In hereditary spherocytosis, which membrane protein defect is most commonly responsible for the disease?

Explanation

## Hereditary Spherocytosis: Membrane Protein Defects **Key Point:** Hereditary spherocytosis (HS) is caused by defects in the vertical linkage system of the red cell membrane, which connects the lipid bilayer to the underlying cytoskeletal network. ### Primary Defects in HS | Protein | Frequency | Consequence | | --- | --- | --- | | Ankyrin | ~50% | Disrupted spectrin-membrane anchoring — **most common** | | Spectrin | 20–30% | Loss of membrane elasticity, reduced RBC deformability | | Band 3 | 15–20% | Impaired vertical linkage | | Protein 4.2 | 5–10% | Reduced membrane stability | **High-Yield:** Ankyrin deficiency (or combined ankyrin + spectrin deficiency) is the **most common** single protein defect in hereditary spherocytosis, accounting for approximately 50% of cases (Robbins & Cotran Pathologic Basis of Disease, 10th ed.; Harrison's Principles of Internal Medicine, 21st ed.). Ankyrin links the cytoskeletal protein spectrin to the transmembrane protein Band 3; its deficiency disrupts the vertical linkage, leading to: - Loss of membrane surface area - Osmotic fragility (cells lyse in hypotonic saline at higher osmolarity than normal) - Formation of spherocytes (loss of biconcave shape) - Increased splenic sequestration and hemolysis **Clinical Pearl:** The osmotic fragility test (OFT) is a classic diagnostic tool in HS — spherocytes lyse at higher saline concentrations than normal RBCs because they have already lost membrane surface area and cannot accommodate further swelling. The EMA (eosin-5-maleimide) binding test is now preferred for diagnosis. **Mnemonic:** **ABSP** — **Ankyrin** is the most common culprit (A = Ankyrin = most common), followed by Band 3, Spectrin, and Protein 4.2. ### Pathophysiology 1. Ankyrin deficiency → disrupted vertical linkage between spectrin and Band 3 2. RBC loses biconcave shape → becomes spherical 3. Spherocytes are less deformable → trapped in splenic sinusoids 4. Splenic macrophages phagocytose → hemolysis 5. Reticulocytosis and jaundice result **Warning:** Do not confuse spectrin deficiency (second most common) with ankyrin deficiency (most common). While spectrin is the backbone of the cytoskeletal lattice, ankyrin is the most frequently mutated protein in HS. HS is a membrane disorder, not a hemoglobinopathy.