A renal biopsy from a 10-year-old boy with steroid-resistant nephrotic syndrome shows normal light microscopy, no immune deposits on immunofluorescence, and diffuse podocyte foot process effacement on electron microscopy. Genetic testing reveals a homozygous missense mutation in NPHS2 encoding podocin. Which of the following correctly describes the molecular role of podocin and how this mutation disrupts the glomerular filtration barrier?

• A Podocin is a transmembrane mechanosensor in the podocyte cytoskeleton; NPHS2 mutations impair response to glomerular hypertension, causing foot process flattening
• B Podocin is a GPI-anchored complement regulatory protein; mutations allow MAC assembly on podocytes, causing direct podocyte lysis and proteinuria
• C Podocin is a component of the slit diaphragm that acts as an intracellular scaffolding protein recruiting nephrin to lipid rafts; NPHS2 mutations cause podocin misfolding, ER retention, and failure to traffic nephrin to the slit diaphragm, disrupting its size-selective filtration properties ✓
• D Podocin functions as an anion channel in the slit diaphragm; mutations reduce negative charge density, allowing albumin passage through electrostatic mechanisms

Explanation

Podocin (NPHS2) is a hairpin-loop membrane protein of the stomatin family, concentrated at the slit diaphragm-plasma membrane junction. It acts as a scaffolding protein, recruiting and anchoring nephrin to detergent-resistant lipid rafts (membrane microdomains), which is critical for nephrin clustering and signaling. Mutations in NPHS2 (e.g., R138Q, R229Q) cause misfolding and ER retention of podocin, impairing nephrin trafficking to the slit diaphragm. The result is morphological foot process effacement and loss of the size-selective and charge-selective barrier, producing steroid-resistant nephrotic syndrome (SRNS) — the most common cause of familial SRNS.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.