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

The DNA juxtaposed to the gamma-globin genes as a result of a large deletion associated with hereditary persistence of fetal hemoglobin (HPFH) was studied to define the role it may play in maintaining active expression of these genes in adult erythroid cells. The DNA located immediately 3' to the deletion breakpoint was found to function as an enhancer element in gene transfer experiments and to be specifically hypomethylated in normal erythroid cells of both fetal and adult origin. This DNA also contains a long open reading frame encoding a polypeptide chain 292 amino acids in length. Therefore, in this form of HPFH (HPFH-1), the continued expression of gamma-globin genes in adult life may result from the inclusion of these genes within a new chromosomal domain that is potentially transcriptionally active in adult erythroid cells. The 3' breakpoint of another large deletion causing delta beta thalassemia rather than HPFH was also identified. This deletion (Spanish G gamma A gamma (delta beta)(0) thalassemia) is nearly identical in size and location to that of HPFH-1, but extends an additional 8.5 to 9 kb in the 3' direction, and therefore results in loss of the sequences near the 3' breakpoint of HPFH-1. Thus, the presence of these sequences appears to be important for the expression of the HPFH phenotype.
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PMID:The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster. 247 23

In the normal fetus, a switch from production of hemoglobin F (alpha 2 gamma 2) to hemoglobin A (alpha 2 beta 2) occurs at 28 to 34 weeks of gestation. In the fetus with beta-hemoglobinopathy or beta-thalassemia, this switch proceeds despite the morbidity that results when production of beta-globin is abnormal or reduced. Since insulin has recently been shown to induce renewed expression of some inactive genes, we studied globin biosynthesis during the natural evolution of the fetal globin switch under conditions of hyperinsulinemia, which occurs in infants of diabetic mothers. Such infants develop in a hyperglycemic environment, which produces reactive hyperinsulinemia. The normal increase in beta-globin production from pre-switch levels did not occur in 9 of 10 such infants at term, as compared with 11 normal infants, in whom the switch occurred by 36 to 39 weeks of gestation (P less than 0.0001). The delay in the switch from gamma-globin to beta-globin in this unique clinical setting may allow identification of physiologic factors that can modulate developmental gene suppression.
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PMID:Delay in the fetal globin switch in infants of diabetic mothers. 257 9

The effect of 5-azacytidine on erythroid precursors and progenitors was studied in nine patients with sickle cell anemia or severe thalassemia. Each patient received the drug intravenously for 5 or 7 d. 5-Azacytidine caused a four- to sixfold increase in gamma-messenger RNA concentration in bone marrow cells of eight of the nine patients and decreased the methylation frequency of a specific cytosine residue in the gamma-globin gene promoter in all nine patients. Within 2 d of the start of drug treatment there was a rise in the percentage of reticulocytes containing fetal hemoglobin (HbF; F-reticulocytes) without a significant change in the total number of reticulocytes, which suggested that there was a direct action of 5-azacytidine on erythroid precursors. Late erythroid progenitors (CFU-E), present in bone marrow after 2 d of drug administration, formed colonies containing an increased amount of HbF as compared with control colonies. Moreover, the number of CFU-E derived colonies was not decreased at these early times, which suggested that there was a direct action of 5-azacytidine on erythroid progenitors in the absence of cytotoxicity. Exposure of normal bone marrow cells in tissue culture to 5-azacytidine for 24 h reproduced both of these effects as judged during subsequent colony formation. The combined direct effects of 5-azacytidine on both the erythroid precursor and progenitor compartments resulted in an increase in HbF synthesis that was sustained for 2-3 wk. Toxicity to bone marrow as reflected by cytoreduction was evident after treatment in some patients but was not accompanied by an increase in HbF production. A correlation was found between the effects of 5-azacytidine on bone marrow, as assessed by in vitro measurements, and the hematological response of the individual patients to drug treatment.
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PMID:5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. 257

