Molecular basis of sickle cell anemia Which specific change in hemoglobin leads to sickle cell disease?
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AA point mutation in the beta chain (Glu→Val at position 6)
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BA large deletion within the beta chain gene
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CReplacement of the beta chain by a delta chain
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DPost-translational glycation of the alpha chain only
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EInsertion of an extra intron in HBB mRNA
Answer
Correct Answer: A point mutation in the beta chain (Glu→Val at position 6)
Explanation
Introduction / Context:Sickle cell anemia is a classic example linking a single nucleotide polymorphism to a protein's altered physicochemical properties and a systemic phenotype.
Given Data / Assumptions:
- The affected gene is HBB (beta-globin).
- The disease phenotype arises from altered hemoglobin polymerization under deoxygenation.
Concept / Approach:A missense mutation substitutes valine for glutamic acid at position 6 of beta-globin (E6V). The loss of negative charge introduces a hydrophobic patch, promoting HbS polymer formation, red cell deformation, and vaso-occlusion.
Step-by-Step Solution:
Identify chain: beta-globin.Identify change: Glu6→Val (single point mutation).Connect to phenotype: polymerization of deoxy-HbS leads to sickling.Verification / Alternative check:Electrophoresis and DNA sequencing confirm the specific E6V substitution in HbS.
Why Other Options Are Wrong:
- Large deletion: not the canonical cause of sickle cell disease.
- Delta-chain replacement: relates to HbA2, not sickle cell pathogenesis.
- Alpha-chain glycation: associated with diabetes biomarkers, not sickling.
- Extra intron insertion: not a known mechanism here.
Common Pitfalls:Confusing sickle cell (E6V) with thalassemias (often deletions or splicing defects).
Final Answer:A point mutation in the beta chain (Glu→Val at position 6)