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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past 15 years there have been remarkable advances in our understanding of the molecular biology of hemoglobin synthesis and the abnormalities in hemoglobinopathies and thalassemia. The globin genes were among the first mammalian structural genes that were cloned and the DNA sequence of the human globin gene clusters has since been completely delineated. During the last ten years, we have also learned of the many deletions and point mutations that give rise to hemoglobin-opathies and thalassemia. In addition, the sequences that control erythroid specific expression of the globin gene has also been revealed. These findings have contributed to our understanding of the pathophysiology of the diseases and have allowed the institution of accurate DNA diagnostic methods to be applied to prenatal diagnosis. As increased fetal hemoglobin synthesis is known to ameliorate the severity of the disease in disorders such as sickle cell anemia and thalassemia, agents which increase the level of fetal hemoglobin synthesis are being tested. Also, the discovery of DNA sequences and transacting factors which are responsible for high erythroid globin gene expression [4] may provide more effective means of gene therapy.
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PMID:Molecular biology of hemoglobin: its application to sickle cell anemia and thalassemia. 172 57

In addition to local sequence elements the regulation of the high-level, development- and tissue-specific expression of the human beta globin gene cluster appears to require distant regulatory sequences which have been termed locus control region. In the chromatin of erythroid cells the locus control region is characterized by four DNaseI hypersensitive sites that are located 6-18 kb 5' of the epsilon globin gene. The definition of the sequences minimally required for locus control region activity is likely to further the understanding of its physiology and will be of interest for the development of somatic gene therapy strategies of the hemoglobinopathies. We present here the analysis of a family with a 3,030-bp deletion of sequences upstream of the epsilon globin gene including the most 3' locus control region element and cosegregating beta(0) thalassemia. The deletion is linked in cis to a structurally and functionally normal beta globin gene. The proximal element of the locus control region does not therefore appear to be necessary for beta globin gene activity in vivo.
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PMID:The proximal element of the beta globin locus control region is not functionally required in vivo. 204 Jun 96

Suggestions that the field of hemoglobin regulation and erythroid cell molecular biology was undergoing a tortuous and slow death, awash in the scientific community several years ago, were dispelled by the findings presented at the Seventh Conference on Hemoglobin Switching. After a phase in which neither the cis-elements nor trans-factors important for globin and erythroid gene expression were evident, recent progress has been rapid. Once again, studies in this area are providing fundamental insights into eukaryotic biology. The long-distance influence of LCR elements on chromatin structure and gene expression is remarkable and likely to be encountered in the analysis of other developmentally regulated, multigene loci. How LCR elements influence chromatin structure and maintain an open configuration is a problem at the core of gene regulation. We can be optimistic that further dissection of LCRs will delineate DNA sequences critical for these effects and associated proteins. The interaction of LCRs with individual genes must depend on specific protein-protein interactions, most likely involving a small, but elite, group of regulators. At least one critical transcriptional regulator of erythroid-expressed genes, GATA-1, is firmly established. Others are being pursued. The mechanisms by which they collaborate with each other should provide the missing pieces to the puzzle of cell-specific gene expression in the erythroid lineage. As the phenomenology of Hb switching is mimicked in transgenic mice, the elements mediating competitive and non-competitive (or autonomous) modes of regulation will be systematically delineated. Whether knowledge of the cis- and trans- components involved in switching will lead to the development of therapeutic approaches aimed at altering their complex interactions is uncertain. Fortunately, recent progress in hematopoietic stem cell biology once again raises hopes that gene transfer strategies for management of hemoglobin disorders may be more than a distant, impractical goal.
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PMID:Globin gene regulation and switching: circa 1990. 222 71

