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)

An assay for the phosphate-eliminating enzyme (PEE) activity in liver was developed which required only 5-10 mg tissue. PEE catalyses the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin (BH4). In the presence of substrate, magnesium, NADPH, and a sepiapterin reductase fraction from human liver, PEE catalysed the formation of BH4 which was measured by HPLC and electrochemical detection. In adult human liver, a PEE activity of 1.02 +/- 0.134 microU/mg protein (mean +/- 1 SD; n = 5) was observed. In liver needle biopsy material from five patients with defective biopterin biosynthesis, no PEE activity was found (less than 2% and 6% of the control values, respectively). The presence of an endogenous inhibitor was excluded. In a patient who died without definite diagnosis and in a patient with beta-thalassaemia liver PEE activity was increased. Sepiapterin reductase activity was present in all cases. Results indicate that in "dihydrobiopterin synthetase" deficiency, the most frequent of the rare BH4-deficient variants of hyperphenylalaninaemia, the molecular defect consists in a defect of PEE.
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PMID:Atypical phenylketonuria with "dihydrobiopterin synthetase" deficiency: absence of phosphate-eliminating enzyme activity demonstrated in liver. 299 Sep 33

Red blood cell (RBC) antioxidant defense was investigated in eight individuals with hemoglobin E (Six EE and two E-B(+) thalassemia) and compared to that in six individuals with thalassemia and ten normal subjects. Individuals with hemoglobin E had increased incubated Heinz body formation (68% +/- 18%; p less than 0.001) compared to normal and thalassemic RBC (10% +/- 2% and 11% +/- 5%, respectively). Stimulated pentose phosphate shunt activity was increased in the thalassemic and decreased in the hemoglobin E RBC as compared to normal. The 2,3-diphosphoglycerate (DPG) content of the EE RBC was increased to 5.59 +/- 0.69 mumol/ml RBC as compared to normal (4.51 +/- 0.77; p less than 0.001). In the EE RBC, there was a direct correlation between Heinz body formation and DPG content (r = 0.73). Ascorbic and dehydroascorbic acid (0.1 and 1.0 mM) were able to decrease the degree of Heinz body formation in the hemoglobin E RBC. Ascorbic acid (0.1 mM) prolonged the response of the pentose shunt. Thus impaired antioxidant defense may account for the persistence of the hemoglobin E gene in areas where malaria is endemic. Oxidant medications should be used with caution in individuals of Southeast Asian origin.
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PMID:Impaired antioxidant defense in hemoglobin E-containing erythrocytes: a mechanism protective against malaria? 367 3

Intracellular calcium (Ca) concentration in erythrocytes (RBCs) is controlled by a low passive influx through a relatively impermeable membrane and by active efflux catalyzed by Ca2+,Mg2+-ATPase. Since precipitation of alpha-globin chains in thalassemic RBCs may interfere with normal membrane function, we studied the RBC intracellular Ca content and the RBC membrane Ca2+,Mg2+-ATPase activity in two groups of patients with nonsplenectomized (n = 9) and splenectomized (n = 9) beta-thalassemia intermedia and in two groups of matched controls. The mean +/- SD Ca concentration in the nonsplenectomized (n = 12) and splenectomized (n = 6) controls were 6.1 +/- 6.0 and 5.8 +/- 3.4 mumol Ca per liter of RBCs, respectively, compared with 26.0 +/- 7.6 (P less than .001) and 85 +/- 24.4 (P less than .001) in the nonsplenectomized and splenectomized thalassemia patients, respectively. The mean +/- SD Ca2+,Mg2+-ATPase activity in the eight nonsplenectomized patients was 0.77 +/- 0.58 mumol inorganic phosphate (Pi) per milligram of protein per hour compared with 0.66 +/- 0.41 in the controls (P = NS). Similar values were obtained for the splenectomized patients and their controls. No correlation was found between either the intracellular Ca content or the Ca2+,Mg2+-ATPase activity with the peripheral nucleated RBC count. These findings suggest that there is a major defect in the membrane of the thalassemic RBC leading to an increased Ca content that is more pronounced in splenectomized patients.
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PMID:Impaired erythrocyte calcium homeostasis in beta-thalassemia. 623 51

