NPHP4 (nephrocystin-4) is a ciliary transition zone protein essential for regulating protein composition and cellular organization. As a structural component of the distal transition zone, NPHP4 functions as a selective barrier controlling entry of membrane proteins and large soluble proteins (>50 kDa) into cilia 1. It localizes independently of CEP290 to define distinct transition zone domains 1. NPHP4 participates in the NPHP1-4-8 module regulating apical junction organization and coordinates ciliary protein composition with ectosome shedding 2. It stabilizes JADE1 protein levels and cooperates with INVS to suppress canonical Wnt signaling while promoting Wnt-PCP pathway activation 34. NPHP4 also negatively regulates hippo pathway signaling through LATS1 interaction 5. Mutations in NPHP4 cause nephronophthisis 4 and Senior-Loken syndrome 4, characterized by progressive renal dysfunction with median ESKD onset at 16 years 6. Patients typically develop nephronophthisis with tubular basement membrane disruption and interstitial cysts 7. NPHP4 mutations also cause photoreceptor degeneration, retinitis pigmentosa, and male infertility 8. Common variants in NPHP4 associate with reduced renal function in non-diabetic populations 9. Unlike CEP290/IQCB1 variants causing early retinopathy onset, NPHP4 patients typically present with nephropathy first 10.