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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A common mutation causing thalassemia in Mediterranean populations is an amber (UAG) nonsense mutation at the 39th codon of the human beta-globin gene, the beta-39 mutation. Studies of mRNA metabolism in erythroblasts from patients with beta-39 thalassemia and studies using heterologous transfection systems have suggested the possibility that this mutation not only affects protein synthesis but also alters mRNA metabolism. The effects of this mutation on several steps in the metabolism of mRNA have been investigated by transfection of the gene into permanent cell lines bearing a temperature-sensitive RNA polymerase II. Several RNA expression studies were performed, including analysis of transcription, mRNA stability, mRNA splicing accuracy, and mRNA polyadenylation. The results suggest that the defect in expression of the beta-39 mRNA occurs at a step prior to the accumulation of mRNA in the cytoplasm.
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PMID:Beta-globin nonsense mutation: deficient accumulation of mRNA occurs despite normal cytoplasmic stability. 155 99

The major steps in haemoglobin synthesis in red cell precursors are now worked out and only details of specific mechanisms remain to be filled in. Thus the major steps in the production of a globin chain are the transcription of large-molecular-weight precursor mRNA (Hn RNA) from the appropriate gene, the cleavage of Hn RNA to produce definitive template mRNA which diffuses into the cell cytoplasm, the processes of chain initiation, translation, and termination, and finally the association of subunits to form a stable tetramer. From what little information there is it appears that this complex series of events is controlled at several levels but that the major control mechanisms are mediated in the processes of transcription rather than translation. There is increasing evidence that the chromatin proteins, particularly the acidic proteins, have specific functions in maintaining areas of DNA repressed and the activation of the haemoglobin loci results from complex interactions with external inducers, the nature of which is not yet known. Virtually nothing is known about the factors involved in the switch from the intrauterine to adult haemoglobins although this appears to be a coordinated event throughout the erythropoietic tissue of the fetus. The isolation and characterization of human mRNA has made possible both the study of the function of thalassaemic mRNA in heterologous systems and , more recently, its quantitation in abnormal red-cell precursors. Furthermore the ability to make cDNA using viral re verse transcriptase has made possible the estimation of the number of haemoglobin genes, both in normal human subjects and in those with different forms of thalassaemia and other genetic disorders of haemoglobin production.
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PMID:The genetic control of protein synthesis: The haemoglobin model. 462 Aug 83

The Hba(th-J) mouse mutation is a deletion on chromosome 11 that spans the alpha-globin complex and causes alpha-thalassemia in heterozygous animals and in utero death of embryos homozygous for the deletion. We hypothesised that one or more genes closely linked to the Hba locus are also deleted in these mutant mice and that deletion of these additional genes is responsible for the embryo lethality. We have analysed the developmental profile of mutant embryos using a PCR assay to distinguish homozygous embryos from wild-type and heterozygous embryos. No homozygous embryos are detectable on Day 6.5 of gestation and morphological analysis of embryos on Day 5.5 shows that both the embryonic and extraembryonic ectoderm of the egg cylinder are reduced in size and contain degenerate cells. Preimplantation homozygous embryos are morphologically normal with the same proportion developing to the blastocyst stage as control embryos. However, the cell number of homozygous embryos on Day 4.5 is significantly reduced due predominantly to a decrease in the cell number of the trophectoderm and not the inner cell mass. When homozygous blastocysts are plated in vitro, outgrowth of giant trophectoderm cells appears similar to that of wild-type embryos but outgrowth of the inner cell mass is affected. Cells from the inner cell mass of homozygous embryos appear to undergo necrosis and dissociate from the trophectoderm outgrowth after 3 to 4 days in culture. These studies demonstrate that the development of both the inner cell mass and the trophectoderm of embryos homozygous for the Hbath-J deletion is affected by the mutation. We have used quantitative Southern blotting to show that 3-methyladenine glycosylase (mpg) and dist1, two genes closely linked to the Hba locus on chromosome 11, are also deleted in this mutation. Reverse transcriptase-polymerase chain reaction analyses demonstrate that mpg and dist1 are normally expressed by preimplantation and early postimplantation embryos, whereas alpha-globin transcripts from the Hba locus are not detected until Day 7.5 of gestation. These studies demonstrate that deletion of the mpg or dist1 genes is likely to be responsible for the homozygote embryo lethality and the potential roles of these gene products in early embryogenesis are discussed.
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PMID:Developmental analysis of the Hba(th-J) mouse mutation: effects on mouse peri-implantation development and identification of two candidate genes. 758 5

