Molecular pathology of sickle cell disease: During sickle cell anemia, which amino acid substitution occurs in the β-globin chain of hemoglobin?

Introduction / Context:Sickle cell disease is a classic example linking a single nucleotide change to a specific amino acid substitution and a profound clinical phenotype. Recognizing the exact substitution is foundational in genetics and molecular medicine education.

Given Data / Assumptions:

• The mutation is in the β-globin gene (HBB).
• The affected residue is at position 6 of the β chain.
• A nonpolar residue replaces a negatively charged residue.

Concept / Approach:A single A→T transversion in codon 6 alters the codon from GAG (glutamic acid) to GTG (valine). The resulting Glu6Val substitution creates a hydrophobic patch on deoxygenated hemoglobin S (HbS), promoting polymerization, red cell sickling, hemolysis, and vaso-occlusion.

Step-by-Step Solution:

Verification / Alternative check:Electrophoretic mobility of HbS differs from HbA due to the charge change, supporting the identity of the substitution; DNA sequencing confirms the A→T transversion.

Why Other Options Are Wrong:

• Valine → glutamine, Asp → Glu, or Glu → Asp do not match the known sickle mutation and would not create the same hydrophobic effect.
• Lys → Thr at position 6 is unrelated to HbS.

Common Pitfalls:Confusing glutamine (neutral amide) with glutamic acid (acidic); mixing up the position or chain (α vs β).

Final Answer:Glutamic acid → valine at position 6 (Glu6Val)