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)

A method is described in which allele-specific oligonucleotides (ASO) are labeled non-enzymatically with digoxigenin (DIG). The ASOs were synthesized in a DNA synthesizer. A primary C6-alkylamine was incorporated at the 5'end of the ASO. The derivative was coupled to digoxigenin-3-0-methylcarbonyl-epsilon-aminocaproic acid-N-hydroxy-succinimide ester. The DIG-ASO probes were isolated from the crude preparation and hybridized with amplified genomic DNA. The annealed probes were detected with an ELISA test. The DIG-ASO probes were successfully used for the identification of sickle cell disease genotypes and the most common beta-thalassemia mutations.
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PMID:[Non-enzymatic marking of gene probes using digoxigenin for the diagnosis of sickle cell mutation and beta thalassemia]. 141 16

The Indian delta beta-thalassaemia, with elevated fetal gamma globin gene expression, was previously found to have a large deletion beginning 1 kb 3' of the (A) gamma globin gene at GenBank HUMHBB coordinate 42151, and extending into a new L1 sequence. We have now determined the 3' breakpoint of this deletion, and in doing so we have extended the known beta-globin gene cluster DNA sequence from its end at 73326 to projected GenBank coordinate 79016. These data show that the deletion is 32.6 kb long, terminating 11 kb 3' of the beta-globin gene. This 3' breakpoint is at 74772, within a 3.4 kb partial L1 repeat at 74263-77665; the Black ((A) gamma delta beta)(0)-thalassaemia also terminates in this L1, at 76508. In addition, two Alu sequences were found, at 73692-73816 and 78171-78441. Among the protein-binding DNA sequence motifs 3' to the Indian delta beta-thalassaemia breakpoint, at 76581/76607 there is a TGATAA/ACACCC pair that binds the erythroid-specific GATA-1 and ubiquitous CACCC-box binding proteins. We hypothesize that elevated fetal haemoglobin may be due to an enhancer or enhancers 3' to the deletion breakpoints and may involve the TGATAA/ACACCC pair.
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PMID:The 32.6 kb Indian delta beta-thalassaemia deletion ends in a 3.4 kb L1 element downstream of the beta-globin gene. 141 24

Characterization of unstable hemoglobins by protein analysis is often difficult. However, it is facilitated by DNA analysis, especially in the case of hyperunstable beta-chain variants, which produce a beta-thalassemia phenotype. We have applied an efficient strategy to the detection of such variants at the DNA level, based on computer-designed denaturing gradient gel electrophoresis (DGGE) of amplified DNA fragments. This approach makes it possible to detect any anomaly in the beta-globin gene. We describe the use of the DGGE method for rapid characterization of beta-chain variants and report a new missense mutation in the beta-globin gene third exon, beta 127 CAG-CGG/Gln-Arg, which is responsible for the synthesis of a highly unstable hemoglobin.
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PMID:Rapid molecular characterization of mutations leading to unstable hemoglobin beta-chain variants. 142 May 7

We have investigated the developmental and tissue specific expression of the human embryonic zeta-globin gene in transgenic mice. A construct containing 550 bp of zeta-globin 5' flanking region, fused to a beta-galactosidase (lacZ) reporter gene and linked to the locus control region (LCR)-like alpha positive regulatory element (alpha PRE) was employed for the production of transgenic mice. Firstly, we compared the number of live born transgenic mice containing this construct to the number of live born transgenic mice containing the entire zeta-globin gene linked to the alpha PRE or the beta LCR. Data showed that 12% of mice generated from eggs injected with zeta-promoter/lacZ/alpha PRE DNA were transgenic compared to only 2% of mice generated from eggs injected with the entire zeta-globin gene linked to the alpha PRE or the beta LCR. The reduced number of live born transgenic mice containing the latter constructs suggests that death of transgenic embryos, possibly due to thalassaemia, may be occurring. X-gal staining of whole embryos containing the lacZ gene revealed that zeta-globin promoter activity was most pronounced at 8.5-9.5 days of development and was restricted to erythroid cells. By 15 days of development, no zeta-globin promoter activity was detected. These results suggest that the alpha PRE can direct high level expression from the zeta-globin promoter and that sequences required for the correct tissue and developmental specific expression of the human zeta-globin gene are present within 550 bp's of 5' flanking region. Sequences within the body of the zeta-globin gene or 3' of the cap site do not appear to be necessary for correct zeta-globin developmental regulation.
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PMID:The developmental regulation of the human zeta-globin gene in transgenic mice employing beta-galactosidase as a reporter gene. 145 28

