A Combination Of The -α3.7 And -medii Alleles Causing Hemoglobin H Disease In A Brazilian Patient

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)39180832014/00984-3, FAPESP, Fundação de Amparo à Pesquisa do Estado de São PauloFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Prevalence Of α-thalassemia 3.7 Kb Deletion In The Adult Population Of Rio Grande Do Norte, Brazil

α-Thalassemia, arising from a defect in α-globin chain synthesis, is often caused by deletions involving one or both of the α-genes on the same allele. With the aim of investigating the prevalence of α-thalassemia 3.7 kb deletion in the adult population of Rio Grande do Norte, 713 unrelated individuals, between 18 and 59 years-of-age, were analyzed. Red blood cell indices were electronically determined, and A 2 and F hemoglobins evaluated by HPLC. PCR was applied to the molecular investigation of α-thalassemia 3.7 kb deletion. Eighty (11.2%) of the 713 individuals investigated presented α-thalassemia, of which 79 (11.1%) were heterozygous (-α 3.7/αα) deletions and 1 (0.1%) homozygous (-α 3.7/-α 3.7). Ethnically, heterozygous deletions were higher (24.8%) in Afro-Brazilians. Comparison of hematological parameters between individuals with normal genotype and those with heterozygous α +-thalassemia showed a statistically significant difference in the number of erythrocytes (p < 0.001), MCV (p < 0.001), MCH (p < 0.001) and Hb A 2 (p = 0.007). This study is one of the first dedicated to investigating α-thalassemia 3.7 kb deletion in the population of the State Rio Grande do Norte state. Results obtained demonstrate the importance of investigating this condition in order to elucidate the causes of microcytosis and hypochromia. © 2012, Sociedade Brasileira de Genética. Printed in Brazil.353594598Adorno, E.V., Couto, F.D., Moura Neto, J.P., Menezes, J.F., Rêgo, M., Reis, M.G., Gonçalves, M.S., Hemoglobinopathies in newborns from Salvador, Bahia, Northeast Brazil (2005) Cad Saúde Pública, 21, pp. 292-298Bezerra, C.M., Meissner, R.V., Diagnóstico molecular da talassemia alfa + (deleção-( 3.7) em indivíduos com microcitose e/ou hipocromia atendidos no Hemocentro Dalton Barbosa Cunha em Natal, Rio Grande do Norte (2010) Rev Bras Hematol Hemoter, 32, pp. 90-91. , (Abstract in English)Borg, J., Georgitsi, M., Aleporou-Marinou, V., Kollia, P., Patrinos, G.P., Genetic recombination as a major cause of mutagenesis in the human globin gene clusters (2009) Clin Biochem, 42, pp. 1839-1850Borges, E., Wenning, M.R.S.C., Kimura, E.M., Gervásio, S.A., Costa, F.F., Sonati, M.F., High prevalence of alpha-thalassemia among individuals with microcytosis and hypochromia without anemia (2001) Braz J Med Biol Res, 34, pp. 759-762Cascudo, L.C., (1984) História do Rio Grande do Norte, p. 524. , 2 edition. Fundação José Augusto, NatalCouto, F.D., Albuquerque, A.B.L., Adorno, E.V., Moura Neto, J.P., Freitas, A.L., Oliveira, J.L.B., Reis, M.G., Gonçalves, M.S., Alpha-thalassemia-2, 3.7 kb deletion and hemoglobin AC heterozygosity in pregnancy: A molecular and hematological analysis (2003) Clin Lab Haematol, 25, pp. 29-34Dacie, J.V., Lewis, S.M., (1995) Practical Haematology., p. 608. , Churchill Livingstone, EdinburghDodé, C., Krishnamoorthy, R., Lamb, J., Rochette, J., Rapid analysis of-α 3.7 thalassaemia and ttt anti3.7 triplication by enzymatic amplification analysis (1992) Br J Haematol, 83, pp. 105-111Harteveld, L.C., Higgs, D.R., H-thalassaemia (2010) Orphanet J Rare Dis, 5, pp. 1-21Higgs, D.R., H-Thalassaemia (1993) Baillière's Clin Haematol, 6, pp. 117-150Higgs, D.R., The pathopysiology and clinical features of H thalassemia (2009) Disorders of Hemoglobin, pp. 266-295. , In: Steinberg MH, Forget BG, Higgs DR and Weatherall DJ (eds) 2 nd edition. Cambridge University Press, New YorkHiggs, D.R., Weatherall, D.J., The alpha thalassaemias (2009) Cell Mol Life Sci, 66, pp. 1154-1162Mouélé, R., Pambou, O., Feingold, J., Galactéros, F., M-thalassemia in Bantu population from Congo-Brazzaville: Its interaction with sickle cell anemia (2000) Hum Hered, 50, pp. 118-125Peres, M.J., Romão, L., Carreiro, H., Picanço, I., Batalha, L., Magalhães, H.A., Martins, M.C., Lavinha, J., Molecular basis of H-thalassemia in Portugal (1995) Hemoglobin, 19, pp. 343-352Rahim, F., Microcytic hypochromic anemia patients with thalassemia: Genotyping approach (2009) J Med, 63, pp. 101-108Sankar, V.H., Arya, V., Tewari, D., Gupta, U.R., Pradhan, M., Genotyping of alpha-thalassemia in microcytic hypochromic anemia patients from North India (2006) Indian J Med Res, 47, pp. 391-395Sonati, M.F., Farah, S.B., Ramalho, A.S., Costa, F.F., High prevalence of alpha-thalassemia in a black population of Brazil (1991) Hemoglobin, 15, pp. 309-311Souza, A.E.S., Takanashi, S.Y.L., Cardoso, G., Guerreiro, J.F., S-thalassemia (3.7 kb deletion) in a population from the Brazilian Amazon region: Santarém, Pará State (2009) Genet Mol Res, 8, pp. 477-481Steinberg, M.H., Nagel, R.L., Hemoglobins of the embryo, fetus and adult (2009) Disorders of Hemoglobin, pp. 119-135. , In: Steinberg MH, Forget BG, Higgs DR and Weatherall DJ (eds) 2 nd edition. Cambridge University Press, New YorkWagner, S.C., Castro, S.M., Gonzalez, T.P., Santin, A.P., Filippon, L., Zaleski, C.F., Azevedo, L.A., Hutz, M., Prevalence of common c-thalassemia determinants in south Brazil: Importance for the diagnosis of microcytic anemia (2010) Genet Mol Biol, 33, pp. 641-645Weatherall, D.J., Clegg, J.B., Inherited haemoglobin disorders: An increasing global health problem (2001) Bull World Health Organ, 79, pp. 704-71

