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)

Consanguineous marriages are usually socially driven and can be genetically harmful. The detrimental effects of inbreeding are the consequence of homozygosity of harmful genes. On the other hand, beneficial effects of inbreeding, theoretically, could be expected in those who are homozygous for protective recessive and codominant genes. Here, we argue that the most common monogenetic conditions in humans, namely, alpha-thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobin C, and Duffy antigen negative red blood cells, which have evolved under pressure from malaria, had their survival and selection enhanced by consanguineous marriages in malaria-infested regions of the world. This hypothesis is supported by several observations. First, the presence of two mutations in homozygotes involving the listed conditions (except G6PD deficiency) imparts better protection against malaria than the presence of one or no mutation (heterozygous or normal genotypes, respectively); consanguinity increases the number of homozygotes, especially at low allele frequency. For G6PD deficiency, inbreeding could increase the allele frequency of the G6PD-deficient allele. Second, there is overlap between, on the one hand, the geographic distributions of malaria, thalassemias, and other red blood cell conditions that protect against malaria and, on the other hand, consanguineous marriages. Third, the distribution of different intensities of malaria infestation is matched with the frequency of human inbreeding. These observations, taken together, offer strong support to the hypothesis that the culture of consanguineous marriages and the genetics of protection against malaria have co-evolved by fostering survival against malaria through better retention of protective genes in the extended family.
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PMID:Genetic benefits of consanguinity through selection of genotypes protective against malaria. 1802 11

Eryptosis, the suicidal death of erythrocytes, is characterised by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing erythrocytes are recognised by macrophages, which engulf and degrade the affected cells. Reported triggers of eryptosis include osmotic shock, oxidative stress, energy depletion, ceramide, prostaglandin E(2), platelet activating factor, hemolysin, listeriolysin, paclitaxel, chlorpromazine, cyclosporine, methylglyoxal, amyloid peptides, anandamide, Bay-5884, curcumin, valinomycin, aluminium, mercury, lead and copper. Diseases associated with accelerated eryptosis include sepsis, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency, hemolytic uremic syndrome and Wilsons disease. Eryptosis may be inhibited by erythropoietin, adenosine, catecholamines, nitric oxide (NO) and activation of G-kinase. Most triggers of eryptosis except oxidative stress are effective without activation of caspases. Their signalling involves formation of prostaglandin E(2) with subsequent activation of cation channels and Ca2+ entry and/or release of platelet activating factor (PAF) with subsequent activation of sphingomyelinase and formation of ceramide. Ca2+ and ceramide stimulate scrambling of the cell membrane. Ca2+ further activates Ca2+-sensitive K+ channels leading to cellular KCl loss and cell shrinkage and stimulates the protease calpain resulting in degradation of the cytoskeleton. Eryptosis allows defective erythrocytes to escape hemolysis. On the other hand, excessive eryptosis favours the development of anemia. Thus, a delicate balance between proeryptotic and antieryptotic mechanisms is required to maintain an adequate number of circulating erythrocytes and yet avoid noneryptotic death of injured erythrocytes.
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PMID:Erythrocyte programmed cell death. 1872 Apr 18

In order to provide a reference range for normal red blood cell enzyme activities in Thai, we analyzed data from 113 healthy non-anemic Thai people (55 males and 58 females) age 1-42 years, who all had a normal pattern of hemoglobin typing (HbA and HbA2 less than 3.5%). Hematological analysis was performed using an automated cell counter and the hemoglobin studies were carried out by low pressure liquid chromatography. Owing to a high frequency of alpha-thalassemia in Thailand, cases with an MCV < 75 fl were excluded from the study since these cases were likely to be heterozygotes for alpha0-thalassemia. Cases with reticulocytes > 2.5% were excluded from the study since reticulocytes have a higher enzyme activity than mature erythrocytes. Cases with abnormal red blood cell morphology, such as spherocytes and ovalocytes, were also excluded. These criteria were applied to select "normal" controls for our analysis. We assayed eight red blood cell enzyme activities in normal subjects: glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), pyruvate kinase (PK), hexokinase (HK), glucose phosphate isomerase (GPI), phosphofructokinase (PFK), aldolase (ALD) and phosphoglycerate kinase (PGK). The mean normal ranges (+/- SD) for G6PD, 6PGD, PK, HK, GPI, PFK, ALD and PGK were 12.7 (+/-2.2), 10.7 (+/-1.3), 18.5 (+/-4.0), 1.5 (+/-0.4), 80.5 (+/-11.8), 11.8 (+/-2.1), 4.5 (+/-1.6) and 370 (+/-43) IU/gHb, respectively. Age-dependent differences for the reference values for these enzyme activities were summarized. All red blood cell enzyme activities were highest during the early childhood period and slightly lower in the adult period. These values will be of clinically useful for future reference.
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PMID:Development of a comprehensive red blood cell enzymopathy laboratory in Thailand: the study of normal activity in eight erythroenzymes in Thais. 1932 17

