Published online before print October 23, 2003, doi: 10.1161/01.RES.0000102957.84247.8F
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© 2003 American Heart Association, Inc.
Clinical Research |
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
From the Department of Medicine, University of Maryland and Veterans Administration Medical Center, Baltimore, Md.
Correspondence to Michael Miller, MD, Division of Cardiology, Room S3B06, University of Maryland Hospital, 22 S Greene St, Baltimore, MD 21201. E-mail mmiller{at}heart.umaryland.edu
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Abstract |
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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 3' acceptor splice site and is outside the lariat branchpoint sequence (IVS46: del T -39...-46). 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 (n=4) exhibited the lowest HDL-C (11±5 mg/dL) and ApoA-I (35±15 mg/dL) compared with wild-type (n=25) (HDL-C 51±14 mg/dL; ApoA-I 133±21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36±8; ApoA-I 117±19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.01). 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.
Key Words: ABCA1 • HDL cholesterol deficiency • mutation • polypyrimidine
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Introduction |
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Low levels of high-density lipoprotein cholesterol (HDL-C) are inversely correlated with coronary heart disease (CHD), even when total cholesterol levels are desirable.1–3 HDL-C possesses several antiatherogenic properties, including its most well-recognized role as a mediator of reverse cholesterol transport (RCT).4 The initial step in RCT, the efflux of cholesterol and phospholipids from peripheral cells (eg, macrophages), is governed by ABCA1, a 220-kDa glycoprotein and a member of the ATP-binding cassette transport family.5 To date, more than 50 mutations in ABCA1 have been reported.6,7 Homozygous mutations in ABCA1 have been implicated in Tangier disease (TD), a disorder of HDL-C deficiency characterized by hepatosplenomegaly and peripheral neuropathy owing to the entrapment of cholesteryl esters within macrophage-laden reticuloendothelial organs or Schwann cells.8 As well, coronary atherosclerosis has been demonstrated in many TD subjects, despite normal or reduced levels of low-density lipoprotein cholesterol (LDL-C).9 Heterozygous ABCA1 mutations are classified as familial hypoalphalipoproteinemia (FHA), and affected subjects often have an increased likelihood of premature CHD, which may reflect mild elevations in LDL-C and triglycerides in addition to reduced HDL-C.10,11
To date, 49 of the 50 ABCA1 variants have been identified in coding regions. The one exception was an intronic splice site mutation (IVS2 +5G/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. The latter variant, which causes exon skipping and predicts an abnormal protein product, has not been previously implicated in human pathology.
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Materials and Methods |
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Study Subjects
The proband, a resident of Plattsburgh, NY, had markedly reduced HDL cholesterol (6 mg/dL) and ApoA-I (24 mg/dL) (Figure 1, arrow). He is a second-generation, nonsmoking white man of French-Canadian (maternal) and Scandinavian (paternal) descent. There was no significant medical history until he developed CHD and underwent percutaneous coronary intervention for a high-grade right coronary artery stenosis at age 44 years. A maternal uncle, with a history of cigarette smoking, died of a myocardial infarction at age 44 years. In addition to the proband, 39 family members of the kindred were screened. No other members of the family have developed premature symptomatic CHD to date. The protocol was approved by the University of Maryland Institutional Review Board and all subjects gave their informed consent before participation.
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PCR Amplification and Single-Strand Conformation Polymorphism (SSCP) Analysis
All exons of ABCA1 were amplified by PCR from genomic DNA using primers and reaction conditions as previously described.13 PCR primers amplified all coding regions, splice site junctions, and intronic regions spanning at least 50 nucleotides upstream to the intron-exon junction. Exons of ABCA1 were designated using the nomenclature of Santamarina-Fojo et al.14 For mutation analysis of ABCA1, PCR products were mixed with 6x loading dye (95% formamide, 20 mmol/L EDTA, 0.05% bromophenol blue, 0.05% xylene cyanol FF), denatured for 10 minutes at 96°C, and placed on ice. SSCP samples were prepared and electrophoresed using nondenaturing 8% or 10% polyacrylamide gels at 5 to 10 watts for approximately 24 hours at room temperature.
