Figure 11-5 Scanning electron micrographs of red cells from a patient with sickle cell disease. A, Oxygenated cells are round and full. B, The classic sickle cell shape is produced only when the cells are in the deoxygenated state. See Sources & Acknowledgments.

Thalassemias, which are diseases that result from the decreased abundance of one or more of the globin chains (Case 44). The decrease can result from decreased production of a globin chain or, less commonly, from a structural variant that destabilizes the chain. The resulting imbalance in the ratio of the α:β chains underlies the pathophysiology of these conditions. Example: promoter mutations that decrease expression of the β-globin mRNA to cause β-thalassemia.

Hereditary persistence of fetal hemoglobin, a group of clinically benign conditions that impair the perinatal switch from γ-globin to β-globin synthesis. Example: a deletion, found in African Americans, that removes both the δ- and β-globin genes but leads to continued postnatal expression of the γ-globin genes, to produce Hb F, which is an effective oxygen transporter (see Fig. 11-3).

Hemoglobin Structural Variants

Variants that cause hemolytic anemia, most commonly because they make the hemoglobin tetramer unstable.

Variants with altered oxygen transport, due to increased or decreased oxygen affinity or to the formation of methemoglobin, a form of globin incapable of reversible oxygenation.

Variants due to mutations in the coding region that cause thalassemia because they reduce the abundance of a globin polypeptide. Most of these mutations impair the rate of synthesis of the mRNA or otherwise affect the level of the encoded protein.

TABLE 11-3

The Major Classes of Hemoglobin Structural Variants


*Hemoglobin variants are often named after the home town of the first patient described.

Additional β-chain structural variants that cause β-thalassemia are depicted in Table 11-5.

AD, Autosomal dominant; AR, autosomal recessive; Hb M, methemoglobin; see text.

Hemolytic Anemias

Hemoglobins with Novel Physical Properties: Sickle Cell Disease.

Clinical Features.

The Molecular Pathology of Hb S.

Sickling and Its Consequences.


Figure 11-6 The pathogenesis of sickle cell disease. See Sources & Acknowledgments.

Modifier Genes Determine the Clinical Severity of Sickle Cell Disease.

Until recently, however, it was not certain whether the variation in Hb F expression was heritable. Genome-wide association studies (GWAS) (see Chapter 10) have demonstrated that single nucleotide polymorphisms (SNPs) at three loci—the γ-globin gene and two genes that encode transcription factors, BCL11A and MYB—account for 40% to 50% of the variation in the levels of Hb F in patients with sickle cell disease. Moreover, the Hb F–associated SNPs are also associated with the painful clinical episodes thought to be due to capillary occlusion caused by sickled red cells (Fig. 11-6).

The genetically driven variations in the level of Hb F are also associated with variation in the clinical severity of β-thalassemia (discussed later) because the reduced abundance of β-globin (and thus of Hb A [α2β2]) in that disease is partly alleviated by higher levels of γ-globin and thus of Hb F (α2γ2). The discovery of these genetic modifiers of Hb F abundance not only explains much of the variation in the clinical severity of sickle cell disease and β-thalassemia, but it also highlights a general principle introduced in Chapter 8: modifier genes can play a major role in determining the clinical and physiological severity of a single-gene disorder.

BCL11A, a Silencer of γ-Globin Gene Expression in Adult Erythroid Cells.

Trisomy 13, MicroRNAs, and MYB, Another Silencer of γ-Globin Gene Expression.


Figure 11-7 A model demonstrating how elevations of microRNAs 15a and 16-1 in trisomy 13 can result in elevated fetal hemoglobin expression. Normally, the basal level of these microRNAs can moderate expression of targets such as the MYB gene during erythropoiesis. In the case of trisomy 13, elevated levels of these microRNAs results in additional down-regulation of MYB expression, which in turn results in a delayed switch from fetal to adult hemoglobin and persistent expression of fetal hemoglobin. See Sources & Acknowledgments.

Unstable Hemoglobins.


Figure 11-8 Visualization of one pathological effect of the deficiency of β chains in β-thalassemia: the precipitation of the excess normal α chains to form a Heinz body in the red blood cell. Peripheral blood smear and Heinz body preparation. AC, The peripheral smear (A) shows “bite” cells with pitted-out semicircular areas of the red blood cell membrane as a result of removal of Heinz bodies by macrophages in the spleen, causing premature destruction of the red cell. The Heinz body preparation (B) shows increased Heinz bodies in the same specimen when compared to a control (C). See Sources & Acknowledgments.

The amino acid substitution in the unstable hemoglobin Hb Hammersmith (β-chain Phe42Ser; see Table 11-3) leads to denaturation of the tetramer and consequent hemolysis. This mutation is particularly notable because the substituted phenylalanine residue is one of the two amino acids that are conserved in all globins in nature (see Fig. 11-2). It is therefore not surprising that substitutions of this phenylalanine produce serious disease. In normal β-globin, the bulky phenylalanine wedges the heme into a “pocket” in the folded β-globin monomer. Its replacement by serine, a smaller residue, creates a gap that allows the heme to slip out of its pocket. In addition to its instability, Hb Hammersmith has a low oxygen affinity, which causes cyanosis in heterozygotes.

In contrast to mutations that destabilize the tetramer, other variants destabilize the globin monomer and never form the tetramer, causing chain imbalance and thalassemia (see following section).

Variants with Altered Oxygen Transport


Hemoglobins with Altered Oxygen Affinity.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Hemoglobinopathies

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