TY - JOUR
T1 - Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome
AU - Castaño, Alejandro García
AU - De Nanclares, Gustavo Pérez
AU - Madariaga, Leire
AU - Aguirre, Mireia
AU - Madrid, Álvaro
AU - Chocrón, Sara
AU - Nadal, Inmaculada
AU - Navarro, Mercedes
AU - Lucas, Elena
AU - Fijo, Julia
AU - Espino, Mar
AU - Espitaletta, Zilac
AU - Nieto, Víctor García
AU - De Frutos, David Barajas
AU - Loza, Reyner
AU - Pintos, Guillem
AU - Castaño, Luis
AU - Braga, Eva
AU - Córdoba, Elizabeth
AU - Coto, Eliecer
AU - García, Enrique
AU - Ramos, Elena
AU - Ordóñez, Flor Ángel
AU - Claverie, Félix
AU - Santos, Fernando
AU - Gil, Helena
AU - González, Hilaria
AU - Rodríguez, Julián
AU - Luis-Yanes, María Isabel
AU - Mejía, Natalia
AU - Fuente, Rocío
AU - Álvarez, Victoria
AU - García, Víctor Manuel
AU - Loredo, Vanessa
AU - Ariceta, Gema
PY - 2017/3/1
Y1 - 2017/3/1
N2 - © 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.
AB - © 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.
U2 - https://doi.org/10.1371/journal.pone.0173581
DO - https://doi.org/10.1371/journal.pone.0173581
M3 - Article
VL - 12
IS - 3
M1 - e0173581
ER -