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 molecular basis of most beta-thalassemia syndromes has been defined, while the spectrum of mutations causing delta-thalassemia is not well characterized. In an attempt to identify such mutations, the region encompassing the delta-globin gene from three Greek Cypriot families suspected of having delta-thalassemia was amplified by polymerase chain reaction (PCR), and DNA sequence determined using an automated fluorescence-based sequencer. Four novel mutations were identified: a G----T change at codon 27 that results in an alanine to serine change; a C----T change at codon 116 converting arginine to cysteine; a T----C change at codon 141 converting leucine to proline; and an AG----GG change at the consensus 3'-acceptor site in IVS-2. While the latter is clearly a thalassemic mutation, the low hemoglobin A2 in the first three may be due to either decreased production or instability of the altered delta-globin chain. All four mutations may be detected by PCR amplification of genomic DNA followed by restriction enzyme digestion. Two mutations abolish restriction sites while two create new cleavage sites. Screening for molecular defects that cause delta-thalassemia or unstable delta-globin by PCR amplification and restriction enzyme digestion will lead to correct diagnosis of beta/delta-thalassemia compound heterozygotes and improved genetic counseling.
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PMID:Identification of four novel delta-globin gene mutations in Greek Cypriots using polymerase chain reaction and automated fluorescence-based DNA sequence analysis. 174 90

The initial report of Hb Indianapolis described two affected individuals with the phenotype of severe beta-thalassemia that was dominantly inherited. The structure of this variant could not be deduced by standard techniques because of its extreme instability. Because of this limitation, the structure was ascertained by analysis of the abnormal globin chain, which had been radioactively labeled. These studies strongly suggested that the structure of this variant was cysteine beta 112 to arginine. Subsequent to this report, two additional families with Hb Indianapolis were found. The carriers were minimally affected and the abnormal hemoglobin was only mildly unstable. This major difference in phenotypic expression suggested that further investigation of the original family should be carried out. Unfortunately, both of the original carriers of the variant succumbed to their severe anemia prior to the subsequent reports. However, by the use of the polymerase chain reaction, enough DNA was obtained to sequence the third exon of the beta-globin gene in the original family from the DNA scraped off a 10-year-old bone marrow microscope slide. These studies revealed a substitution of leucine to arginine at position 106 of the beta-globin chain. The polymerase chain reaction results may be consistent with the original protein structural data, if incomplete tryptic cleavage of this arginine residue occurred in the original sample. We have renamed this variant Hb Terre Haute in an attempt to avoid confusion with the Cys beta 112----Arg substitution.
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PMID:Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis. 200 17

Hb Mississippi was discovered in a 6-year-old Chinese girl with chronic anemia and thalassemia intermedia. Family studies revealed that she had inherited the Hb Mississippi from her father as well as inheriting a gene for beta+-thalassemia from her mother. Electrophoretic analyses of the hemolysate of the father of the father and the proband on polyacrylamide gels at pH 8.6 showed that the abnormal hemoglobin had three distinct mobilities. A similar pattern was also observed by isoelectricfocusing. In addition, multiple abnormal peaks were observed by high performance liquid chromatographic hemoglobin separations as well as high performance liquid chromatographic globin chain separation. Structural analysis of the abnormal hemoglobin demonstrated a single abnormality; the substitution of serine to cysteine at position 44 (CD3) of the beta-globin chain. Since CD3 is on the surface of the beta-globin chain, it was thought that polymerization of the abnormal hemoglobin by disulfide linkages might have been responsible for the anomalous behavior on electrophoresis and high performance liquid chromatography. Gel filtration chromatography on G-200 Sephadex confirmed this supposition and demonstrated that the abnormal globin chain polymerized with itself as well as with other globin chains.
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PMID:Hb Mississippi [beta 44(CD3)Ser----Arg]: a new variant with anomalous properties. 342 43

Variant hemoglobins such as Hb Lepore and Hb Constant Spring, because of their low synthetic rates, produce the phenotypes of beta and alpha-thalassemia respectively. A new hemoglobin variant, Hb Indianapolis, produced the phenotype of severe beta-thalassemia due to its extreme lability. Hb Indianapolis was so unstable that it no detectable protein associated with it could be isolated from the hemolysates of affected individuals. Structural analysis, using only radioactivity, revealed a cysteine to arginine substitution at beta 112 (G14). The extremely rapid precipitation and catabolism of beta Indianapolis and the resulting excess of alpha-chains, both causing membrane damage, may be responsible for the severe clinical manifestations associated with this variant. Another new hemoglobin variant, Hb Vicksburg, was found to produce the phenotype of thalassemia intermedia in the proband who was doubly heterozygous for this variant and beta 0-thalassemia. Structural analysis of Hb Vicksburg demonstrated a deletion of leucine at beta 75 (E19). Hb Vicksburg should have comprised the major portion of the hemolysate in the proband because of the presence of beta 0-thalassemia on the trans chromosome, but comprised instead only 7.6%. Thus, Hb Vicksburg was synthesized at a rate lower than that expected on the basis of gene dosage. Deletion of beta 75, for a number of reasons, would not be expected to lead to diminished synthesis of the variant. The most plausible explanation for the low output of Hb Vicksburg is that a mutation for beta +-thalassemia is present in cis to the structural mutation. Hb Indianapolis and Hb Vicksburg, therefore, are two new hemoglobin variants which produce the phenotype of beta-thalassemia by widely different mechanisms.
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PMID:Low output hemoglobins which produce the phenotype of thalassemia. 689 57

Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the alpha- or the beta-chain of hemoglobin. The expressivity of the phenotype is likely to be influenced by unlinked modifying genes. Indeed, by using a mouse model of alpha-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the alpha-thalassemia mutation resides [129(sv/ev)/129(sv/ev) (severe) or 129(sv/ev)/C57BL/6 (mild)]. Linkage mapping indicates that the modifying gene is very tightly linked to the beta-globin locus (Lod score = 13.3). Furthermore, the severity of the phenotype correlates with the size of beta-chain-containing inclusion bodies that accumulate in red blood cells and likely accelerate their destruction. The beta-major globin chains encoded by the two strains differ by three amino acids, one of which is a glycine-to-cysteine substitution at position 13. The Cys-13 should be available for interchain disulfide bridging and consequent aggregation between excess beta-chains. This normal polymorphic variation between murine beta-globin chains could account for the modifying action of the unlinked beta-globin locus. Here, the variation in severity of the phenotype would not depend on a change in the ratio between alpha- and beta-chains but on the chemical nature of the normal beta-chain, which is in excess. This work also indicates that modifying genes can be normal variants that-absent an apparent physiologic rationale-may be difficult to identify on the basis of structure alone.
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PMID:A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice. 1033 80

Reactive oxygen species (ROS) contribute to the pathogenesis of several hereditary disorders of red blood cells (RBCs), including thalassaemia. We report here on a modified flow cytometric method for measuring ROS in normal and thalassaemic RBCs. RBCs were incubated with 0.4 mM 2',7'-dichlorofluorescin diacetate (DCFH-DA), then washed and further incubated either with or without 2 mM H2O2. Flow cytometric analysis showed that RBC fluorescence increased with time; it increased faster and reached higher intensity (by 10-30-fold) in H2O2-stimulated RBCs as compared to unstimulated RBCs. In both cases, the antioxidant N-acetyl-l-cysteine reduced fluorescence, confirming previous reports that DCFH fluorescence is mediated by ROS. While the fluorescence of unstimulated RBCs increased with time, probably because of exposure to atmospheric oxygen, in H2O2-stimulated RBCs fluorescence decreased after 30 min. The latter effect is most likely related to H2O2 decomposition by catalase as both sodium azide, an antimetabolite that inhibits catalase and low temperature increased the fluorescence of stimulated RBCs. Washing had a similar effect, suggesting that maintenance of the oxidised DCF requires a constant supply of ROS. We next studied RBCs of beta-thalassaemic patients. The results demonstrated a significantly higher ROS generation by stimulated and unstimulated thalassaemic RBCs compared to their normal counterparts. These results suggest that flow cytometry can be useful for measuring the ROS status of RBCs in various diseases and for studying chemical agents as antioxidants.
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PMID:Flow cytometric measurement of reactive oxygen species production by normal and thalassaemic red blood cells. 1258 Nov 89

The ATRX protein, associated with X-linked alpha-thalassaemia, mental retardation and developmental abnormalities including genital dysgenesis, has been proposed to function as a global transcriptional regulator within a multi-protein complex. However, an understanding of the composition and mechanics of this machinery has remained elusive. We applied inter-specific comparative analysis to identify conserved elements which may be involved in regulating the conformation of chromatin. As part of this study, we cloned and sequenced the entire translatable coding region (7.4 kb) of the ATRX gene from a model marsupial (tammar wallaby, Macropus eugenii). We identify an ATRX ancestral core, conserved between plants, fish and mammals, comprising the cysteine-rich and SWI2/SNF2 helicase-like regions and protein interaction domains. Our data are consistent with the model of the cysteine-rich region as a DNA-binding zinc finger adjacent to a protein-binding (plant homeodomain-like) domain. Alignment of vertebrate ATRX sequences highlights other conserved elements, including a negatively charged mammalian sequence which we propose to be involved in binding of positively charged histone tails.
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PMID:Comparative analysis of ATRX, a chromatin remodeling protein. 1536 44

