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.
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Abbreviations
- CD2AP:
-
CD2 associated protein
- ESRF:
-
end-stage renal failure
- FSGS:
-
focal segmental glomerulosclerosis
- KO:
-
knock-out mouse model
- NPHS1:
-
nephrin
- NPHS2:
-
podocin NPHS2
- NS:
-
nephrotic syndrome
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Acknowledgements
The authors thank Professor Rosanna Gusmano for her valuable discussions.
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This work was done with the financial support of the Italian Ministry of Health (Progetto Finalizzato “Patogenesi delle Malattie della Barriera di Filtrazione Glomerulare,” Convenzione N°178/2002, and Ricerca Corrente). We also acknowledge the financial support of KIDney FUND.
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Caridi, G., Perfumo, F. & Ghiggeri, G. NPHS2 (Podocin) Mutations in Nephrotic Syndrome. Clinical Spectrum and Fine Mechanisms. Pediatr Res 57, 54–61 (2005). https://doi.org/10.1203/01.PDR.0000160446.01907.B1
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DOI: https://doi.org/10.1203/01.PDR.0000160446.01907.B1
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