707:114:28
status: NEWX
ABCA1 p.Tyr1532Cys 19765707:114:140
status: NEW115 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).
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ABCA1 p.Tyr1532Cys 19765707:115:124
status: NEW[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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No. Sentence Comment
1064 All three mutations p.A1046D, p. Y1532C and p. W1699C were reported to be deleterious in functional studies (473).
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ABCA1 p.Tyr1532Cys 26546829:1064:33
status: NEW