Recallab › Question bank › Pathology › Blood RBC › #50117
Sickle cell disease
A 14-month-old boy from central India is brought with painful symmetrical swelling of the hands and feet and low-grade fever. Haemoglobin is 7.6 g/dL with sickled forms on the film. Which molecular change underlies his disease?
- correctA. Substitution of valine for glutamic acid at position 6 of the beta globin chain
- B. A point mutation in the beta globin promoter reducing transcription
- C. Deletion of both alpha globin genes on one chromosome
- D. Substitution of lysine for glutamic acid at position 6 of the beta globin chain
Explanation
Key fact
Sickle cell disease is a single missense mutation: GAG to GTG, glutamate to valine at codon 6 of beta globin. One amino acid, one disease.
Valine for glutamic acid at position 6. Swapping a charged residue for a hydrophobic one lets deoxygenated haemoglobin polymerise.
Why
Dactylitis - hand-foot syndrome - is often the first crisis, at 6 months to 2 years.
It appears then because HbF has fallen far enough for HbS to matter.
Glutamate is charged and hydrophilic; valine is hydrophobic.
The valine creates a sticky patch that fits a pocket on an adjacent molecule.
When deoxygenated, HbS molecules polymerise into rigid fibres and distort the cell.
Early sickling is reversible on reoxygenation; repeated cycles make it permanent.
One base, one amino acid, one sticky patch
Why not the others
- B. A point mutation in the beta globin promoter reducing transcription — is a beta thalassaemia mechanism. Again a quantity problem, not a quality one.
- C. Deletion of both alpha globin genes on one chromosome — is alpha thalassaemia. It reduces the amount of normal chain rather than altering its structure.
- D. Substitution of lysine for glutamic acid at position 6 of the beta globin chain — is haemoglobin C, not S. Lysine is still charged, so it does not polymerise; HbC crystallises instead and causes a milder haemolysis.
Remember
Thalassaemia is too little normal haemoglobin; sickle cell is enough abnormal haemoglobin. Quantity against quality.
Go deeper
Heterozygotes are protected against severe Plasmodium falciparum malaria, which is why the gene persists at high frequency in malarial belts.
Hydroxyurea works by raising HbF, which interrupts the polymer.
These children are functionally asplenic from repeated infarction, so they need pneumococcal, meningococcal and Haemophilus vaccination plus penicillin prophylaxis.
Robbins, Cotran & Kumar Pathologic Basis of Disease, 11th ed. (Elsevier, 2025).