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)

Deletions in the DNA of individuals with hereditary persistence of fetal haemoglobin (HPFH) and 8 beta-thalassaemia have been mapped as a means of identifying regulatory sequences involved in the switch from fetal to adult globin gene expression. The end points of these deletions have been precisely located with respect to restriction endonuclease cleavage sites within and surrounding the gamma-, delta- and beta-globin genes in normal human DNA and the deletion maps were used to obtain definitive evidence for the physical linkage of the fetal and adult beta-like globin genes in the order 5'Ggamma-Agamma-delta-beta 3'. Correlation of haematological data and the location of deletions in two cases of HPFH and one case of deltabeta-thalassaemia suggest that a region of DNA located near the 5'-end of the delta-globin gene may be involved in the suppression in cis of gamma-globin gene expression in adults. The interpretation of a second case of deltabeta-thalassaemia is complicated by the fact that the deletion removes the Agamma-gene in addition to the region near the 5'-end of the delta-globin gene.
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PMID:Characterisation of deletions which affect the expression of fetal globin genes in man. 45 Jan 9

Study of Asians has previously indicated that deletion of alpha-globin structural genes is the predominant lesion in alpha-thalassemias and that Hb H disease occurs when three of four normal alpha loci per cell are deleted. To test the generality of this model, Hb H disease DNAs of both Asian and non-Asian origin were analyzed by restriction endonuclease mapping using the technique of Southern (1975). Whereas in normal DNA, alpha sequences are present in a single Eco Rl fragment of cellular DNA approximately 22.5 kb long, fragments of 22.5, 20 and 2.6 kb were found in various Hb H disease DNAs. The 20 kb Eco Rl fragment alone, in which a single alpha-globin structural locus resides, was found in Asian Hb H disease DNA. This finding is consistent with the deletion model of alpha-thalassemia. In contrast, seven of eight non-Asian Hb H disease DNAs displayed a more complex molecular composition. The fragment patterns observed were 22.5 kb alone, 22.5 plus 2.6 kb, 20 plus 2.6 kb and 20 kb alone. Non-Asian Hb H disease DNAs contained one, two or three alpha loci per cell in contrast to the one locus predicted by the simple deletion model of alpha-thalassemia. The data are best explained by the existence of defective alpha loci in certain individuals with alpha-thalassemia, particularly outside the Asian population. Restriction mapping of the 20 kb Eco Rl fragment found in Asian and some non-Asian Hb H disease DNAs demonstrated a striking similarity in the placement of restriction sites about the single alpha gene compared with sites about the two genes in the 22.5 kb Eco Rl fragment seen in normal DNA. These data are consistent with origin of the 20 kb fragment from the 22.5 kb normal Eco Rl fragment by either unequal crossing-over or a deletion event. The molecular heterogeneity and frequent occurrence of defective alpha loci in non-Asian Hb H disease DNAs described here may explain, in part, the clinical heterogeneity of alpha-thalassemias and the absence of the homozygous deletion state (hydrops fetalis) in non-Asians. Further study of cellular DNA fragments containing the defective alpha loci identified in this work may indicate the types of specific mutations responsible for abnormal globin gene expression and complement similar studies on abnormal beta genes in beta-thalassemias.
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PMID:The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease. 45 60

Twenty-one cases of beta 0 and beta +-thalassaemia have been analysed by restriction endonuclease mapping. In most cases no deletion in the regions surrounding the beta- and delta-globin genes could be detected. However, in a single Asian case of beta 0-thalassaemia, homozygous clinically, one of the homologous chromosomes contained a beta-globin gene with a deletion of 600 base pairs of DNA and comprising most or all of the 3' end of the structural gene including the EcoRI restriction site within the beta-globin coding sequence.
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PMID:The structure of the human beta-globin gene in beta-thalassaemia. 46 Dec 3

In an individual homozygous for G gamma-delta beta-thalassemia, a physical alteration in gamma-globin gene organization was detected by restriction enzyme mapping. The data indicated that the absence of A gamma-globin chains resulted from extension of the DNA deletion from the delta beta-globin gene region into the gamma-globin gene region rather than a functional disturbance of gamma-gene expression.
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PMID:Deletion of the A gamma-globin gene in G gamma-delta beta-thalassemia. 46 97

We have constructed a physical map of restriction endonuclease cleavage sites in the (delta (+) beta)-globin gene region in the DNA of patients with (delta beta(0))-thalassaemia. This map shows that a 10 kb deletion has occured in (delta beta (0))-thalassaemia to remove the entire beta-globin gene and the 3' portion of the delta-globin gene. The 5' terminus of the deletion is in the large intron of the delta-globin gene and the 3' terminus 1.8 kb to the 3'-side of the beta-globin gene. A similar deletion of about 7 kb has been described previously in the DNA of patients with Hb Lepore; the 5' terminus of the deletion is also in the delta-globin gene but the 3' terminus is in the beta-globin gene. Comparison of the foetal (gamma) globin gene expression in adults with (delta beta(0))-thalassaemia and Hba Lepore suggests that the 3' extragenic regions of the beta-globin gene contain DNA sequences involved in the regulation of gamma-globulin gene expression.
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PMID:Physical mapping of the globin gene deletion in (delta beta (0)) -thalassaemia. 47 2

