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 mechanism for elevated production of fetal hemoglobin (Hb F) in a Druze patient with beta zero-thalassemia intermedia was investigated. Heterozygous family members exhibited normal Hb F levels, suggesting that the increase in gamma-gene expression in the propositus may be partly due to anemic stress. Erythroid progenitors of these family members cultured in vitro [burst forming units (erythroid); (BFUe)] showed elevated synthesis of Hb F, indicating the existence of a genetically determined intrinsic capacity for high Hb F production in this family. The propositus was found to be homozygous for a IVS2-position 1 mutation, on the background of Mediterranean haplotype I, which is not known to be linked to high Hb F production. Moreover, extensive molecular studies of the beta-globin gene cluster, including sequence analysis of the promoter regions of the gamma-globin genes, did not reveal any cis- actin mechanism that could account for the high Hb F production in the propositus. A young niece of the propositus with beta zero-thalassemia major was recently discovered, who was homozygous for the same beta-globin allele and haplotype as the propositus. However, unlike her uncle, she does not have a high Hb F level and presents with a severe clinical course. Her inability to produce high Hb F suggests that the genetic determinant for increased gamma-gene expression in the propositus is unlinked to the beta-globin gene cluster.
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PMID:Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant. 170 3

We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3' end of the A gamma-gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.
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PMID:Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant. 170 67

The developmental switch from production of fetal (gamma) to adult (beta) globin occurs on a normally set biologic clock which proceeds even if expression of the adult (beta) globin genes is defective and produces little or no protein, as in the beta-thalassemias. Preventing or reversing the globin gene switch could provide a way of keeping the abnormal globin genes "silent" and maintaining expression of the fetal globin gene. We have identified a class of agents which, when present in elevated plasma concentrations during gestation, inhibits the gamma----beta-globin gene switch in developing humans. Further investigation has shown that butyric acid and related compounds can increase gamma-globin and decrease beta-globin expression in cultured erythroid cells of patients with beta-thalassemia. Butyrate compounds were therefore infused in an in vivo fetal animal model, and the globin switch was inhibited and even reversed in some fetal lambs. Histone hyperacetylation, which maintains active chromatin structure, and an effect on the gamma-globin promoter appear to be mechanisms of action involved. These data suggest that inhibiting expression of abnormal beta-globin genes by pharmacologic means may in the future be possible for treatment of individuals with beta-globin disorders.
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PMID:Stopping the biologic clock for globin gene switching. 170 5

We have identified a new stable abnormal hemoglobin called Hb Valletta, which is characterized by a Thr----Pro substitution at position 87 of the beta chain. This mutation was found to be linked to that of the gamma chain variant Hb F-Malta-I with a His----Arg mutation at position 117 of the G gamma chain. Both variants were detected in the blood samples of 34 Maltese and two Italian newborn babies with isoelectrofocusing and reversed phase high performance liquid chromatography. Similar analyses of cord blood from 388 additional Maltese newborns failed to identify either one of these two variants. Additional analyses of 353 Maltese adults (including 39 beta-thalassemia heterozygotes) resulted in the detection of two adult Hb Valletta heterozygotes. Dot-blot hybridization analyses of amplified DNA with a probe specific for the G gamma-F-Malta-I variant showed that both also carried that mutation. These results show close linkage of the mutant forms of the G gamma- and beta-globin genes, 27-28 kb apart, and a failure to identify chromosomes with either the Hb F-Malta-I mutation alone or with the Hb Valletta mutation alone, indicating a low recombination frequency.
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PMID:The linkage of Hb Valletta [alpha 2 beta 287(f3)Thr----Pro] and Hb F-Malta-I [alpha 2G gamma 2117(G19)His----Arg] in the Maltese population. 170 34

The murine mutation dominant white spotting (W) is in the proto-oncogene, c-kit. The receptor tyrosine kinase encoded by this gene has pleiotropic effects on murine development including hemopoietic cells, pigment cells, and germ cells. In this study, mutation in W homozygous mouse was identified as a single base substitution (GT----AT) at the 5'-splice donor site of the exon which encodes the transmembrane domain. Two types of aberrant exon skipping resulted from this mutation, occurred in a tissue specific manner. Either transcript lost the exon coding for transmembrane region and therefore the product might not be functional for signal transduction. Any unusual cryptic splice sites were not activated by this mutation as beta-globin gene in beta-thalassaemia. In addition, twelve base pair sequence of the 3'-end of the exon prior to the exon coding for transmembrane domain was found to be alternatively spliced. These findings should provide the genetic base for not only the receptor function but the splicing mechanism.
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PMID:Exon skipping by mutation of an authentic splice site of c-kit gene in W/W mouse. 170 86

