Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness

Abstract

BackgroundThe transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.MethodsA candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.ResultsWe identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents.ConclusionsBiallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.

Role of collecting duct principal cell NOS1β in sodium and potassium homeostasis

“…A possible explanation for this is that depolarization in the principal cells of these mice stimulates intracellular signaling cascades that stimulate ENaC‐dependent K + secretion (Sorensen et al, 2019 ). This is similar to the concept that K ir 4.1/K ir 5.1 serves as a potassium sensor in the DCT to regulate Na + reabsorption through the sodium chloride cotransporter (Manis et al, 2020 ; Su et al, 2019 ) explaining hypokalemia observed in rodents and humans lacking functional K ir 4.1/K ir 5.1 channels (Celmina et al, 2019 ; Cuevas et al, 2017 ; Malik et al, 2018 ; Palygin, Levchenko, et al, 2017 ; Schlingmann et al, 2021 ; Su et al, 2019 ; Tomilin et al, 2018 ). Thus, the precise effects of changes in K ir 4.1/K ir 5.1 activity on K + homeostasis likely depend on the degree of change as well as the affected nephron segment.…”

“…The importance of basolateral K + channels is also reinforced by clinical data that identify loss of function mutations in KCNJ10 (K ir 4.1) causing EAST/SeSAME syndrome, in which patients have hypokalemia, hypomagnesemia, and salt‐wasting (Celmina et al, 2019 ). Similarly, recent studies revealed that mutations in KCNJ16 (K ir 5.1) cause a novel tubulopathy with hypokalemia, salt‐wasting, and disturbed acid‐base homeostasis (Schlingmann et al, 2021 ). Previous electrophysiological studies determined that CCD basolateral K + channel activity was decreased with inhibition of NOS and this was reversed with exogenous NO (Lu & Wang, 1996 ).…”

Potassium and the kidney: a reciprocal relationship with clinical relevance

“…The "collateral damage" of increased salt reabsorption through NCC is an increase in salt sensitivity localization of the mutations affecting the potassium channel. KCNJ16 mutations causing the predominant proximal tubule phenotype were linked to the pore-forming domain near the selectivity filter of the channel, whereas mutations causing the DCT phenotype were located in the N-or C-terminus [27]. This is reminiscent of the phenotypic variability that can be observed with mutations in the basolateral chloride channel ClC-Kb, which may cause a predominant Bartter or Gitelman phenotype [30].…”

Animal, Human, and 23Na MRI Imaging Evidence for the Negative Impact of High Dietary Salt in Children

“…For instance, there is no place for sodium restriction in patients with Fanconi syndrome [ 66 •]. Another example are patients with KCNJ16 mutations resulting in a novel tubulopathy with salt wasting [ 73 ]. Renal salt wasting may result from cystinosis, Dent disease, disorders of paracellular claudin-10b, and Kir4.1 potassium-channel deficiency [ 74 ].…”