Inherited Defects in Hemoglobin Structure and Function

A number of hemoglobin diseases are produced by inherited (congenital) defects in the protein part of hemoglobin. Sickle-cell anemia—a disease occurring almost exclusively in blacks and carried in a recessive state by 8% to 11% of the African-American population—for example, is caused by an abnormal form of hemoglobin called hemoglobin S. Hemoglobin S differs from normal hemoglobin A in only one amino acid: valine is substituted for glutamic acid in position 6 on the beta chains. This amino acid substitution is caused by a single base change in the region of DNA that codes for the beta chains.

Under conditions of low blood PO2, hemoglobin S comes out of solution and cross-links to form a "paracrystalline gel" within the red blood cells. This causes the characteristic sickle shape of

Table 16.9 Factors That Affect the Affinity of Hemoglobin for Oxygen and the Position of the Oxyhemoglobin Dissociation Curve



Position of Curve




Shift to the right

Called the Bohr effect; increases oxygen delivery during hypercapnia



Shift to the right

Increases oxygen unloading during exercise and fever



Shift to the right

Increases oxygen unloading when there is a decrease in total hemoglobin or total oxygen content; an adaptation to anemia and high-altitude living

red blood cells (fig. 16.36) and makes them less flexible and more fragile. Since red blood cells must be able to bend in the middle to pass through many narrow capillaries, a decrease in their flexibility may cause them to block small blood channels and produce organ ischemia. The decreased solubility of hemoglobin S in solutions of low Po2 is used in the diagnosis of sickle-cell anemia and sickle-cell trait (the carrier state, in which a person has the genes for both hemoglobin A and hemoglobin S). Sickle-cell anemia is treated with the drug hydroxyurea, which stimulates the production of gamma chains (characteristic of hemoglobin F) in place of the defective beta chains of hemoglobin S.

Thalassemia is any of a family of hemoglobin diseases found predominantly among people of Mediterranean ancestry. In alpha thalassemia, there is decreased synthesis of the alpha chains of hemoglobin, whereas in beta thalassemia the synthesis of the beta chains is impaired. one of the compensations for thalassemia is increased synthesis of gamma chains, resulting in the retention of large amounts of hemoglobin F (fetal hemoglobin) into adulthood.

Some types of abnormal hemoglobins have been shown to be advantageous in the environments in which they evolved. A person who is a carrier for sickle-cell anemia, for example (and who therefore has both hemoglobin A and hemoglobin S), has a high resistance to malaria. This is because the parasite that causes malaria cannot live in red blood cells that contain hemoglobin S.

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