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	Gianluca Caridi, Francesco Perfumo, Gian Marco Ghiggeri
Journal	Pediatric research (Pediatr Res) Vol. 57 Issue 5 Pt 2 Pg. 54R-61R (May 2005) ISSN: 0031-3998 [Print] United States
PMID	15817495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References	Intracellular Signaling Peptides and Proteins Membrane Proteins NPHS2 protein
Topics	Adolescent Adult Aged Animals Child Child, Preschool Endoplasmic Reticulum (metabolism) Exons Genetic Testing Heterozygote Homozygote Humans Infant Intracellular Signaling Peptides and Proteins Kidney (pathology) Kidney Transplantation Membrane Proteins (genetics) Mice Middle Aged Mutation Nephrotic Syndrome (diagnosis, genetics, therapy) Phenotype Polymorphism, Genetic Promoter Regions, Genetic Protein Structure, Tertiary Treatment Outcome

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