A child with nephrotic syndrome has normal-appearing glomeruli on light microscopy, effacement of podocyte foot processes on EM, and negative immunofluorescence. In steroid-resistant cases, which gene mutation should be screened?

• A NPHS1 (nephrin)
• B WT1
• C COL4A3
• D NPHS2 (podocin) ✓

Explanation

Podocin (NPHS2) mutations are the most common cause of autosomal recessive steroid-resistant focal segmental glomerulosclerosis (FSGS), accounting for up to 45% of familial pediatric FSGS. Podocin scaffolds the slit diaphragm by linking nephrin to lipid rafts; its absence disrupts signaling and causes foot process effacement. NPHS1 (nephrin) mutations cause congenital nephrotic syndrome of the Finnish type (massive proteinuria at birth). WT1 mutations cause Denys-Drash syndrome (FSGS + diffuse mesangial sclerosis + Wilms tumor risk). COL4A3 mutations cause Alport syndrome (hematuria, progressive renal failure, and hearing loss).

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

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