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 strategy for early prenatal diagnosis of beta-thalassemia in Singapore by direct detection of the mutant beta-globin gene requires the spectrum of mutations producing the disorder in this population to be characterized. We analyzed 134 beta-thalassemia alleles from Singapore by specific oligonucleotide hybridization after DNA amplification, using a nonradioactive enhanced chemiluminescence detection system. The mutations were identified in 90% of the alleles using five oligonucleotide probes for the following mutations: codons 41/42 (deletion-TCTT), IVS II nt 654 (C-->T), codon 17 (A-->T), IVS I nt 5 (G-->C), and -28 TATA box (A-->G). Together with the strategy of direct sequencing, a total of 97% of the mutations were identified. In the Chinese subpopulation, 97% of the mutations were detected by the oligonucleotide probes. Using just four oligonucleotide probes would identify 96% of the mutations, and 76% of the mutations were accounted for by codon 41/42 (-TCTT) and IVS II nt 654 (C-->T) mutations. Thus in this subpopulation early prenatal diagnosis would be possible in virtually all the affected families.
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PMID:Beta-thalassemia mutations in Singapore--a strategy for prenatal diagnosis. 792 34

To characterize mutations rapidly in 43 patients with beta-thalassemia major in Taiwan, we utilized a method of natural and amplified created restriction site (ACRS) analysis for detection of beta-globin gene mutation. After analysis, eight different point mutations were found among 86 known chromosomes. IVS-2 nt 654 (C-->T), accounting for 40 of the 86 mutations with mutant beta-globin genes, is the most common mutation, followed by frameshift codons 41/42 (-TCTT) in 28 mutations, -28 mutation (A-->G) in 7 mutations, nonsense codon 17 (A-->T) in 5 mutations, frameshift codons 27/28 (insertion of C) in 2 mutations, IVS-1 nt 1 (G-->T) in 2 mutations, frameshift codons 71/72 (insertion of A) in 1 mutation, and IVS-1 3' end TAG-->GAG in 1 mutation. The first four mutations account for 80 of all 86 mutations of beta-thalassemia major in Taiwan. Furthermore, the beta-globin gene mutation was identified successfully in one chorionic villi biopsy for prenatal diagnosis and in specimen of blood from one patient who had received bone marrow transplantation (BMT). Complete diagnosis is possible in all of the Chinese families with beta-thalassemia in Taiwan, and the first trimester prenatal diagnosis can be achieved simply by using only 13 oligonucleotide primers and 10 restriction endonucleases. This non-radioactive assay was shown to be a rapid, sensitive, precise and safe method in detecting the mutations of beta-thalassemia in Taiwan.
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PMID:Prenatal and molecular diagnosis of beta-thalassemia major in Taiwan by naturally and amplified created restriction sites. 816 31

We studied 41 patients with beta-thalassaemia major and their parents by using a combination of polymerase chain reaction (PCR) amplification, slot-blot hybridization of allele-specific oligonucleotide (ASO), and direct genomic sequencing. Eight different point mutations were characterized. C to T substitution at nucleotide (nt) 654 of intervening sequences (IVS) 2, accounting for 46.3% of mutant beta-globin genes, is the most common mutation in Taiwan, followed by frameshift codons 41/42 with four nucleotides (TCTT) deletion for 31.7%, A to G substitution at position -28 of promotor area for 8.5%, A to T substitution at codon 17 for 6.1%, frameshift codons 27/28 (insertion of C) for 2.4%, G to T substitution at nucleotide 1 of IVS-1 for 2.4%, frameshift codons 71/72 (insertion of A) and IVS-1 3 end TAG-->GAG for 1.2%. The former four mutations showed no obvious difference between two major ethnic groups in Taiwan. As to mutations in each individual of beta-thalassaemia major, the incidence of compound heterozygotes of two different mutations is much higher than homozygotes of single mutation, 78.0% v 22.0%. Compound heterozygotes of C to T substitution at nt 654 of IVS-2 and frameshift codons 41/42 with four nucleotides deletion is the most common pattern of beta-thalassaemia mutations in each individual (41.5%). The results are somewhat different from other documented reports concerning the mutations of beta-thalassaemia in southern China. This is the first report of mutation of IVS-1 3' end TAG-->GAG which causes consensus change in Chinese people. Patients with heterozygotes of beta zero and -28 beta(+)-thalassaemia mutations would have a greater delay in initial transfusion in comparison to patients with homozygotes of both beta zero-thalassaemia mutation, but their initial clinical manifestation might be aggravated when combined with a glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and an insult such as exposure to infection and certain drugs.
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PMID:Molecular basis and haematological characterization of beta-thalassaemia major in Taiwan, with a mutation of IVS-1 3' end TAG-->GAG in a Chinese patient. 843 18

Genetic diagnosis of a family of beta-thalassemia (beta 90 GAG-->TAG) was carried out by allele-specific polymerase chain reaction (AS-PCR). The proband, her daughter and granddaughter were proved to be heterozygotes of normal and mutant alleles. As some nonsense mutations express a decreased amount of MrNAs, we determined the expression level of the mutant mRNA of beta-thalassemia (beta 90 GAG-->TAG), by application of a combination method of reverse transcription PCR (RT-PCR) and dot-blot hybridization with allele-specific oligonucleotides. The mutant mRNA was not markedly reduced. In conclusion, 1) individuals with the mutant beta-globin gene were diagnosed successfully by AS-PCR, and 2) a significant amount of the mutant beta-globin mRNA was synthesized.
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PMID:Beta-thalassemia (beta 90 GAG-->TAG): genetic diagnosis by allele-specific polymerase chain reaction and estimation of mutant mRNA expression by reverse transcription polymerase chain reaction. 883 97

