{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T09:52:52Z","timestamp":1758361972136,"version":"3.44.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"EU Marie-Sk\u0142odowska Curie Fellowship","award":["101025071","MCSA-IF-2020"],"award-info":[{"award-number":["101025071","MCSA-IF-2020"]}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["24141901300","23ZR1437600"],"award-info":[{"award-number":["24141901300","23ZR1437600"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272519","81772373","92068102","22177073"],"award-info":[{"award-number":["82272519","81772373","92068102","22177073"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hypophosphatemia (HPP) is an inherited metabolic disorder characterized by defective bone and tooth mineralization, resulting from mutations in the gene encoding tissue-nonspecific alkaline phosphatase (ALPL). Despite the wide spectrum of clinical manifestations associated with ALPL mutations, the genotype\u2013phenotype relationship remains poorly understood. In this work, we discovered a novel combination of missense mutations, p.G129E and p.Y263H. The patient with the mutations suffered from chronic musculoskeletal pain, arthralgia, and permanent dentition. Biochemical assays revealed that the Y263H mutation did not impair enzymatic function, but the G129E mutation significantly disrupted catalytic activity. Furthermore, G129E exhibited a dominant-negative effect by suppressing the function of the WT ALPL protein. Molecular dynamics simulations indicated that E129 formed novel salt bridges with R152, altering correlated motions and conformational dynamics of ALPL. These changes likely impair the formation of ALPL octamers, leading to loss of enzymatic activity. These findings establish a novel genotype\u2013phenotype association in HPP and highlight the importance of accurate diagnosis to prevent the inappropriate use of bone resorption inhibitors in misdiagnosed patients.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf135","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T11:40:13Z","timestamp":1754998813000},"source":"Crossref","is-referenced-by-count":0,"title":["A novel dominant negative variant of <i>ALPL<\/i> induces hypophosphatasia"],"prefix":"10.1093","volume":"9","author":[{"given":"Guifeng","family":"Chen","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200011 ,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghua","family":"Liao","sequence":"additional","affiliation":[{"name":"Departament de Qu\u00edmica Inorg\u00e1nica i Org\u00e1nica (Secci\u00f3 de Qu\u00edmica Org\u00e1nica) and Institut de Qu\u00edmica Teorica i Computacional (IQTCUB), Universitat de Barcelona , 08028 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Xing","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200011 ,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Academy of Medical Sciences, Shanxi Medical University , Taiyuan, Shanxi 030001 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailong","family":"Ma","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200011 ,","place":["P.R. China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1409-2068","authenticated-orcid":false,"given":"Yu","family":"Cao","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200125 ,","place":["P.R. 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