{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:29:47Z","timestamp":1787725787252,"version":"build-2784847793"},"reference-count":48,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2013,8,15]]},"abstract":"<jats:p> Mutations in SLC4A4, the gene encoding the electrogenic Na<jats:sup>+<\/jats:sup>-HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> cotransporter NBCe1, cause severe proximal renal tubular acidosis (pRTA), growth retardation, decreased IQ, and eye and teeth abnormalities. Among the known NBCe1 mutations, the disease-causing mechanism of the T485S (NBCe1-A numbering) mutation is intriguing because the substituted amino acid, serine, is structurally and chemically similar to threonine. In this study, we performed intracellular pH and whole cell patch-clamp measurements to investigate the base transport and electrogenic properties of NBCe1-A-T485S in mammalian HEK 293 cells. Our results demonstrated that Ser substitution of Thr485 decreased base transport by \u223c50%, and importantly, converted NBCe1-A from an electrogenic to an electroneutral transporter. Aqueous accessibility analysis using sulfhydryl reactive reagents indicated that Thr485 likely resides in an NBCe1-A ion interaction site. This critical location is also supported by the finding that G486R (a pRTA causing mutation) alters the position of Thr485 in NBCe1-A thereby impairing its transport function. By using NO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> as a surrogate ion for CO<jats:sub>3<\/jats:sub><jats:sup>2\u2212<\/jats:sup>, our result indicated that NBCe1-A mediates electrogenic Na<jats:sup>+<\/jats:sup>-CO<jats:sub>3<\/jats:sub><jats:sup>2\u2212<\/jats:sup> cotransport when functioning with a 1:2 charge transport stoichiometry. In contrast, electroneutral NBCe1-T485S is unable to transport NO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>, compatible with the hypothesis that it mediates Na<jats:sup>+<\/jats:sup>-HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> cotransport. In patients, NBCe1-A-T485S is predicted to transport Na<jats:sup>+<\/jats:sup>-HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> in the reverse direction from blood into proximal tubule cells thereby impairing transepithelial HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> absorption, possibly representing a new pathogenic mechanism for generating human pRTA. <\/jats:p>","DOI":"10.1152\/ajpcell.00044.2013","type":"journal-article","created":{"date-parts":[[2013,5,2]],"date-time":"2013-05-02T07:50:52Z","timestamp":1367481052000},"page":"C392-C405","source":"Crossref","is-referenced-by-count":33,"title":["Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis"],"prefix":"10.1152","volume":"305","author":[{"given":"Quansheng","family":"Zhu","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesi M.","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyo","family":"Kao","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rustam","family":"Azimov","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan M.","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Weill Medical College of Cornell University, Ithaca, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Newman","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixin","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira","family":"Kurtz","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of California, Los Angeles, California;"},{"name":"Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","unstructured":"Alpern RJ , Moe OW , Caplan M , Seldin DW , Geibisch GH.  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