1. Nephrin Mutations Can Cause Childhood-Onset Steroid-Resistant Nephrotic Syndrome
- Author
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Claire Pouteil-Noble, Aurélie Philippe, Ernie L. Esquivel, Corinne Antignac, Michel Fischbach, Fabien Nevo, Patrick Niaudet, Thomas Benzing, Olivier Gribouval, Martin Hoehne, Chantal Loirat, Marie-Josèphe Tête, Stéphane Decramer, Marina Charbit, Jacques Dantal, Dalia Reklaityte, Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de néphrologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut de transplantation et de recherche en transplantation ( ITERT ), service pédiatrique de dialyse et de transplantation rénales, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de néphrologie et transplantation, Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Service de Pédiatrie - Néphrologie, Médecine interne, Hypertension, CHU Toulouse [Toulouse]-Hôpital des Enfants, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Medicine IV, University of Cologne, Service de Génétique Médicale [CHU Necker], Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de transplantation et de recherche en transplantation (ITERT), Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, CHU Toulouse [Toulouse], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,Nephrotic Syndrome ,030232 urology & nephrology ,MESH : Child, Preschool ,Compound heterozygosity ,Severity of Illness Index ,Cohort Studies ,0302 clinical medicine ,MESH : Child ,MESH: Child ,Missense mutation ,MESH : Female ,Age of Onset ,Child ,Congenital nephrotic syndrome ,MESH: Cohort Studies ,MESH : Algorithms ,0303 health sciences ,biology ,Chromosome Mapping ,Glomerulonephritis ,MESH : Infant ,General Medicine ,MESH: Infant ,3. Good health ,MESH : Age of Onset ,Nephrology ,Child, Preschool ,Female ,MESH : Severity of Illness Index ,MESH: Membrane Proteins ,MESH : Mutation ,Algorithms ,medicine.medical_specialty ,MESH: Mutation ,MESH: Age of Onset ,MESH : Nephrotic Syndrome ,MESH : Male ,MESH : Cohort Studies ,MESH: Algorithms ,Brief Communication ,Nephrin ,03 medical and health sciences ,Internal medicine ,MESH: Severity of Illness Index ,medicine ,Humans ,030304 developmental biology ,MESH: Humans ,business.industry ,MESH: Child, Preschool ,MESH : Humans ,Infant ,Membrane Proteins ,medicine.disease ,MESH: Male ,Steroid-resistant nephrotic syndrome ,Endocrinology ,MESH : Membrane Proteins ,Mutation ,biology.protein ,Podocin ,MESH: Nephrotic Syndrome ,business ,MESH: Chromosome Mapping ,Nephrotic syndrome ,MESH: Female ,MESH : Chromosome Mapping - Abstract
International audience; 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.
- Published
- 2008