{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:31:14Z","timestamp":1786113074475,"version":"build-2736575974"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"32","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"HHS | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["Z01-DE000713"],"award-info":[{"award-number":["Z01-DE000713"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"HHS | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["-ZIA-DE000754"],"award-info":[{"award-number":["-ZIA-DE000754"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,11]]},"abstract":"<jats:p>Phosphate plays essential roles within the human body and levels are tightly controlled through conserved feedback loops. FGF23, a phosphate-regulating hormone produced in the bone, is regulated by the glycosyltransferase, GALNT3, whose expression is sensitive to circulating phosphate levels. GALNT3-mediated glycosylation of FGF23 confers protection from inactivating furin cleavage, thus allowing intact FGF23 to modulate phosphate reabsorption in the kidneys. Mutations in either FGF23 or GALNT3 are responsible for diseases of phosphate regulation, which can lead to growth defects, skeletal malformations, soft-tissue calcification, kidney failure, and death. However, the specific effects of many of these mutations remain poorly understood and effective treatments are lacking. Here, we employ an in vivo system that recapitulates the FGF23\/GALNT3 axis to demonstrate the functional consequences of 11 GALNT3 patient mutations. We identify certain GALNT3 mutations that affect stability yet retain catalytic activity and thus may be targets for therapeutic approaches that enhance folding\/stability. We present evidence that one previously reported pathogenic mutation is not pathogenic. We also demonstrate that two additional members of the GALNT family can glycosylate FGF23 and protect it from furin cleavage in cells. Finally, we examine three patient-derived FGF23 mutations and show they have unique effects on stability or secretion. This study provides detailed mechanistic information regarding patient mutations in both GALNT3 and FGF23 that result in disease and a functional platform for developing new approaches to treat diseases of phosphate dysregulation.<\/jats:p>","DOI":"10.1073\/pnas.2603453123","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T17:36:00Z","timestamp":1785951360000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic insights into mutations that cause diseases of phosphate dysregulation"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8637-4975","authenticated-orcid":false,"given":"Liping","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa E.","family":"Lee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]},{"name":"Department of Developmental Biology, Harvard School of Dental Medicine","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Tian","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3676-7644","authenticated-orcid":false,"given":"Michael T.","family":"Collins","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Roszko","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]},{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Mineral Homeostasis Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7152-2939","authenticated-orcid":false,"given":"Nadine L.","family":"Samara","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Structural Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2057-8120","authenticated-orcid":false,"given":"Kelly G.","family":"Ten Hagen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/004a2wv92","id-type":"ROR","asserted-by":"publisher"}],"name":"Developmental Glycobiology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0076-3"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2019.01.006"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00256-009-0808-5"},{"key":"e_1_3_4_4_2","volume-title":"GeneReviews((R))","author":"Ramnitz M. S.","unstructured":"M. S. Ramnitz, R. I. Gafni, M. T. Collins \u201cHyperphosphatemic familial tumoral calcinosis\u201d in GeneReviews((R)), M. P. Adam , Eds. (University of Washington, Seattle, WA, 1993)."},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.0301264"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00293"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2011.10.020"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-015-0254-3"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jbmr\/zjae115"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.123.320455"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2870"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1358"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.418558"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.1613"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1815166116"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi034"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0444-x"},{"key":"e_1_3_4_18_2","first-page":"613","article-title":"A sole case of the FGF23 gene mutation c.202A>G (p.Thr68Ala) associated with multiple severe vascular aneurysms and a hyperphosphatemic variant of tumoral calcinosis-a case report","volume":"14","author":"Ivanova N. G.","year":"2024","unstructured":"N. G. Ivanova, A sole case of the FGF23 gene mutation c.202A>G (p.Thr68Ala) associated with multiple severe vascular aneurysms and a hyperphosphatemic variant of tumoral calcinosis-a case report. 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Zhang Novel mechanistic insights into GALNT3 and FGF23 mutations that cause diseases of phosphate dysregulation. PRIDE\/ProteomeXchange. https:\/\/www.ebi.ac.uk\/pride\/archive\/projects\/PXD078848. Deposited 26 May 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2603453123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T17:36:10Z","timestamp":1785951370000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2603453123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":43,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2026,8,11]]}},"alternative-id":["10.1073\/pnas.2603453123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2603453123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"assertion":[{"value":"2026-01-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2603453123"}}