ABCA1 p.Arg1270*
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[hide] Cyclosporin A decreases apolipoprotein E secretion... J Biol Chem. 2009 Sep 4;284(36):24144-54. Epub 2009 Jul 9. Kockx M, Guo DL, Traini M, Gaus K, Kay J, Wimmer-Kleikamp S, Rentero C, Burnett JR, Le Goff W, Van Eck M, Stow JL, Jessup W, Kritharides L
Cyclosporin A decreases apolipoprotein E secretion from human macrophages via a protein phosphatase 2B-dependent and ATP-binding cassette transporter A1 (ABCA1)-independent pathway.
J Biol Chem. 2009 Sep 4;284(36):24144-54. Epub 2009 Jul 9., [PMID:19589783]
Abstract [show]
Cyclosporin A (CsA) is an immunosuppressant that inhibits protein phosphatase 2B (PP2B/calcineurin) and is associated with hyperlipidemia, decreased cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1), and increased risk of atherosclerosis. Apolipoprotein E (apoE) is an important regulator of lipid metabolism and atherosclerosis, the secretion of which from human macrophages is regulated by the serine/threonine protein kinase A (PKA) and intracellular calcium (Ca(2+)) (Kockx, M., Guo, D. L., Huby, T., Lesnik, P., Kay, J., Sabaretnam, T., Jary, E., Hill, M., Gaus, K., Chapman, J., Stow, J. L., Jessup, W., and Kritharides, L. (2007) Circ. Res. 101, 607-616). As PP2B is Ca(2+)-dependent and has been linked to PKA-dependent processes, we investigated whether CsA modulated apoE secretion. CsA dose- and time-dependently inhibited secretion of apoE from primary human macrophages and from Chinese hamster ovary cells stably transfected with human apoE and increased cellular apoE levels without affecting apoE mRNA. [(35)S]Met kinetic modeling studies showed that CsA inhibited both secretion and degradation of apoE, increasing the half-life of cellular apoE 2-fold. CsA also inhibited secretion from primary human Tangier disease macrophages and from mouse macrophages deficient in ABCA1, indicating that the effect is independent of the known inhibition of ABCA1 by CsA. The role of PP2B in mediating apoE secretion was confirmed using additional peptide and chemical inhibitors of PP2B. Importantly, kinetic modeling, live-cell imaging, and confocal microscopy all indicated that CsA inhibited apoE secretion by mechanisms quite distinct from those of PKA inhibition, most likely inducing accumulation of apoE in the endoplasmic reticulum compartment. Taken together, these results establish a novel mechanism for the pro-atherosclerotic effects of CsA, and establish for the first time a role for PP2B in regulating the intracellular transport and secretion of apoE.
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40 Monocyte-derived macrophages with dysfunctional ABCA1 were obtained from male and female siblings with Tangier disease carrying a novel ABCA1 mutation c.4121CϾT, which converts arginine 1270 into a stop codon (R1270X) (23).
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ABCA1 p.Arg1270* 19589783:40:216
status: NEW38 Monocyte-derived macrophages with dysfunctional ABCA1 were obtained from male and female siblings with Tangier disease carrying a novel ABCA1 mutation c.4121Cb0e;T, which converts arginine 1270 into a stop codon (R1270X) (23).
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ABCA1 p.Arg1270* 19589783:38:216
status: NEW[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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0 Case report A novel ABCA1 nonsense mutation, R1270X, in Tangier disease associated with an unrecognised bleeding tendency Amanda J. Hooper a,b , Ken Robertson a , Lydia Ng c , Joseph S. Kattampallil c , Donald Latchem d , Peter C. Willsher e , James Thom f , Ross I. Baker b,f , John R. Burnett a,b, Ìe; a Department of Core Clinical Pathology & Biochemistry, Royal Perth Hospital, Perth, Australia b School of Medicine & Pharmacology, University of Western Australia, Perth, Australia c Department of Histopathology, Western Diagnostic Pathology, Perth, Australia d Coastal Cardiology, Perth, Australia e Mount Hospital, Perth, Australia f Department of Haematology, Royal Perth Hospital, Perth, Australia a b s t r a c t a r t i c l e i n f o Article history: Received 21 May 2009 Received in revised form 31 July 2009 Accepted 24 August 2009 Available online 31 August 2009 Keywords: Tangier disease ABCA1 Mutation Hypoalphalipoproteinaemia 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).