We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozygotes, and the Senegal haplotype in sickle cell anemia patients are all linked to high G gamma-globin expression. In addition, haplotypes IX and Senegal, but not haplotype III, have high Hb F levels. All of these haplotype have a common subhaplotype (+- ) in the gamma-globin gene region. In addition, haplotypes IX, III, and Senegalese sickle cell anemia patients exhibit hematological amelioration of their disease. Conversely, haplotypes I, V, and A in thalassemia patients, which also have a common subhaplotype (-----), and the Benin subhaplotype (--++-) in sickle cell anemia patients are all associated with low G gamma-globin and low Hb F levels. Low G gamma-globin expression in the adult is associated with two haplotypes that are not common between thalassemia and sickle cell anemia patients. We conclude that the determinant for high G gamma-globin expression is haplotype-linked to common and genetically dominant subhaplotypes in the two diseases. The total Hb F level, unlike the high G gamma-globin expression, however, is linked to haplotypes but not to subhaplotypes, thus dissociating the two genetic effects.
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PMID:Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. 258 Mar 6

Globin gene mapping analyses of DNA from numerous Black babies, and from newborns from Sardinia, Sicily, Turkey, and Spain have identified the following: A high incidence of alpha-thalassemia-2 heterozygotes among Black babies with less than 1% Hb Bart's at birth and a high incidence of alpha-thalassemia-2 among Sardinians, but not among Sicilian, Turkish, and Spanish babies. A relatively high incidence of zeta-thalassemia was present among Black babies only, while triplicated zeta was seen in four of the five populations. Two Black babies were each found to have a different theta 1 deletion; two Sardinian babies had a newly discovered approximately 2.5 kb deletion between zeta and psi zeta; four babies had the rare Bgl II polymorphism between psi zeta and psi alpha; and one Black baby lacked the Eco RI site 3' to zeta. Quantitation of the zeta chain by reversed phase high performance liquid chromatography showed that two-thirds of the babies with four alpha genes (alpha alpha/alpha alpha) had levels between 0.1 and 1.0%, while nearly 90% of the babies with -alpha/alpha alpha had similar levels (averaging 0.2% for alpha alpha/alpha alpha; 0.35% for -alpha/alpha alpha; 0.75% for -alpha/-alpha). Additional data indicated that the occurrence and level of zeta are related to the level of beta, i.e. the gestational age. The presence of a zeta triplication did not affect the level of zeta in cord blood. The extensive search for gamma-globin gene anomalies resulted in the discovery of a chromosome with five gamma genes. gamma-Thalassemia was rare in all populations, while the -G gamma-G gamma- gene arrangement was mainly observed among Black babies; this arrangement is primarily responsible for high G gamma levels in cord blood samples. The strong correlation between the presence or absence of a C----T mutation at position -158 (measured in Xmn I digests) and the level of G gamma was confirmed for adult blood samples. A search for possible anomalies in the -delta-beta- region through gene mapping with Eco RV gave negative results except for the discovery of a polymorphic site 5' to delta in one of the 371 Black babies tested.
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PMID:A search for anomalies in the zeta, alpha, beta, and gamma globin gene arrangements in normal black, Italian, Turkish, and Spanish newborns. 270 65

Clinical, hematologic and hemoglobin composition data on the first case of Hb 0-Arab in association with beta 0-thalassemia in Yugoslavia are reported here. The propositus was a 26-years-old female from Strumica who was admitted to the hospital for several times because of anemia, hepatosplenomegaly, occasional abdominal pains, malaise and fatigue. Laboratory results presented: Hb 10.0 g/dl, RBC 3.84.10(12)/L, PCV 0.260 l/l, MCV 68 fl, MCH 26 pg, reticulocyte count 1.8%, anisopoikilocytosis, polychromasis, numerous target cells, total bilirubin 2.1 mg/dl, (indirect 1.7 mg/dl), serum-Fe 32.3 microM/L. A starch gel electrophoresis of hemolysate provided evidence for the presence of abnormal hemoglobin (approximately 85%) and Hb F (approximately 15%); the Hb A was absent. Familial screening showed her father was heterozygous for the abnormal hemoglobin, whereas the mother was heterozygous for beta-thalassemia. In vitro biosynthesis disclosed a total absence of beta globin and reduced synthesis of beta x x and gamma globin. The alpha/beta x + gamma-globin ratio was 1.77 (normal, 1.0 + 0.1). Amino acid analysis revealed that lysine substituted for glutamic acid at the position one hundred twenty-one of the beta chain (= Hb 0-Arab or beta 121 Glu----Lys).
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PMID:[Hemoglobin O Arab in interaction with beta 0-thalassemia]. 273 98

