Sickle Cell Mutation: β-Globin Gene Change

Sickle cell syndromes arise from a single point mutation in the β-globin gene (HBB), producing abnormal hemoglobin S (HbS) in place of normal HbA. The correct option is "Sixth amino acid-glutamic acid is replaced by valine."

Analysis of Options

• Ninety eighth amino acid-valine is replaced by methionine: Incorrect. This describes a different, unrelated hemoglobin variant type of substitution and has no role in sickle cell disease.
• Twenty-sixth amino acid-glutamic acid is replaced by lysine: Incorrect. This is the mutation seen in Hemoglobin E (HbE), a distinct hemoglobinopathy affecting the β-globin gene at codon 26, not sickle cell disease.
• Sixth amino acid-glutamic acid is replaced by lysine: Incorrect. A lysine substitution at position 6 corresponds to Hemoglobin C (HbC), a different structural hemoglobin variant, not HbS.
• Sixth amino acid-glutamic acid is replaced by valine: Correct. Sickle cell disease results from a missense mutation (GAG→GTG) at codon 6 of the β-globin gene, causing substitution of the hydrophilic glutamic acid by the hydrophobic amino acid valine. This single amino acid change causes deoxygenated HbS molecules to polymerize, distorting red blood cells into the characteristic sickle shape responsible for the clinical features of sickle cell syndromes.

Conclusion

The β⁶ Glu→Val substitution is the defining molecular lesion of sickle cell hemoglobin (HbS), making "Sixth amino acid-glutamic acid is replaced by valine" the correct answer.