title: NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms.
abstract: 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.
authors.affiliation: Laboratory on Pathophysiology of Uremia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Francesco
authors.initials: F
authors.lastname: Perfumo
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D005820:Genetic Testing; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009404:Nephrotic Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D016896:Treatment Outcome
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein