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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isopycnic separations of red cells from cord bloods, and from patients with sickle cell anemia, different forms of HPFH, S-beta O-thalassemia, and a beta +-thalassemia homozygosity were made in order to evaluate the distribution of Hb F and the relative levels of G gamma and A gamma chains over the cell fractions. As expected, the cord blood data showed decreased levels of both Hb-F and G gamma chains in the top cell fractions since the beta leads to gamma and high G gamma: A gamma low G gamma: A gamma switches are operative around the time of birth. Complete cell fractionations were made on the blood of three SS patients with low G gamma values (40%) and three SS patients with high G gamma values (60%). The proportion of G gamma chain was constant in all cell fractions, while the Hb-F level was higher in cells with higher densities. The difference in the quantities of the three types of gamma chain in the fetal hemoglobins of two SS patients with an A gamma T heterozygosity, one having a low G gamma value and the other a high G gamma level, can be explained by assuming an alteration in a regulatory mechanism. Considerable variation both in the level of Hb F and in the percentage of G gamma chain was observed in two G gamma A gamma-HPFH heterozygotes with a relatively low G gamma percentage of 30%; an inverse relationship was present between the two parameters. Such a phenomenon was not evident for the G gamma A gamma-HPFH homozygote, and also did not exist in two additional G gamma A gamma-HPFH heterozygotes with an associated alpha-thalassemia-2 heterozygosity who had a similar amount of Hb F but with higher G gamma values of about 50%. The difference in G gamma values between these two categories of G gamma A gamma-HPFH could be due to a higher affinity of the G gamma chains over A gamma chains for a slightly decreased amount of alpha chains as in an alpha-thalassemia-2 heterozygosity. 2 heterozygosity. Although an increased synthesis of Hb-F with G gamma chains was again observed after in vitro incubation of reticulocytes with [35S]methionine none of the isolated cell fractions contained a Hb F with the alpha 2 G gamma 2 composition.
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PMID:The distribution of fetal hemoglobin and the types of gamma chain in red cell fractions separated by gradient centrifugation from blood of patients with sickle cell anemia and other hemoglobinopathies. 619 88

Hemoglobin synthesis was studied in culture of early erythroid precursors (BFU-E) from the blood of nine patients exhibiting sickle cell anemia and of 14 with various types of beta-thalassemia. The results concerning gamma gene expression and plating efficiency in heterozygotes for sickle cell anemia were similar to those of normal adults (gamma/alpha = 0.05; 65 BFU-E colonies/10(6) plated cells) while, in contrast, homozygotes for sickle cell disease exhibited average values higher than the controls (gamma/alpha = 0.18; 80 BFU-E colonies/10(6) plated cells). However, the results were very heterogeneous from one subject to another. In heterozygotes for beta-thalassemia, gamma gene expression and plating efficiency were both slightly higher than those for normal individuals (gamma/alpha = 0.095; 129 BFU-E colonies/10(6) plated cells). In patients homozygous for beta-thalassemia, a marked increase in plating efficiency and gamma-chain synthesis was constantly observed (gamma/alpha = 0.41; 221 BFU-E colonies/10(6) plated cells). The high proportion of gamma chain synthesis was not related to a positive selection of F cells, since the gamma/alpha ratio remained constant during the in vitro erythroid maturation. Furthermore, a major increase in free alpha chain proteolysis can be ruled out, since the beta/alpha ratio was of the same order of magnitude in culture and in freshly drawn cells. Thus, the increased Hb F synthesis in vitro was the consequence of a true stimulation of gamma gene expression, which permitted partial correction of the globin chain imbalance. Ultrastructural studies in two homozygotes for beta-thalassemia showed a marked decrease in the abnormalities of the erythroblasts derived from erythroid precursors in vitro in comparison to those from fresh bone marrow samples. In particular, Heinz bodies were much less numerous and a high frequency of mature erythroblasts and reticulocytes was observed in culture. These results support the view that, in sickle cell anemia and beta-thalassemia, a high potential for gamma gene expression exists and can be expressed in culture.
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PMID:Beta-thalassemia and sickle cell disease in culture of early erythroid precursors: hemoglobin synthesis and ultrastructural study. 718 47

We examined globin chain synthesis in erythroid bursts (BFU-E) of patients with heterozygous alpha or beta thalassaemia. BFU-E were cloned from circulating mononuclear cells, labelled with [3H]leucine and globin chains purified by gel filtration and column chromatography. In six patients heterozygous for beta thalassaemia, globin synthesis in BFU-E was nearly balanced, with an alpha/non alpha ratio of 1.05 +/- 0.12. These BFU-E produced 33.8 +/- 12.7% gamma globin chain, an amount similar (P > 0.05) to that found in 10 controls with sickle cell anaemia (25.6 +/- 6.7) but greater (P > 0.05) than that of five normal controls (17.2 +/- 2.2). The balanced globin synthesis appeared due to the large amounts of gamma chain made by BFU-E. In two alpha thalassaemia carriers, who also had sickle cell trait, the BFU-E alpha/non-alpha ratio was 0.67 and 0.79. These BFU-E produced 15% and 20% gamma chain and 39% and 45% betaS globin. The synthesis of betaS globin in BFU-E exceeded the erythrocyte levels of 20% and 29% HbS and indicated nearly equal expression of betaA and betaB globin genes in these proliferating erythroid precursors. This provides further evidence that the low levels of HbS in sickle cell carriers with alpha thalassaemia are due to post-translational events resulting from the differing affinity of betaS and betaA globin for alpha chain and the destruction of excessive betaS chain.
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PMID:Globin biosynthesis in erythroid bursts of heterozygous alpha or beta thalassaemia. 743 46