In recent studies, we observed a decrease of KMapp, an abnormally biphasic kinetics of the red cell membrane neutral phosphatase and an increased binding of hemoglobin to the membrane in various forms of beta-thalassemia. Since the gene encoding the beta chain (beta E chain) of hemoglobin E (HbE) is endowed with some thalassemic characteristics, we studied the erythrocyte membrane in 25 individuals with Hb E trait or disease. The apparent Michaelis-Menten constant for p-nitrophenylphosphate (the artificial substrate used) was significantly decreased, as in beta-thalassemia. However, the kinetics was monophasic in all the heterozygotes and in four of the homozygotes. It was biphasic only in the three other homozygotes. Vmax was also significantly reduced, a fact that is masked, when not reversed in beta-thalassemia, owing to the rejuvenation of the red cell population. In 5 mM phosphate buffer (pH 8.00), the binding of Hb E to the erythrocyte ghosts was increased in the homozygotes. In the heterozygotes, Hb A binding was also increased, as is the case in beta-thalassemia. This latter fact suggests that the membrane binding site(s) of hemoglobin is (are) altered. We found a highly significant increase of Hb F in EE subjects. The present study extends to the red cell membrane the beta-thalassemic phenotype associated with the beta E gene.
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PMID:Thalassemia-like abnormalities of the red cell membrane in hemoglobin E trait and disease. 632 76

The zeta (zeta) and various gamma (gamma) chains of Hb Portland I have been separated and isolated from blood samples obtained from neonates with hydrops fetalis due to homozygous alpha-thalassemia. By using developers containing acetonitrile, methanol, and potassium phosphate and either an analytical (3.9 mm x 30 cm) or a preparative (7.8 mm x 30 cm) muBondapak C-18 column (Waters), globin chains from 200 micrograms to 5.0 mg have been isolated in pure forms. Analytical and preparative procedures using short (50-min duration) and extended (186-min duration) gradient programs have been developed. In addition to the type of column and developer conditions, the following factors are found to be important: (a) preparation of sample, (b) sample loading, and (c) cleaning of the column. Preliminary studies indicate that the yield ranges from 40 to 60% depending on the type of globin sample and the age of the column. This procedure also permits the separation of alpha, beta, and various gamma globin chains from fetal and adult samples.
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PMID:Separation of zeta (zeta) and various gamma (gamma) chains of human embryonic hemoglobin Portland I by reverse-phase high-performance liquid chromatography. 668 87

We have analyzed the molecular basis of beta + thalassemia by studying the expression of a cloned beta-globin gene in HeLa cells. This beta-globin gene was isolated from a beta + thalassemic patient and differs from the normal beta-globin genes by only a single point mutation within the first intron. The beta + thalassemic and the normal beta-globin genes were cloned into an SV40-pBR328 vector and introduced into HeLa cells by calcium phosphate coprecipitation. We assayed the RNA from these transfected HeLa cells by S1 nuclease mapping and cDNA sequencing to detect the nature of the defect in beta-globin gene expression. While the transcripts of the normal beta-globin gene are processed correctly, the first intron of the beta + thalassemic beta-globin gene is incorrectly spliced in about 90% of the mRNA because of an additional 3; splice site that has been created by the point mutation. This incorrectly spliced mRNA is effectively exported to the cytoplasm, where it would conceivably be translated to give a truncated globin chain of 35 amino acids. The remaining 10% of the mRNA transcribed from the beta+ thalassemic globin gene is correctly spliced and can therefore be translated to give normal beta-globin. In addition to the incorrect splicing of the first intron, the splicing of both introns is retarded, which results in the accumulation of unspliced pre-mRNA. This suggests that removal of the first intron might facilitate splicing of the second intron.
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PMID:Beta + thalassemia: aberrant splicing results from a single point mutation in an intron. 689 66

