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Division of Endocrinology, Diabetology & Nutrition, University Hospital, Geneva 1211, Switzerland
1 Division of Nephrology, Inselspital, Berne 3010, Switzerland
2 Department of Nephrology, Fremantle Hospital, University of Western Australia, Perth 6160, Australia
(Requests for offprints should be addressed to P Ferrari; Email: paolo.ferrari{at}health.wa.gov.au)
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The exact mechanisms for increased aldosterone synthase activity, associated with the T allele in the CYP11B2 promoter, are still objects of debate. Alternative explanations are increased transcription factor availability at other functional sites of the gene, linkage of the SF-1 and Int2 C sites with a quantitative trait locus in the regulatory elements or the possibility of transcriptional activation of the steroidogenic acute regulatory (StAR) gene by an SF-1-dependent mechanism (Garbers & Dubois 1999). The latter is supported by the observation that only some, but not all, carriers of the T allele show increased aldosterone synthase activity.
Delivery of the substrate cholesterol to the inner mitochondrial membrane and to the cytochrome P450 side-chain cleavage enzyme is the rate-limiting step in steroid hormone synthesis (Crivello & Jefcoate 1980, Privalle et al. 1983). The transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, where it is cleaved to pregnenolone, is mediated by the StAR protein, which was identified and cloned by Clark et al.(1994). Mutations in the StAR gene are the cause of the potentially lethal condition known as congenital lipoid adrenal hyperplasia (lipoid CAH) (Lin et al. 1995). Mutations causing lipoid CAH are all found in the C-terminal region of the StAR protein (Miller 1997). StAR expression can be regulated both positively and negatively by agents that presumably act on its promoter (Stocco 2001). SF-1 was the first transcription factor to be studied as a potential regulator of the StAR gene. Several SF-1 consensus-binding sites have been identified in the StAR promoter (Caron et al. 1997, Sugawara et al. 1997). Two of these sites, located at positions –97 and –42, are highly conserved in several species whose promoter regions have been sequenced. It is presently unknown whether polymorphisms at these sites are present and whether they might affect StAR promoter activity, thereby providing an explanation for the variable aldosterone synthase activity associated with the SF-1 polymorphism in the CYP11B2 promoter. Thus, in search of potential mechanisms underlying primary aldosteronism, we have screened the StAR gene for polymorphisms at SF-1-binding sites in hypertensive patients whose aldosterone and renin status was known.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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We screened for polymorphisms in the SF-1-binding sites of the human StAR gene promoter in 20 control subjects and 40 hypertensive patients, who had measurements of plasma renin and immunoreactive plasma aldosterone under standardised conditions as previously described (Nicod et al. 2003). Thereafter, the prevalence of the identified polymorphism was assessed in an additional cohort of 172 hypertensive patients who also had measurements of plasma immunoreactive renin and plasma aldosterone under standardised conditions and 76 healthy controls. Among all 212 hypertensive patients, 36 had an ARR above the diagnostic cut-off level for primary aldosteronism (Ferrari et al. 2004), but were not homozygous for the T allele of CYP11B2, which is commonly associated with an increased ARR (Nicod et al. 2003). Finally, a group of 98 patients with diabetes mellitus type 2 was also tested for the presence of the same identified polymorphism. Thus, genotyping for the StAR gene promoter was performed on a total of 406 subjects.
Screening for polymorphisms of the human StAR gene promoter
The promoter region of the StAR gene harbouring the two conserved SF-1-binding sites and the TATA box was screened for the presence of polymorphisms by single strand conformation polymorphisms (SSCP) in 60 subjects using genomic DNA, isolated from peripheral blood leucocytes. The DNA (100–200 ng) was amplified in a 50-µl reaction mixture containing 3 mM MgCl2, 0.4 µM of each primer, 0.2 mM dNTP and 1 U AmpliTaq Gold polymerase (Perkin Elmer Corp., Forster City, CA, USA) in the presence of the buffer provided with the enzyme. Thirty two cycles of PCR were performed: 30 s at 94 °C, 30 s at 62 °C and 1 min at 72 °C. Primers were 5'-CTGTCCTCCCTACTCTCCCC-3' and 5'-CTCTCAAGGGTGGTTCTTCG-3' and yielded a 258 bp fragment amplifying the –328 to –71 bp region upstream to the start codon. All PCR products were analysed by SSCP on 12% acrylamide gels containing 7.25% glycerol using a two-buffer system. Four microlitres of the PCR sample were loaded and DNA was visualised by silver staining (Lovati et al. 2001). Any variations detected by this technique were characterised by directly sequencing the PCR amplified fragment with an ABI PRISM Model 3700 (Applied Biosystems, Foster City, CA, USA). This screening allowed us to identify a C/T single nucleotide polymorphism (SNP) in the promoter region of the StAR gene, with loss of a MspA1 I restriction site in the mutant.