The pathogen of malaria, Plasmodium, enters erythrocytes and thus escapes recognition by the immune system. The pathogen induces oxidative stress to the host erythrocyte, which triggers eryptosis, the suicidal death of erythrocytes. Eryptosis is characterized by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling with phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing erythrocytes are identified by macrophages which engulf and degrade the eryptotic cells. To the extent that infected erythrocytes undergo eryptosis prior to exit of Plasmodiaand subsequent infection of other erythrocytes, the premature eryptosis may protect against malaria. Accordingly, any therapeutical intervention accelerating suicidal death of infected erythrocytes has the potential to foster elimination of infected erythrocytes, delay the development of parasitemia and favorably influence the course of malaria. Eryptosis is stimulated by a wide variety of triggers including osmotic shock, oxidative stress, energy depletion and a wide variety of xenobiotics. Diseases associated with accelerated eryptosis include sepsis, haemolytic uremic syndrome, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency and Wilson's disease. Among the known stimulators of eryptosis, paclitaxel, chlorpromazine, cyclosporine, curcumin, PGE2 and lead have indeed been shown to favourably influence the course of malaria. Moreover, sickle-cell trait, beta-thalassemia trait, glucose-6-phosphate dehydrogenase (G6PD)-deficiency and iron deficiency confer some protection against a severe course of malaria. Importantly, counteracting Plasmodia by inducing eryptosis is not expected to generate resistance of the pathogen, as the proteins involved in suicidal death of the host cell are not encoded by the pathogen and thus cannot be modified by mutations of its genes.
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PMID:Suicide for survival--death of infected erythrocytes as a host mechanism to survive malaria. 1971 May 27

Venous blood samples of 368 apparently healthy and unrelated adult individuals (both male and female) belonging to a primitive tribe, Garasiya inhabitating malaria hyperendemic areas of Sirohi district, Rajasthan (India) were investigated by standard and recommended techniques for evidence of erythrocyte genetic disorders; sickle cell haemoglobin, beta-thalassaemia syndromes and glucose-6-phosphate dehydrogenase (G-6-PD) enzyme deficiency (Gd). Sickle cell genes encountered in 23 (6.25%) Garasiya tribals. Of these, 22 (5.97%) showed heterozygous sickle cell gene(Hb-AS or trait) and one (0.27%) homozygous form (Hb-SS or sickle cell disease). beta-thalassaemia syndromes were observed in 30 (8.15%) subjects; 28 (7.60%) beta-thalassaemia traits (beta-thal.) and 2 (0.54%) HbS-thalassaemia (HbS-thal.). Gd was found in 56 (15.21%) subjects. Except these mutant genes no other erythrocyte abnormal genes were encountered in Garasiya tribe. A high incidence or prevalence of these red cell mutant genes in relation to malaria is discussed in the present communication.
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PMID:Sickle cell haemoglobin, thalassaemia and G-6-PD enzyme deficiency genes in Garasiya tribe inhabited malaria endemic areas of Sirohi District, Rajasthan (India). 1988 70

A 14-year-old male child presented with microcytosis, a known alpha(+)-thalassemia (alpha-thal) heterozygote and a hemizygous glucose-6-phosphate dehydrogenase (G6PD) deficiency. Furthermore, cation exchange high performance liquid chromatography (HPLC) revealed an additional peak eluting slightly before Hb A. The peak area of the variant was equal to that of Hb A, suggesting a beta-globin variant. Matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) analysis confirmed the mutation at the protein level. The variant was detectable by isoelectric focusing (IEF) or by reversed phase HPLC. DNA sequencing revealed a heterozygous mutation at codon 135 of the beta gene, already described as Hb Alperton. Hb Alperton showed decreased oxygen affinity. Neither biochemical nor clinical characteristics for Hb Alperton have been reported so far.
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PMID:Hb Alperton [beta135(H13)Ala-->Val] shows decreased oxygen affinity. 1995 96