Sequencing of PCR-Amplified DNA
PCR products showing SSCP shifts of ABCA1 were isolated by using the Qiagen PCR purification kit and sequenced manually. To identify variants in other primary HDL candidate genes, all exon-intron boundary regions of ApoA-I, lecithin cholesterol acyl transferase (LCAT), lipoprotein lipase (LPL), and scavenger receptor class B type I (SR-BI) genes were amplified and sequenced from proband DNA.
Determination of Levels of Plasma Lipids and Lipoproteins
Blood samples were collected after a 12-hour overnight fast. Levels of plasma total cholesterol and triglyceride were measured using enzymatic/colorimetric methods with the Vitros 950 Chemistry Analyzer (Johnson & Johnson, New Brunswick, NJ). HDL-C was determined by the heparin-manganese precipitation method and apolipoproteins A-I and B were measured using radial immunodiffusion as previously described.15 LDL-C was calculated using the formula of Friedewald et al.16
Statistical Analysis
Student’s t test was used to compare the mean differences in lipid, lipoprotein, and apolipoprotein levels in the presence or absence of the ABCA1 variants. The designated level of significance was P<0.05.
Fibroblast Isolation and Growth
Skin biopsies were obtained from the medial aspect of the inner arm in 2 affected family members with the intronic mutation and 2 without the intronic mutation. Fibroblasts were grown according to standard tissue culture protocol as previously described.17 Briefly, cells were grown in 10% FBS (fetal bovine serum), EMEM (Eagles’s MEM in Earle’s balanced salt solution), without glutamine, 1% L-glutamine, and 1% penicillin/streptomycin solution. Cells were grown at 37°C and humidified with 5% CO2.
mRNA Isolation, cDNA Synthesis, and Segment Amplification
Total cytoplasmic RNA from fibroblast cultures was extracted using the RNeasy Mini Kit (Qiagen, Inc, Valencia, Calif). Subsequently, first-strand cDNA synthesis was carried out with the Advantage RT-for-PCR Kit (BD Biosciences, Palo Alto, Calif), using oligo dT primers included in the kit. The sequence of interest in the ABCA1 gene (exon 45+exon 48) was amplified from cDNA using the following primers: 5'-TGCTTTGGGCTCCTGGGAG-3' (forward primer in exon 45), 5'-GCTGGACACTGCCAAGGCA-3' (reverse primer in exon 48). PCR was performed using 20 pmol of each primer in a total volume of 50 µL containing 0.3 mmol/L each dNTP, 0.1 µg cDNA, 0.5 U of DyNAzyme EXT (MJ Scientific, Waltham, Mass), in 1x buffer F-514, containing 50 mmol/L Tris-HCl [pH 9.0 at 25°C, 1.5 mmol/L Mg2+, 15 mmol/L (NH4)2SO4, and 0.1% Triton X-100 (MJ Scientific, Waltham, Mass)]. The PCR reaction was carried out in a Techne Genius Thermocycler (Techne Inc, Princeton, NJ), consisting of an initial denaturation step of 92°C for 5 minutes, followed by 35 cycles: denaturation at 92°C for 30 seconds, annealing at 55°C for 30 seconds, and extension at 72°C for 45 seconds. A final extension step at 72°C for 5 minutes followed the last PCR cycle. PCR products were separated on a 1.2% agarose gel.
Cleaning, Cloning, and Screening of ABCA1 Fragment
PCR products ABCA1 exon 45+ABCA1 exon 48 were cleaned for cloning with the Qiaquick PCR Purification Kit (Qiagen, Inc, Valencia, Calif). The PCR products were then cloned into a pDrive Cloning Vector, Qiagen PCR Cloningplus Kit (Qiagen, Inc, Valencia, Calif), plated, and grown overnight. Positive colonies were PCR-screened using the primers listed above. Colonies were grown overnight in 5 mL of LB media at 37°C, with shaking at 220 rpm. Plasmid DNA was isolated using the Quantum Prep Plasmid Miniprep Kit (Bio-Rad Laboratories, Hercules, Calif). Sequencing was performed using the primers listed above with the Thermo Sequenase Radiolabeled Terminator Cycle Sequencing Kit (USB Corp, Cleveland, Ohio).
