{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:22:17Z","timestamp":1787016137861,"version":"build-2736575974"},"reference-count":72,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T00:00:00Z","timestamp":1470096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008210","name":"Department of Physiology and Biophysics, University at Buffalo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008210","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81070687"],"award-info":[{"award-number":["81070687"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81170805"],"award-info":[{"award-number":["81170805"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["7121012"],"award-info":[{"award-number":["7121012"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            The inheritance of two defective alleles of\n                            <jats:italic>SLC4A4<\/jats:italic>\n                            , the gene that encodes the widely\u2010expressed electrogenic sodium bicarbonate cotransporter NBCe1, results in the bicarbonate\u2010wasting disease proximal renal tubular acidosis (pRTA).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In the present study, we report the first case of compound\u2010heterozygous inheritance of pRTA (p.Arg510His\/p.Gln913Arg) in an individual with low blood pH, blindness and neurological signs that resemble transient ischaemic attacks.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We employ fluorescence microscopy on non\u2010polarized (human embryonic kidney) and polarized (Madin\u2013Darby canine kidney) renal cell lines and electrophysiology on\n                            <jats:italic>Xenopus<\/jats:italic>\n                            oocytes to characterize the mutant transporters (R510H and Q913R).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Both mutant transporters exhibit enhanced intracellular retention in renal cells, an observation that probably explains the HCO\n                            <jats:sub>3<\/jats:sub>\n                            <jats:sup>\u2212<\/jats:sup>\n                            transport deficit in the individual.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Both mutants retain a close\u2010to\u2010normal per molecule Na\n                            <jats:sup>+<\/jats:sup>\n                            \/HCO\n                            <jats:sub>3<\/jats:sub>\n                            <jats:sup>\u2212<\/jats:sup>\n                            cotransport activity in\n                            <jats:italic>Xenopus<\/jats:italic>\n                            oocytes, suggesting that they are suitable candidates for folding\u2010correction therapy. However, Q913R expression is uniquely associated with a depolarizing, HCO\n                            <jats:sub>3<\/jats:sub>\n                            <jats:sup>\u2212<\/jats:sup>\n                            independent, Cl\n                            <jats:sup>\u2212<\/jats:sup>\n                            \u2010conductance in oocytes that could have pathological consequences if expressed in the cells of patients.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Proximal renal tubular acidosis (pRTA) is a rare, recessively\u2010inherited disease characterized by abnormally acidic blood, blindness, as well as below average height and weight. pRTA is typically associated with homozygous mutation of the solute carrier 4 family gene\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      .\n                      <jats:italic>SLC4A4<\/jats:italic>\n                      encodes the electrogenic sodium bicarbonate cotransporter NBCe1, a membrane protein that acts to maintain intracellular and plasma pH. We present the first description of a case of compound\u2010heterozygous inheritance of pRTA. The individual has inherited two mutations in NBCe1: p.Arg510His (R510H) and p.Gln913Arg (Q913R), one from each parent. In addition to the usual features of pRTA, the patient exhibits unusual signs, such as muscle spasms and fever. We have recreated these mutant transporters for expression in model systems. We find that both of the mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. When expressed in\n                      <jats:italic>Xenopus<\/jats:italic>\n                      oocytes, we find that the R510H and Q913R\u2010mutant NBCe1 molecules exhibit apparently normal Na\n                      <jats:sup>+<\/jats:sup>\n                      \/HCO\n                      <jats:sub>3<\/jats:sub>\n                      <jats:sup>\u2212<\/jats:sup>\n                      cotransport activity but that Q913R is associated with an unusual HCO\n                      <jats:sub>3<\/jats:sub>\n                      <jats:sup>\u2212<\/jats:sup>\n                      independent anion\u2010leak. We conclude that a reduced accumulation of NBCe1 protein in the basolateral membrane of proximal\u2010tubule epithelia is the most probable cause of pRTA in this case. We further note that the Q913R\u2010associated anion\u2010leak could itself be pathogenic if expressed in the plasma membrane of mammalian cells, compromising the benefit of strategies aiming to enhance mutant NBCe1 accumulation in the plasma membrane.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp272252","type":"journal-article","created":{"date-parts":[[2016,6,24]],"date-time":"2016-06-24T05:16:43Z","timestamp":1466745403000},"page":"6267-6286","source":"Crossref","is-referenced-by-count":26,"title":["A novel mutant Na\n                    <sup>+<\/sup>\n                    \/HCO3\n                    <sup>\u2212<\/sup>\n                    cotransporter NBCe1 in a case of compound\u2010heterozygous inheritance of proximal renal tubular acidosis"],"prefix":"10.1113","volume":"594","author":[{"given":"Evan J.","family":"Myers","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences University at Buffalo: The State University of New York  Buffalo New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie A.","family":"Felmlee","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences University at Buffalo: The State University of New York  Buffalo New York, NY USA"},{"name":"Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences University of the Pacific  Stockton California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010Yuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Chinese People's Army General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ou","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Ping","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniko","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences University at Buffalo: The State University of New York  Buffalo New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Bo","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital Peking Union Medical College, Chinese Academy of Medical Sciences  Beijing China"}],"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":"Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences University at Buffalo: The State University of New York  Buffalo New York, NY USA"},{"name":"Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences University at Buffalo: The State University of New York  Buffalo New