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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 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.

SUBMITTER: Seys E 

PROVIDER: S-EPMC5533235 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Clinical and Genetic Spectrum of Bartter Syndrome Type 3.

Seys Elsa E   Andrini Olga O   Keck Mathilde M   Mansour-Hendili Lamisse L   Courand Pierre-Yves PY   Simian Christophe C   Deschenes Georges G   Kwon Theresa T   Bertholet-Thomas Aurélia A   Bobrie Guillaume G   Borde Jean Sébastien JS   Bourdat-Michel Guylhène G   Decramer Stéphane S   Cailliez Mathilde M   Krug Pauline P   Cozette Paul P   Delbet Jean Daniel JD   Dubourg Laurence L   Chaveau Dominique D   Fila Marc M   Jourde-Chiche Noémie N   Knebelmann Bertrand B   Lavocat Marie-Pierre MP   Lemoine Sandrine S   Djeddi Djamal D   Llanas Brigitte B   Louillet Ferielle F   Merieau Elodie E   Mileva Maria M   Mota-Vieira Luisa L   Mousson Christiane C   Nobili François F   Novo Robert R   Roussey-Kesler Gwenaëlle G   Vrillon Isabelle I   Walsh Stephen B SB   Teulon Jacques J   Blanchard Anne A   Vargas-Poussou Rosa R  

Journal of the American Society of Nephrology : JASN 20170405 8


Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (<i>CLCNKB</i>), 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 <i>CLCNKB</i> mutations  ...[more]

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