{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:24:24Z","timestamp":1783441464021,"version":"3.54.6"},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Dent disease type 1 is an X-linked proximal tubulopathy caused by mutations in\n                      <jats:italic toggle=\"yes\">CLCN5<\/jats:italic>\n                      , which encodes the chloride\/proton exchanger ClC-5. While loss-of-function mutations impair endocytosis and lead to progressive renal disease, the pathological consequences of uncoupling mutations that selectively disrupt Cl\n                      <jats:sup>-<\/jats:sup>\n                      \/H\n                      <jats:sup>+<\/jats:sup>\n                      exchange remain incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>In this study, we examined the renal phenotype associated with the ClC-5 E211A uncoupling mutation, which abolishes proton transport while preserving chloride conductance, and compared it with that of ClC-5 null mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Contrary to the expectation that partial transport activity would mitigate disease severity, E211A mutant mice developed more severe and progressive kidney pathology than null mutants. Both models exhibited early low-molecular-weight proteinuria, including marked urinary excretion of \u03b22-microglobulin and vitamin D\u2013binding protein. However, E211A mutants displayed progressive polyuria, reduced body weight, and pronounced interstitial fibrosis at 5 and 18 months of age, changes not observed in ClC-5 null mice. Renal injury in E211A mutants was characterized by glomerular abnormalities, including enlarged Bowman\u2019s spaces, cyst formation, reduced podocyte markers Wilms tumor protein and nephrin, and age-dependent tubular degeneration. ClC-5 E211A protein showed altered localization and reduced expression in vivo, suggesting disrupted trafficking or stability. Phenotypic severity was strongly influenced by genetic background, underscoring its modulatory role in disease expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Together, these findings demonstrate that the ClC-5 E211A uncoupling mutation induces additional adverse effects that exceed those caused by complete loss of ClC-5. Our results reveal that uncoupling mutations can drive progressive kidney damage through mechanisms distinct from gene knockout and highlight the need for mutation-specific therapeutic strategies for Dent disease type 1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.34067\/kid.0000001258","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:00:52Z","timestamp":1783440052000},"update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["The Missense Mutant ClC-5 (E211A), associated with Proton\/Chloride Uncoupling Exacerbates Renal Pathology Compared to the ClC-5 null Mutant"],"prefix":"10.34067","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6855-0645","authenticated-orcid":false,"given":"Aykut","family":"Bostanci","sequence":"first","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Lyu","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuili","family":"Jiang","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Whan","family":"Yoo","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8510-3759","authenticated-orcid":false,"given":"Rhyston","family":"Broadhurst","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2444-6587","authenticated-orcid":false,"given":"Mckenzie","family":"Paul","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5938-0261","authenticated-orcid":false,"given":"Jonah","family":"Zaas","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8186-2160","authenticated-orcid":false,"given":"Anthony","family":"Atala","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9240-558X","authenticated-orcid":false,"given":"Baisong","family":"Lu","sequence":"additional","affiliation":[{"name":"Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,7,7]]},"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.34067\/KID.0000001258","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:00:52Z","timestamp":1783440052000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.34067\/KID.0000001258"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":0,"URL":"https:\/\/doi.org\/10.34067\/kid.0000001258","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]},"assertion":[{"value":"2026-01-30","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-25","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}