{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:35:54Z","timestamp":1791275754981,"version":"4.1.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"32","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,8,10]]},"abstract":"<jats:p>\n                    Mutations of the\n                    <jats:italic>KCNJ10<\/jats:italic>\n                    (\n                    <jats:italic>Kir4.1<\/jats:italic>\n                    ) K\n                    <jats:sup>+<\/jats:sup>\n                    channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of\n                    <jats:italic>KCNJ10<\/jats:italic>\n                    mutations found in our patients with EAST syndrome. Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts. In the human kidney, KCNJ10 staining was additionally observed in the basolateral membrane of the cortical thick ascending limb of Henle's loop. EM of distal tubular cells of a patient with EAST syndrome showed reduced basal infoldings in this nephron segment, which likely reflects the morphological consequences of the impaired salt reabsorption capacity. When expressed in CHO and HEK293 cells, the KCNJ10 mutations R65P, G77R, and R175Q caused a marked impairment of channel function. R199X showed complete loss of function. Single-channel analysis revealed a strongly reduced mean open time. Qualitatively similar results were obtained with coexpression of KCNJ10\/KCNJ16, suggesting a dominance of KCNJ10 function in native renal KCNJ10\/KCNJ16 heteromers. The decrease in the current of R65P and R175Q was mainly caused by a remarkable shift of pH sensitivity to the alkaline range. In summary, EAST mutations of KCNJ10 lead to impaired channel function and structural changes in distal convoluted tubules. Intriguingly, the metabolic alkalosis present in patients carrying the R65P mutation possibly improves residual function of KCNJ10, which shows higher activity at alkaline pH.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1003072107","type":"journal-article","created":{"date-parts":[[2010,7,22]],"date-time":"2010-07-22T23:50:13Z","timestamp":1279842613000},"page":"14490-14495","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":207,"title":["KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function"],"prefix":"10.1073","volume":"107","author":[{"given":"Markus","family":"Reichold","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anselm A.","family":"Zdebik","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Medicine and Institute of Child Health and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn","family":"Lieberer","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Rapedius","sequence":"additional","affiliation":[{"name":"Department of Physiology, University Hospital Jena, 07743 Jena, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Bandulik","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Sterner","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Tegtmeier","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Penton","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Baukrowitz","sequence":"additional","affiliation":[{"name":"Department of Physiology, University Hospital Jena, 07743 Jena, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally-Anne","family":"Hulton","sequence":"additional","affiliation":[{"name":"Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Witzgall","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of Regensburg, 93053 Regensburg, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruria","family":"Ben-Zeev","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Edmond and Lilly Safra Children\u2019s Hospital, Sheba Medical Center, Ramat-Gan 46425, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Howie","sequence":"additional","affiliation":[{"name":"Department of Pathology, University College London, London NW3 2PF, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Kleta","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Medicine and Institute of Child Health and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Bockenhauer","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Medicine and Institute of Child Health and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Warth","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,7,22]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1159\/000094001"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810276"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0901749106"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(96)00502-9"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.27.16339"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.012961"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00288.2007"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0601-7"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1958.tb01563.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-010X(19971201)279:5<476::AID-JEZ10>3.0.CO;2-6"},{"key":"e_1_3_3_11_2","first-page":"F517","article-title":"Coupling between transepithelial Na transport and basolateral K conductance in renal proximal tubule","volume":"266","author":"Beck JS","year":"1994","unstructured":"JS Beck, R Laprade, JY Lapointe, Coupling between transepithelial Na transport and basolateral K conductance in renal proximal tubule. 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