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J Am Soc Nephrol 2017 Aug 01;288:2540-2552. doi: 10.1681/ASN.2016101057.
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Clinical and Genetic Spectrum of Bartter Syndrome Type 3.

Seys E , Andrini O , Keck M , Mansour-Hendili L , Courand PY , Simian C , Deschenes G , Kwon T , Bertholet-Thomas A , Bobrie G , Borde JS , Bourdat-Michel G , Decramer S , Cailliez M , Krug P , Cozette P , Delbet JD , Dubourg L , Chaveau D , Fila M , Jourde-Chiche N , Knebelmann B , Lavocat MP , Lemoine S , Djeddi D , Llanas B , Louillet F , Merieau E , Mileva M , Mota-Vieira L , Mousson C , Nobili F , Novo R , Roussey-Kesler G , Vrillon I , Walsh SB , Teulon J , Blanchard A , Vargas-Poussou R .

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.

PubMed ID: 28381550
PMC ID: PMC5533235
Article link: J Am Soc Nephrol

Species referenced: Xenopus laevis
Genes referenced: clcnkb
GO keywords: chloride channel activity [+]

Disease Ontology terms: Bartter disease type 3
References [+] :
Akil, A patient with Bartter syndrome accompanying severe growth hormone deficiency and focal segmental glomerulosclerosis. 2010, Pubmed