NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome

Familial idiopathic nephrotic syndromes represent a heterogeneous group of kidney disorders, and include autosomal recessive steroid-resistant nephrot ic syndrome, which is characterized by early childhood onset of proteinuria , rapid progression to end-stage renal disease and focal segmental glomerul osclerosis. A causative gene for this disease, NPHS2, was mapped to 1q25-31 and we report here its identification by positional cloning. NPHS2 is almo st exclusively expressed in the podocytes of fetal and mature kidney glomer uli, and encodes a new integral membrane protein, podocin, belonging to the stomatin protein family. We found ten different NPHS2 mutations, comprisin g nonsense, frameshift and missense mutations, to segregate with the diseas e, demonstrating a crucial role for podocin in the function of the glomerul ar filtration barrier.