**Question:** The type mutation that leads to replacement of valine for glutamate in sickle cell disease is

A. Glutamic Acid -> Valine
B. Glutamic Acid -> Alanine
C. Glutamic Acid -> Glycine
D. Glutamic Acid -> Aspartic Acid

**Core Concept:**
The core concept being tested is the molecular basis of sickle cell disease, specifically focusing on the genetic mutation involved in the disease. Sickle cell disease is an inherited disorder resulting from a single gene mutation. In this case, the mutation is a point mutation (point mutation refers to a single nucleotide change in the DNA sequence) that alters the amino acid sequence of hemoglobin, the protein found in red blood cells that carries oxygen.

**Why the Correct Answer is Right:**
The correct answer (A) is right because the mutation involves the substitution of Glutamic Acid (E) with Valine (V). This substitution occurs in the beta-globin chain of hemoglobin, leading to the formation of abnormal hemoglobin molecules that cause red blood cells to become rigid and sickle-shaped when oxygen levels drop, such as during hypoxia or illness. This abnormal shape causes red blood cells to pass through narrow blood vessels with difficulty, leading to blockages and pain crises.

**Why Each Wrong Option is Incorrect:**

B. This option incorrectly states that Glutamic Acid is replaced with Alanine (A). This mismatch results from a different amino acid being involved in the mutation process, which is not the correct answer.

C. The incorrect option (C) states that Glutamic Acid is replaced with Glycine (G). The correct answer involves a substitution of Glutamic Acid with Valine, not Glycine.

D. This option (D) incorrectly claims that Glutamic Acid is replaced with Aspartic Acid (D). As mentioned earlier, the correct answer involves the substitution of Glutamic Acid with Valine, not Aspartic Acid.

**Clinical Pearl:**
In sickle cell disease, the mutation leads to the formation of abnormal hemoglobin molecules, known as hemoglobin S (HbS), which leads to the characteristic sickle-shaped red blood cells. This genetic disorder is a common example of a monogenic disorder (a disorder caused by a single gene mutation) and is prevalent in regions where malaria is endemic. The mutation primarily occurs in black Africans, but it also exists in other populations like Arabs, Indians, and Turks.

**Explanation of the Correct Answer:**
The correct answer (A) represents the substitution of Glutamic Acid (E) with Valine (V) in the beta-globin chain of hemoglobin. This substitution leads to the formation of hemoglobin S (HbS), which results in the sickle-shaped red blood cells. This mutation is caused by a single nucleotide change at the sixth position of the beta-globin gene, replacing the AUG codon for methionine with TCG codon for leucine. This results in the substitution of valine for glutamic acid, causing the abnormal hemoglobin molecule (Hb