York, NY USA"},{"name":"State University of New York Eye Institutes University at Buffalo: The State University of New York  Buffalo New York, NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,2]]},"reference":[{"issue":"16","key":"e_1_2_6_2_1","first-page":"S57","article-title":"Familial renal tubular acidosis","volume":"23","author":"Alper SL","year":"2010","journal-title":"J Nephrol"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4335"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.278.6.C1200"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.2001.281.5.F920"},{"key":"e_1_2_6_6_1","first-page":"652","volume-title":"Medical Physiology. A Cellular and Molecular Approach, 2nd updated edn","author":"Boron WF","year":"2012"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.81.1.53"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1656"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00914.x"},{"key":"e_1_2_6_10_1","first-page":"71A","article-title":"Targeted NBCe1A Deletion Causes Proximal RTA: Whole nbce1 (sh_nbce1) KO versus nbce1A KO Mice","volume":"25","author":"Chen A\u2010P","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.15-17802"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/35014615"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00131.2002"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.276.3.C576"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057062"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408646200"},{"key":"e_1_2_6_17_1","first-page":"324","article-title":"Proximal renal tubular acidosis and ocular pathology: a novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1)","volume":"12","author":"Demirci FYK","year":"2006","journal-title":"Mol Vis"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406591200"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-12-43"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2015.7"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1995.tb00200.x"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607041200"},{"key":"e_1_2_6_23_1","first-page":"851","volume-title":"Medical Physiology. A Cellular and Molecular Approach, 2nd updated edition","author":"Giebisch G","year":"2012"},{"key":"e_1_2_6_24_1","first-page":"A797","article-title":"Surface\u2010pH gradient measurements in Xenopus oocytes co\u2010expressing the Na+\u2010driven Cl\u2010HCO3 exchanger (NDCBE1) and CAIV: evidence for CO3\n                  = transport","volume":"16","author":"Grichtchenko II","year":"2002","journal-title":"FASEB J"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00219.2015"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004240050916"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004080667"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/15440"},{"key":"e_1_2_6_29_1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1681\/ASN.V124713","article-title":"Novel nonsense mutation in the Na+\/HCO3\n                  \u2013 cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma","volume":"12","author":"Igarashi T","year":"2001","journal-title":"J Am Soc Nephrol"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000025281.70901.30"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-004-1278-1"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-1935-4"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.320"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-001-0109-y"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-201X.2004.01297.x"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.115188"},{"key":"e_1_2_6_37_1","first-page":"656.9","article-title":"Distinguishing HCO3\n                  \u2013 from CO3\n                  2\u2013 transport by NBCe1\u2010A","volume":"25","author":"Lee S\u2010K","year":"2011","journal-title":"FASEB J"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00032.2005"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00405.2004"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-007-9018-z"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2011.04.010"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.523"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00267.2006"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.05.037"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2009.12.012"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00023.2012"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.224733"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.128389"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/387409a0"},{"key":"e_1_2_6_50_1","first-page":"F11","article-title":"Mechanism of bicarbonate exit across basolateral membrane of rabbit proximal straight tubule","volume":"252","author":"Sasaki S","year":"1987","journal-title":"Am J Physiol"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00166.2002"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-18-06839.2000"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_6_54_1","first-page":"F611","article-title":"Cation and voltage dependence of rat kidney electrogenic Na+\u2010HCO3\n                  \u2013 cotransporter, rkNBC, expressed in oocytes","volume":"277","author":"Sciortino CM","year":"1999","journal-title":"Am J Physiol"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00374866"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00270"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036215"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00008363"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2009.12.001"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05598"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008705107"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0319-y"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2010.01.034"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.42.26332"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00094.2006"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(99)00135-2"},{"key":"e_1_2_6_67_1","first-page":"720","article-title":"Niflumic and flufenamic acids are potent reversible blockers of Ca2+\u2010activated Cl\u2013 channels in Xenopus oocytes","volume":"37","author":"White MM","year":"1990","journal-title":"Mol Pharmacol"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.001438"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00595689"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401380200"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.169201"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00044.2013"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.sj.6300139"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP272252","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP272252","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP272252","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T05:31:37Z","timestamp":1696138297000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP272252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,2]]},"references-count":72,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2016,11]]}},"alternative-id":["10.1113\/JP272252"],"URL":"https:\/\/doi.org\/10.1113\/jp272252","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,2]]}}}