{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T14:22:03Z","timestamp":1747146123239,"version":"3.40.5"},"reference-count":21,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A 54\u2010year\u2010old man with a history of unimelic, post\u2010traumatic multifocal heterotopic ossification (HO) and normal genetic analysis of <jats:italic>ACVR1<\/jats:italic> and <jats:italic>GNAS<\/jats:italic> had variants of unknown significance (VUS) in <jats:italic>PDLIM\u20107<\/jats:italic> (PDZ and LIM Domain Protein 7), the gene encoding LMP\u20101 (LIM Mineralization Protein\u20101), an intracellular protein involved in the bone morphogenetic protein (BMP) pathway signaling and ossification. In order to determine if the LMP\u20101 variants were plausibly responsible for the phenotype observed, a series of in vitro experiments were conducted. C2C12 cells were co\u2010transfected with a BMP\u2010responsive reporter as well as the LMP\u20101 wildtype (wt) construct or the LMP\u20101<jats:sup>T161I<\/jats:sup> or the LMP\u20101<jats:sup>D181G<\/jats:sup> constructs (herein designated as LMP\u2010161 or LMP\u2010181) corresponding to the coding variants detected in the patient. A significantly increased BMP\u2010reporter activity was observed in LMP\u2010161 or LMP\u2010181 transfected cells compared to the wt cells. The LMP\u2010181 variant exhibited BMP\u2010reporter activity with a four\u2010fold increase over the LMP\u20101 wt protein. Similarly, mouse pre\u2010osteoblastic MC3T3 cells transfected with the patient's LMP\u20101 variants expressed higher levels of osteoblast markers both at mRNA and protein levels and preferentially mineralized when stimulated with recombinant BMP\u20102 compared to control cells. Presently, there are no pathogenic variants of LMP\u20101 known to induce HO in humans. Our findings suggest that the germline variants in LMP\u20101 detected in our patient are plausibly related to his multifocal HO (LMP1\u2010related multifocal HO). Further observations will be required to firmly establish this gene\u2013disease relationship.<\/jats:p>","DOI":"10.1002\/ajmg.a.63304","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T09:14:33Z","timestamp":1684833273000},"page":"2164-2174","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multifocal heterotopic ossification in a man with germline variants of <scp>LIM<\/scp> Mineralization Protein\u20101 (<scp>LMP<\/scp>\u20101)"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-1187","authenticated-orcid":false,"given":"Sreedhara","family":"Sangadala","sequence":"first","affiliation":[{"name":"The Department of Orthopaedic Surgery Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2609-6971","authenticated-orcid":false,"given":"Eileen M.","family":"Shore","sequence":"additional","affiliation":[{"name":"The Departments of Orthopaedic Surgery and Genetics, and The Center for Research in FOP &amp; Related Disorders The Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9481-239X","authenticated-orcid":false,"given":"Meiqi","family":"Xu","sequence":"additional","affiliation":[{"name":"The Department of Orthopaedic Surgery and The Center for Research in FOP &amp; Related Disorders The Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7518-249X","authenticated-orcid":false,"given":"Clemens","family":"Bergwitz","sequence":"additional","affiliation":[{"name":"Section of Endocrinology and Metabolism Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0681-9004","authenticated-orcid":false,"given":"Santiago A.","family":"Lozano\u2010Calderon","sequence":"additional","affiliation":[{"name":"The Department of Orthopaedics Massachusetts General Hospital and Harvard University School of Medicine  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-4572","authenticated-orcid":false,"given":"Angela E.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical Genetics Unit Mass General for Children and Harvard University School of Medicine  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6210-5487","authenticated-orcid":false,"given":"Scott D.","family":"Boden","sequence":"additional","affiliation":[{"name":"The Department of Orthopaedic Surgery Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1277-5420","authenticated-orcid":false,"given":"Frederick S.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"The Departments of Orthopaedic Surgery and Medicine, and The Center for Research in FOP &amp; 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