Red Cell Indices And Alpha-thalassemia

[No abstract available]15368769

Haptoglobin polymorphism in a HIV‐1 seropositive Brazilian population

BACKGROUND: Haptoglobin (Hp) is a plasma protein with antioxidant and immunomodulatory properties. Three main genotypes/phenotypes (Hp1‐1, Hp2‐1, Hp2‐2) show distinctive efficiencies in their activities and have been related to susceptibility and outcome in different diseases, including HIV infection. OBJECTIVE: To compare Hp genotype distribution between HIV‐1 seropositive patients and healthy controls. METHODS: 387 Brazilian HIV‐1 seropositive patients, subclassified as A, B, and C according to the Centers for Disease Control, were compared with 142 healthy controls. The influence of the polymorphism on iron status (serum iron, ferritin, transferrin, transferrin saturation), acute phase proteins (Hp, C reactive protein, fibrinogen, albumin), the HIV‐1 viral load, and CD4+ T lymphocyte counts was examined. RESULTS: Apart from finding lower Hp concentrations among individuals with genotype Hp2‐2, no other significant difference was observed. CONCLUSIONS: No association was found between Hp genotype and either HIV status or indices of HIV progression

Pipkiiα Is Widely Expressed In Hematopoietic-derived Cells And May Play A Role In The Expression Of Alpha- And Gamma-globins In K562 Cells

