A 10-year-old boy with nephrotic syndrome fails steroid therapy. Kidney biopsy shows no light-microscopic abnormality, effacement of podocyte foot processes on EM, and negative immunofluorescence. NPHS2 mutation is found on genetic testing. Which protein is encoded by NPHS2 and why does its defect cause proteinuria?

• A Podocin — a scaffold protein of the slit diaphragm that anchors nephrin and is essential for lipid-raft-mediated signalling at the filtration barrier ✓
• B Nephrin — the principal transmembrane adhesion protein whose extracellular Ig-domains form the filtration slit
• C CD2AP — a cytoplasmic adaptor linking nephrin to actin and required for podocyte actin polymerisation
• D TRPC6 — a calcium channel in podocytes whose activation causes actin cytoskeleton disruption

Explanation

NPHS2 encodes podocin, a hairpin-shaped integral membrane protein of the slit diaphragm that colocalises with nephrin in cholesterol-enriched lipid rafts. Podocin anchors nephrin to the membrane and is critical for downstream PI3K/nephrin signalling that maintains podocyte integrity. Mutations in NPHS2 cause autosomal-recessive steroid-resistant nephrotic syndrome (SRNS). Nephrin (NPHS1) mutations cause congenital Finnish nephrosis; CD2AP mutations cause a focal segmental pattern; TRPC6 gain-of-function mutations cause autosomal dominant FSGS.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.