Kidney Week

Abstract: SA-OR064

CLDN10 Mutations Cause a Novel Autosomal Recessive Hypokalemic-Alkalotic Salt-Losing Tubulopathy

Session Information

• Tipping the Balance: Fluid and Electrolytes in Health and Disease
  November 04, 2017 | Location: Room 385, Morial Convention Center
  Abstract Time: 05:06 PM - 05:18 PM

Category: Fluid, Electrolytes, and Acid-Base

• 704 Fluid, Electrolyte, Acid-Base Disorders

Authors

• Nijenhuis, Tom, Radboud university medical center, Lent, gelderland, Netherlands

Tom Nijenhuis, MD, PhD

• Bongers, Ernie M.H.F., Radboud university medical center, Lent, gelderland, Netherlands

Ernie M.H.F. Bongers,

• Shelton, Luke M, Radboud university medical center, Lent, gelderland, Netherlands

Luke M Shelton,

• Milatz, Susanne, Christian Albrechts University Kiel, Kiel, Germany

Susanne Milatz,

• Verkaart, Sjoerd, Radboud university medical center, Lent, gelderland, Netherlands

Sjoerd Verkaart,

• Bech, Anneke, Radboud university medical center, Lent, gelderland, Netherlands

Anneke Bech,

• Schoots, Jeroen, Radboud university medical center, Lent, gelderland, Netherlands

Jeroen Schoots,

• Cornelissen, Elisabeth A.M., Radboud university medical center, Lent, gelderland, Netherlands

Elisabeth A.M. Cornelissen,

• Bleich, Markus, Christian Albrechts University Kiel, Kiel, Germany

Markus Bleich,

• Hoenderop, Joost, Radboud university medical center, Lent, gelderland, Netherlands

Joost Hoenderop,

• Wetzels, Jack F., Radboud university medical center, Lent, gelderland, Netherlands

Jack F. Wetzels,

• Lugtenberg, Dorien, Radboud university medical center, Lent, gelderland, Netherlands

Dorien Lugtenberg,

Background

Hypokalemic alkalosis result from acquired causes or rare (genetic) tubular disorders. Salt-losing nephropathies, due to mutations affecting transcellular sodium reabsorption, induce hypokalemic alkalosis by increasing distal tubular flow and sodium delivery. However, the importance of paracellular transport across tight junctions, involving the claudin protein family, is increasingly acknowledged.

Methods

We phenotyped two unrelated patients with hypokalemic alkalosis, including tubular function testing, performed whole exome sequencing and characterized the identified CLDN10 sequence variations in vitro.

Results

The first patient was diagnosed with Bartter syndrome (BS) over 30 years ago. Re-evaluation demonstrated 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 either GS or BS. A reduced urinary concentrating ability with a preserved aquaporin-2 response to desmopressin was demonstrated, with an intact to exaggerated response to furosemide. These findings are not in line with any known salt-losing nephropathy. Whole exome sequencing revealed compound heterozygous CLDN10 sequence variants. A second unrelated patient was thereafter identified demonstrating a similar phenotype and compound heterozygous CLND10 sequence variants. Both patients’ phenotypes resemble a mouse model lacking distal tubular Claudin-10, that demonstrates a reduced TAL paracellular sodium permeability leading to a urine concentrating defect, and enhanced paracellular magnesium and calcium permeability. Cell surface biotinylation and immunofluorescence experiments in cells expressing the Claudin-10 mutants showed that the phenotype is not explained by mere lack of Claudin-10 membrane localization or tight junction strand formation.

Conclusion

Pathogenic CLDN10 mutations cause a novel tight junction disease, possibly affecting TAL paracellular ion transport, characterized by a non-Bartter non-Gitelman hypokalemic-alkalotic salt-losing phenotype and a renal concentration defect, with hypocalciuria and unexpectedly normal to high serum magnesium levels.

Funding

• Private Foundation Support