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**69**

**1. Introduction**

**Chapter 5**

*Mark D. Scott*

**Abstract**

Model Human β Thalassemic

Normal Erythrocytes

Erythrocytes: Effect of Unpaired

Purified α-Hemoglobin Chains on

β thalassemias arise from genetic defects that interfere with the synthesis of the β hemoglobin chain and the subsequent production of the normal α2β2 hemoglobin tetramer. As a consequence of this decreased β-chain synthesis, unpaired α-hemoglobin chains are found within the red blood cell (RBC). The unstable α-chains are associated with a number of cellular defects, including: membranebound globin; membrane thiol oxidation; altered cytoskeletal proteins; decreased cellular and membrane deformability; and increased susceptibility to both endogenous and exogenous oxidants. Surprisingly, while significant injury to human thalassemic RBC arise from the unpaired α-chains, the underlying intra-RBC mechanisms are not easily studied in patient samples or in mouse models. To better study the *fate of excess α-chains* in human RBC, the model β Thalassemic cell was developed. Model human β thalassemic RBC is made by entrapping purified human α-chains within normal RBC via osmotic lysis and resealing. This human model allows for the systematic examination of the mechanisms underlying the α-chain mediated damage in the β thalassemic RBC. Studies utilizing the model β thalassemic RBC have demonstrated that the α-chains give rise to an iron and glutathione-

dependent, self-amplifying and self-propagating oxidative reaction.

oxidation, free radicals, glutathione, deformability

**Keywords:** β thalassemia, α-hemoglobin chains, iron, red blood cell, erythrocyte,

The thalassemias are a major cause of morbidity and mortality throughout much of the world [1–9]. Thalassemias are characterized by the disruption of the synthesis of normal adult hemoglobin (HbA; an α2β2 tetramer; **Figure 1**) consequent to a diverse array of genetic mutations/deletions to either the β or α-hemoglobin chain genes (Chromosomes 11 and 16, respectively). As a consequence of reduced/absent production of β-chains, β thalassemia is characterized by the presence of highly unstable monomeric α-chains as these chains cannot self-associate and indeed require a chaperone protein to prevent precipitation [10]. In contrast, α thalassemia is characterized by the presence of relatively stable tetrameric β chains. Interestingly, as schematically shown in **Figure 1**, unlike most genes, there are four copies of the α-globin genes;
