In hereditary spherocytosis (HS) due to ankyrin-1 mutation, the molecular defect leads to spherocyte formation through which primary mechanism?

• A Deficiency of ankyrin causes complement dysregulation, leading to direct C3b-mediated lipid bilayer lysis
• B Ankyrin mutation activates calpain-mediated cleavage of spectrin heterodimers, causing horizontal linkage failure
• C Loss of spectrin-ankyrin-band 3 vertical linkage destabilises lipid bilayer-membrane skeleton attachment, causing membrane vesiculation and surface area loss ✓
• D Reduced ankyrin leads to defective ATP-dependent flippase activity, altering phospholipid asymmetry

Explanation

Ankyrin-1 forms the critical vertical link connecting the spectrin-actin cytoskeleton to band 3 (the major transmembrane protein) in the red cell membrane. Ankyrin mutations weaken this vertical linkage, reducing membrane stability at the lipid bilayer-cytoskeleton interface. This causes progressive release of lipid bilayer vesicles (microspherocytosis), reducing the surface-area-to-volume ratio and producing spherocytes with decreased deformability. These cells are mechanically trapped in the splenic sinusoids and destroyed by macrophages (extravascular haemolysis). Complement is not directly involved; calpain-mediated spectrin cleavage and flippase defects are not the primary mechanism in HS.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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