Translational stop mutations of the human beta-globin gene cause a reduction of cytoplasmic mRNA accumulation in thalassemia patients and in transfection models. The exact mechanism underlying this phenomenon has remained enigmatic but is known to be post-transcriptional. We have used transfected HeLa cells to study the expression of beta-globin mRNAs with nonsense or frameshift mutations within the three exons of this gene. Mutations in exons 1 or 2 reduce cytoplasmic mRNA accumulation whereas a mutation in exon 3 permits essentially normal expression. We report here that the post-transcriptional fate of mutated beta-globin mRNAs is differentially affected by the type of RNA polymerase II promoter driving expression. Replacement of the beta-globin promoter with the herpes simplex virus type 1 thymidine kinase gene promoter but not the cytomegalovirus immediate early promoter rescues the cytoplasmic accumulation of mutated mRNA to wild-type levels. This effect is shown to be independent of the absolute quantity and the kinetics of accumulation of mutated mRNA synthesized, and primer-extension analyses confirm that both viral promoters accurately utilize identical transcription start sites. These data thus reveal an unexpected property of RNA polymerase II promoters: determination of the post-transcriptional fate of the maturing mRNA, presumably by influencing alternative choices between as yet undefined processing and/or transport pathways.
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PMID:Determination of mRNA fate by different RNA polymerase II promoters. 823 61

Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the alpha 2/alpha 1-, alpha/beta-, and gamma/beta-mRNA ratios in subjects with beta-thalassemia (beta-thal), hereditary persistence of fetal hemoglobin (HPFH), and normal adults. The alpha- and beta-globin gene mutations were characterized with gene mapping, PCR, and DNA sequencing. The average alpha 2/alpha 1-mRNA ratio was the same in normal adults and beta-thal heterozygotes with four alpha-globin genes (2.61-2.63) or with an alpha-thal-2 trait (1.48-1.55). The average alpha/beta-mRNA ratios were 4.47 and 3.84 in normal adults with four alpha-globin genes and with alpha-thal-2 trait (-alpha/alpha alpha), respectively. There was an increase of approximately 50% in beta-thal heterozygotes with transcriptional mutants [-88 (C-->T) and -29 (A-->G)] with lower values (approximately 25%) in those with alpha-thal-2 trait (-alpha/alpha alpha). High alpha/beta ratios were also observed for heterozygotes for nonsense or frameshift mutants located in exon 1 or exon 2. Increases of approximately 150-165% were seen in subjects with RNA processing defects; an exception was the IVS-1-110 (G-->A) mutation with a normal value in the heterozygote. The increases were also less pronounced in heterozygotes for the codon (CD) 121 (G-->T) mutation and the CDs 134-137 insertion/deletion. Normal alpha/(gamma + beta) values were seen in 3 heterozygotes each with a different deletion involving part of the beta-globin gene. The presence of the silent beta-thal allele, -101 (C-->T), in trans to a CD 8 (-AA) allele has a minor effect on the alpha/beta-mRNA ratio. The alpha/beta-mRNA ratio in HPFH heterozygotes was approximately 145% of normal, but with a gamma-mRNA level of 35.4-44.7% the calculated alpha/(gamma + beta) ratio became as in normal adults. The RT-PCR methodology appears useful in expression studies in beta-thal (and HPFH) and values of mRNA appear to correspond to the type of prevailing mutation(s) and concomitant alpha-thal.
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PMID:Globin mRNA in beta-thalassemia heterozygotes with different beta-thalassemia alleles and in heterozygotes for hereditary persistence of fetal hemoglobin. 887 14

