## Membrane Protein Defects in Hereditary Spherocytosis **Key Point:** Hereditary spherocytosis (HS) is caused by defects in RBC membrane skeletal proteins, most commonly spectrin, leading to loss of the biconcave shape and formation of rigid spherocytes. ### Membrane Protein Architecture The RBC membrane cytoskeleton consists of: - **Spectrin** (α and β chains) — primary structural protein forming the lattice - **Ankyrin** — links spectrin to band 3 - **Band 3** — anion exchanger; anchors membrane to cytoskeleton - **Protein 4.2** — stabilizes ankyrin-band 3 interaction - **Glycophorins** — cell surface glycoproteins ### Why Spectrin Deficiency Causes HS 1. Spectrin forms the main structural scaffold of the RBC membrane 2. Deficiency → loss of membrane stability and elasticity 3. RBC loses biconcave shape → becomes spherical 4. Spherocytes have reduced surface area-to-volume ratio 5. Osmotic fragility increases (spherocytes lyse in hypotonic solution) 6. Splenic trapping and hemolysis occur ### Frequency of Defects in HS | Protein Defect | Frequency | Inheritance | |---|---|---| | Spectrin | ~50% | AD or AR | | Ankyrin | ~25% | AD | | Band 3 | ~20% | AD | | Protein 4.2 | ~3% | AR | | RhAG | Rare | AR | **High-Yield:** Spectrin deficiency is the most common molecular defect in hereditary spherocytosis, accounting for approximately 50% of cases. ### Clinical Features **Mnemonic: SPHERES** — Spherocytes, Phototherapy (for jaundice), Hemolysis, Elevated reticulocyte count, Reduced osmotic fragility test, Extravascular hemolysis, Splenectomy (definitive treatment) **Clinical Pearl:** The osmotic fragility test shows increased fragility in HS — spherocytes lyse at higher saline concentrations than normal RBCs because they are already near their osmotic limit. **Warning:** Do not confuse HS with immune hemolytic anemias (positive DAT/Coombs test) or enzyme deficiencies like G6PD (Heinz bodies, X-linked inheritance). 
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