Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The red cells of a patient heterozygous for beta-thalassaemia contained 19% fetal Hb. Study of his family suggested that the proband had inherited the Swiss type of hereditary persistence of fetal Hb (HPFH) from his mother who is not thalassaemic and possessed 1.37% of Hb and 11% F-cells. Studies of globin synthesis showed a similar imbalance in the heterocellular HPFH-beta-thalassaemia compound heterozygotes and in the heterozygous beta-thalassaemic members of the family. Age stratification of the red cells showed a slight enrichment in Hb F and a decreased Hb A2 level in the older cell populations. Hb F production in the BFU-E colonies of the proband was higher than that found in vivo and in other beta-thalassaemic heterozygotes in culture. Study of single erythroid burst colonies showed a marked heterogeneity in Hb F synthesis from one colony to another, while the pool of free alpha-chains remained of similar magnitude. It is suggested that in the proband, the HPFH gene, which is in trans with respect to the beta-thal-gene, increases the size of the F-cell population and its activity is carried on at the expense of the normal beta A gene.
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PMID:Elevated Hb F associated with beta-thalassaemia trait: haemoglobin synthesis in reticulocytes and in blood BFU-E. 616 96

Colonies derived from erythroid burst-forming units (BFU-E) synthesize fetal hemoglobin (HbF) in amounts that far exceed in vivo levels. There is some evidence that HbF synthesis is controlled at the level of a primitive erythroid precursor cell. Dexamethasone may potentiate the development of BFU-E. Since a means of augmenting HbF production in sickle cell anemia or severe beta-thalassemia would be of great therapeutic value, we studied the effects of dexamethasone on HbF and gamma-globin chain synthesis in BFU-E from patients with sickle cell anemia and controls. HbF was measured by radioimmunoassay of BFU-E lysate and gamma-chain synthesis by the incorporation of 3H-leucine into globin, which was then purified by gel filtration and column chromatography. Dexamethasone (10(-9) M) produced an increase in the number of BFU-E in 16 of 19 subjects when compared with numbers of BFU-E cultured with only erythropoietin. The individual BFU-E were larger and contained more subcolonies. Dexamethasone did not increase HbF or gamma-chain synthesis, and there was no relationship between proliferation of BFU-E and augmented HbF production. Thus, although dexamethasone augmented the development of erythroid bursts, there was no increment in HbF.
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PMID:Effects of dexamethasone on fetal hemoglobin synthesis in peripheral blood erythroid burst-forming units. 616 63

Individuals heterozygous for the Greek (A gamma) variant of hereditary persistence of fetal haemoglobin (HPFH) synthesize Hb F whose gamma-globin chains are predominantly of the A gamma type. DNA obtained from Greek HPFH heterozygotes was used to test for abnormalities in the organization of non alpha-globin genes. In addition, gamma- and beta-globin expression was studied in BFUe cultures. Restriction endonuclease mapping showed that the G gamma, delta and beta genes in cis to the Greek HPFH determinant are intact. Overproduction of gamma-globin chains synthesis was observed in the BFUe cultures. A significant portion of the gamma chain synthesis was of the G gamma type, suggesting that the G gamma genes cis and trans to the HPFH chromosome are active in culture. DNA mapping data indicate that in contrast to G gamma A gamma HPFH and the G gamma (delta beta) thalassaemia, the Greek (A gamma) HPFH is not due to a large deletion in the non-alpha globin gene region. It is possible that the anomaly may result either from a small deletion or point mutation which influences non alpha-globin transcription. The in vitro synthesis data suggest that the low level of G gamma-globin chain synthesis in vivo is not the result of transcriptional inactivation of the G gamma gene, since this gene appears to be expressed in erythroid cell cultures. We speculate that the genetic lesion in Greek (A gamma) HPFH is in regulatory sequences which control the level of G gamma and A gamma expression during development.
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PMID:Greek (A gamma) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures. 617 32

Twelve patients with homozygous beta-thalassemia from Azerbaijan are described. From biosynthetic studies, we have established that seven children had beta +-thalassemia, while five had beta 0-thalassemia. In six patients with beta +-thalassemia a close correlation has been found between alpha/beta globin chain synthesis and alpha/beta mRNA content determined by molecular hybridization. In one case of beta +-thalassemia no such correlation has been observed. It was possible to study nuclear and cytoplasmic RNA from spleen erythroid cells in one of the patients. alpha/beta globin RNA ratio was 5 in both cases, suggesting the possibility of a defect in beta-globin gene transcription. In cases of beta 0-thalassemia, heterogeneity of the relative content of beta-globin mRNA was revealed: either it is found in considerable amounts, or it is completely absent. Mapping of DNA from two beta-thalassemic patients by restriction enzymes yielded a normal pattern for the beta-globin gene region.
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PMID:[Molecular causes of thalassemia. III. Molecular genetic variants of beta-thalassemia in Azerbaijan]. 618 Sep 57

5-Azacytidine is a cytidine analogue that is capable of activating repressed genes in tissue-culture cells and has been shown to increase hemoglobin-F production in anemic baboons. This drug was administered to a patient with severe beta-thalassemia in an attempt to stimulate hemoglobin-F production. After seven days of 5-azacytidine treatment, gamma-globin synthesis increased approximately sevenfold, temporarily normalizing the patient's unbalanced globin synthesis. Erythropoiesis became more effective, leading to a temporary increase in the absolute reticulocyte count (from 5000 to 22,000 per cubic millimeter) and in hemoglobin concentration (from 8.0 to 10.8 g per deciliter). Hypomethylation of bone-marrow DNA near both the gamma-globin and epsilon-globin genes was directly demonstrated. At the time of peak drug effect, about 7000 gamma-globin messenger RNA molecules were present per erythroid bone-marrow cell, in contrast to 10 to 15 epsilon-globin messenger RNA molecules per cell. 5-Azacytidine selectivity increases gamma-globin synthesis and therefore provides a new approach to the treatment of severe beta-thalassemia. Further studies will be required to evaluate the efficacy, risks, and long-term toxicity of 5-azacytidine (or related compounds) before this approach can be used as a therapy for patients with disorders of hemoglobin synthesis.
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PMID:5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. 618 86

