{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:49:09Z","timestamp":1790020149257,"version":"4.0.1"},"reference-count":28,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[1999,10,1]]},"abstract":"<jats:p>Gitelman\u2019s syndrome is an autosomal recessive disorder of salt wasting and hypokalemia caused by mutations in the thiazide-sensitive Na-Cl cotransporter. To investigate the pathogenesis of Gitelman\u2019s syndrome, eight disease mutations were introduced into the mouse thiazide-sensitive Na-Cl cotransporter and studied by functional expression in Xenopus oocytes. Sodium uptake into oocytes that expressed the wild-type clone was more than sevenfold greater than uptake into control oocytes. Uptake into oocytes that expressed the mutated transporters was not different from control. Hydrochlorothiazide reduced Na uptake by oocytes expressing the wild-type gene to control values but had no effect on oocytes expressing the mutant clones. Western blots of oocytes injected with the wild-type clone showed bands representing glycosylated (125 kDa) and unglycosylated (110 kDa) forms of the transport protein. Immunoblot of oocytes expressing the mutated clones showed only the unglycosylated protein, indicating that protein processing was disrupted. Immunocytochemistry with an antibody against the transport protein showed intense membrane staining of oocytes expressing the wild-type protein. Membrane staining was completely absent from oocytes expressing mNCC<jats:sub>R948X<\/jats:sub>; instead, diffuse cytoplasmic staining was evident. In summary, the results show that several mutations that cause Gitelman\u2019s syndrome are nonfunctional because the mutant thiazide-sensitive Na-Cl cotransporter is not processed normally, probably activating the \u201cquality control\u201d mechanism of the endoplasmic reticulum.<\/jats:p>","DOI":"10.1152\/ajprenal.1999.277.4.f643","type":"journal-article","created":{"date-parts":[[2017,12,23]],"date-time":"2017-12-23T12:29:22Z","timestamp":1514032162000},"page":"F643-F649","source":"Crossref","is-referenced-by-count":34,"title":["Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman\u2019s syndrome"],"prefix":"10.1152","volume":"277","author":[{"given":"Shanti","family":"Kunchaparty","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Palcso","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver, Colorado 80220; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Berkman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver, Colorado 80220; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heino","family":"Vel\u00e1zquez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary V.","family":"Desir","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Reilly","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver, Colorado 80220; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Ellison","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver, Colorado 80220; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)80594-3"},{"key":"B2","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1681\/ASN.V981347","volume":"9","author":"Bostanjoglo M.","year":"1998","journal-title":"J. Am. Soc. Nephrol."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/358761a0"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.23.8998"},{"key":"B6","doi-asserted-by":"crossref","first-page":"17713","DOI":"10.1016\/S0021-9258(17)32499-7","volume":"269","author":"Gamba G.","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.7.2749"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.27.16237"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.11.8.3886"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.126.1.41"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s004670050158"},{"key":"B12","doi-asserted-by":"crossref","first-page":"19867","DOI":"10.1016\/S0021-9258(18)54860-2","volume":"266","author":"Kozak M.","year":"1991","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199812033392307"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1998.00070.x"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(92)90239-A"},{"issue":"38","key":"B18","first-page":"F900","volume":"269","author":"Oberm\u00fcller N.","year":"1995","journal-title":"Am. J. Physiol."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1996.300"},{"key":"B20","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1681\/ASN.V7102244","volume":"7","author":"Pollak M. R.","year":"1996","journal-title":"J. Am. Soc. Nephrol."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.44.29150"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/ng1097-171"},{"key":"B23","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1681\/ASN.V961032","volume":"9","author":"Simon D. B.","year":"1998","journal-title":"J. Am. Soc. Nephrol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-183"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ng1096-152"},{"key":"B26","first-page":"1623","volume":"7","author":"Simon D. B.","year":"1996","journal-title":"J. Am. Soc. Nephrol."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/00041552-199801000-00008"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/ng0196-24"},{"key":"B29","first-page":"4496","volume":"81","author":"Takeuchi K.","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1998.00036.x"}],"container-title":["American Journal of Physiology-Renal Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajprenal.1999.277.4.F643","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T03:39:21Z","timestamp":1660189161000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajprenal.1999.277.4.F643"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,10,1]]},"references-count":28,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1999,10,1]]}},"alternative-id":["10.1152\/ajprenal.1999.277.4.F643"],"URL":"https:\/\/doi.org\/10.1152\/ajprenal.1999.277.4.f643","relation":{},"ISSN":["1931-857X","1522-1466"],"issn-type":[{"value":"1931-857X","type":"print"},{"value":"1522-1466","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,10,1]]}}}