Amounts of radio-labelled substances as low as 10(-18) moles incorporated into individual cells can be measured by utilizing techniques of quantitative autoradiography. For this purpose, radioactive standard sources are processed with the labelled cells smeared to slides. Carbon-14 is a favourable isotope with regard to minimal loss of beta-disintegrations due to self-absorption, and to limited cross-fire effects complicating the attribution of silver grains to individual cells. Silver grain densities can be counted by automated microphotometry allowing on-line data processing by an interfaced computer. Rate measurements of 14C-thymidine incorporation into individual cells yield values of the DNA synthesis rate provided that the endogenous pathway of thymidine-phosphate formation has been previously blocked. From the rate values of individual cells the DNA synthesis time of a cell compartment is derived. This is an essential time parameter for the evaluation of kinetic events in proliferating cell populations. This method is applicable to human cells without radiation hazard to man, and provides an optimal source of detailed information on the kinetics of normal and diseased human haematopoiesis. Examples of application consist of thalassaemia, malaria infection, iron deficiency anaemia and acute myelogenous leukaemia.
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PMID:Quantitative carbon-14 autoradiography at the cellular level: principles and application for cell kinetic studies. 701 61

Calcium and phosphate metabolism were studied in 22 patients with homozygous thalassemia. The overall results showed no significant difference for serum calcium, phosphorus, alkaline phosphatase, immunoreactive parathyroid hormone, or 25-hydroxyvitamin D between thalassemic and control children. However, during the winter, serum 25-hydroxycholecalciferol levels were very significantly decreased in thalassemic children. A study of the hands showed thin metacarpal cortices related to increased resorption. Histomorphometric study of four iliac bone biopsies showed normal osteoclastic resorption and decreased bone formation. Prussian blue staining and x-ray electron microprobe analysis showed iron deposits inside the bone. Whether this finding is critical in the pathogenesis of the bone disease in unknown.
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PMID:Calcium phosphate metabolism and bone disease in patients with homozygous thalassemia. 705 21

It was demonstrated in heterozygous alpha 1- and beta-thalassaemia, that the slow rate of red-cell metabolism of vitamin B6, previously shown to be inherited, is regulated by the FMN-dependent pyridoxine (pyridoxamine) phosphate oxidase, as in control subjects. In this study, 60% of the patients with thalassaemia had a low B6 oxidase activity. An inverse correlation with the stimulation of the FAD-dependent glutathione reductase activity by FAD confirmed that red-cell riboflavin status was responsible. The inherited nature and lack of signs of nutritional riboflavin deficiency led to the conclusion that this was the result of a slow rate of red-cell metabolism of riboflavin. Stimulation of glutathione reductase activity by FAD correlated inversely with its basic activity in thalassaemia and control subjects. There was a high incidence of a low activity of this enzyme per red cell in patients with thalassaemia. The possibility that a low activity of glutathione reductase and a slow metabolism of B6 and riboflavin in the red-cell might play a part in the degree of severity of the thalassaemic disease is discussed.
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PMID:Low red cell activity of pyridoxine (pyridoxamine) phosphate oxidase and glutathione reductase associated with thalassaemia. 733 97

We have studied the prevalence and molecular nature of hereditary anaemias (abnormal haemoglobins, beta-thalassaemia, alpha-thalassaemia, and Glucose 6 phosphate dehydrogenase (G6PD) deficiency) in a primitive central Indian tribe, the Baiga. 43% of the population appear to be iron-deficient. Hereditary anaemia gene frequencies are, sickle cell 0.0824, G6PD deficiency (in males) 0.0457, beta-thalassaemia 0.0057, and deletional alpha-plus thalassaemia 0.65. Both -alpha 3.7 and -alpha 4.2 deletions were observed and non-deletional alpha-thalassaemia was suspected. The overall gene frequency of Xmn I+polymorphism (C-->T - 158 cap site; upstream of G gamma region) is 0.35. This polymorphism is preferentially linked to beta s genes. It appears that sickle cell disease covers a wide range of severity in the Baiga tribe based on higher mortality in the offspring of AS x AS parents (2.5/couple) compared to AA x AS (0.75/couple) and AA x AA (0.76/couple) parents. This is compatible with the high frequency of genetic modifying factors, i.e., the Xmn I polymorphism and alpha-thalassaemia. The results also indicate that "normal" red cell values must be defined for each population where thalassaemias, G6PD deficiency and iron deficiency are common.
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PMID:Hereditary anaemias and iron deficiency in a tribal population (the Baiga) of central India. 762 84


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