Three recombinant mutants of human fetal hemoglobin (Hb F) have been constructed to determine what effects specific amino acid residues in the gamma chain have on the biophysical and biochemical properties of the native protein molecule. Target residues in these recombinant fetal hemoglobins were replaced with the corresponding amino acids in the beta chain of human normal adult hemoglobin (Hb A). The recombinant mutants of Hb F included rHb F (gamma 112Thr --> Cys), rHb F (gamma 130Trp --> Tyr), and rHb F (gamma 112Thr --> Cys/gamma 130Trp --> Tyr). Specifically, the importance of gamma 112Thr and gamma 130Trp to the stability of Hb F against alkaline denaturation and in the interaction with sickle cell hemoglobin (Hb S) was investigated. Contrary to expectations, these rHbs were found to be as stable against alkaline denaturation as Hb F, suggesting that the amino acid residues mentioned above are not responsible for the stability of Hb F against the alkaline denaturation as compared to that of Hb A. Sub-zero isoelectric focusing (IEF) was employed to investigate the extent of hybrid formation in equilibrium mixtures of Hb S with these hemoglobins and with several other hemoglobins in the carbon monoxy form. Equimolar mixtures of Hb A and Hb S and of Hb A(2) and Hb S indicate that 48-49% of the Hb exists as the hybrid tetramer, which is in agreement with the expected binomial distribution. Similar mixtures of Hb F and Hb S contain only 44% hybrid tetramer. The results for two of our recombinant mutants of Hb F were identical to the results for mixtures of Hb F and Hb S, while the other mutant, rHb F (gamma 130Trp --> Tyr), produced 42% hybrid tetramer. The sub-zero IEF technique discussed here is more convenient than room-temperature IEF techniques, which require Hb mixtures in the deoxy state. These recombinant mutants of Hb F were further characterized by equilibrium oxygen binding studies, which indicated no significant differences from Hb F. While these mutants of Hb F did not have tetramer-dimer dissociation properties significantly altered from those of Hb F, future mutants of Hb F may yet prove useful to the development of a gene therapy for the treatment of patients with sickle cell anemia.
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PMID:A biochemical and biophysical characterization of recombinant mutants of fetal hemoglobin and their interaction with sickle cell hemoglobin. 1041 33

Sickle cell disease is caused by a mutation in the beta globin gene leading to hemoglobin S (Hb S) production. Several approaches have been explored to prevent Hb S polymerization in red blood cells and the symptoms associated with this disorder. To this end we tested a mammalian expression vector carrying a human beta globin antisense cDNA (pZeobetaAS) fragment in a mouse erythroleukemia cell line expressing the human gamma and beta globin genes. We observed a relative reduction in beta globin mRNA levels compared with gamma mRNA levels in the presence of pZeobetaAS. Moreover, analysis at the protein level showed an average 76% decrease in beta chains and a 517% increase in gamma chain biosynthesis. The inhibitory effect of the antisense vector on globin expression was maintained long term in culture. The expression vector pZeobetaAS was also transfected into primary erythroid progenitors to test its effects on globin genes undergoing normal developmental switching during differentiation. We observed a relative reduction of beta globin mRNA levels compared with gamma mRNA levels. These results support a novel role for antisense cDNA expression vectors as an alternative gene therapy strategy to inhibit betas gene expression in sickle cell disease. Gene Therapy (2000) 7, 438-444.
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PMID:Beta globin gene inhibition by antisense RNA transcripts. 1069 26

The relative proportions of the two gamma chain species (G gamma and A gamma) have been reinvestigated in newborns, during the physiological switch from foetal to adult haemoglobin, and in adults with some persistent expression of HbF. In newborns, with about 80% HbF, the G gamma percentage was close to 70% while in adult RBC, with less than 0.5% HbF, the G gamma chain was almost non-detectable and may reflect the completion of the foetal to adult switch. Conversely, in adult patients with HbF above 0.6%, usually accompanying some degree of marrow stimulation, the relative ratio of G gamma varied between 40 and 60%, independently of HbF level. This ratio corresponds to what has been described in the literature as being the adult type of HbF. In all the cases where we found higher levels of G gamma, the results could be explained by the presence of a specific genetic background such as the Senegalese haplotype in sickle cell disease.
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PMID:HbF in the adult: could its composition discriminate normal from abnormal foetal globin gene expression? 1114 30

Fetal hemoglobin (HbF), the predominant hemoglobin in the fetus, is a mixture of two molecular species (alpha(2)(G)gamma(2) and alpha(2)(A)gamma(2)) that differ only at position 136 reflecting the products of two nonallelic gamma-globin genes. At the time of birth, HbF accounts for approximately 70% of the total Hb. The (G)gamma:(A)gamma globin ratio in the HbF of normal newborn is 70:30 whereas in the trace amounts of HbF that is found in the adult it reverses to 40:60 because of a gamma- to beta-globin gene switch. Alterations of these ratios are indicative of a molecular defect at the level of the HbF synthesis. Qualitative hemoglobinopathies due to (G)gamma and (A)gamma chain structural variants, and quantitative hemoglobinopathies affecting the synthesis of HbF such as gamma-thalassemias, duplications, triplications, and even sextuplications of the gamma-globin genes, which may be detected in newborn blood lysates, have been described. Moreover, several pathological and nonpathological conditions affecting the beta-globin gene cluster, such as beta-thalassemia, sickle cell disease, deltabeta-thalassemia, and hereditary persistence of HbF syndromes, are characterized by the continued synthesis of gamma-globin chains in the adult life. Studies of these natural mutants associated with increased synthesis of HbF in adult life have provided considerable insight into the understanding of the control of globin gene expression and Hb switching.
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PMID:Disorders of the synthesis of human fetal hemoglobin. 1837 99


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