Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2 +5G&gt;C mutation in ABCA1 gene

Altilia, Serena; Pisciotta, Livia; Garuti, Rita; Tarugi, Patrizia; Cantàfora, Alfredo; Calabresi, Laura; Tagliabue, Jacopo; Maccari, Sergio; Bernini, Franco; Zanotti, Ilaria; Vergani, Carlo; Calandra, Sebastiano

doi:10.1194/jlr.m200248-jlr200

Cited by 30 publications

(18 citation statements)

References 39 publications

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“…The one exception was an intronic splice site mutation (IVS2 ϩ5G/C) that causes skipping of exons 2, 4, or both as a consequence of an alteration in the donor splice site junction. 12 In the present study, 2 additional novel ABCA1 mutations are reported in a family with FHA. Whereas one variant was isolated within a coding domain, the second is an intronic variant in the polypyrimidine tract located upstream to the lariat branchpoint.…”

mentioning

confidence: 55%

Novel Polypyrimidine Variation (IVS46: del T −39…−46) in ABCA1 Causes Exon Skipping and Contributes to HDL Cholesterol Deficiency in a Family With Premature Coronary Disease

Hong

Rhyne

Miller

2003

Circulation Research

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Abstract-Recent studies have implicated mutations in the ATP-binding cassette transporter A1, ABCA1, as a cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). We investigated a proband with very low levels of high-density lipoprotein cholesterol (HDL-C, 6 mg/dL) and a history of premature coronary heart disease (CHD). Sequencing of the ABCA1 gene revealed 2 distinct variants. The first mutation was a G5947A substitution (R1851Q).The second mutation was a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. This mutation does not involve the 3Ј acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T Ϫ39. . .Ϫ46). Amplification of cDNA obtained in cultured fibroblasts of the proband and affected family member revealed an abnormally spliced cDNA sequence with skipping of exon 47. These variants were not identified in over 400 chromosomes of healthy whites. Compound heterozygotes (nϭ4) exhibited the lowest HDL-C (11Ϯ5 mg/dL) and ApoA-I (35Ϯ15 mg/dL) compared with wild-type (nϭ25) (HDL-C 51Ϯ14 mg/dL; ApoA-I 133Ϯ21 mg/dL) (PϽ0.0005) or subjects affected with either R1851Q (nϭ6) (HDL-C 36Ϯ8; ApoA-I 117Ϯ19) or IVS46: del T Ϫ39. . .Ϫ46 (nϭ5) (HDL-C 31ϩ9; ApoA-I 115ϩ28 (PϽ0.01). These data suggest that polypyrimidine tract variation may represent a novel mechanism for altered splicing and exon skipping that is independent of traditional intronic variants as previously identified in acceptor/donor splice regions or the lariat branchpoint domain.

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mentioning

confidence: 55%

Novel Polypyrimidine Variation (IVS46: del T −39…−46) in ABCA1 Causes Exon Skipping and Contributes to HDL Cholesterol Deficiency in a Family With Premature Coronary Disease

Hong

Rhyne

Miller

2003

Circulation Research

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“…To assess if ABCA1, a protein known to be involved in cell surface cholesterol efflux, plays a role in the cholesterol efflux described here, Tangier fibroblast cell lines derived from two independent patients (kindly donated by Dr. Calandra, University Modena, Italy) (54,55) were used.…”

Section: Hdl Holoparticle Uptake Proceeds While Selective Cholesterylmentioning

confidence: 99%

SR-BI-mediated High Density Lipoprotein (HDL) Endocytosis Leads to HDL Resecretion Facilitating Cholesterol Efflux