5-Azacytidine, a cytidine analog, stimulated fetal hemoglobin synthesis in five patients who had either severe beta-thalassemia or sickle cell anemia. After treatment, a reduction in the frequency of methylated cytosine residues was observed at all Hpa II sites examined. Despite causing "global" hypomethylation, 5-azacytidine augmented the synthesis of gamma-globin only. Although gamma-gene hypomethylation and increased gamma-gene expression seem to be linked, hypomethylation near other genes was not sufficient to activate transcription. These data suggest that the gamma genes lie in a unique "preactivational" state responsive to hypomethylation, and that other genes are repressed in bone marrow cells by different mechanisms. DNA hypomethylation and an increased concentration of gamma-mRNA were observed in bone marrow cells 2 days after initiation of treatment, indicating that 5-azacytidine may act directly on differentiated erythroid precursors. This compound probably affects early erythroid progenitors as well, since an increased level of gamma-globin synthesis persists for 1-2 weeks after the drug is stopped. A direct effect on erythroid progenitors was also suggested by in vitro assays: Erythroid colonies derived from progenitor cells obtained on day 2 of treatment produced more Hb F than colonies derived from progenitors obtained before 5-azacytidine was given.
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PMID:DNA methylation and globin gene expression in patients treated with 5-azacytidine. 619 60

To determine whether hemoglobin regulation is normal in diseases affecting beta-globin gene expression, globin synthesis was examined in members of a family of a patient with hereditary persistence of fetal hemoglobin/beta o-thalassemia (HPFH/beta o-thal). The HPFH defect is the Ghanian type II, with a deletion from psi beta 1 to at least 20 kb 3' to beta. The beta o-thal gene has the haplotype II restriction enzyme pattern and has the beta 39 nonsense mutation. Erythroid colonies from blood BFU-E were radiolabeled, and globin chains were separated by gel electrophoresis. Colonies from the beta o-thal heterozygote had non-alpha/alpha ratios more balanced than in the reticulocytes. Gamma synthesis was 11% of non-alpha, which is higher than in reticulocytes, but within the range seen in normal adult colonies. Both HPFH heterozygotes produced 20%-30% gamma in erythroid colonies as well as reticulocytes, although non-alpha/alpha was more balanced in the colonies. The HPFH/beta o-thal patient produced 100% gamma in reticulocytes and in colonies. G gamma and gamma-synthetic proportions were not correlated at the individual colony level in the heterozygotes, suggesting that they had "adult" and not "fetal" progenitor cells. The Hb expression of these adult progenitors is presumably modulated normally in vivo in beta o-thal, but the normal decrease in HbF production does not occur in gene deletion HPFH.
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PMID:Fetal hemoglobin synthesis in erythroid cultures in hereditary persistence of fetal hemoglobin and beta o-thalassemia. 620 41

Globin chain synthesis, RNA and DNA of beta-thalassemic patients from Azerbaidzhan were analyzed. A beta-mRNA deficiency was found in beta +-thalassemic reticulocytes. In one case of beta +-thalassemia, it was possible to study nuclear and cytoplasmic RNA from spleen erythroid cells. The alpha/beta mRNAs sequence ratio was 5 in the nuclear and cytoplasmic RNAs. In patients with beta o-thalassemia a different level of beta-globin mRNA was demonstrated. Gene mapping analysis indicated that the general organization of the beta-globin gene was normal in the investigated cases of beta-thalassemia.
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PMID:Heterogeneity of beta-thalassemia in Azerbaidzhan. 624 15

DNA sequence analysis of a cloned beta-globin gene from a Chinese patient with beta-thalassemia revealed a single nucleotide substitution (A leads to G) within the ATA box homology and 28 base pairs upstream from the cap site. The patient was homozygous for this particular allele based on restriction mapping at nine different polymorphic sites in the beta-globin gene cluster. Upon transient expression in HeLa cells this gene directed the production of 3-5-fold less beta-globin mRNA than the normal beta-gene. In RNA isolated from the patient's erythroid cells beta-RNA was 10-fold less abundant relative to alpha-RNA than normal, indicating close approximation of the heterologous cell expression results and the in vivo state. These findings support the validity of such transient expression assays for analysis of phenotypes associated with naturally occurring mutant genes and establish the functional significance of nucleotide substitutions at position -28 for human beta-globin gene transcription.
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PMID:ATA box transcription mutation in beta-thalassemia. 630 58

Proteolytic activity against native hemoglobin polypeptide chains is demonstrated, under strictly physiological conditions, in human reticulocytes of both normal subjects and individuals suffering from a variety of pathologic conditions involving erythrocytes, including beta-thalassemia. Two thirds of the activity are found in the cytoplasm and the remainder of it is associated with the reticulocyte membrane. That this proteolytic activity is due to contamination by WBC is excluded. The activity preferentially degrades the alpha-hemoglobin chains. An increase in this substrate within the erythroid cells, as observed in beta-thalassemia, does not enhance proteolysis. Protease inhibitors produce a variable decrease in proteolysis. None inhibit completely, thus showing that several enzymes, with different specificities, are involved.
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PMID:Erythrocytic proteases: preferential degradation of alpha hemoglobin chains. 640 66


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