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Red blood cell is essentially a bag of hemoglobin. The red cell is unique amongst other eukaryotic cells in that it is a nuclear without cytoplasmic structures or organelles. Red blood cell membrane is composed of 40% lipid bilayer, 52% membrane proteins and 8% carbohydrates (Delaunay, 2007, pp. 1-20). The planes of design consist of the vertical and horizontal interactions that stabilize the lipid bilayer membrane and support the structural integrity of the red cell, respectively (Mohandas & Reid 2006). The red cell membrane skeleton is a hexagonal lattice with 6 spectrin molecules, each of which is linked to the next complex by multiple spectrin tetramers. Skeleton protein include regular organization of spectrin dimmers linked horizontally by actin and protein 4.1 complexes (An, et al. 2005, pp. 10681–10688). There are many additional proteins including adducing and dematin (Reid & Mohandas 2004, pp. 93–117).
In addition, ankyrin links the lipid to the membrane skeleton via the interaction with band 3. Deformability in red cell is an important property for it to function. It is influenced by the cell shape, cytoplasmic viscosity as well as membrane deformability and stability. The red cell has a biconcave disc shape that creates an advantageous surface area to volume relationship. It also facilitates deformation whilst maintaining the surface area. The molecular basis of disorders An increased rate of red cell destruction is donated by hemolytic anemia. The disorder may be classified on the basis whether the defect is intrinsic or extrinsic to the red cell. Intrinsic defects include defects in the red cell membrane, defects in the cell enzymes as well as defects in the globin structure and synthesis (Achille, Piscopo & Loredana, 2008, p. 303). They are generally congenital although there are a few rare acquired intrinsic erythrocyte defects. These include hereditary spherocytosis, hereditary elliptocytosis, South East Asian Ovalocytosis, Acanthocytosis due to cholesterol content as well as stomatocytosis/ xerocytosis caused by hydration (An & Mohandas, 2008 pp. 367-75; An et al. 2006, pp. 5725–5732; Bosman G. et al. 2007, pp. 13-18). Hereditary spherocytosis is a congenital haemolytic anemia characterized by a reduction in red cell osmotic resistance (Eber & Lux 2004, 118–141). The inheritance can be autosomal dominant or recessive. Research has shown that it is caused by spherocytic red cells (Eyssette-Guerreau et al. 2006, pp.:439-442). In addition, the disease is represented by a variety of genetic mutations in the proteins that form the cytoskeleton. For instance, 70% of the cases of hereditary spherocytosis are linked with anykrin gene abnormalities, 20% of which occur in de novo (Ichiche et al. 2006 pp. 460-462). The protein is produced in various forms due to alternative splicing of the mRNA. Many of these mutations are private to the affected relatives. Mutations may lead to amino acid substitutions and an absence of one haploid set of anykrin (Bruce et al. 2005, pp. 1258–1263). The anion exchanger abnormalities have been reported to cause spherocytosis. The mutations either stop codons leading to the failure of synthesis of one anion exchanger 1 (AE1) haploid or mutations that prevent AE1 being conveyed to or inserted into the membrane. The mutations affect the binding site of AE1 and protein 4.2. Clinical presentations with abnormal protein 4.2, has clearly shown a disorder as an autosomal recessive pattern of inheritance Walensky, Narla & Lux 2003). Protein 4.2 gene abnormalities are caused by amino acid substitutions. Further study has suggested that the spectrin chain is responsible for heterozygotes of hereditary spherocytosis in man (Jay, 1996, pp. 853-4). Hereditary elliptocytosis is diagnosed by the appearance of the characteristic elliptocytes microscopically. Inheritance can be autosomal dominant or recessive. It is caused by spectrin, protein 4.1, glycophorin C gene abnormalities (Gallagher 2004, pp. 85–91). Due to the complexity and length of the protein 4.1 gene, only a few mutations which cause its reduction have been described and many alleles are likely to be private alleles. Some individuals with abnormal protein 4.1 have been described to be suffering from