A rare beta-thalassemia mutation at the splicing junction [namely, G-->C in intervening sequence (IVS) I-1] was found in a Japanese family. The proband and his mother were heterozygous for the mutation. Analysis of mRNA extracted from the reticulocyte-rich fraction obtained from the proband's mother revealed that the mutant beta-globin gene did not produce any detectable, stable mRNA including exon 1 and exon 2, since the polymorphism in exon 1 on her mutant gene was not detected in the RT-PCR products.
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PMID:Novel beta-thalassemia trait (IVS I-1 G-->C) in a Japanese family. 1250 70

The correction of mutant beta-globin genes has long been a therapeutic goal for patients with beta-thalassemia or hemoglobinopathies. The use of homologous recombination (HR) to achieve this goal is an attractive approach because it eliminates the need to include regulatory sequences in the therapeutic construct, and it eliminates mutagenesis induced by random integration. However, HR is a very inefficient process for gene correction, and its efficiency is probably locus dependent. The length of targeting arms is thought to be a determinant of targeting efficiency, so we compared the ability of standard (8-kb) versus very long (16-, 24-, and 110-kb) regions of homology to correct a mutant murine beta-globin gene in embryonic stem cells. Increasing the length of the targeting sequences did not increase the efficiency of HR in this locus, suggesting that alternative approaches will be required to improve the efficiency of this approach for globin gene correction.
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PMID:Long targeting arms do not increase the efficiency of homologous recombination in the beta-globin locus of murine embryonic stem cells. 1273 Jan 7

Hemoglobinopathies represent the most common genetic disorder worldwide, with a higher prevalence among populations with a history of malaria endemicity. More than 690 mutations in the human beta-globin gene are usually the cause of beta-type hemoglobinopathies. Here, we report a rapid and highly sensitive beta-globin gene mutation screening approach based on denaturing high-performance liquid chromatography (DHPLC), which contrary to the previously described ones can be used in every HPLC apparatus. The sensitivity and specificity of the method were tested in 120 healthy Greek subjects and 25 beta-thalassemia heterozygotes and homozygotes, in which 11 different beta-globin sequence variations had been previously characterized by denaturing gradient gel electrophoresis. Using this method, we were able to rapidly identify the commonest beta-globin gene mutations, accounting for more than 90% of the mutant beta-globin alleles reported for the Hellenic population. Compared to classical mutation screening approaches, our DHPLC approach provides the means for rapid, highly sensitive, cost-effective, and semi-automated simultaneous mutational scanning of a large number of samples.
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PMID:A versatile denaturing HPLC approach for human beta-globin gene mutation screening. 1692 51

Peptide nucleic acid (PNA) is highly stable and binds to complementary RNA and DNA with high affinity, but it resists cellular uptake, thereby limiting its bioavailability. We investigated whether protectiveantigen (PA, a non-toxic component of anthrax toxin) could transport antisense PNA oligomers into reporter cells that contain luciferase transgenes with mutant beta-globin IVS2 intronic inserts, which permit aberrant pre-mRNA splicing and impair luciferase expression. PNA oligomers antisense to mutant splice sites in these IVS2 inserts induced luciferase expression when effectively delivered into the cells. PNA 18-mers with C-terminal poly-lysine tails [PNA(Lys)(8)] demonstrated modest sequence-specific antisense activity by themselves at micromolar concentrations in luc-IVS2 reporter cell cultures. However, this activity was greatly amplified by PA. Antisense PNA(Lys)(8) with but not without PA also corrected the IVS2-654 beta-globin splice defect in cultured erythroid precursor cells from a patient with beta-thalassemia [genotype, IVS2-654(beta(0)/beta(E))], providing further evidence that anthrax PA can effectively transport antisense PNA oligomers into cells.
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PMID:Effective delivery of antisense peptide nucleic acid oligomers into cells by anthrax protective antigen. 1877 71

The beta-thalassemias and sickle cell anemia are severe congenital anemias for which there is presently no curative therapy other than allogeneic bone marrow transplantation. This therapeutic option, however, is not available to most patients due to the lack of an HLA-matched bone marrow donor. Emerging modalities based on cell engineering offer new prospects for potentially curative approaches that are applicable to more patients. The first is based on the transfer of a regulated globin gene in autologous hematopoietic stem cells (HSCs). This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid-specific, differentiation and stage-restricted, elevated, position-independent, and sustained over time. Following the original report by May et al., several groups have reported that lentiviral vectors encoding slightly different combinations of proximal and distal transcriptional control elements of the normal human beta-globin gene permit lineage-specific and elevated beta-globin expression in vivo, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Clinical studies utilizing the TNS.3 vector are likely to be initiated in the US in 2009. While the addition of the wild-type beta-globin gene is naturally suited for treating beta-thalassemia, several alternatives have been proposed for the treatment of sickle cell disease, using either gamma- or mutant beta-globin gene addition, trans-splicing or RNA interference. The recent discovery that adult somatic cells can be reprogrammed to become pluripotent stem cells from which HSCs can be derived, provides yet another venue for developing stem cell engineering using either lentiviral vectors or homologous recombination techniques. Altogether, these recent advances bode well for the advent of curative stem cell-based therapies.
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PMID:Stem cell engineering for the treatment of severe hemoglobinopathies. 1899 54


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