Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The Indian rubber estate workers in Negri Sembilan, Malaysia, who originated from Orissa in India were found to have a high frequency of Hb S (Joishy SK, Hassan K: Clin Res 28:280, 1980). Unlike the usually severe clinical picture of sickle cell anemia seen in African and American blacks, the clinical picture of the disease in this population was mild and many have reached old age. We studied the leukocyte DNA of 12 patients with sickle cell anemia, ranging in age from 4 to 61 years and 30 sickle cell trait carriers, ranging in age from 7 to 63 years, for the presence of alpha-globin gene deletions by gene mapping according to Southern (Southern EM: J Mol Biol 98:503, 1975), using alpha- and zeta-globin gene probes obtained by nick translation of the alpha- and zeta-globin genes cloned into plasmid. All 12 sickle cell anemia patients were found to have alpha-thalassemia2 (alpha-thal2), either in the homozygous or heterozygous condition. Of the Hb S trait carriers, six did not have alpha-thal2 or alpha-thal1 and 24 had alpha-thal2 (15 heterozygous, 9 homozygous). Seven of these Hb S trait carriers with alpha-thal2 had an additional gene abnormality. Five of them had a fast-moving Eco RI fragment 5.6 kb long that hybridized with zeta-specific probe but not with alpha-specific probe. An unusual DNA pattern of a different type was further found in the other two. Bgl II restriction analysis showed that the alpha-thal2 was mostly of the rightward deletion alpha-thal1 genotype. None of the sickle cell anemia patients and Hb S trait carriers had deletion type alpha-thal1. The sickle cell anemia patients had very high levels of Hb F and low levels of Hb A2. The Hb S trait carriers with alpha-thal2 had relatively low levels of Hb S.
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PMID:Sickle cell anemia associated with alpha-thalassemia in Malaysian Indians. 242 2

The effects of several membrane-acting drugs on malaria and sickle cell anemia was studied. In the initial experiments, propranolol and W-7 were shown to increase red cell density. In vitro, these drugs inhibited the growth of P. falciparum. However, in vivo experiments using the murine malarial parasite, P. vinckei, demonstrated little, if any, anti-parasite activity with the doses of drugs employed. Subsequently, prostaglandin oligomeric derivatives were found to inhibit the growth of P. falciparum in vitro and P. vinckei in vivo. Since prostaglandin oligomers inhibited the formation of dense, dehydrated cells (irreversible sickle cells), they may also have therapeutic efficacy in sickle cell anemia.
Mol Cell Biochem
PMID:Effects of membrane acting-drugs on plasmodium species and sickle cell erythrocytes. 269 29

Membrane phospholipid asymmetry is considered to be a general property of biological membranes. Detailed information is presently available on the non-random orientation of phospholipids in red cell- and platelet membranes. The outer leaflet of the lipid bilayer membrane is rich in choline-phospholipids, whereas amino-phospholipids are abundant in the inner leaflet. Studies with blood platelets have shown that these asymmetries are not maintained when the cells are activated in various ways. Undoing the normal asymmetry of membrane phospholipids in activated blood cells is presumably mediated by increased transbilayer movement of phospholipids. This process, which leads to increased exposure of negatively charged phosphatidylserine at the outer surface, plays an important physiological role in local blood clotting reactions. A similar phenomenon occurs in sickled red cells. Phospholipid vesicles breaking off from reversibly sickled cells contribute similarly to intravascular clotting in the crisis phase of sickle cell disease. The loss of membrane phospholipid asymmetry in activated platelets seem to be strictly correlated with degradation of cytoskeletal proteins by endogenous calpain. It is remarkable that membrane phospholipid asymmetry can be (partly) restored when activated platelets are treated with reducing agents. This leads to disappearance of phosphatidylserine from the outer leaflet where it was previously exposed during cell activation. These observations will be discussed in relation to two mechanisms which have been recognized to play a role in the regulation of membrane phospholipid asymmetry; i.e. the interaction of amino-phospholipids to cytoskeletal proteins, and the involvement of a phospholpid-translocase catalyzing outward-inward transbilayer movement of amino-phospholipids.
Mol Cell Biochem
PMID:Loss of membrane phospholipid asymmetry during activation of blood platelets and sickled red cells; mechanisms and physiological significance. 269 31