Characterized for the first time in erythrocytes, phosphatidylinositol phosphate kinases (PIP kinases) belong to a family of enzymes that generate various lipid messengers and participate in several cellular processes, including gene expression regulation. Recently, the PIPKIIα gene was found to be differentially expressed in reticulocytes from two siblings with hemoglobin H disease, suggesting a possible relationship between PIPKIIα and the production of globins. Here, we investigated PIPKIIα gene and protein expression and protein localization in hematopoietic-derived cells during their differentiation, and the effects of PIPKIIα silencing on K562 cells. PIPKIIα silencing resulted in an increase in α and γ globins and a decrease in the proliferation of K562 cells without affecting cell cycle progression and apoptosis. In conclusion, using a cell line model, we showed that PIPKIIα is widely expressed in hematopoietic-derived cells, is localized in their cytoplasm and nucleus, and is upregulated during erythroid differentiation. We also showed that PIPKIIα silencing can induce α and γ globin expression and decrease cell proliferation in K562 cells. © 2014 Springer Science+Business Media.39301/02/15145153Doughman, R.L., Firestone, A.J., Anderson, R.A., Phosphatidylinositol phosphate kinases put PI4,5P2 in its place (2003) Journal of Membrane Biology, 194 (2), pp. 77-89. , DOI 10.1007/s00232-003-2027-7Michell, R.H., Conroy, L.A., Finney, M., French, P.J., Bunce, C.M., Anderson, K., Baxter, M.A., Jenkinson, E.J., Inositol lipids and phosphates in the proliferation and differentiation of lymphocytes and myeloid cells (1992) Ciba Found Symp, 164, pp. 2-11. , discussion 12-16Anderson, R.A., Boronenkov, I.V., Doughman, S.D., Kunz, J., Loijens, J.C., Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes (1999) J Biol Chem, 274, pp. 9907-9910Bunce, M.W., Boronenkov, I.V., Anderson, R.A., Coordinated activation of the nuclear ubiquitin ligase Cul3-SPOP by the generation of phosphatidylinositol 5-phosphate (2008) J Biol Chem, 283, pp. 8678-8686Clarke, J.H., Wang, M., Irvine, R.F., Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases (2010) Adv Enzyme Regul, 50, pp. 12-18Ling, L.E., Schulz, J.T., Cantley, L.C., Characterization and purification of membrane-associated phosphatidylinositol-4-phosphate kinase from human red blood cells (1989) Journal of Biological Chemistry, 264 (9), pp. 5080-5088Hinchliffe, K.A., Irvine, R.F., Divecha, N., Aggregation-dependent, integrin-mediated increases in cytoskeletally associated PtdInsP2 (4,5) levels in human platelets are controlled by translocation of PtdIns 4-P 5-kinase C to the cytoskeleton (1996) EMBO Journal, 15 (23), pp. 6516-6524Wenning, M.R., Mello, M.P., Andrade, T.G., Lanaro, C., Albuquerque, D.M., Saad, S.T., Costa, F.F., Sonati, M.F., PIP4KIIA and beta-globin: Transcripts differentially expressed in reticulocytes and associated with high levels of Hb H in two siblings with Hb H disease (2009) Eur J Haematol, 83, pp. 490-493Heck, J.N., Mellman, D.L., Ling, K., Sun, Y., Wagoner, M.P., Schill, N.J., Anderson, R.A., A conspicuous connection: Structure defines function for the phosphatidylinositol-phosphate kinase family (2007) Critical Reviews in Biochemistry and Molecular Biology, 42 (1), pp. 15-39. , DOI 10.1080/10409230601162752, PII 772605596Boronenkov, I.V., Loijens, J.C., Umeda, M., Anderson, R.A., Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing Pre-mRNA processing factors (1998) Molecular Biology of the Cell, 9 (12), pp. 