Pagler

Rhode

Neuhofer

et al. 2006

Journal of Biological Chemistry

123

102

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The high density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediates selective cholesteryl ester uptake from lipoproteins into liver and steroidogenic tissues but also cholesterol efflux from macrophages to HDL. Recently, we demonstrated the uptake of HDL particles in SR-BI overexpressing Chinese hamster ovarian cells (ldlA7-SRBI) using ultrasensitive microscopy. In this study we show that this uptake of entire HDL particles is followed by resecretion. After uptake, HDL is localized in endocytic vesicles and organelles en route to the perinuclear area; many HDL-positive compartments were classified as multivesiculated and multilamellated organelles by electron microscopy. By using 125 I-labeled HDL, we found that ϳ0.8% of the HDL added to the media is taken up by the ldlA7-SRBI cells within 1 h, and almost all HDL is finally resecreted.125 I-Labeled low density lipoprotein showed a very similar association, uptake, and resecretion pattern in ldlA7-SRBI cells that do not express any low density lipoprotein receptor. Moreover, we demonstrate that the process of HDL cell association, uptake, and resecretion occurs in three physiologically relevant cell systems, the liver cell line HepG2, the adrenal cell line Y1BS1, and phorbol myristate acetate-differentiated THP-1 cells as a model for macrophages. Finally, we present evidence that HDL retroendocytosis represents one of the pathways for cholesterol efflux.Numerous studies have demonstrated the protective role of HDL 4 in the development of atherosclerosis and coronary artery disease (for review see Ref. 1). HDL exerts this atheroprotective effect mainly by transporting cholesterol from peripheral tissues back to the liver for biliary secretion, in a process referred to as "reverse cholesterol transport" (2). Moreover, HDL represents an important source of cholesterol for adrenal steroid hormone synthesis. The molecular details of the efflux of cellular cholesterol in the periphery and of cholesterol delivery to hepatocytes and adrenal cells are not completely understood. In particular, the fate and route of HDL particles taken up by cells and the physiological relevance of this process have not been delineated.The scavenger receptor class B, type I (SR-BI), a cell surface glycoprotein that binds HDL, LDL, very low density lipoprotein, modified LDL, and anionic phospholipids (3-6), can mediate the last step in reverse cholesterol transport, namely the delivery of cholesteryl esters from HDL to liver without HDL degradation, termed selective cholesteryl ester uptake (7-9). SR-BI is highly expressed in liver, adrenals, and ovaries with the highest mass of SR-BI protein localized in the liver (7). In addition to cholesterol uptake, SR-BI participates in the internalization of hepatitis C virus particles (10, 11) and lipopolysaccharide (12, 13). Serum amyloid A, a ligand of SR-BI, blocks the selective cholesteryl ester uptake (14). Furthermore, several small chemical inhibitors termed BLTs (block lipid transports) have been described to enh...

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“…One mutation in intron 2 leads to an abnormally spliced transcripts lacking exon 2 or exon 4 or both. 48 All mutations by definition result in decreased lipid efflux. The extremely high correlation between phospholipid and cholesterol efflux (rϭ0.86, PϽ0.0001) in more than 15 mutations tested (Singaraja and Hayden, unpublished data, 2003) indicates that ABCA1 influences efflux of both lipid types.…”

Section: Mutations In Abc Genes Cause Many Human Genetic Diseasesmentioning

confidence: 99%

Efflux and Atherosclerosis

Singaraja

Brunham

Visscher

et al. 2003

ATVB

225

114

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Abnormal splicing of ABCA1 pre-mRNA in Tangier disease due to a IVS2 +5G>C mutation in ABCA1 gene

Cited by 30 publications

References 39 publications

Novel Polypyrimidine Variation (IVS46: del T −39…−46) in ABCA1 Causes Exon Skipping and Contributes to HDL Cholesterol Deficiency in a Family With Premature Coronary Disease

Novel Polypyrimidine Variation (IVS46: del T −39…−46) in ABCA1 Causes Exon Skipping and Contributes to HDL Cholesterol Deficiency in a Family With Premature Coronary Disease

SR-BI-mediated High Density Lipoprotein (HDL) Endocytosis Leads to HDL Resecretion Facilitating Cholesterol Efflux

Efflux and Atherosclerosis

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