Genotyping
In the remaining sample of 366 subjects, genotyping of the identified SNP in the promoter of the StAR gene was done by specific restriction enzyme digestion. In all subjects, genomic DNA was amplified using the primers and conditions designed for the SSCP screening analysis. After amplification, the 258-bp long PCR fragments were digested for 2 h at 37 °C with the MspA1 I restriction enzyme (New England Biolabs, Beverly, MA, USA), and the digestion products were separated by gel electrophoresis. The wild-type allele contains a recognition site for the restriction endonuclease so that digestion leads to two fragments of 103 and 155 bp. In the mutant allele, the recognition site is disrupted and therefore the amplified fragment is not digested.
Plasmids and construction of StAR promoter mutants
The wild-type pGL2-hStAR promoter construct was kindly provided by D Stocco (Texas Tech University, Lubbock, TX, USA). The mutated pGL2-hStAR bearing the C/T substitution in the position –33 bp from the transcription start site was generated by using the QuickChange site-directed mutagenesis kit (Stratagene, Cedar Creek TX, USA) according to the instructions of the manufacturer. Mutagenic primers (StAR-mutprom-fwd 5'-GATGCACAGCCTTCAGTGGGGGACATTTAAGAC-3' and StAR-mutprom-rev 5'-GTCTTAAATGTCCCCCACTGAAGGCTGTGCATC-3') were designed according to the GenBank sequence U29098. [GenBank] The mutated nucleotide is underlined. Four separate clones were obtained and tested, which gave comparable results in the reporter gene assays.
Cell culture and transfections
The human adrenocortical carcinoma NCI H295R cell line was kindly provided by Dr W E Rainey (University of Texas Southwestern Medical Center, Dallas, TX, USA) and maintained in a 1:1 mixture of Dulbecco’s modified eagle medium (DMEM) and Ham’s F12 medium containing pyridoxine, L-glutamine, and 15 mM HEPES (Life Technologies). The culture medium was supplemented with 1% insulin, transferrin, selenium (ITS+, Becton Dickinson and Co. Labware, Bedford, MA, USA), and 2% Ultroser (Ciphergen, Biosepra, France) as well as antibiotics (125 µg/ml streptomycin and 125 IU/ml penicillin). Transfections were performed using the Nucleofector Transfection system (Amaxa, Cologne, Germany) according to the instructions of the manufacturer. Briefly, 5x106 cells were transfected with 3 µg of either the wild type or the mutated pGL2-hStAR promoter construct. Cells were then plated on 12-well culture plates (3x105 cells/well). Following 48 h of post-transfection, the cells were stimulated with various agents for the indicated periods of time in serum-free medium. Cells were then harvested and luciferase assay performed using the Dual-Luciferase Reporter Assay System (Promega). The pRLSV40 vector was used as an internal control to normalise transfection efficiency.
The mouse adrenocortical cancer cell line Y-1 was obtained from Cell Line Service (Heidelberg, Germany). The adherent cells were maintained in DMEM supplemented with 10% fetal calf serum and 200 nM L-glutamine as well as with antibiotics as described elsewhere. The cells were plated on 12-well culture plates (1.5x105 cells/well) and transfections were performed using FuGENE 6 transfection reagent (Roche) according to the instructions of the manufacturer. Briefly, the cells were transfected with 1 µg/well of either the wild type or the mutated pGL2-hStAR promoter construct. The pRLSV40 vector was used as an internal control to normalise transfection efficiency. Forty-eight hours after transfection, cells were stimulated with various stimuli for the indicated periods of time in serum-free media. Cells were then harvested and luciferase assay was performed as stated above. Both cell lines were grown at 37 °C under an atmosphere of 5% CO2–95% air.