Increased levels of hemoglobin A(2) (HbA(2)) are present in most beta-thalassemia carriers. The mechanism of this effect is not understood, although the increase may result from transcriptional and posttranscriptional changes. In the present study, we quantitate delta-globin mRNA levels in peripheral-blood-enriched reticulocytes and characterize the variation of delta-mRNA levels in 30 beta-thalassemia heterozygotes who individually carry one of the four common Chinese beta-thalassemia alleles [codons 41/42 (-TTCT); codon 17 (A-->T); IVS-II-654 (C-->T); -28 (A-->G)]. A sensitive and quantitative competitive reverse-transcriptase polymerase chain reaction method was developed and used to assess the absolute amounts of delta-mRNA transcripts in these peripheral erythroid cells. The results showed a large increase in delta-mRNA amounts in all the carriers examined (72.3 +/- 9.0 amol/microg RNA) as compared with those in 12 controls (1.2 +/- 0.2 amol/ microg RNA). There was a direct correlation between the delta-mRNA levels and types of beta-thalassemia alleles; generally, the delta-mRNA levels are higher in heterozygotes for beta(0)-thalassemia mutations than beta(+)-thalassemia mutations. The delta-mRNA levels correlated inversely with hemoglobin and red cell indices but directly with HbA(2) levels in heterozygotes of each of the group of beta-thalassemia mutations. These results suggest that a greater impairment in beta-globin gene expression results in increased transcription of delta-globin gene and in a higher level of HbA(2).
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PMID:The delta-globin RNA transcript level in beta-thalassemia carriers. 1047 80

High-level alpha-globin expression depends on cis-acting regulatory sequences located far upstream of the alpha-globin cluster. Sequences that contain the alpha-globin positive regulatory element (PRE) activate alpha-globin expression in transgenic mice. The alpha-globin PRE contains a pair of composite binding sites for the transcription factors activating protein 1 and nuclear factor erythroid 2 (AP1/NFE2). To determine the role of these binding sites in alpha-globin gene transcription, we mutated the AP1/NFE2 sites in the alpha-globin PRE in mice. We replaced the AP1/NFE2 sites with a neomycin resistance gene (neo) that is flanked by LoxP sites (floxed). Mice with this mutation exhibited increased embryonic death and alpha-thalassemia intermedia. Next, we removed the neo gene by Cre-mediated recombination, leaving a single LoxP site in place of the AP1/NFE2 sites. These mice were phenotypically normal. However, alpha-globin expression, measured by allele-specific RNA polymerase chain reaction (PCR), was decreased 25%. We examined the role of the hematopoietic-restricted transcription factor p45Nfe2 in activating expression through these sites and found that it is not required. Thus, we have demonstrated that AP1/NFE2 binding sites in the murine alpha-globin PRE contribute to long-range alpha-globin gene activation. The proteins that mediate this effect remain to be determined.
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PMID:Role of AP1/NFE2 binding sites in endogenous alpha-globin gene transcription. 1292 35

