{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T19:57:06Z","timestamp":1786132626435,"version":"build-2736575974"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,6]]},"abstract":"\n Significance Statement<\/jats:title>\n \n Recessive\n SLC4A4<\/jats:italic>\n mutations are a cause of proximal renal tubular acidosis (pRTA), a rare but devastating disorder associated with loss of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) function in kidney and other organs. Alkali therapy is the preferred treatment for pRTA, which is characterized by acidemia, developmental impairment, and vision loss, and often enamel hypomineralization. However, which nonrenal findings are secondary to acidemia is poorly understood. The authors describe the phenotype of a line of transgenic mice in which NBCe1 expression is blocked in all tissues except the proximal tubule. These mice are not acidemic but still exhibit many of the extrarenal signs associated with pRTA, revealing the potential limitations of pH correction by alkali therapy in pRTA and the need to develop novel therapies.\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n The\n SLC4A4<\/jats:italic>\n gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in\n SLC4A4<\/jats:italic>\n causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy.\n SLC4A4<\/jats:italic>\n encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n To explore the consequences of Nbce1b\/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b\/c-null mice and assessed them for signs of pRTA.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Nbce1b\/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n The correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b\/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.2018050545","type":"journal-article","created":{"date-parts":[[2019,4,30]],"date-time":"2019-04-30T17:34:17Z","timestamp":1556645657000},"page":"979-989","source":"Crossref","is-referenced-by-count":15,"title":["Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b\/c-Null Mice"],"prefix":"10.1681","volume":"30","author":[{"given":"Emily E.","family":"Salerno","sequence":"first","affiliation":[{"name":"Physiology and Biophysics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangita P.","family":"Patel","sequence":"additional","affiliation":[{"name":"Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York;"},{"name":"State University of New York Eye Institute, Buffalo, New York; and"},{"name":"Research and Ophthalmology Services, VA Western New York Healthcare System, Buffalo, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniko","family":"Marshall","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Marshall","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamer","family":"Alsufayan","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheikh S. Alassane","family":"Mballo","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca N.","family":"Quade","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1761-5282","authenticated-orcid":false,"given":"Mark D.","family":"Parker","sequence":"additional","affiliation":[{"name":"Physiology and Biophysics and"},{"name":"Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York;"},{"name":"State University of New York Eye Institute, Buffalo, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,4,30]]},"reference":[{"key":"B1-20230929","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1152\/physrev.00023.2012","article-title":"The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters.","volume":"93","author":"Parker","year":"2013","journal-title":"Physiol Rev"},{"key":"B2-20230929","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/387409a0","article-title":"Expression cloning and characterization of a renal electrogenic Na+\/HCO3 - 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