NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms

Nephrotic syndrome (NS) is the most frequent cause of proteinuria in children and is emerging as a leading cause of uremia. Molecular studies in families with recessive NS have led to the discovery of specialized molecules endowed in podocytes that play a role in proteinuria. This review focalizes the key position of podocin (NPHS2 gene) in this rapidly evolving field and furnishes a compendium to those involved in clinics and genetics of NS. Screening for NPHS2 mutations have been done in sporadic NS and familial cases with recessive inheritance, documenting a mutation detection rate of 45-55% in families and 8-20% in sporadic NS according to the different groups and considering all the clinical phenotypes. Almost 50 NPHS2 mutations have been reported and variants and/or non silent polymorphisms potentially involved in proteinuria were recognized. Personalized data on clinical aspects related to responsiveness to drugs, evolution to end stage renal failure and post-transplant outcome are reported. Functional studies and cell sorting experiments demonstrated retention in the endoplasmic reticulum of most mutants involving the stomatin domain. Pull-down experiments with the common R229Q polymorphism demonstrated an altered interaction with nephrin that affects the stability of the functional unit. Overall, data are here presented that underscore a major role of inherited defects of NPHS2 in NS in children (including a relevant impact in sporadic cases) and give the functional rationale for the association. A practical compendium is also given to clinicians involved in the management of NS that should modify the classic therapeutic approach.