{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:30:29Z","timestamp":1786379429712,"version":"build-2736575974"},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"abstract":"\n Background:<\/jats:title>\n \n The pivotal role of K\n ir<\/jats:sub>\n 5.1 (\n KCNJ16<\/jats:italic>\n ) in maintaining electrolyte and acid-base homeostasis has been demonstrated in animal studies and highlighted by the identification of disease-causing variants in\n KCNJ16<\/jats:italic>\n resulting in Hypokalemia Tubulopathy and Deafness (HkTD) with variable severity. Although the underlying molecular mechanisms remain elusive, the modus operandi of K\n ir<\/jats:sub>\n 5.1 is deeply rooted in its heteromeric association with K\n ir<\/jats:sub>\n 4.1 (\n KCNJ10<\/jats:italic>\n ) and K\n ir<\/jats:sub>\n 4.2 (\n KCNJ15<\/jats:italic>\n ). The ubiquitous expression of\n KCNJ16<\/jats:italic>\n and the heterogenous clinical picture point towards the importance of protein-protein interactions and membrane trafficking of the heteromeric channels involving K\n ir<\/jats:sub>\n 5.1.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n In this study we performed whole exome sequencing for genetic screening. Functional studies were performed in\n Xenopus<\/jats:italic>\n oocytes using two electrode voltage clamp recordings. Protein-protein interactions were determined by co-immunoprecipitation. Live cell imaging was performed using confocal microscopy to visualize the subcellular localization of the fluorescence tagged proteins using appropriate sub-cellular markers.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n Here, we report 4 patients from 3 families with salt-losing tubulopathy, hypokalemia and acidosis secondary to pathogenic biallelic variants in\n KCNJ16<\/jats:italic>\n . In addition to two previously described variants with phenotypic consistency (R137C) or phenotypic variability (I132R+R176*), we report a variant (K48*-Y57*) possibly lacking deafness, expanding the variant spectrum. Our results show that the pathogenic variants of K\n ir<\/jats:sub>\n 5.1 maintain interactions with K\n ir<\/jats:sub>\n 4.1 and K\n ir<\/jats:sub>\n 4.2 but differentially disrupt membrane trafficking of the heteromeric channels, offering a molecular explanation for the observed clinical heterogeneity.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n HkTD is a clinically heterogenous disorder, where the onset, presentation and severity may be influenced by the type and location of the\n KCNJ16<\/jats:italic>\n variants. These variant specific effects on channel assembly, trafficking and residual function provide a mechanistic explanation for the broad spectrum of renal and auditory phenotypes and underscore the importance of molecular characterization for accurate diagnosis and personalized therapies.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.34067\/kid.0000001296","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:00:36Z","timestamp":1786377636000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Type, Location and Zygosity of KCNJ16 Variants May Determine the Clinical Severity of Hypokalemia Tubulopathy and Deafness (HkTD)"],"prefix":"10.34067","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3848-0196","authenticated-orcid":false,"given":"Leire","family":"Gondra","sequence":"first","affiliation":[{"name":"Pediatric Nephrology Department, Cruces University Hospital, Barakaldo, Spain"},{"name":"University of the Basque Country (EHU), Leioa, Bizkaia, Spain"},{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3111-8405","authenticated-orcid":false,"given":"Shivani","family":"Mora","sequence":"additional","affiliation":[{"name":"Marburg University, Department of Pediatric Nephrology, University Children\u2019s Hospital, 35043, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4581-252X","authenticated-orcid":false,"given":"Imran G.","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Marburg University, Department of Pediatric Nephrology, University Children\u2019s Hospital, 35043, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9734-6600","authenticated-orcid":false,"given":"Alejandro","family":"Garcia-Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"},{"name":"Biomedical Research Network Center for Diabetes and Associated Metabolic Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas, CIBERDEM), Biomedical Research Network Center for Rare Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER), EndoERN, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4215-8015","authenticated-orcid":false,"given":"Franziska","family":"Schilling","sequence":"additional","affiliation":[{"name":"Marburg University, Department of Pediatric Nephrology, University Children\u2019s Hospital, 35043, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1763-1098","authenticated-orcid":false,"given":"Gema","family":"Ariceta","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology. Hospital Vall d\u2019Hebron. University Autonomous Barcelona. Renal Physiopathology Group. Vall d`Hebron Research Institute. Ricords