Molecular basis of sickle cell anemia Which specific change in hemoglobin leads to sickle cell disease?

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:

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)