A 6-year-old child with steroid-resistant nephrotic syndrome undergoes biopsy showing focal segmental glomerulosclerosis (FSGS) with tip lesion variant. Genetic testing reveals a NPHS1 mutation. NPHS1 encodes which protein critical to the slit diaphragm?

• A Podocin — a stomatin-family protein that anchors nephrin to lipid rafts
• B CD2AP — an adaptor protein linking nephrin and podocin to the actin cytoskeleton
• C Alpha-actinin-4 — an actin crosslinking protein in podocyte foot processes
• D Nephrin — a transmembrane immunoglobulin superfamily protein forming the structural backbone of the slit diaphragm zipper ✓

Explanation

NPHS1 encodes nephrin, a transmembrane protein of the immunoglobulin superfamily located in the slit diaphragm between adjacent podocyte foot processes. Nephrin molecules from opposing foot processes form a zipper-like structure that provides both the structural filter and signaling scaffold. Podocin (NPHS2) anchors nephrin; CD2AP is an adaptor; alpha-actinin-4 (ACTN4) mutations also cause FSGS but via actin cytoskeletal disruption. Congenital nephrotic syndrome of the Finnish type is caused by NPHS1 mutations.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.