Treatment of hepatitis C virus (HCV) in the general population has improved over the last decade. Patients treated with peginterferon alfa (PegIFN) and ribavirin (RBV) combination therapy demonstrate overall 50-55% sustained viral response (SVR) with rates as high as 80% in patients with genotypes 2 and 3. Because RBV induces hemolysis and subsequently increases blood transfusion requirements, combination therapy has been considered contraindicated for hemoglobinopathies. This report reviews the response to interferon alfa and RBV (IFN/RBV) and PegIFN/RBV combination therapies in patients treated in the Northern California Comprehensive Thalassemia Center. A total of six thalassemia major patients were treated with IFN/RBV (n = 5; age: 4-38 years) or with PegIFN/RBV (n = 1; age: 26 years). Quantitative HCV RNA polymerase chain reaction and liver iron level assessment were completed. Transfusion volumes were obtained from patients' medical records. On IFN/RBV combination, four of five patients demonstrated SVR. The one patient on PegIFN/RBV showed end-treatment viral response after 6 months of therapy (genotype 3), but subsequently relapsed. Liver iron pretreatment level ranged from 0.2 to 22 mg/g dry weight, with a mean +/- SD of 7.9 +/- 7.7. Transfusion requirement increased by a median of 43.5% (range: 32-137%). Five of the six patients had liver iron measurements within 1 year following completion of treatment, with quantitative liver iron increasing in two patients by 2.5 mg/g dry weight, decreasing in two patients by 3 and 14 mg/g dry weight, and remaining unchanged in one patient. All patients were able to complete combination therapy, although dose reductions were required. Patients with thalassemia and high iron overload can obtain SVR after combination therapy with rates similar to those in the general population and without significant complications. Although transfusion requirements increased in most patients, iron burden was not necessarily increased.
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PMID:Treatment of hepatitis C virus infection in thalassemia. 1633 77

Histone deacetylase (HDAC) inhibitors are one of promising drugs to induce fetal hemoglobin (HbF) for treatment of sickle cell disease (SCD) and beta-thalassemia. The HDAC inhibitor apicidin was recently reported as a powerful inducer of HbF via a mechanism involving p38 signaling. In this study, we further investigated the signaling effects on the transcriptional activation of gamma-globin gene. First, we compared histone 3 (H3) acetylation patterns of approximately 70kb beta-globin loci in K562 erythroid versus HeLa cells upon apicidin treatment by chromatin immunoprecipitation assays. The results showed that the level of H3 acetylation was globally increased from the LCR to the promoter of gamma-globin gene in K562 cells, but not in non-erythroid, HeLa cells. Inhibition of p38 signaling blocks the effects of apicidin-induced gamma-globin expression and H3 acetylation. In parallel, we assessed the recruitment of transcriptional complex to beta-globin locus following apicidin treatment. The binding of GATA-1, Sp1 and RNA polymerase II (pol II) were observed to increase over several regulatory regions of beta-globin locus. Inhibitor study revealed that p38 pathway was not involved in their recruitments by apicidin. Collectively, our results provide a molecular basis to elucidate the underlying mechanisms involving p38 signaling pathway in the inducement of gamma-globin transcriptional expression by apicidin.
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PMID:Mechanisms of human gamma-globin transcriptional induction by apicidin involves p38 signaling to chromatin. 1791 Aug 85

The architectural layout of a eukaryotic RNA polymerase II core promoter plays a role in general transcriptional activation. However, its role in tissue-specific expression is not known. For example, differing modes of its recognition by general transcription machinery can provide an additional layer of control within which a single tissue-restricted transcription factor may operate. Erythroid Kruppel-like factor (EKLF) is a hematopoietic-specific transcription factor that is critical for the activation of subset of erythroid genes. We find that EKLF interacts with TATA binding protein-associated factor 9 (TAF9), which leads to important consequences for expression of adult beta-globin. First, TAF9 functionally supports EKLF activity by enhancing its ability to activate the beta-globin gene. Second, TAF9 interacts with a conserved beta-globin downstream promoter element, and ablation of this interaction by beta-thalassemia-causing mutations decreases its promoter activity and disables superactivation. Third, depletion of EKLF prevents recruitment of TAF9 to the beta-globin promoter, whereas depletion of TAF9 drastically impairs beta-promoter activity. However, a TAF9-independent mode of EKLF transcriptional activation is exhibited by the alpha-hemoglobin-stabilizing protein (AHSP) gene, which does not contain a discernable downstream promoter element. In this case, TAF9 does not enhance EKLF activity and depletion of TAF9 has no effect on AHSP promoter activation. These studies demonstrate that EKLF directs different modes of tissue-specific transcriptional activation depending on the architecture of its target core promoter.
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PMID:Distinct modes of gene regulation by a cell-specific transcriptional activator. 1925 49


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