Molecular pathology of sickle cell disease: During sickle cell anemia, which amino acid substitution occurs in the β-globin chain of hemoglobin?
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AGlutamic acid → valine at position 6 (Glu6Val)
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BValine → glutamine at position 6
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CAspartic acid → glutamic acid at position 6
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DGlutamic acid → aspartic acid at position 6
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ELysine → threonine at position 6
Answer
Correct Answer: Glutamic acid → valine at position 6 (Glu6Val)
Explanation
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:
Recall that normal β-globin has glutamic acid at position 6.In HbS, glutamic acid (acidic, charged) is replaced by valine (nonpolar).Choose the option stating Glu → Val at position 6.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)