beta-Thalassaemia is characterized by a decrease in globin beta-chain synthesis and an excess in free alpha-globin chains. This induces alterations in membrane lipids and proteins resulting from a reduction in spectrin/band 3 ratio, partial oxidation of band 4.1 and clustering of band 3. The membrane injury provokes hyperhaemolysis and bone marrow hyperplasia. The pathophysiology of thalassaemia is associated with iron overload that generates oxygen free radicals and oxidative tissue injury with ocular vessel alterations. The aim of this research is to investigate the influence of oxidative stress on band 3 efficiency, which is an integral membrane protein of RBCs (red blood cells). Band 3 protein, of which there are more than 1 million copies per cell, is the most abundant membrane protein in human RBCs. It mediates the anion exchange and acid-base equilibrium through the RBC membrane. Some experiments were performed on thalassaemic cells and beta-thalassaemia-like cells and tested for sulfate uptake. To test the antioxidant effect of Mg(2+), other experiments were performed using normal and pathological cells in the presence of Mg(2+). The oxidant status in thalassaemic cells was verified by increased K(+) efflux, by lower GSH levels and by increased G6PDH (glucose-6-phosphate dehydrogenase) activity. The rate constant of SO(4)(2-) uptake decreases in thalassaemic cells as well as in beta-thalassaemia-like cells when compared with normal cells. It increases when both cells are incubated with Mg(2+). Our data show that oxidative stress plays a relevant role in band 3 function of thalassaemic cells and that antioxidant treatment with Mg(2+) could reduce oxidative damage to the RBC membrane and improve the anion transport efficiency regulated by band 3 protein.
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PMID:Erythrocytes anion transport and oxidative change in beta-thalassaemias. 2045 Apr 94

In order to obtain an approximate assessment of the public health burden that will be posed by the inherited disorders of haemoglobin in southern Vietnam, several thousand individuals were screened for these conditions. A smaller sample was screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency. The important haemoglobin disorders identified were beta thalassaemia, haemoglobin E and a variety of different forms of alpha thalassaemia. There were sufficient G6PD-deficient individuals to materially affect malaria control programme design. The most remarkable finding was wide variation in the gene frequencies of these conditions among the ethnic groups sampled. The approximate number of babies expected to be born with clinically significant haemoglobin disorders in Vietnam was estimated from the gene-frequency data. This study emphasizes the importance of wide-scale population screening, including ethnic subgroups, to establish the requirements for inherited haemoglobin disorder programmes in resource-limited settings.
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PMID:Large scale screening for haemoglobin disorders in southern Vietnam: implications for avoidance and management. 2049 77

The suicidal death of erythrocytes or eryptosis is characterized by cell shrinkage, membrane blebbing and cell membrane phospholipid scrambling resulting in phosphatidylserine exposure at the cell surface. Eryptosis is stimulated in a wide variety of diseases including sepsis, haemolytic uremic syndrome, malaria, sickle-cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase (G6PD)-deficiency, phosphate depletion, iron deficiency and Wilson's disease. Moreover, eryptosis is elicited by osmotic shock, oxidative stress, energy depletion as well as a wide variety of endogenous mediators and xenobiotics. Excessive eryptosis is observed in erythrocytes lacking the cGMP-dependent protein kinase type I (cGKI) or the AMP-activated protein kinase AMPK. Inhibitors of eryptosis include erythropoietin, nitric oxide NO, catecholamines and high concentrations of urea. Eryptosis-triggering diseases and chemicals are partially effective by stimulating the formation of ceramide, which in turn fosters cell membrane scrambling. Accordingly, ceramide-induced eryptosis participates in the pathophysiology of several diseases and contributes to the effects of a large number of xenobiotics. The mechanisms underlying ceramide formation in erythrocytes are, however, still ill defined. In case of osmotic cell shrinkage, ceramide formation is apparently due to activation of phospholipase 2, leading to formation of platelet activating factor PAF and PAF-dependent stimulation of ceramide formation, which possibly involves acid sphingomyelinase. Additional experiments are needed to conclusively define the ceramide-generating enzyme and the ceramide-dependent cellular events eventually leading to suicidal erythrocyte death.
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PMID:Ceramide in suicidal death of erythrocytes. 2050 1

A pilot study was conducted to determine the prevalence and haematological characteristics of the interaction between thalassaemia or/and glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients with sickle-cell disorder (SCD) in Taiz city, Yemen, where the prevalence of sickle-cell trait (HbAS) is 8.2%. Blood samples were collected from 31 SCD patients. Complete blood count and haemoglobin electrophoresis, G6PD activity and serum ferritin were determined. Thalassaemia was found in 6 patients (19.4%) and G6PD deficiency (6 mild and 1 severe) was detected in 7 patients (22.6%). The frequency ofthalassaemia and/or G6PD deficiency with SCD was high and this may have an effect on the severity of the clinical course of SCD in Taiz. The study should be repeated with DNA analysis to define the nature of the globin gene defect and to clarify its role in the severity of SCD
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PMID:Thalassaemia and glucose-6-phosphate dehydrogenase deficiency in sickle-cell disorder patients in Taiz, Yemen. 2179 53


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