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Results |
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The first mutation was a G5947A substitution that predicts conversion of arginine to glutamine (R1851Q) (Figure 2). The second mutation was a deletion of thymidine upstream to the 3' splice site of intron 46 (Figure 3). The intronic mutation was identified after amplification of genomic DNA (Figure 4A). Fibroblast cDNA sequencing demonstrated deletion of exon 47, which predicts a truncated protein product of 2072 amino acids compared with the normal ABCA1, translated protein of 2261 amino acids (Figure 4B). The proband was a compound heterozygote for these variants (Figure 1, arrow). While neither mutations altered restriction sites, they were detected by SSCP analysis and confirmed by comparative sequencing of affected subjects and unaffected controls. These 2 mutations were not detected during the screening of more than 400 chromosomes from normolipidemic subjects.
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Mean levels of plasma lipids, lipoproteins, and apolipoproteins of the FHA kindred are shown in Table 1. Compound heterozygotes (n=4) exhibited the lowest HDL-C (11±5 mg/dL) and ApoA-I (35±15 mg/dL) compared with wild-type (n=25) (HDL-C 51±14 mg/dL; ApoA-I 133±21 mg/dL) (P<0.0005) or subjects affected with either R1851Q (n=6) (HDL-C 36±8; ApoA-I 117±19) or IVS46: del T -39...-46 (n=5) (HDL-C 31+9; ApoA-I 115+28 (P<0.05) (Table 2). Thus, affected family members with either ABCA1 variant exhibited low levels of HDL-C and ApoA-I, although extremely low HDL-C and ApoA-I levels were only detected in the proband and family members who were genetic compounds.
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To rule out the possibility of additional variants causing HDL-C deficiency in the proband, all coding regions and splice site junctions for the following HDL candidate genes were sequenced: ApoA-I, LCAT, LPL, and SR-BI. However, no other mutations were identified, indicating that the 2 defective ABCA1 alleles represented the most likely origin for the HDL-C deficiency.
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Discussion |
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Although the clinical sequelae of TD (eg, tonsillar discoloration, hepatosplenomegaly) have been recognized for decades, the genetic basis of this disorder has only recently been uncovered.18–20 Identification of the molecular culprit, ABCA1, has facilitated genotype-phenotype characterization for both TD and FHA.18–26 While considerable phenotypic heterogeneity exists for both disorders, homozygous mutations in ABCA1 resulting in TD generally display HDL-C below the 20th percentile (adjusted for age and gender) whereas heterozygous alterations in ABCA1 leading to FHA result in HDL-C levels approximating the 20th to 50th percentile.7 Despite greater reduction in HDL-C, not all subjects with TD develop premature CHD, suggesting that HDL-C levels per se do not necessarily correlate with efficiency of RCT. Moreover, several noncoding (eg, C-17G) and coding (eg, R219K) single-nucleotide polymorphisms that do not affect levels of HDL-C have coincided with reduced CHD.23,24 In contrast, most but not all studies evaluating ABCA1 variants have demonstrated an association between premature CHD and either increased carotid intimal-medial thickness or reduced ABCA1-mediated cholesterol efflux.25–27 The premature CHD identified in the proband extends previous observational data in normolipidemic individuals1–3 and may not only reflect alterations in RCT but other recently identified antiatherogenic effects potentially subserved by HDL including reduced ischemic-reperfusion injury28 and improved vascular function.29
To date, only a small proportion of ABCA1 variants have been characterized in pivotal regions (eg, extracellular loop, transmembrane domain, nucleotide binding folds, C-terminus) that when altered, result in marked reduction in ABCA1 activity and/or function.6,7
The G5947A/ R1851Q mutation occurs within the extracellular loop proximal to the final transmembrane spanner and bears regional similarity to the C5946T/R1851X variant recently reported in a compound heterozygote with TD.30 Variants located within the extracellular loop (between amino acids 1370 to 1650) have been shown to adversely affect the interaction of ABCA1 and ApoA-I resulting in reduced cholesterol efflux.31 Whether distal variants (eg, N1800H, R1851G) exhibit similar interactions with ApoA-I has not been studied, but the marked reductions in HDL-C that have been observed in affected subjects suggest that binding may be similarly disrupted. The second mutation (IVS46: del T -39...-46) results in a truncated protein product ending at amino acid 2072, abolishing the C-terminus. Although the functional implications of previously identified ABCA1 variants affecting the C-terminus have not been studied, disruption of this segment as previously identified in other ABC transporters, most notably CFTR, leads to reduced stability of the translated protein.32 Not surprisingly, the 4 subjects who were compound heterozygotes (CH) (R1851Q/IVS46: del T -39...-46) exhibited the most pronounced reduction in HDL-C and ApoA-I compared with either wild-type or subjects with either of the 2 ABCA1 variants because these relatively delipidated (eg, devoid of free cholesterol) particles are unstable in the circulation and prone to enhanced catabolism.33 CH subjects also had lower TC levels compared with wild-type, reflecting lower HDL-C and LDL-C. However, there were no significant differences in either HDL-C or ApoA-I levels between the 2 ABCA1 variants. Moreover, while the intronic variant yielded the highest mean TG and ApoB, the levels were well within the range observed in the general population. Nevertheless, as recent data have demonstrated that LDL and ApoB reductions in TD result from enhanced catabolism of abnormal LDL particles,34 it is plausible that there may be differential effects of ABCA1 variants on ApoB metabolism.
