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

Significance Statement A novel disease phenotype comprises a tubulopathy with severe hypokalemia, renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness associated with variants in KCNJ16 (K ir 5.1). In the kidney, the inwardly rectifying potassium channel subunit KCNJ16 forms functional heteromers with KCNJ10 in the distal nephron and with KCNJ15 in the proximal tubule. Functional studies of mutant KCNJ16 in Xenopus oocytes demonstrate a disturbed function of channel complexes with both KCNJ10 and KCNJ15. Individuals with KCNJ16 variants may present with metabolic acidosis or alkalosis, reflecting a differential effect on proximal tubular bicarbonate reabsorption as well as distal tubular salt and potassium conservation. These findings together establish a multifaceted role of KCNJ16 in tubular transport processes and potassium and pH sensing. Background The 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. Methods A 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. Results We 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. Conclusions Biallelic 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.