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Previous studies have suggested that mutations in\n                    <jats:italic>ATP6V0A4<\/jats:italic>\n                    consistently result in a loss of function, impairing the hydrogen ion transport efficacy of V-ATPase and leading to distal renal tubular acidosis and sensorineural hearing loss. Here, we identified a 32-year-old male patient and his father, both of whom harbored a heterozygous\n                    <jats:italic>ATP6V0A4<\/jats:italic>\n                    p.V512L mutation and exhibited hypochloremic metabolic alkalosis, acidic urine, and hypokalemia. Through a series of protein structural analyses and functional experiments, the V512L mutation was confirmed as a gain-of-function mutation in the\n                    <jats:italic>ATP6V0A4<\/jats:italic>\n                    gene. V512-a4 increased a4 subunit expression abundance by enhancing V512L-a4 stability and reducing its degradation, which in turn potentiated the capacity of V-ATPase to acidify the tubular lumen, leading to acidic urine and metabolic alkalosis. Through mutant V512L-a4 subunit structure-based virtual and experimental screening, we identified F351 (C\n                    <jats:sub>25<\/jats:sub>\n                    H\n                    <jats:sub>26<\/jats:sub>\n                    FN\n                    <jats:sub>3<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    S), a small-molecule inhibitor specifically targeting the V512L-a4 mutant. In conclusion, we identified a gain-of-function mutation in the\n                    <jats:italic>ATP6V0A4<\/jats:italic>\n                    gene, broadening its phenotypic and mutational spectrum, and we provide valuable insights into potential therapeutic approaches for diseases associated with\n                    <jats:italic>ATP6V0A4<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1172\/jci188807","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T12:00:22Z","timestamp":1745928022000},"source":"Crossref","is-referenced-by-count":11,"title":["A gain-of-function mutation in ATP6V0A4 drives primary distal renal tubular alkalosis with enhanced V-ATPase activity"],"prefix":"10.1172","volume":"135","author":[{"given":"Si-qi","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-qian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Science, Nanjing Medical University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-ning","family":"Zhou","sequence":"additional","affiliation":[{"name":"Nanjing Jiangbei New Area Biopharmaceutical Public Service Platform Co. 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