The rarity of hemoglobin (Hb) H disease in combination with sickle trait may be due in part to the absence of actual Hb H in individuals who, nonetheless, have inherited the deletion of three alpha-globin genes. We describe here a boy with persistent microcytic, hypochromic anemia despite adequate iron stores, who exhibited splenomegaly with a normal reticulocyte count and only rare inclusions in circulating erythrocytes. Starch gel electrophoresis and isoelectric focusing at age 5 yr showed 21% Hb S, persistent Hb Bart's, but no Hb H. Recticulocyte alpha/non-alpha globin chain synthesis ratio was 0.58 at age 5. The mother (Asian) had laboratory evidence of alpha-thalassemia trait and the father (Black) had sickle trait. The nature of alpha-thalassemia in this patient was investigated both by liquid hybridization and by the Southern method of gene mapping, in which DNA is digested with restriction endonucleases and the DNA fragments that contained the alpha-globin structural gene identified by hybridization with complementary DNA. The patient had only one alpha-globin structural gene, located in a DNA fragment shorter than that found in normal or alpha-thalassemia trait individuals, but similar to that present in other patients with Hb H disease. Morphologic studies of bone marrow by light and electron microscopy revealed erythroid hyperplasia with inclusions in polychromatic and orthochromatic erythroblasts, suggesting early precipitation of an unstable hemoglobin. The lack of demonstrable Hb H may be the result of both diminished amounts of beta(A) available for Hb H formation (since one beta-globin gene is beta(S)) and the greater affinity of alpha-chains for beta(A) than beta(S)-globin chains leading to the formation of relatively more Hb A than Hb S. The presence of a beta(S) gene may thus modify the usual clinical expression of Hb H disease.
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PMID:Modification of hemoglobin H disease by sickle trait. 47 66

Two Chinese patients with HbQ-alpha 2 74 Asp replaced by His beta 2-alpha-thalassemia, one HbQ-alpha 2 74 or 75 Asp replaced by His beta 2 carrier, and one HbG-alpha 2 30 Glu replaced by Gln beta 2 carrier were studied to determine the number of alpha-globin genes in their chromosomes. DNA was isolated from white blood cells and bone marrow cells and studied by liquid hybridization and by hybridization of DNA fragments obtained by restriction enzyme endonuclease digestion (Ecr to nitrocellulose filters. The liquid hybridization analysis showed that in HbQ-alpha 2 74 Asp replaced by His beta 2-alpha-thalassemia, as in HbH disease, only one-fourth of the usual number of alpha-globin genes is present. Hybridization patterns of DNA restriction enzyme fragments showed that in HbQ-alpha 2 74 Asp replaced by His beta 2-alpha-thalassemia one chromosome has both alpha-globin genes deleted and the other chromosome, which carries the alpha-mutant gene, has one alpha-globin gene deleted. Our results show that the HbQ-alpha 74 Asp replaced by His structural gene is located adjacent to a deleted alpha-globin gene, whereas the alpha-globin gene adjacent to HbG-alpha 30 Glu replaced by Gln gene is not deleted.
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PMID:The alpha-globin gene adjacent to the gene for HbQ-alpha 74 Asp replaced by His is deleted, but not that adjacent to the gene for HbG-alpha 30 Glu replaced by Gln; three-fourths of the alpha-globin genes are deleted in HbQ-alpha-thalassemia. 50 45

We investigated the molecular basis of hemoglobin-H disease by hybridization and restriction endonuclease mapping of the DNA in the Mediterranean populations. Of the 12 patients studied from Cyprus and Sardinia, 8 had the typical deletion defect with a single remaining alpha-globin gene. The nondeletion type of alpha-thalassemia was found in 3, and a "dysfunctional" gene in one. We conclude that the predominant cause of alpha-thalassemia in these populations is gene deletion.
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PMID:Molecular basis of hemoglobin-H disease in the Mediterranean population. 50 46

We applied a recently developed and more direct technic to diagnose thalassemia syndromes associated with deletion of particular globin structural genes and to assess a fetus at risk for one of those conditions, deltabeta-thalassemia. The method allows assessment of the globin genes present in total cellular DNA and is applicable to amniotic-fluid cell DNA. Cellular DNA fragments produced by cleavage using two specific restriction endonucleases are separated on the basis of size by agarose-gel electrophoresis, and the distribution of specific sequences among the DNA fragments determined by molecular hybridization. We observed the total deletion of alpha-globin genes in homozygous alpha-thalassemia (hydrops fetalis with hemoglobin Bart's) and the deletion of particular beta and beta-like sequences in cases homozygous for hereditary persistence of fetal hemoglobin and deltabeta-thalassemia. Analysis of amniotic-fluid cell DNA from a fetus at risk for deltabeta-thalassemia demonstrated the feasibility of these improved methods for antenatal diagnosis. The molecular studies confirmed the diagnosis predicted by analysis of fetal blood and established at birth.
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PMID:Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion. 66 90

A number of cases of beta0 thalassemia have been examined for the presence or absence of beta-globin mRNA. Total RNA extracted from peripheral blood was hybridized to purified complementary DNA specific for beta-globin mRNA, and to beta-cDNA probes specific for the 5' and 3' noncoding regions of beta-globin mRNA. Three clear-cut categories of beta0 thalassemia were identified. The first type had no detectable beta-globin mRNA. A second typed had beta-globin mRNA sequences which hybridized incompletely to the cDNA probes and probably represented mRNAs with grossly altered structures. A third type appeared to have essentially intact, though untranslatable, beta-globin mRNA. Depurination products from 5' and 3' beta-cDNAs synthesized from this latter mRNA were identical to those from normal beta-globin mRNA, but the relative yields were different, suggesting a possible defect near the initiation codon.
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PMID:Characterization of beta-globin mRNA in the beta0 thalassemias. 66 41


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