NPHP4

NPHP4, or nephrocystin-4, is a human gene that encodes a ciliary protein involved in kidney development and maintenance. The NPHP4 protein localizes to the primary cilium and the ciliary transition zone, where it participates in a network of nephrocystin proteins that support proper ciliary function in renal tubular cells. It is thought to act as a scaffolding protein that coordinates interactions among other nephrocystins, including NPHP1 and NPHP3, helping to regulate ciliary gating and signaling.

Clinical significance of NPHP4 arises from mutations in the gene, which cause nephronophthisis, a recessive kidney disorder characterized by tubulointerstitial fibrosis, cystic kidneys, polyuria, polydipsia, growth retardation, and progressive kidney failure that often begins in childhood. In some individuals, NPHP4 mutations are associated with extrarenal features such as retinal dystrophy (seen in Senior-Løken syndrome) or other ciliopathy-related manifestations, though these associations vary among patients.

Genetics and expression: NPHP4 is expressed in the kidney and other ciliated tissues. Inheritance is typically autosomal recessive, with biallelic mutations leading to disease. Animal models, including mouse and zebrafish, show that loss of Nphp4 function disrupts ciliary structure and function and can produce kidney- and eye-related phenotypes, supporting its role in ciliopathies.

Structure: The protein contains coiled-coil domains typical of cytoskeletal and scaffolding proteins and is part of the transition-zone complex that regulates ciliogenesis and intracellular trafficking of ciliary proteins.