Question

Describe the genetic and molecular basis of sickle-cell anemia.

Short answer

Answer: Sickle cell anemia is caused by a mutation in the HBB gene, which leads to the production of abnormal hemoglobin called HbS. This results in red blood cells adopting a sickle shape, causing various complications. The disease is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of the mutated gene to develop the condition.

Step-by-step solution

1. Overview of Sickle Cell Anemia

Sickle cell anemia is a genetic disorder affecting red blood cells, which contain hemoglobin, a protein that carries oxygen. Healthy red blood cells have a normal biconcave shape, which helps them move easily through blood vessels. However, in sickle cell anemia, the red blood cells become sickle-shaped (like a crescent), which can cause pain, organ damage, and other complications.

2. Genetic Mutation in the HBB Gene

The genetic basis of sickle cell anemia is a mutation in the HBB (hemoglobin beta) gene located on chromosome 11. This gene provides instructions for creating a protein called beta-globin, which is a subunit of hemoglobin. Hemoglobin is a tetramer composed of two alpha-globin and two beta-globin subunits. A single base change in the DNA sequence of the HBB gene – from an adenine (A) to a thymine (T) – results in the change from a glutamic acid to a valine at the 6th position of the beta-globin protein.

3. Abnormal Hemoglobin Formation (HbS)

The mutation in the HBB gene leads to the production of an abnormal hemoglobin known as HbS (sickle hemoglobin), which occurs due to the single amino acid substitution (glutamic acid to valine) in the beta-globin chain. This small change in the protein's structure significantly affects its properties. Under low oxygen conditions, HbS molecules tend to aggregate and form long fibers that deform the red blood cells into a sickle shape.

4. Sickle Cell Formation and Complications

Sickle-shaped red blood cells have a shorter lifespan compared to healthy biconcave red blood cells. This leads to anemia, a deficiency of red blood cells, as the bone marrow is unable to produce red blood cells at the same rate as they are destroyed. Additionally, the sickle-shaped cells can become stuck in small blood vessels, blocking blood flow and causing pain, swelling, organ damage, and other health issues.

5. Inheritance Pattern

Sickle cell anemia is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of the mutated gene to develop the condition. An individual with only one mutated copy of the gene is said to have sickle cell trait – they usually do not display symptoms of the disorder but can pass the mutated gene onto their offspring. If both parents have sickle cell trait, their child has a 25% chance of inheriting two copies of the mutated gene and developing sickle cell anemia, a 50% chance of inheriting sickle cell trait, and a 25% chance of inheriting two normal copies of the gene.