3547-3560York, J.D., Odom, A.R., Murphy, R., Ives, E.B., Wente, S.R., A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export (1999) Science, 285 (5424), pp. 96-100. , DOI 10.1126/science.285.5424.96Bazenet, C.E., Ruano, A.R., Brockman, J.L., Anderson, R.A., The human erythrocyte contains two forms of phosphatidylinositol-4- phosphate 5-kinase which are differentially active toward membranes (1990) J Biol Chem, 265, pp. 18012-18022Jenkins, G.H., Fisette, P.L., Anderson, R.A., Type I phosphatidylinositol 4-phosphate 5-kinase isoforms are specifically stimulated by phosphatidic acid (1994) Journal of Biological Chemistry, 269 (15), pp. 11547-11554Boronenkov, I.V., Anderson, R.A., The sequence of phos-phatidylinositol- 4-phosphate 5-kinase defines a novel family of lipid kinases (1995) J Biol Chem, 270, pp. 2881-2884Martin, T.F., PI(4,5)P(2) regulation of surface membrane traffic (2001) Curr Opin Cell Biol, 13, pp. 493-499Matsui, T., Yonemura, S., Tsukita, S., Tsukita, S., Activation of ERM proteins in vivo by Rho involves phosphatidylinositol 4-phosphate 5-kinase and not ROCK kinases (1999) Current Biology, 9 (21), pp. 1259-1262Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2-DeltaDeltaCT method (2001) Methods, 25 (4), pp. 402-408. , DOI 10.1006/meth.2001.1262Machado-Neto, J.A., Favaro, P., Lazarini, M., Costa, F.F., Olalla Saad, S.T., Traina, F., Knockdown of insulin receptor substrate 1 reduces proliferation and downregulates Akt/mTOR and MAPK pathways in K562 cells (2011) Biochim Biophys Acta, 1813 (8), pp. 1404-1411Chang, C.W., Chou, H.Y., Lin, Y.S., Huang, K.H., Chang, C.J., Hsu, T.C., Lee, S.C., Phosphorylation at Ser473 regulates heterochromatin protein 1 binding and corepressor function of TIF1beta/KAP1 (2008) BMC Mol Biol, 9, p. 61Di Pietro, R., Di Giacomo, V., Caravatta, L., Sancilio, S., Rana, R.A., Cataldi, A., Cyclic nucleotide response element binding (CREB) protein activation is involved in K562 erythroleukemia cells differentiation (2007) J Cell Biochem, 100, pp. 1070-1079Pass, M.B., Borregaard, N., Cowland, J.B., Derangement of transcription factor profiles during in vitro differentiation of HL60 and NB4 cells (2007) Leukemia Research, 31 (6), pp. 827-837. , DOI 10.1016/j.leukres.2006.07.019, PII S0145212606002670Ferreira, R., Ohneda, K., Yamamoto, M., Philipsen, S., GATA1 function, a paradigm for transcription factors in hematopoiesis (2005) Molecular and Cellular Biology, 25 (4), pp. 1215-1227. , DOI 10.1128/MCB.25.4.1215-1227.2005Stachura, D.L., Chou, S.T., Weiss, M.J., Early block to erythromegakaryocytic development conferred by loss of transcription factor GATA-1 (2006) Blood, 107 (1), pp. 87-97. , http://www.bloodjournal.org/cgi/reprint/107/1/87, DOI 10.1182/blood-2005-07-2740Bultsma, Y., Keune, W.J., Divecha, N., PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha (2010) Biochem J, 430, pp. 223-235Luoh, S.-W., Venkatesan, N., Tripathi, R., Overexpression of the amplified Pip4k2beta gene from 17q11-12 in breast cancer cells confers proliferation advantage (2004) Oncogene, 23 (7), pp. 1354-1363. , DOI 10.1038/sj.onc.1207251Clarke, J.H., Richardson, J.P., Hinchliffe, K.A., Irvine, R.F., Type II PtdInsP kinases: Location, regulation and function (2007) Biochem Soc Symp, 74, pp. 149-159Wang, M., Bond, N.J., Letcher, A.J., Richardson, J.P., Lilley, K.S., Irvine, R.F., Clarke, J.H., Genomic tagging reveals a random association of endogenous PtdIns5P 4-kinases IIalpha and IIbeta and a partial nuclear localization of the IIalpha isoform (2010) Biochem J, 430, pp. 215-22