[(Dihydroindenyl)oxy]alkanoic acid (DIOA) was recently introduced as a potent inhibitor of the K+Cl- cotransport system without side effects on other cation transport systems [Garay, R. P., Nazaret, C., Hannaert, P.A. & Cragoe, E. J., Jr. (1988) Mol. Pharmacol. 33, 696-701]. In sickle cells, an abnormal activation of this K+Cl- cotransport system was proposed to be involved in cell K+ loss and dehydration. We found that DIOA inhibited the abnormal sickle cell K+ loss and specifically reduced sickle cell density upon stimulation of the net outward K+Cl- cotransport--i.e., low pH, hypoosmolarity, and activation by N-ethylmaleimide. DIOA opens another therapeutic approach to sickle cell disease by inhibiting cell dehydration, which favors HbS polymerization and reduces erythrocyte deformability.
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PMID:Inhibition of K+ efflux and dehydration of sickle cells by [(dihydroindenyl)oxy]alkanoic acid: an inhibitor of the K+ Cl- cotransport system. 272 72

We have used the "osmotic stress" method to determine the phase diagram of deoxyhemoglobin S polymerization. This method involves equilibration, through a semipermeable membrane, of the protein with solutions of inert polymers of known osmotic pressure. With deoxyhemoglobin A and S solutions, in which we have demonstrated achievement of equilibrium, plots of osmotic pressure versus concentration initially agree closely with the results of other methods of measurement of colligative properties. However, once the known solubility value is exceeded for the deoxyhemoglobin S solutions at various temperatures, there is a rapid rise in hemoglobin concentration over a narrow osmotic pressure range and then a more gradual increase in concentration. We believe that these two regions correspond, respectively, to the onset of the polymerization process, and of subsequent continuing growth and compression or alignment of polymer. We derive the thermodynamic values for these processes and show that the behavior of the deoxyhemoglobin S system is analogous to the phase transition for a simple chemical system. These results are relevant to understanding the intracellular polymerization of deoxyhemoglobin S in sickle cell disease, and these concepts are applicable to other protein assembly systems.
J Mol Biol 1985 Aug 05
PMID:Chemical potential measurements of deoxyhemoglobin S polymerization. Determination of the phase diagram of an assembling protein. 404 25

Among the class of non-covalent inhibitors of deoxyhemoglobin S gelation, the aromatic amino acids have been shown to be the most effective. We have examined several synthetic chemical modifications of phenylalanine in order to determine the stereospecific constraints for inhibition of gelation by this class of compounds. The phenylalanine derivatives with ring modification by electron-donating groups (NH2, CH3, or OH) inhibited gelation to the same order of magnitude as phenylalanine (10-20% increase in deoxyhemoglobin S solubility at 32 mM). The phenylalanine derivative with the electron-withdrawing group NO2 in the p-position behaved similarly, but the inhibitory effect was eliminated by NO2 in the m- and possibly o-positions. Furthermore, side-chain modifications also eliminated the inhibitory effect. These studies, in conjunction with crystallographic analyses of the binding sites of gelation inhibitors, may provide a rational strategy for finding suitable compounds (whether covalent or non-covalent inhibitors) with appropriate physicochemical and biological properties to pursue as potential therapies with sickle cell disease.
Mol Pharmacol 1983 Jan
PMID:The effect of phenylalanine derivatives on the solubility of deoxyhemoglobin S. A model class of gelation inhibitors. 686 93

The drugs tolazoline, clonidine, lofexidine, and fenmetozole were found to inhibit the gelation of hemoglobin S in the order of increasing effectiveness. Only the latter, however, reduced the sickling of red cells significantly and normalized the oxygen affinity of SS blood at 5-10 mM concentrations. Since this level of drug is lower than those reported for many other anti-sickling agents to achieve comparable effects, the 2-imidazoline class of compounds may provide important clues for the development of therapy for sickle cell anemia.
Mol Pharmacol 1983 May
PMID:Identification of 2-imidazolines as anti-sickling agents. 686 16