The mechanism of stimulation of Hb F in stressed erythropoiesis is examined. Conditions known to produce a transient elevation of F-cells (acute anemia; acute expansion; treatment with cytotoxic compounds) have a common element, the acute kinetic perturbations of erythroid differentiation/maturation they trigger. Cell cycling must be shortened and the total time of differentiation (from BFUe to erythroblast) must be shortened. We propose that F-cells are formed either because of the shortening of erythroid differentiation time or because of shortening of cell cycle of erythroid cells. With the model of shortened differentiation time F-cell formation is attributed to "premature commitment" of progenitors. gamma-gene expression occurs either because chromatin changes that normally inactivate the gamma genes are not completed or because critical divisions in which the gamma genes are normally inactivated are skipped. The model of faster cycling explains F-cell formation by assuming that gamma-gene transcription is activated when the cycle (and especially the duration of G0/G1) of progenitors or erythroblasts falls below a critical time. The proposed models can readily explain the F-cells of the normal adult as the products of random deviation from normal erythroid kinetics. The two models can also explain F-cell formation in chronic erythropoietic stress (chronic hemolytic anemias, patients with hemoglobinopathies). Differences in the degree of F-cell elevation in such patients may reflect differences in the intensity of kinetic perturbation of their erythropoiesis.
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PMID:Hb F production in stressed erythropoiesis: observations and kinetic models. 240 71

Fetal hemoglobin production can be reactivated in vivo in adult persons with various hemoglobinopathies and other hemopoietic disorders, and in cultures of adult erythroid progenitors. We show that the activation of Hb F in adult cells is transcriptional in nature and is accompanied by the appearance of DNase I-hypersensitive sites and undermethylation of Hpa II sites 5' to the gamma-globin genes. Production of Hb F in culture is strongly modulated by the environment, and the repression of Hb F synthesis by specific culture conditions has been reported. By nuclear runoff, chromatin, and methylation analyses, we show that this inhibition of Hb F production in vitro is at the level of transcription with the concomitant loss of characteristic gamma hypersensitive sites and methylation of gamma Hpa II sites. These data indicate, first, that the organization of globin chromatin of adult cells that produce fetal hemoglobin resembles that of fetal erythroid cells and, second, that this organization switches from a fetal to an adult pattern in response to changes in the environment of the erythroid cells.
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PMID:The modulation of Hb F synthesis in adult erythroid progenitor (burst-forming unit) cultures reflects changes in gamma-globin gene transcription and chromatin structure. 242 43

The absolute adult and fetal hemoglobin (HbF) contents of the erythroid cells derived from the differentiation of normal human and simian erythroid progenitors and of the peripheral blood erythroid burst-forming units (BFU-E) of patients with nondeletion hemoglobinopathies have been measured with a sensitive radioligand immunoassay. The HbF content varied between 0.13 and 2.96 pg/cell, representing between 0.7% and 19.6% of the total hemoglobin with a mean value of 7.0%. The absolute content of HbF was indistinguishable in the well-hemoglobinized progeny of marrow erythroid colony-forming units, marrow or blood BFU-E, or of mixed colony-forming units. The term HbF program refers to this inherent capacity to produce fetal hemoglobin (HbF) in the erythroid cells derived from these progenitors in vitro. The HbF content of marrow erythroblasts as determined by the same radioligand immunoassay was similar to that found in the peripheral blood, suggesting that the switch off of gamma-chain production occurs after the erythroid colony-forming unit stage of maturation. Increasing concentrations of a crude erythropoietin-containing preparation induced higher numbers of erythroid colonies, which were larger in size, but the HbF program was unaffected. In contrast to the hemoglobin accumulation in human progenitor-derived colonies, simian progenitor-derived colonies produced considerably more HbF, and the amount of HbF was strongly influenced by progenitor maturity. Assays of the HbF content of erythroblasts derived from culture of the peripheral blood BFU-E of patients with nondeletion hemoglobinopathies and their parents showed that the HbF program in the progenitors of such patients is highly variable. Some produce only a slight excess of HbF in progenitor-derived erythroblasts, whereas others have extraordinarily high HbF programs. The molecular basis of this variability is presently unknown.
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PMID:Determination of the hemoglobin F program in human progenitor-derived erythroid cells. 258 Aug 59

