Sickle cell anemia is a genetic blood disorder that impacts red blood cells, which transport oxygen throughout the body. This condition alters the normal, flexible disc shape of red blood cells into a rigid, crescent or “sickle” shape. This change hinders their ability to flow smoothly through blood vessels and deliver oxygen efficiently to tissues and organs. It affects millions worldwide, with a high prevalence in regions like sub-Saharan Africa, India, and the Middle East, where hundreds of thousands of infants are born with the condition annually.
The Affected Gene and Chromosome
Sickle cell anemia originates from a specific alteration in the HBB gene. This gene provides instructions for creating beta-globin, a component of hemoglobin, the protein in red blood cells that binds to oxygen. Hemoglobin in adults consists of two beta-globin and two alpha-globin subunits.
The HBB gene is situated on the short arm of chromosome 11, specifically at position 15.5. This gene is part of a larger cluster of beta-globin-like genes that regulate hemoglobin production.
The Specific Genetic Change
The precise genetic alteration causing sickle cell anemia is a single nucleotide substitution within the HBB gene. This mutation involves the replacement of an adenine (A) nucleotide with a thymine (T) nucleotide at the sixth codon of the beta-globin gene, transforming the codon from GAG to GTG.
This single codon change has a consequence at the protein level. The original GAG codon codes for the amino acid glutamic acid. The mutated GTG codon, however, codes for valine. This substitution of valine for glutamic acid at the sixth position of the beta-globin protein results in the production of an abnormal hemoglobin, known as hemoglobin S (HbS).
How the Mutation Leads to Sickle Cells
The substitution of valine for glutamic acid in the beta-globin chain alters the properties of hemoglobin, particularly when oxygen levels are low. Under deoxygenated conditions, the hydrophobic valine residues on the surface of HbS molecules become exposed. These exposed valine molecules stick together through hydrophobic interactions, causing HbS molecules to polymerize into long, rigid fibers inside red blood cells.
This polymerization distorts the red blood cells, changing their normal flexible disc shape into a stiff, sickle or crescent shape. Unlike healthy red blood cells that flex and pass through narrow blood vessels, these rigid, sickled cells become less flexible and sticky. They clump and get stuck, obstructing blood flow in small capillaries and depriving tissues and organs of oxygen.
The repeated cycles of sickling and unsickling, as red blood cells travel through areas of varying oxygen concentration, cause damage to the cell membrane, leading to increased fragility and a shortened lifespan for these cells. Normal red blood cells live for about 120 days, but sickled cells may only survive for 10 to 20 days. This premature destruction of red blood cells results in chronic anemia, a symptom of sickle cell anemia, causing fatigue, weakness, and shortness of breath.
Blockages in blood flow, known as vaso-occlusive crises, lead to pain episodes in various body parts, including the chest, abdomen, and joints. Over time, these blockages and the lack of oxygen can damage multiple organs, such as the kidneys, liver, spleen, and even the brain, leading to chronic pain, organ failure, and serious complications like stroke or acute chest syndrome.
Inheritance Pattern
Sickle cell anemia is an autosomal recessive genetic disorder. This means an individual must inherit two copies of the mutated HBB gene, one from each parent, to develop the condition. The gene is located on an autosome, a non-sex chromosome.
Individuals who inherit only one copy of the mutated HBB gene and one normal copy are considered carriers of the sickle cell trait. Carriers do not experience symptoms of sickle cell anemia because the presence of one normal gene is sufficient for producing enough functional hemoglobin. However, they can still pass the mutated gene on to their children.
If both parents are carriers of the sickle cell trait, there is a 25% chance with each pregnancy that their child will inherit two copies of the mutated gene and develop sickle cell anemia. There is also a 50% chance that the child will be a carrier, inheriting one mutated and one normal gene. There is a 25% chance that the child will inherit two normal genes and be completely unaffected.