What is the molecular basis of sickle cell disease?

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-Yield:** 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.