Disease relevance of beta-Thalassemia

• The increase in fetal-hemoglobin synthesis in patients with beta-thalassemia or sickle-cell anemia induced by 5-azacytidine has been attributed to hypomethylation of DNA in the region of the gamma-globin genes [1].
• Genotypic and phenotypic analyses following SFHR have shown specific modification of disease-causing genetic loci associated with cystic fibrosis, beta-thalassemia, and Duchenne muscular dystrophy, suggesting that SFHR has potential as a therapeutic modality for the treatment of monogenic inherited disease [2].
• Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia [3].
• The risk for HCC also is increased among patients with African iron overload and possibly in other iron-loading disorders such as homozygous beta thalassemia [4].
• The overexpression of individual SR proteins in HeLa cells affected the choice of alternative 5' splice sites of adenovirus E1A and/or human beta-thalassemia reporters [5].

Psychiatry related information on beta-Thalassemia

• BACKGROUND: Apolipoprotein (APOE) epsilon4 allele has been associated with cardiac dysfunction in Alzheimer's disease and beta-thalassemia [6].

High impact information on beta-Thalassemia

• A similar role for SPF45 is demonstrated in the activation of a cryptic 3' ss generated by a mutation that causes human beta-thalassemia [7].
• Successful use of hydroxyurea in beta-thalassemia major [8].
• Ten weeks of intravenous arginine butyrate did not produce a hematologic response in 10 patients with either severe beta-thalassemia or sickle cell disease [9].
• Brief report: treatment with azacitidine of patients with end-stage beta-thalassemia [10].
• Analysis of beta-thalassemia splicing mutations revealed that lariat formation in the first intron of the human beta-globin gene occurs at the same site in normal and mutant precursors, even though alternate 5' and 3' splice sites are utilized in the mutants [11].

Chemical compound and disease context of beta-Thalassemia

• Vitamin E therapy in homozygous beta-thalassemia [12].
• Remarkably, cleavage at the 5' splice site and lariat formation do not occur when the precursor contains a beta-thalassemia deletion removing the polypyrimidine stretch and AG dinucleotide at the 3' splice site [11].
• Two missense mutations in the beta-globin gene can cause severe beta thalassemia. Hemoglobin Medicine Lake (beta 32[B14]leucine-->glutamine; 98 [FG5] valine-->methionine) [13].
• A gamma Sardinian-(isoleucine-75 leads to threonine) is found in Spanish patients and accounts for all of the A gamma production in heterozygotes, indicating that persistent production of gamma chains occurs cis to the delta beta-thalassemia gene [14].
• Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease [15].

Biological context of beta-Thalassemia

• The reduced beta-globin synthesis characterizing the beta+ thalassemia phenotype has been shown to be caused by anomalous processing within the small intervening sequence (IVS1) of the beta-globin mRNA precursor [16].
• The feasibility of this method for localizing base substitutions directly in genomic DNA samples is demonstrated by the detection of single base mutations in DNA obtained from individuals with beta-thalassemia, a genetic disorder in beta-globin gene expression [17].
• Finally, loss of AHSP worsened the phenotype of beta-thalassemia, a common inherited anemia characterized by excess free alpha-Hb [18].
• A distant gene deletion affects beta-globin gene function in an atypical gamma delta beta-thalassemia [19].
• As the compound HPFH/beta-thalassemia heterozygote synthesizes HbA, these data prove that the HPFH beta-globin gene is functional, although at a decreased rate; its lower activity is likely to be due to a distant mutation [20].

Anatomical context of beta-Thalassemia

• A murine beta-thalassemia was corrected by the transfer of cloned beta-globin genes into the mouse germ line [21].
• Selective erythroid replacement in murine beta-thalassemia using fetal hematopoietic stem cells [22].
• Left ventricular inflow and pulmonary vein flow patterns were assessed by Doppler echocardiography in 88 beta-thalassemia major patients with normal left ventricular systolic function; 34 were young (age, 15.1 +/- 3.2 years) and 54 were adults (age, 25.1 +/- 3.6 years) [23].
• Erythrocyte survival, fecal stercobilinogen, and the alpha/beta-chain synthesis ratio in recticulocytes and bone marrow (six cases only) were determined and related to the hemoglobin levels in ten heterozygous carriers of beta-thalassemia with different degrees of anemia [24].
• We found that treatment of normal RBCs with phenylhydrazine produced rigid and mechanically unstable membranes in conjunction with selective association of oxidized alpha-globin chains with the membrane skeleton, features characteristic of RBCs in severe beta-thalassemia [25].

Gene context of beta-Thalassemia

• This is also the first example of beta-thalassemia in humans caused by a mutation in an erythroid transcription factor [26].
• To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with beta-thalassemia major undergoing BMT [27].
• Using this design, in a single diagnostic assay, we tested samples for 66 cystic fibrosis (CF) mutations, 14 beta-thalassemia mutations, two sickle cell anemia (SCA) mutations, three Tay-Sachs mutations, eight Gaucher mutations, four mutations in Canavan disease, four mutations in Fanconi anemia, and five mutations in BRCA1 [28].
• A 3.7-kilobase pair deletion including the entire beta major globin gene results in beta-thalassemia in a murine model of the disease (Skow, L. C., Burkhart, B. A., Johnson, F. M., Popp, R. A., Popp, D. M., Goldberg, S. Z., Anderson, W. F., Barnett, L. B., and Lewis, S. E. (1983) Cell 34, 1043-1052) [29].
• Compensatory increase in levels of beta minor globin in murine beta-thalassemia is under translational control [29].

Analytical, diagnostic and therapeutic context of beta-Thalassemia

• To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate [30].
• DNA at the end point of the gene deletion associated with one form of hereditary persistence of fetal hemoglobin (HPFH) was cloned and used as a probe in gene mapping experiments to analyze the extent and approximate 3' end points of various deletions associated with HPFH and delta beta-thalassemia [31].
• We have used the techniques of pulsed-field gel electrophoresis and polymerase chain reaction to study a patient with a clinical gamma delta beta-thalassemia phenotype [32].
• This new generation of globin retroviral vectors may prove useful for gene therapy of human beta-globin gene disorders such as sickle cell disease and beta-thalassemia [33].
• Extensive restriction endonuclease mapping defined the 5' breakpoint within the IVS II of the delta-globin gene, between positions 775 to 781 very similar to the 5' breakpoint of the Sicilian delta beta-thalassemia [34].

References