Sickle-cell anemia is primarily caused by a genetic mutation in the hemoglobin gene, specifically in the beta-globin subunit. The normal adult hemoglobin molecule is composed of two alpha-globin subunits and two beta-globin subunits (hemoglobin A), encoded by the HBB gene.
The genetic basis of sickle-cell anemia involves a single nucleotide substitution in the HBB gene. This mutation results in the substitution of a single amino acid in the beta-globin chain. Specifically, adenine (A) is substituted for thymine (T) at the sixth codon of the beta-globin gene, leading to the replacement of glutamic acid with valine at the sixth position of the beta-globin subunit.
This mutation results in the production of abnormal hemoglobin known as hemoglobin S (HbS), rather than the normal hemoglobin A. Hemoglobin S tends to polymerize under conditions of low oxygen tension, causing the affected red blood cells to become rigid and assume a sickle shape. These sickled red blood cells are less flexible and can block small blood vessels, leading to tissue damage, pain, and other complications associated with sickle-cell disease.
Sickle-cell anemia is an autosomal recessive genetic disorder, meaning that individuals must inherit two copies of the mutated HBB gene (one from each parent) to develop the disease. Individuals who inherit one normal copy of the HBB gene and one mutated copy are carriers of the sickle-cell trait. They may have some resistance to malaria, as the presence of sickle hemoglobin can inhibit the growth of the malaria parasite within red blood cells. However, carriers of the sickle-cell trait do not typically experience the symptoms of sickle-cell disease.
