Peripheral smear of a patient with hereditary spherocytosis (HS) is examined. Flow cytometry using eosin-5-maleimide (EMA) binding shows reduced fluorescence. Which membrane protein deficiency most commonly underlies HS in Northern European populations?

• A Band 3 protein (AE1/SLC4A1) deficiency
• B Protein 4.2 deficiency (EPB42 mutations)
• C Alpha-spectrin deficiency (SPTA1 mutations)
• D Ankyrin-1 deficiency (ANK1 mutations), accounting for ~40–65% of HS cases ✓

Explanation

Ankyrin-1 (ANK1) mutations are the most common cause of hereditary spherocytosis in Northern European populations, accounting for 40–65% of cases. Ankyrin links the cytoskeletal spectrin network to the Band 3 integral membrane protein; its deficiency destabilises the lipid bilayer, leading to membrane vesiculation and spherocyte formation. EMA binds Band 3, and EMA binding is reduced in HS because Band 3 is secondarily reduced even when the primary defect is in ankyrin. Band 3 mutations are the next most common cause (~25%); protein 4.2 defects predominate in Japanese HS; alpha-spectrin defects are less common.

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

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