NPHS2 Mutations in Steroid‐Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum |
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Authors: | Karim Bouchireb Fabien Nevo Evelyne Huynh‐Cong Vincent Morinière Raphaëlle Campait Elisabet Ars Damien Brackman Jacques Dantal Philippe Eckart Maddalena Gigante Beata S. Lipska Aurélia Liutkus André Megarbane Nabil Mohsin Fatih Ozaltin Moin A. Saleem Franz Schaefer Kenza Soulami Roser Torra Nicolas Garcelon Géraldine Mollet Karin Dahan Corinne Antignac |
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Affiliation: | 1. Assistance Publique‐H?pitaux de Paris, Service de Néphrologie Pédiatrique, Centre de Référence des Maladies Rénales Héréditaires (MARHEA), H?pital Necker‐Enfants Malades, Paris, France;2. Inserm U983, Institut Imagine, H?pital Necker‐Enfants Malades, Paris, France;3. Université Paris Descartes‐Sorbonne Paris Cité, Paris, France;4. Assistance Publique‐H?pitaux de Paris, Département de Génétique, H?pital Necker‐Enfants Malades, Paris, France;5. Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB‐Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain;6. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway;7. Service de Néphrologie et Immunologie Clinique, ITERT, CHU H?tel Dieu, Nantes, France;8. Service de pédiatrie médicale, CHU de Caen, Caen, France;9. Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy;10. Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland;11. Service de Néphrologie et Rhumatologie Pédiatriques, Centre de référence des Maladies Rénales Rares, H?pital Femme Mère Enfant, Bron, France;12. Unité de Génétique Médicale, Faculté de Médecine, Université Saint Joseph, Beirut, Lebanon;13. Department of Nephrology, Royal Hospital, Muscat, Oman;14. Nephrogenetics Laboratory, Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey;15. Department of Paediatric Nephrology, Bristol Royal Hospital for Children, Academic Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, UK;16. PodoNet Consortium, Division of Pediatric Nephrology, Heidelberg University Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany;17. CHU Ibn Rochd, Service de Néphrologie Dialyse Transplantation, Casablanca, Morocco;18. Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB‐Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Spain;19. Inserm U872, Institut Imagine, H?pital Necker‐Enfants Malades, Paris, France;20. Centre de Génétique Humaine, Université Catholique de Louvain, Bruxelles, Belgique |
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Abstract: | Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal‐recessive form of nonsyndromic steroid‐resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid‐resistant nephrotic syndrome before the age of 6 years and rapidly progress to end‐stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype–phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database ( www.lovd.nl/NPHS2 ) software that will allow the inclusion of future reports. |
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Keywords: | NPHS2 steroid‐resistant nephrotic syndrome podocin FSGS |
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