The identification of this intronic variant (the deletion of a thymidine base approximately 40 nucleotides upstream to the 3' splice site of intron 46) (Figure 3), leads to exon skipping and occurs independent of the two well-acknowledged regions necessary for proper splicing. These regions include the donor-acceptor junction defined by the first intronic nucleotides "gt" on the donor splice site and the final intronic nucleotides "ag" on the acceptor splice site. The second potential splicing domain is the lariat branchpoint region, which resides 10 to 50 nucleotides upstream of the acceptor splice site,35 which consists of a "CTRAY," where y represents either "t" or "c" and r represents an "a" or "g." The closest branchpoint sequence in intron 46 appears to be approximately 10 bps upstream from exon 47 (Figure 3). Variants within either the acceptor-donor splice site or lariat branchpoint sequence may result in abnormal splicing.36 Exon skipping has been shown to occur in approximately 60% of mutant transcripts resulting from a lariat branchpoint defect in 2 families with Ehlers-Danlos syndrome type II.37 In the present study, the donor-acceptor splice site in intron 46 is normal, and the "t" occurs outside of a known lariat branchpoint. Therefore, the novel intronic variant identified herein is associated with exon skipping, independent of the two known splicing consensus regions. Sequencing of genomic DNA identified a single-nucleotide deletion of thymidine in a polypyrimidine tract located 33 to 46 bps upstream to the start of exon 47. Previous data have demonstrated that reduction in the polypyrimidine tract within 12 nucleotides upstream of the acceptor site may adversely affect splicing.38 To our knowledge, this case represents the first to demonstrate that alteration in the polypyrimidine tract outside the known consensus splicing domains results in exon skipping and a predicted truncated protein product. Potential explanations include distortion in RNA secondary structuring that may lead to aberrant splicing,39 which is important for splicing of double-stranded DNA near the branchpoint region.
In conclusion, we have identified a novel splicing variant involving a polypyrimidine tract upstream from the lariat branchpoint and donor/acceptor consensus regions. This results in exon skipping, truncation of the ABCA1 protein, and contributes to HDL-C deficiency in a family with premature CHD. These data raise the possibility that polypyrimidine tract variation represents a novel means for altered splicing and exon skipping that is independent of other established mechanisms. Thus, limiting screening of genetic variants to promoter and coding regions, as well as the lariat branchpoint and intron/exon junctions may fail to identify other potentially important variant intronic regions that may contribute to a pathological phenotype.
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Acknowledgments |
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Acknowledgments
This study was supported by an American Heart Association Grant-in-Aid (Mid-Atlantic Region), Veterans Affair Merit Award, and NIH Grant (HL-61369). The authors acknowledge Dr Frank Ultee (Plattsburgh, NY) for referring the proband and family for genetic evaluation and Gina Friel, CRNP, for her exhaustive efforts in contacting family members, arranging shipment of blood samples, and obtaining demographic information.
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Footnotes |
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Original received June 25, 2003; revision received October 10, 2003; accepted October 14, 2003.
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