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After studying this chapter, you should be able to:

  • Outline the changes in globin gene expression that occur during fetal development.

  • Explain the molecular genetics and inheritance of alpha (α)- and beta (β)-thalassemias.

  • Grasp the cellular pathogenesis of α- and β-thalassemias.

  • Describe the clinical and laboratory features of β-thalassemia minor (trait) and β-thalassemia major and the different types of α-thalassemia.

  • Understand the pathophysiologic principles underlying treatment of β-thalassemia major.

The thalassemias are an inherited group of disorders in which mutations in globin genes result in impaired hemoglobin synthesis and microcytic anemia of varying severity. The thalassemias are subdivided into alpha (α) or beta (β) according to which globin genes are defective. Heterozygotes are generally asymptomatic, whereas individuals who inherit thalassemia alleles from each parent often have life-threatening clinical manifestations. The thalassemias have attracted worldwide interest and attention because of their high prevalence and clinical importance. Moreover, an ever-expanding body of information on the molecular pathogenesis of the thalassemias has provided critical insights into fundamental problems in biology, particularly tissue-specific and development-specific gene regulation.


A diagram of the layout of the human globin genes is shown in Figure 8-1. A tandem pair of α-globin genes is located on chromosome 16, downstream from an embryonic α-like gene called zeta (ζ). The high homology of the α-globin genes leads frequently to unequal meiotic crossover, which is the basis for the deletions that cause the α-thalassemias, discussed at the end of this chapter.


Organization of the α-globin family on chromosome 16 and the β-globin family on chromosome 11. IVS, intervening segments (also called introns); ψ designates nonexpressing pseudogenes. The three exons of the globin genes are shown in pale blue.

The β-globin gene is a member of a family located on chromosome 11. As in the α-globin gene family, epsilon (ε), the most 5′ (upstream) of these genes, is expressed only in early embryos. Downstream from this gene are two tandem gamma (γ) genes whose product is found in fetal hemoglobin (Hb F, α2γ2), the hemoglobin that predominates throughout most of gestation. The delta (δ) gene product forms a minor hemoglobin component, Hb A22δ2), which has no functional importance but is useful in the diagnosis of thalassemia (discussed later in this chapter). The most 3′ (downstream) member of the family is the β gene, whose product combines with α-globin to form Hb A (α2β2), the major hemoglobin component of adult red cells.

Figure 8-2 shows the expression of globin genes during development. Throughout gestation, there is coordinated synthesis of globin products from the two chromosomes, permitting the sequential and orderly production of functional tetrameric hemoglobins. In the transition from embryo to fetus to ...

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