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Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome

Authors
  • Dorval, Guillaume1, 2
  • Gribouval, Olivier1, 2
  • Martinez-Barquero, Vanesa1, 2
  • Machuca, Eduardo1
  • Tête, Marie-Josèphe1, 2
  • Baudouin, Véronique3
  • Benoit, Stéphane4
  • Chabchoub, Imen5
  • Champion, Gérard6
  • Chauveau, Dominique7
  • Chehade, Hassib8
  • Chouchane, Chokri9
  • Cloarec, Sylvie4
  • Cochat, Pierre10
  • Dahan, Karin11
  • Dantal, Jacques12
  • Delmas, Yahsou13
  • Deschênes, Georges3
  • Dolhem, Phillippe14
  • Durand, Dominique7
  • And 30 more
  • 1 Imagine Institute, INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, 24 Boulevard du Montparnasse, Paris, 75015, France , Paris (France)
  • 2 Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France , Paris (France)
  • 3 Robert Debré Hospital, Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
  • 4 University Hospital of Tours, Department of Nephrology, Tours, France , Tours (France)
  • 5 Sfax University, Department of Pediatrics, Sfax, Tunisia , Sfax (Tunisia)
  • 6 University Hospital of Angers, Department of Pediatrics, Angers, France , Angers (France)
  • 7 University Hospital Rangueil, Department of Nephrology and Organ Transplantation, Toulouse, France , Toulouse (France)
  • 8 Lausanne University Hospital, Department of Pediatrics, Division of Pediatric Nephrology, Lausanne, Switzerland , Lausanne (Switzerland)
  • 9 Monastir University, Department of Pediatrics, Monastir, Tunisia , Monastir (Tunisia)
  • 10 Claude-Bernard Lyon 1 University, Department of Pediatric Nephrology, Bron, France , Bron (France)
  • 11 Institute of Pathology and Genetics, Department of Human Genetics, Gosselies, Belgium , Gosselies (Belgium)
  • 12 University Hospital of Nantes, Nephrology and Immunology Department, Nantes, France , Nantes (France)
  • 13 University Hospital of Bordeaux, Department of Nephrology, Bordeaux, France , Bordeaux (France)
  • 14 Saint-Quentin Hospital, Department of Pediatrics, Saint-Quentin, France , Saint-Quentin (France)
  • 15 Kocaeli Academy for Solidarity, Kocaeli, Turkey , Kocaeli (Turkey)
  • 16 Necker-Enfants Malades Hospital, Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
  • 17 University Hospital Hautepierre, Nephrology Dialysis Transplantation Children’s Unit, Strasbourg, France , Strasbourg (France)
  • 18 University Hospital of Limoges, Department of Pediatrics, Limoges, France , Limoges (France)
  • 19 Armand Trousseau Hospital, Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
  • 20 University Hospital Hautepierre, Department of Nephrology, Strasbourg, France , Strasbourg (France)
  • 21 University Hospital of Bordeaux, Department of Genetics, Bordeaux, France , Bordeaux (France)
  • 22 University Hospital of Bordeaux, Department of Pediatrics, Bordeaux, France , Bordeaux (France)
  • 23 Tenon Hospital, Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
  • 24 Sorbonne University, UPMC University Paris 06, Paris, France , Paris (France)
  • 25 INSERM, UMR_S 1155, Paris, 75020, France , Paris (France)
  • 26 Sultan Qaboos University, College of Medicine, Muscat, Oman , Muscat (Oman)
  • 27 Necker-Enfants Malades Hospital, Department of Pediatric Nephrology, Centre de référence du syndrome néphrotique idiopathique de l’enfant et l’adulte, Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
  • 28 Centre de Référence Syndrome Néphrotique Idiopathique de l’enfant et de l’adulte, Paris, France , Paris (France)
  • 29 Geneva University Hospital, Department of Pediatrics, Division of Pediatric Nephrology, Geneva, Switzerland , Geneva (Switzerland)
  • 30 University Hospital of Reims, Departement of Pediatrics, Nephrology Unit, Reims, France , Reims (France)
  • 31 University of Champagne-Ardenne, Faculty of Medicine, Laboratory of Biochemistry and Molecular Biology, UMR, CNRS/URCA n°7369, Reims, France , Reims (France)
  • 32 Jean Verdier Hospital, Department of Pediatrics, Assistance Publique-Hôpitaux de Paris, Bondy, France , Bondy (France)
  • 33 University Hospital of Lyon, Department of Nephrology and Transplantation, Lyon, France , Lyon (France)
  • 34 The Conception Hospital, Department of Nephrology and Kidney Transplantation, Marseille, France , Marseille (France)
  • 35 Aix-Marseille University, Department of Multidisciplinary Pediatrics Timone, Assistance Publique Hôpitaux de Marseille, Marseille, France , Marseille (France)
  • 36 Necker-Enfants malades Hospital, Department of Genetics, Assistance Publique-Hôpitaux de Paris, Paris, France , Paris (France)
Type
Published Article
Journal
Pediatric Nephrology
Publisher
Springer-Verlag
Publication Date
Oct 23, 2017
Volume
33
Issue
3
Pages
473–483
Identifiers
DOI: 10.1007/s00467-017-3819-9
Source
Springer Nature
Keywords
License
Yellow

Abstract

BackgroundFamilial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease.MethodsClinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort.ResultsTransmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing.ConclusionsTaken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

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