Chronic platelet activation may be involved in thromboembolic complications, a leading cause of morbidity and mortality in beta-thalassemia. Oxidative stress, with the generation of reactive oxygen species (ROS), is suspected to play a role in the patho-physiology of thalassemia and cardiovascular disorders. In the present study, we adapted flow cytometric techniques to measure oxidative state markers, ROS generation and reduced glutathione (GSH) content in platelets. Our results show that platelets obtained from beta-thalassemic patients contain higher ROS and lower GSH levels than do platelets from normal donors, indicating a state of oxidative stress. In the absence of any known inherent abnormality in thalassemia platelets, this may be attributed to continuous exposure to oxidative insults from extra-platelet sources. We found that exposure of platelets to oxidants such as hydrogen peroxide and tertbutylhydroperoxide or to the platelet activators thrombin, calcium ionophore or phorbol myristate acetate stimulated the platelets' oxidative stress. This was also increased by plasma of thalassemia patients, and decreased following treatment of the plasma with the iron-chelator Desferoxamin. Iron and hemin, the levels of which are augmented in plasma of thalassemia patients, stimulated the platelets' oxidative stress. The oxidative status of the platelets was also affected by red blood cells (RBC); it was higher in normal platelets incubated with thalassemic RBC than with normal RBC. Normal RBC stimulated with hydrogen peroxide had a greater effect on platelets than did unstimulated RBC. The platelets' oxidative stress was ameliorated by antioxidants such as N-acetyl-L-cysteine and vitamin C. Our findings indicate that in thalassemia, platelets undergo a state of oxidative stress, leading to their activation and potentially to thromboembolic consequences, and suggest that this hypercoagulable state might be treated with antioxidants.
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PMID:Oxidative status of platelets in normal and thalassemic blood. 1554 33

Beta-thalassaemia patients are susceptible to infections by mechanisms that are not fully understood. Polymorphonuclear neutrophils (PMN) destroy microbes by producing a burst of reactive oxygen species (ROS) (respiratory burst) in response to bacterial components, as well as to phorbol-myristate-acetate (PMA). In the present study, we compared ROS generation by normal and beta-thalassaemia PMN and assessed their response to PMA. Blood cells were subjected to gelatin separation, staining with dichlorofluorescin-diacetate and flow cytometry. At basal level, the fluorescence (mean fluorescence channel) of normal and thalassaemia PMN were 12.7 +/- 4.5 and 95.6 +/- 19.8 respectively; it changed to 283.4 +/- 72.5 and 39.5 +/- 14.3, respectively, upon PMA stimulation, indicating that thalassaemia PMN have a higher basal ROS but a reduced response to PMA. When normal PMN were treated with the oxidants hydrogen peroxide and butyl-hydroxyperoxide, as well as iron and haemin, which are elevated in thalassaemia, their basal ROS increased 5-22-fold, but the PMA response was abolished. Treating thalassaemic PMN with antioxidants (N-acetyl-L-cysteine or vitamins C and E) reduced their basal ROS but enhanced their PMA response. Our findings indicate that chronically stressed PMN, e.g. in thalassaemia, have reduced capacity to elicit a respiratory burst, which may compromise their antibacterial capacity, and imply prophylactic treatment with antioxidants for recurrent infections.
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PMID:Chronic oxidative stress reduces the respiratory burst response of neutrophils from beta-thalassaemia patients. 1584 69

Sickle cell disease (SCD) is basically a red blood cell (RBC) disorder characterised by sickling and haemolysis, but platelets and polymorphonuclear neutrophils (PMN) are also involved. Oxidative damage may play a role in the pathogenesis of SCD. Using flow cytometry, we measured oxidative-state markers simultaneously in RBC, platelets and PMN obtained from 25 normal donors, nine homozygous (SS) patients and six SS/beta-thalassaemia patients. Reactive oxygen species (ROS) and reduced glutathione (GSH) were measured following staining of blood samples with fluorescence probes and gating on specific subpopulations based on size and granularity. Ten- to 30-fold higher ROS production and 20-50% lower GSH content were found in RBC, platelets and PMN from SCD patients versus those of their normal counterparts. This could in part account for the clinical manifestations, such as haemolysis, a hypercoagulable state, recurrent bacterial infections and vaso-occlusive incidences, in SCD. We further showed that exposure of SCD samples to antioxidants, such as N-acetyl-cysteine, vitamin C and vitamin E, decreased their oxidative stress. These results suggest that antioxidant treatment of patients with SCD could reduce oxidative damage to RBC, PMN and platelets, thereby alleviating symptoms associated with their pathology. The flow cytometry techniques presented herein could assist in monitoring the efficacy of such treatment.
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PMID:Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants. 1637 Oct 26


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