Detailed hematological and fetal hemoglobin data as well as results from gene mapping analyses are reported for nine members of an Indonesian-Dutch family. An alpha-thalassemia-1 heterozygosity (Southeast Asian type) was present in five subjects and a gamma-globin gene triplication of the type-G gamma-G gamma-A gamma in three; the propositus and one of her daughters had both conditions. Comparison of gene mapping data with quantitative results of the fetal hemoglobin analyses provided an explanation for the slight increases in fetal hemoglobin levels and for the extremely high G gamma levels of this fetal hemoglobin.
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PMID:An Indonesian family with the Southeast Asian type of alpha-thalassemia-1 and a gamma-globin gene triplication. 282 24

The synthesis of globin proteins in blood reticulocytes of homozygous beta-thalassemic patients from Tadzhikistan has been previously studied. beta-thalassemia with sharp repression of beta-globin protein synthesis (alpha/beta greater than 10) has been shown to be most representative for the region. In this work, the synthesis of globin proteins has been studied in bone marrow cells of homozygous beta-thalassemic patients. Comparison of data on globin synthesis in bone marrow cells and in blood reticulocytes of the patients has revealed that in some cases the disbalance of chain synthesis in both cell types is equal. In other cases the disbalance in bone marrow cells is less than in blood cells, indicating the instability of beta-globin mRNA that is partially degrading in the process of cell maturation. Homozygous beta-thalassemic cases with low content of Hb F in blood cells (5-10%), with substantial disbalance of alpha and beta-globin synthesis and marked production of gamma-globins in bone marrow cells and in blood reticulocytes are of special interest. It has been assumed that parallel to beta-thalassemia some instability of gamma-globin proteins takes place in these patients.
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PMID:[Heterogeneity of globin protein synthesis in bone marrow cells of patients with homozygous beta-thalassemia from Tadzhikistan]. 297 80

High molecular weight DNA from a Japanese individual homozygous for delta beta-thalassemia was analyzed by the blot hybridization technique of Southern. Results indicated a large deletion of the non-alpha-globin gene cluster, starting in the vicinity of 3' to the A gamma-globin gene and extending through the 3' side of the beta-globin gene. Persistent expression of the gamma-globin gene in adult life has been supposed to be caused by loss of a region located about 3-4 kb 5' to the delta-globin gene from comparison of the extents of deletions in several different forms of delta beta-thalassemia and HPFH (hereditary persistence of fetal hemoglobin). But the novel deletion found in the present case of delta beta-thalassemia suggests that the above putative regulatory region does not have this effect on expression of the gamma-globin gene. Some explanations of expression of fetal type globin genes in this delta beta-thalassemia are discussed.
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PMID:A novel deletion in delta beta-thalassemia found in Japan. 298 69

We describe an English family with an atypical gamma delta beta-thalassemia syndrome. Heterozygosity results in a beta-thalassemia phenotype with normal hemoglobin A2. However, unlike previously described cases, no history of neonatal hemolytic anemia requiring blood transfusion was obtained. Gene mapping showed a deletion that extended from the third exon of the G gamma-globin gene upstream for approximately 100 kilobases (kb). The A gamma-globin, psi beta-, delta-, and beta-globin genes in cis remained intact. The malfunction of the beta-globin gene on a chromosome in which the deletion is located 25 kb away suggests that chromatin structure and conformation are important for globin gene expression.
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PMID:A distant gene deletion affects beta-globin gene function in an atypical gamma delta beta-thalassemia. 299 83


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