Fetal haemoglobin (Hb F) levels shows significant variations in health and disease states. In this study we investigated Hb F level in 75 cord bloods, 1266 healthy individuals, 1582 Hb S heterozygotes, 464 sickle cell anaemia, 93 Hb S/beta(0) -thalassaemia and 65 beta-thalassemia major patients. The age range of the study groups varied from newborn to over 60 years of age. Hb F level was measured by an alkali denaturation procedure and by radial immunodiffusion. The ratio of the level of G gamma-globin chains to the level of A gamma-globin chains (G gamma/A gamma) was determined in the patients group by high performance liquid chromatography. The Hb F level was significantly higher in the sickle cell anaemia and beta-thalassemia major patients compared to the Hb S heterozygotes and the normal individuals. Within each group Hb F level was higher in the female population compared to the age-matched male groups. This difference was statistically significant (P < 0.05) in the sickle cell disease patients and beta-thalassemia major patients but not in the normal individuals. After the age of 30 years, the difference in the value of Hb F in the male and female population become more apparent (P < 0.05) in the sickle cell disease and beta-thalassaemia major patients. No statistically significant sex differences were found in the G gamma/A gamma ratio in the patient groups, and the range of G gamma/A gamma ratio in the patients groups were similar to those in the control group. The results showed that age, sex and genetic disorders of haemoglobin are factors that affect Hb F level and indicate the possible involvement of an X-linked factor in control of Hb F production.
Mol Cell Biochem 1994 Jun 29
PMID:Fetal haemoglobin level--effect of gender, age and haemoglobin disorders. 753 Aug 9

Sickle cell anaemia (SCA) exhibits significant variations in clinical presentation in different populations for which several genetic factors including SCA-associated alpha- and beta-thalassaemias, G-6-PD deficiency and elevated Hb F level have been implicated as possible ameliorating factors. Saudi Arabia is unique in that mild and severe forms of the disease occur at a high frequency. We investigated the G gamma/A gamma ratio and Hb F level and correlated these values with the severity of SCA. The results showed that Hb F level varies significantly in both groups of patients with no evident correlation with the mild clinical manifestations. However, G gamma/A gamma ratio correlated significantly with the disease severity where a high ratio was observed in patients with the mild and a low ratio in patients with the severe disease. The results are evaluated and discussed in the light of correlation studies and regression analysis.
Mol Cell Biochem 1993 Jul 07
PMID:Does G gamma/A gamma ratio and Hb F level influence the severity of sickle cell anaemia. 769 72

Permanent correction of genetic deficiencies of the hematopoietic system requires gene transfer into stem cells and long-term lineage specific expression after autologous transplantation. However, progress to develop gene therapy protocols has been hampered by the absence of in vivo assays that detect genetically deficient human hematopoietic stem cells and their diseased differentiated progeny. The establishment of systems to transplant human cells into immune-deficient SCID mice provides such an assay. We report that primitive bone marrow cells from beta-thalassemia major and sickle cell anemia patients engraft immune-deficient mice, giving rise to high levels of human erythroid and myeloid cells in response to treatment with human cytokines. The bone marrow of transplanted mice contained the entire erythroid lineage from BFU-E to mature erythrocytes expressing human gamma, beta or beta s-globin. Moreover, human erythroid cells from mice transplanted with sickle cell anemia bone marrow showed characteristic sickling under reducing conditions in an in vitro assay. This model provides a powerful in vivo system that can be used to evaluate the efficiency of globin gene transfer into primitive human hematopoietic cells, lineage-specific expression in mature erythrocytes, and ultimately correction of the cellular defect found in the erythroid lineage.
Hum Mol Genet 1995 Feb
PMID:Engraftment of immune-deficient mice with primitive hematopoietic cells from beta-thalassemia and sickle cell anemia patients: implications for evaluating human gene therapy protocols. 775 63


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