Network, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1693-314X","authenticated-orcid":false,"given":"Leire","family":"Garc\u00eda-Suarez","sequence":"additional","affiliation":[{"name":"Pediatric Department. Hospitalario General de Fuerteventura. Puerto del Rosario, Las Palmas, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9727-2218","authenticated-orcid":false,"given":"Patricia","family":"Tejera-Carre\u00f1o","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Department. Complejo Hospitalario Universitario Insular-Materno Infantil. Las Palmas de Gran Canaria, Las Palmas, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6641-7763","authenticated-orcid":false,"given":"Gema","family":"Fern\u00e1ndez-Juarez","sequence":"additional","affiliation":[{"name":"Nephrology Department. Hospital Universitario La Paz, Instituto de Investigaci\u00f3n La Paz, IdiPAZ, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1075-9948","authenticated-orcid":false,"given":"Alfredo Santana","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department. Complejo Hospitalario Universitario Insular-Materno Infantil. Las Palmas de Gran Canaria, Las Palmas, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9951-1390","authenticated-orcid":false,"given":"Jonai","family":"Pujol-Gim\u00e9nez","sequence":"additional","affiliation":[{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4933-525X","authenticated-orcid":false,"given":"Marta","family":"Garc\u00eda-Alonso","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Department, Cruces University Hospital, Barakaldo, Spain"},{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8863-4870","authenticated-orcid":false,"given":"Sara","family":"G\u00f3mez-Conde","sequence":"additional","affiliation":[{"name":"University of the Basque Country (EHU), Leioa, Bizkaia, Spain"},{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"},{"name":"Biomedical Research Network Center for Diabetes and Associated Metabolic Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas, CIBERDEM), Biomedical Research Network Center for Rare Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER), EndoERN, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4523-9440","authenticated-orcid":false,"given":"Ainhoa Camille","family":"Aranaga-Decori","sequence":"additional","affiliation":[{"name":"University of the Basque Country (EHU), Leioa, Bizkaia, Spain"},{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"},{"name":"Biomedical Research Network Center for Diabetes and Associated Metabolic Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas, CIBERDEM), Biomedical Research Network Center for Rare Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER), EndoERN, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6499-5313","authenticated-orcid":false,"given":"Martin","family":"Koemhoff","sequence":"additional","affiliation":[{"name":"Marburg University, Department of Pediatric Nephrology, University Children\u2019s Hospital, 35043, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4123-4447","authenticated-orcid":false,"given":"Vijay","family":"Renigunta","sequence":"additional","affiliation":[{"name":"Marburg University, Institute for physiology and pathophysiology, 35037, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9498-2337","authenticated-orcid":false,"given":"Stefanie","family":"Weber","sequence":"additional","affiliation":[{"name":"Marburg University, Department of Pediatric Nephrology, University Children\u2019s Hospital, 35043, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-9842","authenticated-orcid":false,"given":"Leire","family":"Madariaga","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology Department, Cruces University Hospital, Barakaldo, Spain"},{"name":"University of the Basque Country (EHU), Leioa, Bizkaia, Spain"},{"name":"Biobizkaia Health Research Institute. Plaza de Cruces 12, 48903, Barakaldo, Bizkaia, Spain"},{"name":"Biomedical Research Network Center for Diabetes and Associated Metabolic Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Diabetes y Enfermedades Metab\u00f3licas Asociadas, CIBERDEM), Biomedical Research Network Center for Rare Diseases (Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER), EndoERN, Barakaldo, Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5559-2053","authenticated-orcid":false,"given":"Aparna","family":"Renigunta","sequence":"additional","affiliation":[{"name":"Marburg University, Department of Pediatric Nephrology, University Children\u2019s Hospital, 35043, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,8,10]]},"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000001296","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T16:00:36Z","timestamp":1786377636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000001296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":0,"URL":"https:\/\/doi.org\/10.34067\/kid.0000001296","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]},"assertion":[{"value":"2026-01-15","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-16","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}