doi: 10.1093/ndt/gfu231 Full Review Protein trafficking defects in inherited kidney diseases

The nephron, the basic structural and functional unit of the kidney, is lined by different, highly differentiated polarized epithelial cells. Their concerted action modifies the compos-ition of the glomerular ultrafiltrate through reabsorption and secretion of essential solutes to finally produce urine. The highly specialized properties of the different epithelial cell types of the nephron are remarkable and rely on the regulated delivery of specific proteins to their final subcellular localiza-tion. Hence, mutations affecting sorting of individual proteins or inactivating the epithelial trafficking machinery have severe functional consequences causing disease. The presence of mutations leading to protein trafficking defect is indeed a mech-anism of pathogenesis seen in an increasing number of disor-ders, including about one-third of monogenic diseases affecting the kidney. In this review, we focus on representative diseases to discuss different molecular mechanisms that primarily lead to defective protein transport, such as endoplasmic reticulum re-tention, mistargeting, defective endocytosis or degradation, eventually resulting in epithelial cell and kidney dysfunction. For each disease, we discuss the type of reported mutations, their molecular and cellular consequences and possible strat-egies for therapeutic intervention. Particular emphasis is given to new and prospective therapies aimed at rescuing the traffick-ing defect at the basis of these conformational diseases