Hb S-são Paulo: A New Sickling Hemoglobin With Stable Polymers And Decreased Oxygen Affinity

Hb S-São Paulo (SP) [HBB:c.20A > T p.Glu6Val; c.196A > G p.Lys65Glu] is a new double-mutant hemoglobin that was found in heterozygosis in an 18-month-old Brazilian male with moderate anemia. It behaves like Hb S in acid electrophoresis, isoelectric focusing and solubility testing but shows different behavior in alkaline electrophoresis, cation-exchange HPLC and RP-HPLC. The variant is slightly unstable, showed reduced oxygen affinity and also appeared to form polymers more stable than the Hb S. Molecular dynamics simulation suggests that the polymerization is favored by interfacial electrostatic interactions. This provides a plausible explanation for some of the reported experimental observations. © 2012 Elsevier Inc. All rights reserved.51912331Steinberg, M.H., (1999) New Engl. J. Med., 340, pp. 1021-1030Stuart, M.J., Nagel, R.L., (2004) Lancet, 364, pp. 1343-1360Barabino, G.A., Platt, M.O., Kaul, D.K., (2010) Annu. Rev. Biomed. Eng., 12, pp. 345-367Goossens, M., Garel, M.C., Auvinet, J., Basset, O., Ferreira Gomes, P., Rosa, J., Arous, N., (1975) FEBS Lett., 58, pp. 149-154Bookchin, R.M., Nagel, R.L., Ranney, H.M., (1967) J. Biol. Chem., 242, pp. 248-255Langdown, J.V., Williamson, D., Knight, C.B., Rubenstein, D., Carrell, R.W., (1989) Br. J. Haematol., 71, pp. 443-444Moo-Penn, W.F., Schmidt, R.M., Jue, D.L., Bechtel, K.C., Wright, J.M., Horne III, M.K., Haycraft, G.L., Nagel, R.L., (1977) Eur. J. Biochem., 77, pp. 561-566Monplaisir, N., Merault, G., Poyart, C., Rhoda, M.D., Craescu, C., Vidaud, M., Galacteros, F., Rosa, J., (1986) Proc. Natl. Acad. Sci. USA, 83, pp. 9363-9367Geva, A., Clark, J.J., Zhang, Y., Popowicz, A., Manning, J.M., Neufeld, E.J., (2004) New Engl. J. Med., 351, pp. 1532-1538Karplus, M., McCammon, J.A., (2002) Nat. Struct. Biol., 9, pp. 646-652Dacie, J.V., Lewis, S.M., (1995) Practical Haematology, , Churchill Livingstone EdinburghAdachi, K., Asakura, T., (1979) J. Biol. Chem., 254, pp. 7765-7771Miranda, S.R.P., Fonseca, S.F., Figueiredo, M.S., Yamamoto, M., Grotto, H.Z.W., Saad, S.T.O., Costa, F.F., (1997) Braz. J. Genet., 20, pp. 745-748Chong, S.S., Boehm, C.D., Higgs, D.R., Cutting, G.R., (2000) Blood, 95, pp. 360-362Kattamis, A.C., Camaschella, C., Sivera, P., Surrey, S., Fortina, P., (1996) Am. J. Hematol., 53, pp. 81-91Rossi-Fanelli, A., Antonini, E., (1958) Arch. Biochem. Biophys., 77, pp. 478-492Benesch, R.E., Benesch, R., Yu, C.I., (1969) Biochemistry-Us, 8, pp. 2567-2571Martinez, L., Andrade, R., Birgin, E.G., Martinez, J.M., (2009) J. Comput. Chem., 30, pp. 2157-2164MacKerell, A.D., Bashford, D., Bellott, M., Dunbrack, R.L., Evanseck, J.D., Field, M.J., Fischer, S., Karplus, M., (1998) J. Phys. Chem. B, 102, pp. 3586-3616Ryckaert, J.-P., Ciccotti, G., Berendsen, H.J.C., (1977) J. Comp. Phys., pp. 327-341Park, S.-Y., (2006) J. Mol. Biol., 360, pp. 690-701Humphrey, W., Dalke, A., Schulten, K., (1996) J. Mol. Graph., 14, pp. 33-38Harrington, D.J., Adachi, K., Royer, Jr.W.W., (1997) J. Mol. Biol., 272, pp. 398-407Adachi, K., Konitzer, P., Pang, J., Reddy, K.S., Surrey, S., (1997) Blood, 90, pp. 2916-2920Benesch, R., Benesch, R.E., Yu, C.I., (1968) Proc. Natl. Acad. Sci. USA, 59, pp. 526-532Edalji, R., Benesch, R.E., Benesch, R., (1976) J. Biol. Chem., 251, pp. 7720-7721Antonini, E., Brunoni, M., (1971) Hemoglobin and Myoglobin in Their Reactions with Ligands, , North-Holland Publishing Company AmsterdanCapece, L., Marti, M.A., Crespo, A., Doctorovich, F., Estrin, D.A., (2006) J. Am. Chem. Soc., 128, pp. 12455-12461Marti, M.A., Crespo, A., Capece, L., Boechi, L., Bikiel, D.E., Scherlis, D.A., Estrin, D.A., (2006) J. Inorg. Biochem., 100, pp. 761-770Young, R.C., Rachal, R.E., Del Pilar Aguinaga, M., Nelson, B.L., Kim, B.C., Winter, W.P., Castro, O., (2000) J. Natl. Med. Assoc., 92, pp. 430-435Eaton, W.A., Hofrichter, J., (1987) Blood, 70, pp. 1245-1266Kuczera, K., Gao, J., Tidor, B., Karplus, M., (1990) Proc. Natl. Acad. Sci. USA, 87, pp. 8481-8485Bihoreau, M.T., Baudin, V., Marden, M., Lacaze, N., Bohn, B., Kister, J., Schaad, O., Pagnier, J., (1992) Protein Sci., 1, pp. 145-150Salzano, F.M., Bortolini, M.C., (2002) The Evolution and Genetics of Latin American Population, , Cambridge University Press CambridgeMosca, A., Paleari, R., Ivaldi, G., Galanello, R., Giordano, P.C.P.C., (2009) J. Clin. Pathol., 62, pp. 13-1

