nefrin

Nephrin, sometimes spelled nefrin in some languages, is a transmembrane protein that is a major component of the slit diaphragm, the specialized intercellular junction between podocyte foot processes in the kidney glomerulus. It is encoded by the NPHS1 gene. Nephrin has an extracellular region containing multiple immunoglobulin-like domains, a single transmembrane segment, and a cytoplasmic tail that participates in intracellular signaling and cytoskeletal organization.

Function: Nephrin contributes to the integrity and selective permeability of the glomerular filtration barrier, helping to prevent leakage of proteins into the urine. At the slit diaphragm, nephrin forms a network with other junctional proteins and recruits intracellular adaptors such as CD2AP, ZO-1, and Nck. Phosphorylation of its cytoplasmic tail by Src-family kinases (for example Fyn) regulates these interactions and downstream actin remodeling, thereby influencing podocyte foot-process architecture.

Clinical significance: Loss of nephrin function, typically due to NPHS1 mutations, causes congenital nephrotic syndrome, characterized by severe proteinuria, hypoalbuminemia, edema, and usually early infancy onset. Mutations can also contribute to steroid-resistant nephrotic syndrome in children, and animal models lacking nephrin exhibit severe glomerular defects and proteinuria.

Discovery and research: Nephrin was identified in the late 1990s as a podocyte-specific component of the slit diaphragm, and extensive studies have since shown its essential role in maintaining filtration barrier integrity. Therapeutic approaches aiming to stabilize slit diaphragm signaling or compensate for nephrin loss are under investigation for proteinuric kidney diseases.