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Pediatr Nephrol. 2018 Mar;33(3):473-483. doi: 10.1007/s00467-017-3819-9. Epub 2017 Oct 23.

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

Author information

1
INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France. guillaume.dorval@inserm.fr.
2
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. guillaume.dorval@inserm.fr.
3
INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.
4
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
5
Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France.
6
Department of Nephrology, University Hospital of Tours, Tours, France.
7
Department of Pediatrics, Sfax University, Sfax, Tunisia.
8
Department of Pediatrics, University Hospital of Angers, Angers, France.
9
Department of Nephrology and Organ Transplantation, University Hospital Rangueil, Toulouse, France.
10
Department of Pediatrics, Division of Pediatric Nephrology, Lausanne University Hospital, Lausanne, Switzerland.
11
Department of Pediatrics, Monastir University, Monastir, Tunisia.
12
Department of Pediatric Nephrology, Claude-Bernard Lyon 1 University, Bron, France.
13
Department of Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium.
14
Nephrology and Immunology Department, University Hospital of Nantes, Nantes, France.
15
Department of Nephrology, University Hospital of Bordeaux, Bordeaux, France.
16
Department of Pediatrics, Saint-Quentin Hospital, Saint-Quentin, France.
17
Kocaeli Academy for Solidarity, Kocaeli, Turkey.
18
Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France.
19
Nephrology Dialysis Transplantation Children's Unit, University Hospital Hautepierre, Strasbourg, France.
20
Department of Pediatrics, University Hospital of Limoges, Limoges, France.
21
Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Armand Trousseau Hospital, Paris, France.
22
Department of Nephrology, University Hospital Hautepierre, Strasbourg, France.
23
Department of Genetics, University Hospital of Bordeaux, Bordeaux, France.
24
Department of Pediatrics, University Hospital of Bordeaux, Bordeaux, France.
25
Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France.
26
Sorbonne University, UPMC University Paris 06, Paris, France.
27
INSERM, UMR_S 1155, 75020, Paris, France.
28
College of Medicine, Sultan Qaboos University, Muscat, Oman.
29
Department of Pediatric Nephrology, Centre de référence du syndrome néphrotique idiopathique de l'enfant et l'adulte, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France.
30
Centre de Référence Syndrome Néphrotique Idiopathique de l'enfant et de l'adulte, Paris, France.
31
Department of Pediatrics, Division of Pediatric Nephrology, Geneva University Hospital, Geneva, Switzerland.
32
Departement of Pediatrics, Nephrology Unit, University Hospital of Reims, Reims, France.
33
Faculty of Medicine, Laboratory of Biochemistry and Molecular Biology, UMR, CNRS/URCA n°7369, University of Champagne-Ardenne, Reims, France.
34
Department of Pediatrics, Assistance Publique-Hôpitaux de Paris, Jean Verdier Hospital, Bondy, France.
35
Department of Nephrology and Transplantation, University Hospital of Lyon, Lyon, France.
36
Department of Nephrology and Kidney Transplantation, The Conception Hospital, Marseille, France.
37
Department of Multidisciplinary Pediatrics Timone, Assistance Publique Hôpitaux de Marseille, Aix-Marseille University, Marseille, France.
38
Department of Genetics, Assistance Publique-Hôpitaux de Paris, Necker-Enfants malades Hospital, Paris, France.

Abstract

BACKGROUND:

Familial 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.

METHODS:

Clinical 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.

RESULTS:

Transmission 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.

CONCLUSIONS:

Taken 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.

KEYWORDS:

EMP2; Familial nephrotic syndrome; Genetics; HLA-DQA1; Immunity; Podocyte; Steroid resistance; Steroid sensitivity

PMID:
29058154
DOI:
10.1007/s00467-017-3819-9
[Indexed for MEDLINE]

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