hereditary elliptocytosis. In addition, individuals who lack glycophorin C are described to have hereditary elliptocytosis. These persons also have reduced protein 4.1 as a secondary phenomenon. Diagnosis for this disease is the presence of rod shaped elliptocytes on peripheral blood smear (Gallagher 2004, pp.142–164). Southeast Asian ovalocytosis is an autosomal dominant disease characterized by the presence of typical ovalocytes in the peripheral blood film. The disorder is very common in individuals from Malaysia, Papua New Guinea and the Philippines. The heterozygote is described as asymptotic but the homozygous form is described as lethal in utero. The molecular defect has been identified as a deletion of nine codons in the anion exchanger gene that occur with a mutation (O’Donnell, et al. 1998, pp. 407–12). On the other hand, the AE1 is crucial in the maintenance of the red cell internal environment by passive anion transport and also the shape through the attachment of ankyrin and spectrin. Recent analysis has demonstrated that the mutation leads to deficient anion transport coupled with cell rigidity. Individuals who are heterozygotes have red cells that are prone to reticuloendothelial destruction when infected by malaria. Hereditary stomatocytosis defects leads to abnormal permeability of sodium and potassium cations by the red cell membrane (Delaunay, J. 2004, pp. 165–172). Some results have shown classical stomatocytes on morphological examination. Although extensive research has been carried out on this defect so far, molecular causes remain unknown (Gallagher & Lux 2003). Recent studies have suggested that, abnormalities that lead to stomatocytosis may be hydrocytosis or xerocytosis whereby the red cell either increases or decreases in shape as a result of cation permeability. Another hallmark associated with this defect is that patients with Rh deficiency syndrome have reported cases of stomatocytosis. Red cells from these patients have low concentration of Rh antigen expression. In addition, rare cases of hemolytic anemia have so far been reported. Another common dysfunction on the red cell membrane is the Paroxysmal nocturnal haemoglobinuria (PNH). The clonal nature of this acquired disorder has been shown by classic G6PD heterozygosity studies. Medically it is characterized by intravascular haemolysis, aplastic, anemia as well as venous thrombosis. In addition, experiments have shown that several proteins miss in PNH red cell such as the delay accelerating factor (CD 55), alkaline phosphatase and acetylcholinesterase (Devetten et al. 1997 pp. 99–110). These missing proteins are linked to the red cell membrane, the glycosylphosphatidylinositol (GPI) anchor. Haemolytic anemia is linked to this defect although it does not completely explain all the features of PHN (Rees et al. 2005, pp. 297–309). Treatment Patients suffering from hereditary spherocytosis and hereditary elliptocytosis are treated by splenectomy which involves red cell blood packet transfusion (Delaunay et al. 1999, pp. 209–21; Rice et al., 2003, 281–288).
The literature review of the erythrocyte membrane dysfunction has given us insight into the disease mechanisms. Some of the defects are clearly understood like hereditary spherocytosis and hereditary elliptocytosis whereas others like the PHN disorder remain unclear (Hassoun & Palek 1996, pp.129–47).
References
- Achille, I., Piscopo, C. & Loredana, B. 2008, ‘Red Cell Membrane Disorders in Pediatrics’, Pediatric Annals, vol. 37, no. 5, pp. 303-10.
- An, X., Debnath, G., Guo, X. et al. 2005, ‘Identification and functional characterization of protein 4.1R and actin-binding sites in erythrocyte beta spectrin: regulation of the interactions by phosphatidylinositol-4,5-bisphosphate’, Biochemistry, vol. 44, pp. 10681–10688.
- An, X. & Mohandas, N. 2008, ‘Disorders of red cell membrane’ British Journal of Haematology, vol. 141, no. 3, pp. 367-75.
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- Gallagher, P.G. & Jarolim, S. 2005, Red cell membrane disorders. In: Hematology, Basis Principles and Practice, 4th edn. (ed. by R. Hoffman, E.J. Benz Jr, S.J. Shattil, B. Furie, H.J. Cohen, L.E. Silverstein & P. McGlave), pp. 669–691. WB Saunders, Philadelphia, PA
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