Electrophoretic mobility shift assay (EMSA)
Double-stranded DNA corresponding to nucleotides –42 to –24 of the human StAR promoter according to the sequence published by Sugawara et al.(1997), was [
-32P]dATP-labelled by Klenow fill-in (Promega). Wild-type sense 5'-gatcAGCCTTCAGCGGGGGACAT-3' annealed with wild-type antisense 5'-gatcATGTCCCCCGCTGAAGGCT-3' and mutated sense 5'-gatcAGCCTTCAGTGGGGGACAT-3' annealed with mutated antisense 5'-gatcATGTCCCCCACTGAAGGCT-3'. Nuclear protein extracts (7 µg) were incubated for 20 min at room temperature with 30 000 c.p.m. of labelled probe and 2 µg of poly[d(IC)] in EMSA-binding buffer. The reaction mixture was loaded onto a non-denaturing 5% polyacrylamide gel for 1 h 30 min at 150 V in a cold room. Gels were dried and exposed to autoradiography films (Kodak and Sigma) for 72 h. In supershift experiments, 1 µg of purified rabbit polyclonal anti-chicken ovalbumin upstream promoter-transcription factor-I (COUP-TFI) (kindly provided by Dr M.L. Dufau, National Institutes of Health, NICHD, Behesda, MD, USA), anti-SF-1 (kindly provided by Prof. K Morohashi, Okasaki, Japan) or anti-DAX-1 (kindly provided by Dr E. Lalli, Strasbourg, France) antibody was added to the mixture 30 min prior to the labelled probe. In chase experiments, 100-fold excess of cold Sp1 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) or SF-1 (5'-CAGCCTT-3') consensus sequence oligonucleotides were added to the mixture 30 min prior to the labelled probe.
Analysis of data
Results are expressed as means±S.E.M. The mean values were compared by ANOVA using Fisher’s test. A value of P<0.05 was considered as statistically significant.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The initial screening of the 40 hypertensive and 20 control subjects identified a potentially functional C/T polymorphism located 33 bp upstream from the transcription start site of the human StAR gene promoter, 3 bp downstream of the SF-1 site and 9 bp upstream of the TATA box (Fig. 1
). To date, this novel mutation is not described in public SNP databases (NCBI dbSNP or www.ensembl.org). The mutant allele was present in nine (2.2%) of the 406 subjects investigated. The prevalence of this novel mutation was 1.3% (4/308) in the non-diabetic population. When this polymorphism was investigated in the 98 type 2 diabetics a prevalence of 5.1% was found (
2=6.27, P<0.01 for diabetics versus non-diabetics). Four (11.1%) of the 36 hypertensive patients with raised ARR were carriers of the mutant T allele of the StAR gene promoter.
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In order to determine whether the C/T substitution affects StAR promoter activity, we transiently transfected murine adrenocortical Y-1 cells with either the wild type or the mutated StAR promoter cloned into the pGL2 vector containing firefly luciferase as reporter gene (Fig. 2). Basal promoter activity did not differ between the wild type and mutant promoter. As expected, forskolin treatment increased wild-type StAR promoter activity to 230±33% of control cells. In contrast, this response was markedly reduced with the mutated promoter, the maximal induction obtained with 25 µM forskolin reaching only 150±27% of controls (P<0.05, n=3). This suggests that the C/T substitution may play a crucial role in adequate StAR promoter transcriptional activity in response to activation of the cAMP messenger pathway.
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We then analysed whether the C/T substitution also affects StAR promoter activity in response to activators of aldosterone biosynthesis. To this end, human H295R adrenocortical carcinoma cells were transiently transfected as above with either the wild type or the mutated StAR promoter cloned into the pGL2 vector (Fig. 3). As expected, AngII treatment increased wild-type StAR promoter activity to 265±22% of controls (P<0.01, n=3). In contrast, this response was markedly reduced with the mutated promoter, the maximal induction obtained with 10 nM AngII reaching only 180±29% of controls (P<0.01, n=3). This suggests that the C/T substitution may also play a crucial role in adequate StAR promoter transcriptional activity in response to activation of the calcium messenger pathway.
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EMSAs were performed in order to evaluate whether the mutation affects the interaction with the StAR promoter of various putative transcription factors known to be involved in the modulation of steroidogenesis, as compared with the wild-type StAR promoter. For this purpose we used a 23-bp DNA sequence spanning the mutation as well as the proximal SF-1 response element and half of the TATA box in the human StAR promoter as a probe for the experiment.
As expected from previous studies (Sugawara et al. 1997, Zazopoulos et al. 1997, Sandhoff et al. 1998), SF-1 and DAX-1, an activator and a repressor of StAR expression, respectively, specifically bound the StAR promoter probe, as demonstrated by supershifts induced with specific antibodies (Fig. 4A, lanes 2–3 and 6–7, and Fig. 4B, lanes 2–3 and 4–5). Interestingly, the band that was supershifted with the SF-1 antibody was also super-shifted with a purified antibody directed against COUP-TF (Fig. 4A, lanes 4–5 and 4'–5') suggesting aninteraction of COUP-TF with the StAR promoter and/or SF-1. These results were similar, whether we used the wild type or the mutated 23-bp probe. In contrast, the mutated probe induced an additional DAX-1 shift as demonstrated in supershift experiments using the DAX-1 antibody (Fig. 4B, lanes 2'–3' and 4'–5').
