## **Core Concept**
Sickle cell anemia is a genetic disorder caused by a mutation in the *HBB* gene that codes for the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin, known as sickle hemoglobin or hemoglobin S (HbS), which polymerizes under low oxygen conditions, causing red blood cells to assume a sickle shape. The disorder affects hemoglobin synthesis.

## **Why the Correct Answer is Right**
The correct answer involves the replacement of glutamic acid with valine at position 6 of the beta-globin chain due to a point mutation in the *HBB* gene. This substitution of glutamic acid (a negatively charged amino acid) with valine (a nonpolar amino acid) results in the production of HbS. This change causes hemoglobin to polymerize under deoxygenated conditions, leading to the sickling of red blood cells.

## **Why Each Wrong Option is Incorrect**
- **Option A:** This option does not accurately describe the specific amino acid substitution seen in sickle cell anemia.
- **Option B:** This option suggests a different substitution that is not associated with sickle cell anemia.
- **Option C:** While similar, this does not accurately represent the mutation causing sickle cell disease.

## **Clinical Pearl / High-Yield Fact**
A key clinical pearl is that sickle cell anemia is an autosomal recessive disorder, meaning that a person must inherit two mutated copies of the *HBB* gene (one from each parent) to express the disease. Carriers, who have one normal and one mutated gene, typically have a milder form of the disease known as sickle cell trait.

## **Correct Answer:** . Glutamic acid replaced by Valine.