We have analyzed the hemoglobins of a young German patient with beta-thalassemia intermedia and of his immediate family and included in these studies an evaluation of possible nucleotide changes in the beta-globin genes through sequencing of amplified DNA. One chromosome of the propositus and one of his father's carried the GTG-->GGG mutation at codon 126 leading to the synthesis of Hb Dhonburi or alpha 2 beta (2)126(H4)Val-->Gly; this variant is slightly unstable and is associated with mild thalassemic features. His second chromosome and one of his mother's had the common IVS-I-5 (G-->C) mutation that leads to a rather severe beta(+)-thalassemia and the GTG-->ATG mutation at codon 18, resulting in the replacement of a valine residue by a methionine residue. This newly discovered beta-chain variant, named Hb Baden, was present for only 2-3% in both the patient and his mother. This low amount results from a decreased splicing of RNA at the donor splice-site of the first intron that is nearly completely deactivated by the IVS-I-5 (G-->C) thalassemic mutation. The chromosome with the codon 18 (GTG-->ATG) and the IVS-I-5 (G-->C) mutations has thus far been found only in this German family; analysis of 51 chromosomes from patients with the IVS-I-5 (G-->C) mutation living in different countries failed to detect the codon 18 (GTG-->ATG) change.
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PMID:Heterozygosity for the IVS-I-5 (G-->C) mutation with a G-->A change at codon 18 (Val-->Met; Hb Baden) in cis and a T-->G mutation at codon 126 (Val-->Gly; Hb Dhonburi) in trans resulting in a thalassemia intermedia. 146 68

A family of Asian-Indian descent has a variant form of beta-thalassaemia characterized by unusually high levels of Hb A2 in the heterozygous state. The propositus who is homozygous for the mutation has thalassaemia intermedia. Restriction endonuclease mapping suggested the presence of a 10.3 kilobase (kb) deletion removing the whole of the beta-globin gene. Subsequently, molecular analysis was performed by directly sequencing a specifically amplified region of genomic DNA. A 10329 basepair deletion was precisely defined which results in the loss of the 5' beta promoter region and the entire beta-globin gene. The deletion extends from 3011 bp 5' to the mRNA cap site to an L1 repeat element downstream of the beta-globin gene and is very similar to the 12.6 kb deletion of Dutch beta zero-thalassaemia. In common with four other mutations, both these deletions remove the 5' promoter region of the beta gene and all are associated with unusually elevated levels of Hb A2 in the heterozygous state.
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PMID:Molecular characterization of a novel 10.3 kb deletion causing beta-thalassaemia with unusually high Hb A2. 148 61

The genetics of sickle cell anemia may be considered as a model. Its mendelian transmission was hypothesized even before the molecular era. Once the mutation identified, it could be studied at the protein and DNA level; a consistent pathophysiological mechanism was proposed; the various genetic forms of the disease could be identified; the way by which a balanced polymorphism with Plasmodium falciparum malaria is obtained was analyzed. More recently, investigations were run in order to understand how modulating, or epistatic factors could modify the pathophysiological mechanism and contribute to the high clinical diversity of the disease. Several factors have been identified, among which a concomitant alpha-thalassemia, an overproduction of fetal hemoglobin, due either to an activation of the gamma genes or to an increase of the F-cell number, and finally a quantitative control of the beta s chains themselves. Such a high number of genetic active factors questions the concept itself of a monogenic disease.
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PMID:[Genetic aspects of sickle cell anemia]. 148 80