Human alpha- and beta-globin genes were separately fused downstream of two erythroid-specific deoxyribonuclease (DNase) I super-hypersensitive sites that are normally located 50 kilobases upstream of the human beta-globin gene. These two constructs were coinjected into fertilized mouse eggs, and expression was analyzed in transgenic animals that developed. Mice that had intact copies of the transgenes expressed high levels of correctly initiated human alpha- and beta-globin messenger RNA specifically in erythroid tissue. An authentic human hemoglobin was formed in adult erythrocytes that when purified had an oxygen equilibrium curve identical to the curve of native human hemoglobin A (Hb A). Thus, functional human hemoglobin can be synthesized in transgenic mice. This provides a foundation for production of mouse models of human hemoglobinopathies such as sickle cell disease.
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PMID:Synthesis of functional human hemoglobin in transgenic mice. 277 49

Molecular mechanisms involved in control of globin gene expression are a prominent target in current basic biologic research. A better understanding of these mechanisms might also impinge on a clinical goal: amelioration of the human hemoglobinopathies. Recent reports have established the coexistence of embryonic and adult globins in rodent yolk-sac erythroid cells, raising the possibility that globin ontogeny takes place in these cells. The present study was undertaken to define the extent of this putative ontogenic process. We measured daily rates of synthesis of individual globins in hamster yolk-sac erythroid cells from the earliest day in gestation that these cells are available (day 7) until the day they cease to replicate (day 13). Converted to a per-cell basis, the rates demonstrate an ontogenic progression in globin synthesis, from embryonic globins to adult globins, that encompasses nearly entirely the total globin ontogeny of this mammal. Synthesis of adult alpha globin is already detectable on day 7, whereas synthesis of the two adult beta globins does not appear until day 9. Synthesis of embryonic y globin stands in contrast to that of the other two embryonic globins (x and z), rising as they fall, a phenomenon reminiscent of the gamma globin of primates and certain ruminants. This physiologic primitive erythroid cell appears to be an unusually appropriate target for studies directed at globin ontogeny.
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PMID:The globin gene expression program in the hamster embryo. 333 31

Recombinant DNA technology now provides the strategies required to identify genes whose expression controls the development of normal and pathologic blood cells. Characterization of the gene families responsible for synthesis of hemoglobins, immunoglobulins, histocompatibility antigens, and cellular enzymes have already, or are about to, provide major insights into the mechanisms producing normal erythroid cells, immunocytes, and immune surface features. Hemoglobinopathies, leukemias, and autoimmune diseases of the bone marrow can now be examined to a degree of detail previously inaccessible to investigators. Oncogene translocation analysis is shedding new light on the pathogenesis of leukemias and lymphomas. Recent basic advances now permit direct cloning and identification of genes in host organisms which express their protein products, thus allowing isolation of genes coding for the hematopoietic surface markers and growth factors which characterize and regulate blood cell progenitors. This review summarizes the molecular genetic approach to analysis of normal and pathologic hematopoiesis, surveys major findings which have resulted, and examines the potential use of refined gene cloning strategies for improved understanding of blood cell development.
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PMID:Analysis of gene expression during hematopoiesis: present and future applications. 390 64

Concurrent synthesis of two or more hemoglobins occurs in normal man, the human hemoglobinopathies, and certain animal species. Duck erythrocytes produced in response to acutely induced anemic hypoxia (hemolysis or blood loss) contained reciprocally altered proportions of Hb I (alpha(2) (I) beta(2) (I)) and Hb II (alpha(2) (II) beta(2) (II)); the relative proportion of Hb II was 50-100% increased. Relative rates of synthesis of the two hemoglobins remained proportional to their new concentrations throughout erythroid maturation. This information favors the proposal that relatively increased activity, not delayed decay, of biosynthetic processes responsible for net synthesis of Hb II had occurred. These studies support the concept that the individual biosyntheses of multiple hemoglobins, presumably under genetic control, are potentially manipulable, and they provide evidence for one mechanism leading in a reproducible fashion to alterations in net synthesis in vivo.
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PMID:Disproportional synthesis of the adult duck's two hemoglobins during acute anemia. 563 50


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