The Mutation that Causes Sickle Cell Anemia
More specifically, beta-globin, one of the two polypeptides that is coded by the HBB gene, becomes defective as a consequence of a single DNA base, point mutation in the sixth codon of the HBB gene: adenine is changed into thymine. This, in turn, leads to a mutation in the finished beta-globin polypeptide: an amino acid substitution where glutamic acid is replaced with valine at position 6 in beta-globin, as shown in the following figure.
Figure 5 (Carr): Depicts the amino acid substitution that characterizes Hemoglobin S
This missense mutation creates the defective beta-globin Hemoglobin S (Hb S), and when deoxygenated, the solubility of Hb S tends to decrease. A gel-like substance called tactoids that contains Hb crystals is then formed. This in turn causes hemoglobin molecules to clump together within red blood cells when oxygen levels in the blood lower. This also occurs because valine is hydrophobic, whereas glutamic acid is hydrophilic. As a result, the hemoglobin molecules form long, rigid strands which cause the red blood cells to lose their normal shape and become sickle-shaped (Barrett).
Sickle-shaped cells are more rigid, stiff, and elongated than normal red blood cells. They also have a shorter life span than normal red blood cells due to these qualities—sickle cells survive around 10 to 12 days while normal red blood cells can last up to approximately 120 days. Due to their rigid, stiff, and elongated characteristics, sickle cells can often become trapped in small blood vessels, such as capillaries. Oxygenated blood would not be able to reach various tissues and organs as a consequence. This can create several complications, as mentioned in the Introduction, such as stroke, an impaired immune system, painful crises, an enlarged spleen, acute chest syndrome, and other problems.
In sickle cell anemia, both beta-globin subunits become replaced by Hb S. When one beta-globin subunit is replaced with the Hb S and the other subunit remains unaffected, a person is a carrier of the sickle cell trait. Other types of sickle cell disease occur when the other subunit is replaced with different types of mutated beta-globin, such as Hemoglobin C or Hemoglobin E. For example, when one beta globin subunit is replaced with Hb S and other is replaced with Hemoglobin C, a person has Hemoglobin SC disease, which can be as severe as sickle cell anemia. All these mutations are caused by different one amino acid substitutions.