Rare α0-thalassemia deletions detected by MLPA in five unrelated Brazilian patients

Abstract Alpha-thalassemias are among the most common genetic diseases in the world. They are characterized by hypochromic and microcytic anemia and great clinical variability, ranging from a practically asymptomatic phenotype to severe anemia, which can lead to intrauterine or early neonatal death. Deletions affecting the α-globin genes, located on chromosome 16p13.3, are the main causes of α-thalassemia. Multiplex ligation-dependent probe amplification (MLPA) can be used to detect rearrangements that cause α-thalassemia, particularly large deletions involving the whole α cluster and/or deletions in the HS-40 region. Here, MLPA was used to investigate the molecular basis of α-thalassemia in five unrelated patients, three of whom had Hb H disease. In addition to the -α3.7 deletion identified in the patients with Hb H disease, four different α0 deletions removing 15 to 225 kb DNA segments were found: two of them remove both the α genes, one affects only the regulatory element (HS-40) region, and another one extends over the entire α cluster and the HS-40 region. These results illustrate the diversity of α-thalassemia deletions in the Brazilian population and highlight the importance of molecular investigation in cases that present with microcytosis and hypochromia without iron deficiency and normal or reduced Hb A2 levels.

The Ccr5Δ32 Polymorphism In Brazilian Patients With Sickle Cell Disease

Background. Previous studies on the role of inflammation in the pathophysiology of sickle cell disease (SCD) suggested that the CCR5Δ32 allele, which is responsible for the production of truncated C-C chemokine receptor type 5 (CCR5), could confer a selective advantage on patients with SCD because it leads to a less efficient Th1 response. We determined the frequency of the CCR5Δ32 polymorphism in 795 Afro-Brazilian SCD patients followed up at the Pernambuco Hematology and Hemotherapy Center, in Northeastern Brazil, divided into a pediatric group (3 months-17 years, n = 483) and an adult group (18-70 years, n = 312). The adult patients were also compared to a healthy control group (blood donors, 18-61 years, n = 247). Methods. The CCR5/CCR5Δ32 polymorphism was determined by allele-specific PCR. Results. No homozygous patient for the CCR5Δ32 allele was detected. The frequency of heterozygotes in the study population (patients and controls) was 5.8%, in the total SCD patients 5.1%, in the children 5.4%, in the adults with SCD 4.8%, and in the adult controls 8.1%. These differences did not reach statistical significance. Conclusions. Our findings failed to demonstrate an important role of the CCR5Δ32 allele in the population sample studied here.2014Steinberg, M.H., Pathophysiologically based drug treatment of sickle cell disease (2006) Trends in Pharmacological Sciences, 27 (4), pp. 204-210Steinberg, M.H., Sickle cell anemia, the firstmolecular disease: Overviewofmolecular etiology, pathophysiology, and therapeutic approaches (2008) The Scientific World Journal, 8, pp. 1295-1324Marotta, C.A., Wilson, J.T., Forget, B.J., Weissman, S.M., Human β globin messenger RNA III. 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