Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome

Alejandro García Castaño, Gustavo Pérez De Nanclares, Leire Madariaga, Mireia Aguirre, Álvaro Madrid, Sara Chocrón, Inmaculada Nadal, Mercedes Navarro, Elena Lucas, Julia Fijo, Mar Espino, Zilac Espitaletta, Víctor García Nieto, David Barajas De Frutos, Reyner Loza, Guillem Pintos, Luis Castaño, Eva Braga, Elizabeth Córdoba, Eliecer CotoEnrique García, Elena Ramos, Flor Ángel Ordóñez, Félix Claverie, Fernando Santos, Helena Gil, Hilaria González, Julián Rodríguez, María Isabel Luis-Yanes, Natalia Mejía, Rocío Fuente, Victoria Álvarez, Víctor Manuel García, Vanessa Loredo, Gema Ariceta

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Abstract

© 2017 García Castaño et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction: Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKBgene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS. Methods: Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses. Results: Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype. Conclusion: A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort.
Original languageEnglish
Article numbere0173581
JournalPLoS ONE
Volume12
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

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