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J Am Soc Nephrol. 2017 Aug;28(8):2540-2552. doi: 10.1681/ASN.2016101057. Epub 2017 Apr 5.

Clinical and Genetic Spectrum of Bartter Syndrome Type 3.

Author information

1
Pediatric Nephrology Unit, American Memorial Hospital, Reims University Hospital, Reims, France.
2
Unité Mixte de Recherche en Santé 1138, Team 3, Université Pierre et Marie Curie, Paris, France.
3
Faculté de Médecine, Université Paris Descartes, Paris, France.
4
Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche en Santé 872, Paris, France.
5
Department of Genetics and.
6
Centre d'Investigation Clinique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
7
Cardiology Department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
8
Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé; Centre National de la Recherche Scientifique Unité Mixte de Recherche 5220; Institut National de la Santé et la Recherche Médicale, Unité 1044; Institut National de Sciences Appliquées-Lyon; Université Claude Bernard Lyon 1, France.
9
Pediatric Nephrology Unit, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.
10
Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.
11
Néphrogones, Centre de Référence des Maladies Rénales Rares, Pediatric Nephrology, Rhumatology and Dermatology Unit, Hôpital Femme-Mère-Enfant and.
12
Nephrology Unit, Clinique du Vert Galant, Tremblay-en-France, France.
13
Nephrology Unit, Centre hospitalier de Saintonge, Saintes, France.
14
Departement of Pediatrics, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
15
Departement of Pediatrics and.
16
Pediatric Nephrology Unit, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
17
Pediatric Nephrology Unit and.
18
Nephrology Unit, Centre Hospitalier du Pays d'Aix, Aix-en-Provence, France.
19
Pediatric Nephrology Unit, Hôpital Trousseau, Assistance Publique des Hôpitaux de Paris, Paris, France.
20
Exploration Fonctionnelle Rénale et Métabolique, Groupement Hospitalier est Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
21
Departement of Nephrology, Centre de Référence des Maladies Rénales Rares du Sud-Ouest, Hôpital de Toulouse, Université Paul Sabatier, Toulouse, France.
22
Pediatric Nephrology Unit, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
23
Faculté de Médecine, Centre de Référence des Maladies Rénales Rares du Sud-Ouest, Aix-MarseilleUniversité-Vascular Research Center of Marseille, Marseille, France.
24
Nephrology Unit, Hôpital de la Conception, Assistance Publique des Hopitaux de Marseille, Marseille,France.
25
Department of Nephrology, Hôpital Necker-Enfants-malades, Assistance Publique des Hôpitaux de Paris, Paris, France.
26
Departement of Pediatrics, Hôpital Nord, Centre Hospitalier Universitaire de Saint Etienne, Saint Etienne, France.
27
Department of Pediatrics and Adolescent Medicine, Centre Hospitalier Universitaire d'Amiens, Amiens, France.
28
Service de Néphrologie Pédiatrique, Groupement Hospitalier Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Centre de Référence des Maladies Rénales Rares du Sud-Ouest, Bordeaux, France.
29
Department of Pediatrics, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France.
30
Nephrology Unit,Centre Hospitalier Universitaire Tours, Tours, France.
31
Department of Pediatrics, Centre Hospitalier Pierre Oudot de Bourgoin-Jallieu, Bourgoin-Jallieu, France.
32
Molecular Genetics Unit, Hospital do Divino Espírito Santo de Ponta Delgada, Entidade Pública Empresarial Regional, Açores, Portugal.
33
Nephrology Unit, Centre Hospitalier Universitaire de Dijon, Dijon, France.
34
Pediatric Nephrology Unit, Centre Hospitalier Universitaire de Besançon, Besançon, France.
35
Pediatric Nephrology Unit, Hôpital Jeanne de Flandre, Centre Hospitalier Universitaire de Lille, Lille, France.
36
Pediatric Nephrology Unit, Centre Hospitalier Universitaire de Nantes, Nantes, France.
37
Pediatric Nephrology Unit, Hôpitaux de Brabois, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France.
38
Centre for Nephrology, University College London, London, UK; and.
39
Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche en Santé 970, Paris-Cardiovascular Research Center, Paris, France.

Abstract

Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.

KEYWORDS:

Bartter-s syndrome; chronic kidney disease; human genetics; proteinuria

PMID:
28381550
PMCID:
PMC5533235
DOI:
10.1681/ASN.2016101057
[Indexed for MEDLINE]
Free PMC Article

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