Sickle Cell Anaemia

Abstract

Sickle cell anaemia is a genetic disease, whose indispensable feature is the presence of a mutation in the beta globin gene that specifies one of the chains of haemoglobin. This mutation endows the haemoglobin with a new property: the capacity of polymerizing when deoxygenated. This mutation has several untoward consequences: haemolytic anaemia, acute chest syndrome, stroke, renal insufficiency, leg ulcers, osteonecrosis, etc. Lifespan is compromised and the only accepted treatment is hydroxyurea, which is capable of ameliorating the phenotype and extending the life of the patient.

Figure 1.

Deoxygenated red cell containing over 90% HbS and observed by Nomarski optics. Notice that the red cells are deformed, some with a ‘sickle’ shape; but more frequently with multiple protuberances. Each one of these contains a fascicle of sickle fibres, the product of the polymerization of deoxyHbS.

Figure 2.

Haplotypes of the β‐gene cluster. The β‐gene cluster corresponds to a 60 kb stretch of DNA that contains the β‐gene and other β‐like globin genes. Depicted by arrows are also the location of the sites recognized by several endonuclease enzymes. These sites are polymorphic in human populations, which means that they can be present (+) or absent (−) in different individuals. Haplotypes corresponds to the set of + and − sites. Although about 20 different ones are found in different ethnic groups, only 5–7 are frequent. The βS gene is linked over 90% of the time to a haplotype present in the specific geographical area, depicted as Senegal, Benin, Bantu or Arab‐India. The remaining are very likely to have arisen by recombination in a ‘hot site’ around the δ gene.

Figure 3.

Kidney from a transgenic sickle mouse, in which the medulla exhibits areas of vascular obstruction.

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Further Reading

Atweh GF, DeSimone J, Saunthararajah Y et al. (2003) Hemoglobinopathies. American Society for Hematological Education Program 14–39. Review (solicited contribution).

Chen Q, Bouhassira EE, Besse A et al. (2004) Generation of transgenic mice expressing human hemoglobin E. Blood Cells Molecules and Diseases 33: 303–307.

Chen Q, Vekilov PG, Nagei RL and Hirsch RE (2004) Liquid–liquid phase separation in hemoglobins: distinct aggregation mechanisms of the beta6 mutants. Biophys Journal 86: 1702–1712.

Embury SH, Clark MR, Monroy G and Mohandas N (1984) Concurrent sickle cell anemia and ‐thalassaemia: effect on pathological properties of sickle erythrocytes. Journal of Clinical Investigation 73: 116–123.

Fablet C, Chen Q, Baudin‐Creuza V et al. (2003) Beta7E‐beta132K salt bridge and sickle haemoglobin stability and conformation. British Journal of Haematology 122: 317–325.

Feeling‐Taylor AR, Yau ST, Petsev DN et al. (2004) Crystallization mechanisms of hemoglobin C in the R state. Biophys Journal 87: 2621–2629.

Forget BG, Higgs DR, Nagel RL and Steinberg MH (eds) (1999) Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management. Cambridge, UK: Cambridge University Press.

Hebbel RP (1994) Sickle cell adherence. In: Embury SH, Hebbel RP and Mohandas N (eds) Sickle Cell Disease: Basic Principles and Clinical Practice. New York: Raven Press.

Hofrichter J, Ross PD and Eaton WA (1974) Kinetics and mechanism of deoxyhemoglobin S gelation: a new approach to understanding sickle cell disease. Proceedings of the National Academy of Sciences of the USA 71: 4864–4868.

Imren S, Fabry ME, Westerman KA et al. (2004) High‐level beta‐globin expression and preferred intragenic integration after lentiviral transduction of human cord blood stem cells. Journal of Clinical Investigation 114: 953–962.

Kaul DK, Fabry ME and Nagel RL (1989) Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications. Proceedings of the National Academy of Sciences of the USA 86: 3356–3360.

Kaul DK, Liu XD, Chang HY, Nagel RL and Fabry ME (2004) Effect of fetal hemoglobin on microvascular regulation in sickle transgenic‐knockout mice. Journal of Clinical Investigation 114: 1136–1145.

Nagel RL (1994) Origins and dispersion of the sickle gene. In: Embury SH, Hebbel RP, Mohandas N and Steinberg MH (eds) Sickle Cell Disease: Basic Principles and Clinical Practice, chap. 24, pp. 353–380. New York: Raven Press, Ltd.

Nagel RL (2004) Beta‐globin‐gene haplotypes, mitochondrial DNA, the Y‐chromosome: their impact on the genetic epidemiology of the major structural hemoglobinopathies. Cell and Molecular Biology (Noisy‐le‐grand) 50: 5–21.Review, (solicited contribution).

Nagel RL, Fabry MF, Pagnier J et al. (1985) Hematologically and genetically distinct forms of sickle cell anemia in Africa: the Senegal type and the Benin type. New England Journal of Medicine 312: 880–886.

Oh IH, Fabry ME, Humphries RK et al. (2004) Expression of an anti‐sickling beta‐globin in human erythroblasts derived from retrovirally transduced primitive normal and sickle cell disease hematopoietic cells. Experimental Hematology 32: 461–469.

Romero JR, Suzuka SM, Nagel RL and Fabry ME (2004) Expression of HbC and HbS, but not HbA, results in activation of K–Cl cotransport activity in transgenic mouse red cells. Blood 103: 384–390.

Rybicki AC, Fabry ME, Does MD, Kaul DK and Nagel RL (2003) Differential gene expression in the kidney of sickle cell transgenic mice: upregulated genes. Blood Cells Molecules and Diseases 31: 370–380.

Serjeant G, Serjeant B, Stephens A et al. (1996) Determinant of haemoglobin level in steady state homozygous sickle cell disease. British Journal of Haematology 92: 143–149.

Srinivasulu S, Manjula BN, Nagel RL et al. (2004) Hemoglobin Einstein: semisynthetic deletion in the B‐helix of the alpha‐chain. Protein Science 13: 1266–1275.

Steinberg MH, Adams JG and Lovell WJ (1977) Sickle cell anemia: erythrokinetics, blood volumes, and a study of possible determinants of severity. American Journal of Hematology 2: 17–23.

Stuart MJ and Nagel RL (2004) Sickle‐cell disease. Lancet 364: 1343–1360.Review..

Vichinsky EP, Haberkern CM, Neumayr L et al. (1995) A comparison of conservative and aggressive transfusion regimens in the peri‐operative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. New England Journal of Medicine 333: 206–213.

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How to Cite close
Nagel, Ronald L(Jan 2006) Sickle Cell Anaemia. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0001454]