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Nephrin Mutations Can Cause Childhood-Onset Steroid-Resistant Nephrotic Syndrome

Aurélie Philippe^*,, Fabien Nevo^*,, Ernie L. Esquivel^*,, Dalia Reklaityte^*,, Olivier Gribouval^*,, Marie-Josèphe Tête^*,, Chantal Loirat, Jacques Dantal^||, Michel Fischbach^¶, Claire Pouteil-Noble^**, Stéphane Decramer, Martin Hoehne, Thomas Benzing, Marina Charbit, Patrick Niaudet^*,, and Corinne Antignac^*,,

^* Inserm U574, Hôpital Necker-Enfants Malades, Université Paris Descartes, Faculté de Médecine René Descartes, Pediatric Nephrology and Department of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, and Pediatric Nephrology Department, Université Paris VII, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, ^|| ITERT, Department of Nephrology and Clinical Immunology, CHU Nantes, Nantes, ^¶ Nephrology Dialysis Transplantation Children's Unit, Hôpital de Hautepierre, Strasbourg, ^** Transplantation and Nephrology Unit, Centre Hospitalier Lyon-Sud, Pierre-Bénite, and Department of Pediatric Nephrology, Hôpital des Enfants, and Inserm, U858/I2MR, Department of Renal and Cardiac Remodeling, Toulouse, France; and Department of Medicine IV, University of Cologne, Cologne, Germany

Correspondence: Dr. Corinne Antignac, Inserm U574, 6ème étage, Tour Lavoisier, Hôpital Necker-Enfants Malades, 147, rue de Sèvres, 75015 Paris, France. Phone: +33-1-44-49-50-98; Fax: +33-1-44-49-02-90; E-mail: antignac{at}necker.fr

Received for publication January 17, 2008. Accepted for publication May 14, 2008.

Classically, infants with mutations in NPHS1, which encodes nephrin, present with nephrotic syndrome within the first 3 mo of life (congenital nephrotic syndrome of the Finnish-type), and children with mutations in NPHS2, which encodes podocin, present later with steroid-resistant nephrotic syndrome. Recently, however, NPHS2 mutations have been identified in children with congenital nephrotic syndrome. Whether NPHS1 mutations similarly account for some cases of childhood steroid-resistant nephrotic syndrome is unknown. In this study, 160 patients who belonged to 142 unrelated families and presented with nephrotic syndrome at least 3 mo after birth were screened for NPHS1 variants once mutations in NPHS2 had been excluded. Compound heterozygous NPHS1 mutations were identified in one familial case and nine sporadic cases. Mutations included protein-truncating nonsense and frameshift mutations, as well as splice-site and missense variants. Mutations were classified as "severe" or "mild" using prediction algorithms and functional assays. Most missense variants trafficked normally to the plasma membrane and maintained the ability to form nephrin homodimers and to heterodimerize with NEPH1, suggesting retained function. The presence of at least one "mild" mutation in these patients likely explains the later onset and milder course of disease. These results broaden the spectrum of renal disease related to nephrin mutations.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673