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In order to further identify the additional DNA–protein interactions that occur on the mutated StAR promoter, we incubated nuclear extracts (NEs) incubated with excess cold probe of the consensus response element for either Sp1 or SF-1, two transcription factors known to positively regulate the StAR gene (Sugawara et al. 2000) (Fig. 5).
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(left), the major shift observed when an NE of H295R cells was incubated in the presence of the labelled wild-type StAR promoter probe was abolished by an excess cold Sp1 oligonucleotide (lanes 4 and 5). In contrast, three of the four shifts observed with the mutated StAR promoter disappeared when a chase was performed with the Sp1 cold probe, suggesting that the mutation promotes the formation of an additional Sp1–DNA complex (Fig. 5A, lanes 4' and 5'). The remaining protein–DNA complex observed with the mutant probe disappeared when competition was performed with a 100-fold excess of an SF-1 cold probe, indicating that the mutation promotes the reassembling of various crucial transcription factors over the proximal StAR promoter (Fig. 5B, lane 4). Also, the abundance of a slower migrating species was increased in the presence of excess unlabelled SF-1 oligonucleotide (Fig. 5B, lane 4). Although we have presently no explanation for this observation, it is possible that, due to the availability of extra probe displaced by excess SF-1 oligonucleotide, there is increased binding of the probe to a non-specific complex. |
Discussion |
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Herein, we report a newly identified C/T mutation located at position –33 from the transcription start site of the human StAR gene promoter, 3 bp downstream of the SF-1-binding site and 9 bp upstream of the TATA box. To our knowledge, this is the first description of a mutation within the StAR promoter. This polymorphism lies in a crucial region for adequate StAR gene activity that bears a major response element for SF-1 (Sugawara et al. 2000). The identified mutation in the human StAR promoter is associated with a reduced promoter activity. As the region of the mutation is critically involved in the regulation of StAR gene expression, this finding may be relevant for adrenal steroid response to physiological stimulators.
Since the StAR protein mediates the crucial rate-limiting step of steroidogenesis, i.e. the transfer of cholesterol from the outer to the inner mitochondrial membrane, its expression must be finely regulated. The polymorphism we observed in the present study is located in a region of the StAR gene known to bear important response elements for the activation of steroidogenesis (Caron et al. 1997, Manna et al. 2003). This polymorphism is associated with the marked changes in promoter activity of the 1.3 kb 5'-flanking region of the StAR gene, as shown in two different adrenocortical cell lines, murine adrenocortical Y-1 cells and human H295R cells, with two different agonists.
Various mechanisms can concur to the observed reduction in StAR promoter activity. First, the mutation is located in close proximity to the most proximal response element for SF-1, an important–although not the sole–factor responsible for StAR gene expression (Manna et al. 2003). Secondly in the human promoter, the mutation is located within a nucleotide sequence which matches almost perfectly a GC box or consensus Sp1 box (GGCGGG, see Fig. 1) and Sp1 is a transcription factor known to activate the StAR gene by interacting with SF-1 (Sugawara et al. 2000). The presence of an Sp1-binding site in this proximal region of the StAR promoter was confirmed by the fact that a consensus GC box was able to compete with the labelled oligonucleotide probe and chase it in EMSA assays (see Fig. 5A). It is, therefore, conceivable that the binding of Sp1 to its response element might be hampered in the mutated promoter and, as a consequence, the binding of SF-1 to its neighbouring response element. Thirdly the orphan nuclear receptor DAX-1, a repressor of StAR gene expression (Zazopoulos et al. 1997, Lalli et al. 1998, Osman et al. 2002), binds to a hairpin structure located at position –61 to –27 of the StAR promoter, a sequence which includes the present mutation. Zazopoulos and co-workers have shown that the binding of DAX-1 is stronger when the hairpin loop is rich in thymines (Zazopoulos et al. 1997). Interestingly, in the C/T polymorphism we describe here, the hairpin loop is richer in thymines, a condition that should favour DAX-1 binding to the promoter and repression of the StAR gene. Indeed, when DNA–protein interactions were analysed, gel shift assays revealed striking differences in the binding pattern of the probe (Fig. 4). As expected, SF-1 and DAX-1 specifically bound the StAR promoter probe. Both factors were shown to be involved in adequate StAR promoter activity (Caron et al. 1997, Sugawara et al. 1997, Osman et al. 2002). However, when NEs were incubated with the mutated probe, an additional DAX-1–DNA complex was formed. This result strongly supports the hypothesis suggesting increased binding of DAX-1 to a thymine-rich hairpin structure and thereby providing an explanation for the decrease in StAR promoter activity observed in the luciferase assays with the mutated construct.