In Sardinia, the beta-39 nonsense mutation is the primary cause of beta 0-thalassaemia. This mutation is found mainly on beta-globin gene cluster haplotypes I and II, which differ in their A gamma globin types (A gamma I and A gamma T, respectively). This report presents data on G gamma, A gamma I and A gamma T levels, and the presence or absence of a 4 base pair (bp) deletion at -225 to -222 of the A gamma globin promoter, in 55 poly-transfused beta 0-thalassaemia major patients. Six patients were homozygotes for the normal (N) A gamma promoter lacking the 4 bp deletion, had no A gamma T globin, and their mean G gamma:A gamma I: A gamma T ratio was 52.9:47.1:0. Twenty-five patients were homozygotes for the mutant (M) A gamma promoter with the 4 bp deletion, had no A gamma I globin, and the mean G gamma:A gamma I: A gamma T ratio was 62.1:0:37.9. For M/M compared to N/N, the lower A gamma T than A gamma I was significant by the t-test (P less than 0.001). Twenty-four N/M cases had mean G gamma:A gamma I:A gamma T of 56:24.4:19.6, and the lower A gamma T than A gamma I was also significant (P less than 0.001). Partial haplotype analysis on these and 17 other beta 0-thalassaemia patients suggested that the 4 bp deletion was strongly associated with haplotype II. Of 33 M/M, 32 were haplotype II/II and one was II/5a; of 31 N/M, 29 were I/II and two were II/IX; of eight N/N, seven were haplotype I/I and one was I/IX. These data show a strong association of the 4 bp promoter deletion with decreased expression of the A gamma T globin gene on haplotype II.
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PMID:Diminished A gamma T fetal globin levels in Sardinian haplotype II beta 0-thalassaemia patients are associated with a four base pair deletion in the A gamma T promoter. 171 Apr 78

We report a relatively mild phenotype associated with two siblings who are compound heterozygotes for Hb S and a beta zero-thalassemia mutation due to a approximately 1.4-kb deletion of the 5' region of the beta-globin gene. Each is found to have unusually high levels of Hb A2 and Hb F, accounting for more than 20% of the total hemoglobin. These may interfere with intracellular Hb S polymerization, thus leading to a mild clinical course.
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PMID:Hb S/beta zero-thalassemia due to the approximately 1.4-kb deletion is associated with a relatively mild phenotype. 171 7

The Corfu delta beta thalassaemia mutation, a 7.2 kb deletion partially removing the delta-globin gene and a single nucleotide mutation (G----A) at intervening sequence I (IVSI-n5) in the beta-globin gene in cis, was first described in a family from Corfu; the carriers for this mutation had the unusual haematological phenotype of heterozygous beta-thalassaemia with normal levels of HbA2. To investigate the frequency and haematological characteristics of Corfu delta beta thalassaemia in Greece we analysed 25 unrelated normal HbA2 type 2 beta-thalassaemia heterozygotes and their 23 clinically affected offspring. Gene mapping demonstrated that nine (36%) of the 25 normal HbA2 beta-thalassaemia heterozygotes were in fact Corfu delta beta thalassaemia heterozygotes and of the 23 patients, two were Corfu delta beta thalassaemia homozygotes and five compound heterozygotes for Corfu delta beta thalassaemia and another beta-thalassaemia defect. Detailed haematological analysis demonstrated that: the Corfu delta beta thalassaemia mutation does not completely abolish the expression of the beta-globin gene; the HbA2 levels are slightly lower (P less than 0.01) and the HbF levels slightly higher (P less than 0.01) in Corfu delta beta thalassaemia heterozygotes compared to beta-thalassaemia heterozygotes with the normal HbA2-type 2 phenotype who do not have the Corfu delta beta chromosome.
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PMID:The Corfu delta beta thalassaemia mutation in Greece: haematological phenotype and prevalence. 172 Mar 25

We investigated the molecular bases for a mild phenotype by alpha-, beta- and gamma-globin gene analyses in 22 patients with transfusion-independent thalassemia intermedia (15) or a late-presenting form of thalassemia major (7) originating from Puglia, a region of southern Italy. Twenty-two patients with thalassemia major served as controls. The beta+ IVS-I nt 6 of the beta-globin gene and the C----T substitution at position -158 5' of the G gamma-globin gene were detected more frequently in patients with thalassemia intermedia or late-presenting thalassemia major considered together as compared to those affected by typical transfusion-dependent thalassemia major. Three of 15 patients with thalassemia intermedia had the triple alpha-globin gene arrangement in the heterozygous (2) or homozygous state (1) in association with heterozygous beta zero-thalassemia. From these results, we may conclude that the inheritance of a mild beta-thalassemia allele such as the beta+ IVS-I nt 6 mutation, in the homozygous or heterozygous state, the coinheritance with homozygous beta zero-thalassemia of the -158 (C----T) G gamma gene promoter mutation and the presence of heterozygous beta-thalassemia/triple alpha-globin gene arrangement are the most common reasons accounting for the development of attenuated forms of beta-thalassemia in Puglia.
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PMID:Molecular basis of beta-thalassemia intermedia in a southern Italian region (Puglia). 172 29

The aim of the present work was to understand the pathophysiology of the severe human thalassemias as represented by beta-thalassemia intermedia and hemoglobin (Hb) H (alpha-thalassemia) disease. We have previously shown that the material properties of the red blood cell (RBC) and its membrane differ in severe alpha- and beta-thalassemia, and we now show that this difference is probably caused by accumulation of alpha-globin chains at the cytoskeleton in beta-thalassemia, whereas beta-globin chains are associated with the cytoskeleton in alpha-thalassemia. In both alpha- and beta-thalassemia, some of these globin chains have become oxidized as evidenced by loss of the free thiols. Furthermore, there is similar evidence of oxidation of protein 4.1 in beta-thalassemia, whereas beta-spectrin appears to be subject to oxidation in alpha-thalassemia. These observations support the idea that the association of partly oxidized globin chains with the cytoskeleton results in oxidation of adjacent skeletal proteins. The abnormality of protein 4.1 in beta-thalassemia is consistent with a prior observation, and is also in accord with the known importance of protein 4.1 in maintenance of membrane stability, a property that is abnormal in beta-thalassemic membranes.
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PMID:Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia. 173 89


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