Sickle cell disease
Sickle cell anemia (also called homozygous sickle cell disease or HbSS disease) is the most common form of sickle cell disease. This form is caused by a particular variant in the HBB gene that results in the production of an abnormal version of beta-globin called hemoglobin S (HbS). In people with this condition, hemoglobin S replaces both beta-globin subunits in hemoglobin.
The variant that causes hemoglobin S changes a single protein building block (amino acid) in beta-globin. Specifically, the amino acid glutamic acid is replaced with the amino acid valine at position 6 in beta-globin, written as Glu6Val (E6V). Replacing glutamic acid with valine causes the abnormal hemoglobin S subunits to stick together and form long, rigid molecules that bend red blood cells into a sickle or crescent shape. The sickle-shaped cells die too early, which can lead to a shortage of red blood cells (anemia). The rigid sickle-shaped cells can block small blood vessels, causing severe pain and organ damage.
Variants in the HBB gene can also cause other abnormalities in beta-globin, leading to other types of sickle cell disease. In these other types of sickle cell disease, just one beta-globin subunit is replaced with hemoglobin S. The other beta-globin subunit is replaced with a different version of beta-globin, such as hemoglobin C (HbC) or hemoglobin E (HbE).
In hemoglobin SC (HbSC) disease, the beta-globin subunits are replaced by hemoglobin S and hemoglobin C. Hemoglobin C occurs when the amino acid lysine replaces glutamic acid at position 6 in beta-globin (written as Glu6Lys or E6K). The severity of hemoglobin SC disease varies, but it can be as severe as sickle cell anemia. Hemoglobin E occurs when glutamic acid is replaced with lysine at position 26 in beta-globin (written as Glu26Lys or E26K). In some cases, hemoglobin E is present with hemoglobin S. In these cases, a person may have more severe signs and symptoms that are similar to those seen in people with sickle cell anemia, such as episodes of pain, anemia, and abnormal spleen function.
Another condition, known as hemoglobin S-beta thalassemias (HbSBetaThal), is caused when the variants that result in hemoglobin S and beta thalassemia (described above) occur together. Variants that combine sickle cell disease with beta-zero (β0) thalassemia lead to severe disease, while sickle cell disease combined with beta-plus (β+) thalassemia is generally milder.
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