In addition, this same additional complex also disappeared when competition was performed in the presence of a cold Sp1-response element. Since the sequence of the hairpin structure also includes the mutated Sp1 response element or GC box, these data suggest that the mutation may lead to decreased binding of Sp1, in addition to the increase in binding affinity of DNA for DAX-1.
In contrast, basal activity was not reduced in the mutated promoter. This may be due to the fact that repression of the StAR promoter is already maximal in the resting state. Indeed, we have recently shown that both DAX-1 (Osman et al. 2002) and COUP-TF (Buholzer et al. 2005), two repressors of the StAR promoter, are robustly expressed in adrenal glomerulosa cells and that overexpression of either factor does not affect basal promoter activity.
The second additional protein–DNA complex formed with the mutated probe disappeared when the NE was incubated in the presence of an excess of cold SF-1 consensus sequence and of the labelled mutated probe (Fig. 5B). However, a similar supershift could not be obtained with a specific antibody directed against SF-1 (Fig. 4A), suggesting that the mutation induces the binding of an yet unidentified factor to the SF-1 response element.
In addition to binding specific DNA sequences, Sp1, SF-1 and DAX-1 interact with each other and promote or counteract each other’s binding to the promoter, bringing an additional degree of complexity to the regulation of the StAR proximal promoter (Ito et al. 1997, Sugawara et al. 2000, Babu et al. 2002, Suzuki et al. 2003). It is, therefore, likely that the change in binding affinity of one factor for the StAR promoter resulting from the mutation may affect the binding of its partner to this same promoter. Moreover, recent studies have demonstrated that the regulatory actions of SF-1 and Sp1 may be mediated by components of the chromatin environment such as the ubiquitous co-activator CBP/ 300 or histone deacetylases (Monte et al. 1998, Zhang & Dufau 2003, Hiroi et al. 2004). Thus, in vivo, the genomic environment may play an additional role in modulating the activity of the mutated StAR promoter.
Interestingly, a supershift was also observed with the antibody to COUP-TF for the same band that was also supershifted with the SF-1 antibody. This suggests an interaction with the StAR promoter and/or SF-1. COUP-TF is known to play a role as a repressor of steroidogenesis and, in particular, of StAR gene expression (Shibata et al. 2001, 2003, Buholzer et al. 2005). In addition, the competition between SF-1 and COUP-TF for a common binding site has been reported in the transcriptional regulation of the bovine CYP17 gene (Bakke & Lund 1995) and modulation of the activity of the murine DAX-1 and aromatase P450 promoters (Zeitoun et al. 1999, Cooney et al. 2001). Our supershift assay results, however, do not suggest an involvement of COUP-TF in the effects induced by the mutation. Thus, we can conclude that a point mutation on the locus for a key regulator may induce a complete remodelling of the various transcription factors involved in the regulation of the StAR gene, and therefore, its activity.
We focused on the gene for the StAR protein because of its rate-limiting role in steroid biosynthesis and because an increased supply of steroid precursors could result in increased aldosterone production. Clearly, based on the in vitro expression studies, the functional effect of this novel mutation in the StAR promoter argues against the hypothesised mechanism. We would like to propose an alternative explanation for the present findings. The described StAR promoter mutation, the first of its kind, leads to reduced StAR promoter activity in response to adrenocorticotrophin (ACTH) and AngII. The main effect is likely to be a slight reduction in cortisol levels in response to ACTH. In turn, normal feedback regulation should result in a resetting of the hypothalamic–pituitary–adrenal axis such that cortisol levels are maintained. Consequently, there will be a subtle increase in the ACTH drive to the adrenal cortex. In the long term this is likely to cause hyperplasia of both zona fasciculata and zona glomerulosa of the adrenal cortex, resulting in increased synthetic capacity for both cortisol and aldosterone. In turn, this might lead to hypertension associated with altered regulation of aldosterone and possibly cause insulin resistance and increased predisposition to diabetes associated with altered cortisol secretion.
In view of the pleiotropic action of the StAR protein and because of the complex interactions between the various factors induced by this mutation, further experiments are needed to elucidate the exact role this polymorphism may play in states of altered function of the mineralocorticoid, glucocorticoid and sex hormone axes.
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Acknowledgements |
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Received in final form 20 April 2006
Accepted 21 April 2006
Made available online as an Accepted Preprint 4 May 2006
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