Research Research themes Renal disorders The discovery of a new rare kidney disorder
Societal relevance:Clinical expertise regarding rare kidney disorders, especially renal tubular disorders, is sparse. Hypokalemic alkalosis is often due to increased water and sodium delivery to the collecting duct with concomitant enhanced aldosterone action due to volume contraction. Frequently, secondary electrolyte disorders due to reduced or enhanced renal tubular reabsorption occur. After the exclusion of acquired and/or drug-induced causes of hypokalemic alkalosis, the differential diagnosis includes several rare (genetic) renal tubular disorders. We show how a collaborative approach including in-depth clinical phenotyping, specialized renal tubular function testing and genetic analyses excluded all known genetic hypokalemic-alkalotic renal tubular disorders in these patients, and eventually led to the discovery of a new disorder for which the pathogenesis could be elucidated by further clinical, genetic and in vitro analyses.
Discovery:We identified and characterized mutations in CLDN10, the gene encoding the tight junction protein Claudin-10, 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. 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. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants. Mice lacking distal tubular expression of 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 remained previously undetermined. 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.
This was the first publication of pathogenic CLDN10 mutations affecting TAL paracellular ion transport and causing a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.