A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations.

Autor:	Bongers EMHF; Departments of Human Genetics., Shelton LM; Physiology., Milatz S; Institute of Physiology, Christian Albrechts University Kiel, Kiel, Germany., Verkaart S; Physiology., Bech AP; Nephrology, and., Schoots J; Departments of Human Genetics., Cornelissen EAM; Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands; and., Bleich M; Institute of Physiology, Christian Albrechts University Kiel, Kiel, Germany., Hoenderop JGJ; Physiology., Wetzels JFM; Nephrology, and., Lugtenberg D; Departments of Human Genetics., Nijenhuis T; Nephrology, and Tom.Nijenhuis@Radboudumc.nl.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2017 Oct; Vol. 28 (10), pp. 3118-3128. Date of Electronic Publication: 2017 Jul 03.
DOI:	10.1681/ASN.2016080881
Abstrakt:	Mice lacking distal tubular expression of CLDN10 , the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype. (Copyright © 2017 by the American Society of Nephrology.)
Databáze:	MEDLINE
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