We have analysed the molecular basis of beta-thalassaemia in 22 Anglo-Saxon individuals, all of whom were heterozygous for beta-thalassaemia except for one, who was a compound heterozygote. Using a combination of allele-specific priming of the polymerase chain reaction (PCR) and direct sequencing of genomic DNA amplified by the PCR, 20/23 beta-thalassaemic genes were characterized. Nine different mutations were identified; four are commonly found in the Mediterranean, one in Asia, one has been described previously in both Europe and Asia, and three are rare mutations associated with a dominant beta-thalassaemia phenotype. In three individuals the mutation remains uncharacterized despite sequence analysis of the beta-globin gene and its immediate flanking regions. We report our findings and discuss the diversity of these mutations.
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PMID:Beta thalassaemia in the indigenous British population. 148 39

In order to clarify the reasons for the reduced Hb A2 levels in Sardinian delta beta-thalassemia, we characterized, both by cloning and sequence analysis and by direct sequencing of amplified DNA, the delta-globin gene from an individual of Sardinian descent who is a compound heterozygote for the beta zero-thalassemia codon 39 (C-->T) nonsense mutation and the Sardinian delta beta-thalassemia [codon 39(C-->T)/-196(C-->T)A gamma]. The analysis of the delta-globin gene from the delta beta-thalassemia chromosome revealed an entirely normal sequence. The defective function of the delta-globin gene in this determinant is thus likely related to a suppressive effect of the in cis nondeletional high persistence of fetal hemoglobin mutation of the A gamma gene, probably resulting from an increased capability of the relative promoter to interact with the locus control region.
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PMID:Normal delta-globin gene sequences in Sardinian nondeletional delta beta-thalassemia. 148 21

This paper summarizes information on the epidemiology and molecular basis of hemoglobinopathies in Yugoslavia. Over the past 25 years, population surveys of more than 28,000 school children from all over the country, except Slovenia, have shown that the average incidence of beta-thalassemia (beta-thal) trait is 1.2%, ranging from 2.9% in the south (Macedonia) to 0.8% in the northwest (Croatia). The frequency of delta beta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.4%. Screening of 6,400 newborns has shown that the frequency of alpha-thal trait is 1.6%. The molecular basis of the different forms of beta-thal among Yugoslavians has been almost completely defined. Over 250 beta-thal chromosomes have been studied, and in over 90% the molecular defect was determined. Eighteen different beta-thal mutations have been detected, three of which (IVS-I-110, G-->A; IVS-I-6, T-->C; IVS-I-1, G-->A) account for more than 70% of all beta-thal chromosomes. Four new mutations [-87 (C-->A); IVS-II-850 (G-->C); initiation codon mutation T-->C; poly A (AATAAA-->AATGAA)] and one new deletion (1605 bp) have been characterized. Molecular analyses of DNA from over 30 unrelated cases with delta beta-thal have shown that this condition is mainly caused by a 13 kb deletion (Sicilian type); in one family a deletion of > 18 to 23 kb (Macedonian type), and in another family a deletion of 148 kb (Yugoslavian type of epsilon gamma delta beta-thal) of the globin gene complex was discovered. Limited studies of alpha-thal in Yugoslavia have shown the following types of molecular defects: approximately 20.5 kb deletion, approximately 17.5 kb deletion, -3.7 kb deletion, 5 nucleotide (nt) deletion, and Hb Icaria. The incidence of abnormal hemoglobins (Hbs) in Yugoslavia is 0.3%. Five different alpha chain variants among 21 families, 15 different beta chain variants among 53 families, one delta chain variant in one family, one variant with a deleted residue in one family, and two types of Hb Lepore among 122 families, have been observed.
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PMID:Hemoglobinopathies in Yugoslavia: an update. 148 26


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