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

• Published in: Journal of the American Society of Nephrology 2021-06, Vol.32 (6), p.1498-1512
• Main Authors: Schlingmann, Karl P, Renigunta, Aparna, Hoorn, Ewout J, Forst, Anna-Lena, Renigunta, Vijay, Atanasov, Velko, Mahendran, Sinthura, Barakat, Tahsin Stefan, Gillion, Valentine, Godefroid, Nathalie, Brooks, Alice S, Lugtenberg, Dorien, Lake, Jennifer, Debaix, Huguette, Rudin, Christoph, Knebelmann, Bertrand, Tellier, Stephanie, Rousset-Rouvière, Caroline, Viering, Daan, de Baaij, Jeroen H F, Weber, Stefanie, Palygin, Oleg, Staruschenko, Alexander, Kleta, Robert, Houillier, Pascal, Bockenhauer, Detlef, Devuyst, Olivier, Vargas-Poussou, Rosa, Warth, Richard, Zdebik, Anselm A, Konrad, Martin
• Format: Article
• Language: English
• Subjects: Acid-Base Imbalance - genetics; Adolescent; Adult; Alleles; Animals; Child, Preschool; Clinical Research; Exome Sequencing; Female; Hearing Loss, Sensorineural - genetics; Humans; Hypokalemia - genetics; Infant; Infant, Newborn; Kidney Diseases - genetics; Kidney Tubules; Loss of Function Mutation; Male; Mice; Nephrons - metabolism; Oocytes; Pedigree; Phenotype; Potassium Channels, Inwardly Rectifying - genetics; Renal Reabsorption - genetics; RNA, Messenger - metabolism; Salts - metabolism; Xenopus laevis; Young Adult
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2020111587

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 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness. 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. We identified mutations in the 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 oocytes significantly reduced currents. Biallelic variants in 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.