A child presents with nephrotic syndrome. Renal biopsy on light microscopy appears normal, but electron microscopy reveals diffuse effacement of podocyte foot processes. Which of the following podocyte-specific proteins is mutated in the autosomal recessive congenital form of this condition?

• A Podocin (NPHS2), encoded by NPHS2 gene on chromosome 1
• B Alpha-actinin-4, encoded by ACTN4 gene
• C WT1 transcription factor
• D Nephrin (NPHS1), encoded by NPHS1 gene on chromosome 19 ✓

Explanation

Congenital nephrotic syndrome of the Finnish type is caused by mutations in NPHS1, encoding nephrin — a transmembrane protein forming the zipper-like structure of the slit diaphragm between podocyte foot processes. Loss of nephrin causes foot process effacement and massive proteinuria from birth. NPHS2 (podocin) mutations cause early-onset (infantile/childhood) steroid-resistant nephrotic syndrome, not strictly congenital. ACTN4 and WT1 mutations cause adult-onset FSGS and Denys-Drash syndrome, respectively.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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