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ABCA1 p.Arg1270* 19723515:0:45
status: NEW6 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).
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ABCA1 p.Arg1270* 19723515:6:145
status: NEW7 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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ABCA1 p.Arg1270* 19723515:7:161
status: NEW20 Here, we report 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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ABCA1 p.Arg1270* 19723515:20:150
status: NEW44 DNA sequence analysis of the proband's ABCA1 gene revealed that he was homozygous for a novel mutation c.4121C>T, which is predicted to change arginine 1270 to a stop codon (R1270X) (Fig. 3).
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ABCA1 p.Arg1270* 19723515:44:174
status: NEW55 Discussion We report a novel ABCA1 gene mutation, R1270X, in a case of Tangier disease with a bleeding tendency.
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ABCA1 p.Arg1270* 19723515:55:50
status: NEW57 The R1270X mutation is predicted to truncate ABCA1 such that it is missing the C-terminal ~40% of the protein, which includes the second set of membrane-spanning domains.
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ABCA1 p.Arg1270* 19723515:57:4
status: NEW74 In this report, we have described a novel nonsense mutation in ABCA1, R1270X, in Tangier disease associated with an unrecognised bleeding tendency.
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ABCA1 p.Arg1270* 19723515:74:70
status: NEW[hide] Protein kinase C controls vesicular transport and ... J Biol Chem. 2013 Feb 15;288(7):5186-97. doi: 10.1074/jbc.M112.428961. Epub 2013 Jan 3. Karunakaran D, Kockx M, Owen DM, Burnett JR, Jessup W, Kritharides L
Protein kinase C controls vesicular transport and secretion of apolipoprotein E from primary human macrophages.
J Biol Chem. 2013 Feb 15;288(7):5186-97. doi: 10.1074/jbc.M112.428961. Epub 2013 Jan 3., [PMID:23288845]
Abstract [show]
Macrophage-specific apolipoprotein E (apoE) secretion plays an important protective role in atherosclerosis. However, the precise signaling mechanisms regulating apoE secretion from primary human monocyte-derived macrophages (HMDMs) remain unclear. Here we investigate the role of protein kinase C (PKC) in regulating basal and stimulated apoE secretion from HMDMs. Treatment of HMDMs with structurally distinct pan-PKC inhibitors (calphostin C, Ro-31-8220, Go6976) and a PKC inhibitory peptide all significantly decreased apoE secretion without significantly affecting apoE mRNA or apoE protein levels. The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated apoE secretion, and both PMA-induced and apoAI-induced apoE secretion were inhibited by PKC inhibitors. PKC regulation of apoE secretion was found to be independent of the ATP binding cassette transporter ABCA1. Live cell imaging demonstrated that PKC inhibitors inhibited vesicular transport of apoE to the plasma membrane. Pharmacological or peptide inhibitor and knockdown studies indicate that classical isoforms PKCalpha/beta and not PKCdelta, -epsilon, -theta, or -iota/zeta isoforms regulate apoE secretion from HMDMs. The activity of myristoylated alanine-rich protein kinase C substrate (MARCKS) correlated with modulation of PKC activity in these cells, and direct peptide inhibition of MARCKS inhibited apoE secretion, implicating MARCKS as a downstream effector of PKC in apoE secretion. Comparison with other secreted proteins indicated that PKC similarly regulated secretion of matrix metalloproteinase 9 and chitinase-3-like-1 protein but differentially affected the secretion of other proteins. In conclusion, PKC regulates the secretion of apoE from primary human macrophages.
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131 HMDMs were isolated from three separate Tangier disease subjects, who have documented extremely low HDL cholesterol, with homozygous and compound heterozygous mutations in the ABCA1 gene (Patient 1, homozygous for c.4121Cb0e;T (R1270X) in exon 27 (27, 62); Patients 2 and 3, c.1759Cb0e;T (p.Arg587Trp) in exon 14 and c.4957_4961del (p.Val1653CysfsX48) in exon 37 (63)).
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ABCA1 p.Arg1270* 23288845:131:231
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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1051 A patient homozygous for the R1270X in the ABCA1 gene mutation presented with a bleeding tendency and anemia secondary to spontaneous splenic hematoma (468).
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ABCA1 p.Arg1270* 26546829:1051:29
status: NEW