{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:12:20Z","timestamp":1788966740072,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010504","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000}}],"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T00:00:00Z","timestamp":1670457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"NHGRI","doi-asserted-by":"crossref","award":["UM1 HG006542"],"award-info":[{"award-number":["UM1 HG006542"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Gabriella Miller Kids First Pediatric Research Program","award":["X01HL140517"],"award-info":[{"award-number":["X01HL140517"]}]},{"name":"NCI","award":["R03CA256535"],"award-info":[{"award-number":["R03CA256535"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in\n                    <jats:italic>IDH1<\/jats:italic>\n                    and\n                    <jats:italic>IDH2<\/jats:italic>\n                    have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in\n                    <jats:italic>HIF1A<\/jats:italic>\n                    , 6 had rare germline missense variants in\n                    <jats:italic>VHL<\/jats:italic>\n                    , and 3 had\n                    <jats:italic>IDH1<\/jats:italic>\n                    variants including 2 with mosaic\n                    <jats:italic>IDH1<\/jats:italic>\n                    -p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in\n                    <jats:italic>HIF1A<\/jats:italic>\n                    ,\n                    <jats:italic>VHL<\/jats:italic>\n                    , and\n                    <jats:italic>IDH1<\/jats:italic>\n                    were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in\n                    <jats:italic>HIF1A<\/jats:italic>\n                    ,\n                    <jats:italic>VHL<\/jats:italic>\n                    , and\n                    <jats:italic>IDH1<\/jats:italic>\n                    in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1010504","type":"journal-article","created":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T13:38:29Z","timestamp":1670506709000},"page":"e1010504","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-1203","authenticated-orcid":true,"given":"Sarah R.","family":"Poll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6747-8784","authenticated-orcid":true,"given":"Renan","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6189-9839","authenticated-orcid":true,"given":"Elizabeth","family":"Wohler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3995-6742","authenticated-orcid":true,"given":"Elizabeth S.","family":"Partan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Walek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaima","family":"Salman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-2988","authenticated-orcid":true,"given":"Daniel","family":"Groepper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Kratz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirlene","family":"Cernach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7895-5729","authenticated-orcid":true,"given":"Reynaldo","family":"Jesus-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7581-5333","authenticated-orcid":true,"given":"Chad","family":"Haldeman-Englert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Jae","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol D.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Hoover-Fong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0913-211X","authenticated-orcid":true,"given":"Gregg L.","family":"Semenza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nara L. 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Mole","year":"2009","journal-title":"J Biol Chem"},{"issue":"23","key":"pgen.1010504.ref025","doi-asserted-by":"crossref","first-page":"e207","DOI":"10.1182\/blood-2010-10-314427","article-title":"High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq","volume":"117","author":"J Schodel","year":"2011","journal-title":"Blood"},{"issue":"14","key":"pgen.1010504.ref026","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1093\/nar\/gkp425","article-title":"An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia","volume":"37","author":"Y Benita","year":"2009","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pgen.1010504.ref027","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1093\/nar\/gkp1205","article-title":"Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico 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