A 25-year-old man with nephrotic syndrome undergoes renal biopsy showing segmental sclerosis and hyalinosis in some glomeruli on PAS stain, with foot process effacement on EM. Mutations in which structural protein are commonly identified in the hereditary forms of this condition?

• A Type IV collagen (COL4A3)
• B Nephrin (NPHS1) ✓
• C Alpha-actinin 4 (ACTN4)
• D WT1 transcription factor

Explanation

Focal segmental glomerulosclerosis (FSGS) in hereditary forms most commonly involves mutations in NPHS1 (nephrin), a key component of the slit diaphragm that bridges adjacent podocyte foot processes. Nephrin deficiency disrupts the filtration barrier, leading to massive proteinuria. COL4A3 mutations cause Alport syndrome. ACTN4 mutations cause a rare autosomal dominant FSGS. WT1 mutations cause Denys-Drash syndrome, which can also manifest with FSGS but through a different mechanism.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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