What is the molecular basis of sickle cell disease?
A. Insertion of a trinucleotide repeat in the β-globin coding sequence
B. Substitution of glutamic acid by valine at the 6th position of the β-globin chain
C. Deletion of the entire β-globin gene
D. Point mutation in the promoter region of the β-globin gene
Explanation
Molecular Basis of Sickle Cell Disease
Key Point
Sickle cell disease results from a single nucleotide substitution in the β-globin gene (GAG → GTG), causing glutamic acid (hydrophilic) to be replaced by valine (hydrophobic) at codon 6.
Consequence of the Substitution
The valine substitution causes hemoglobin S (HbS) to polymerize under low oxygen tension, forming rigid fibers that distort the RBC into the characteristic sickle shape.
Genetic Inheritance
Autosomal recessive inheritance pattern
Homozygous state (SS) → Sickle cell disease (symptomatic)
Heterozygous state (AS) → Sickle cell trait (asymptomatic, protective against malaria)
High-YieldNEET PG
This single amino acid substitution (Glu → Val at position 6) is the ONLY change in the entire β-globin protein, yet it causes severe hemolytic anemia and vaso-occlusive crises.
Clinical Pearl
The mutation is a transversion (purine to purine: A→T in the DNA template strand), resulting in the codon change GAG → GTG.
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