title: Clinical and Genetic Spectrum of Bartter Syndrome Type 3.
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 withCLCNKBmutations. Functional analyses were performed inXenopus laevisoocytes 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 expressedin vitrodecreased 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.
authors.affiliation: Pediatric Nephrology Unit, American Memorial Hospital, Reims University Hospital, Reims, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Seys
authors.affiliation: Unité Mixte de Recherche en Santé 1138, Team 3, Université Pierre et Marie Curie, Paris, France.|Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Andrini
authors.affiliation: Unité Mixte de Recherche en Santé 1138, Team 3, Université Pierre et Marie Curie, Paris, France.|Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche en Santé 872, Paris, France.
authors.forename: Mathilde
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authors.lastname: Keck
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Paris, France.|Department of Genetics and.
authors.forename: Lamisse
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authors.lastname: Mansour-Hendili
authors.affiliation: Centre d'Investigation Clinique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.|Cardiology Department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.|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.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Courand
authors.affiliation: Department of Genetics and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Simian
authors.affiliation: Pediatric Nephrology Unit, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.|Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Deschenes
authors.affiliation: Pediatric Nephrology Unit, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.|Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.
authors.forename: Theresa
authors.initials: T
authors.lastname: Kwon
authors.affiliation: Néphrogones, Centre de Référence des Maladies Rénales Rares, Pediatric Nephrology, Rhumatology and Dermatology Unit, Hôpital Femme-Mère-Enfant and.
authors.forename: Aurélia
authors.initials: A
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authors.affiliation: Nephrology Unit, Clinique du Vert Galant, Tremblay-en-France, France.
authors.forename: Guillaume
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authors.lastname: Bobrie
authors.affiliation: Nephrology Unit, Centre hospitalier de Saintonge, Saintes, France.
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Borde
authors.affiliation: Departement of Pediatrics, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
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authors.affiliation: Departement of Pediatrics and.
authors.forename: Stéphane
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authors.affiliation: Pediatric Nephrology Unit, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France.
authors.forename: Mathilde
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authors.affiliation: Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.|Pediatric Nephrology Unit and.
authors.forename: Pauline
authors.initials: P
authors.lastname: Krug
authors.affiliation: Nephrology Unit, Centre Hospitalier du Pays d'Aix, Aix-en-Provence, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Cozette
authors.affiliation: Pediatric Nephrology Unit, Hôpital Trousseau, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: Jean Daniel
authors.initials: JD
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authors.affiliation: Exploration Fonctionnelle Rénale et Métabolique, Groupement Hospitalier est Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
authors.forename: Laurence
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authors.affiliation: Departement of Nephrology, Centre de Référence des Maladies Rénales Rares du Sud-Ouest, Hôpital de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chaveau
authors.affiliation: Pediatric Nephrology Unit, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.
authors.forename: Marc
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authors.affiliation: Faculté de Médecine, Centre de Référence des Maladies Rénales Rares du Sud-Ouest, Aix-MarseilleUniversité-Vascular Research Center of Marseille, Marseille, France.|Nephrology Unit, Hôpital de la Conception, Assistance Publique des Hopitaux de Marseille, Marseille,France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Jourde-Chiche
authors.affiliation: Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.|Department of Nephrology, Hôpital Necker-Enfants-malades, Assistance Publique des Hôpitaux de Paris, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Knebelmann
authors.affiliation: Departement of Pediatrics, Hôpital Nord, Centre Hospitalier Universitaire de Saint Etienne, Saint Etienne, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Lavocat
authors.affiliation: Exploration Fonctionnelle Rénale et Métabolique, Groupement Hospitalier est Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
authors.forename: Sandrine
authors.initials: S
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authors.affiliation: Department of Pediatrics and Adolescent Medicine, Centre Hospitalier Universitaire d'Amiens, Amiens, France.
authors.forename: Djamal
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authors.lastname: Djeddi
authors.affiliation: Service de Néphrologie Pédiatrique, Groupement Hospitalier Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Centre de Référence des Maladies Rénales Rares du Sud-Ouest, Bordeaux, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Llanas
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire Charles Nicolle, Rouen, France.
authors.forename: Ferielle
authors.initials: F
authors.lastname: Louillet
authors.affiliation: Nephrology Unit,Centre Hospitalier Universitaire Tours, Tours, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Merieau
authors.affiliation: Department of Pediatrics, Centre Hospitalier Pierre Oudot de Bourgoin-Jallieu, Bourgoin-Jallieu, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Mileva
authors.affiliation: Molecular Genetics Unit, Hospital do Divino Espírito Santo de Ponta Delgada, Entidade Pública Empresarial Regional, Açores, Portugal.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mota-Vieira
authors.affiliation: Nephrology Unit, Centre Hospitalier Universitaire de Dijon, Dijon, France.
authors.forename: Christiane
authors.initials: C
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authors.affiliation: Pediatric Nephrology Unit, Centre Hospitalier Universitaire de Besançon, Besançon, France.
authors.forename: François
authors.initials: F
authors.lastname: Nobili
authors.affiliation: Pediatric Nephrology Unit, Hôpital Jeanne de Flandre, Centre Hospitalier Universitaire de Lille, Lille, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Novo
authors.affiliation: Pediatric Nephrology Unit, Centre Hospitalier Universitaire de Nantes, Nantes, France.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Roussey-Kesler
authors.affiliation: Pediatric Nephrology Unit, Hôpitaux de Brabois, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vrillon
authors.affiliation: Centre for Nephrology, University College London, London, UK; and.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Walsh
authors.affiliation: Unité Mixte de Recherche en Santé 1138, Team 3, Université Pierre et Marie Curie, Paris, France.|Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche en Santé 872, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Teulon
authors.affiliation: Faculté de Médecine, Université Paris Descartes, Paris, France.|Cardiology Department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.|Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.|Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche en Santé 970, Paris-Cardiovascular Research Center, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.affiliation: Department of Genetics and.|Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.|Institut National de la Santé et la Recherche Médicale, Unité Mixte de Recherche en Santé 970, Paris-Cardiovascular Research Center, Paris, France.
authors.forename: Rosa
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mesh_terms: D000293:Adolescent; D000328:Adult; D001477:Bartter Syndrome / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D055815:Young Adult
keywords: Bartter-s syndrome; chronic kidney disease; human genetics; proteinuria