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ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor

2016-02Journal article Restricted
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dc.contributor.authorDivisato, Giuseppina
dc.contributor.authorFormicola, Daniela
dc.contributor.authorEsposito, Teresa
dc.contributor.authorMerlotti, Daniela
dc.contributor.authorPazzaglia, Laura
dc.contributor.authorDel Fattore, Andrea
dc.contributor.authorSiris, Ethel
dc.contributor.authorOrcel, Philippe
dc.contributor.authorBrown, Jacques P.
dc.contributor.authorNuti, Ranuccio
dc.contributor.authorStrazzullo, Pasquale
dc.contributor.authorBenassi, Maria Serena
dc.contributor.authorCancela, Leonor
dc.contributor.authorMichou, Laetitia
dc.contributor.authorRendina, Domenico
dc.contributor.authorGennari, Luigi
dc.contributor.authorGianfrancesco, Fernando
dc.date.accessioned2017-04-07T15:57:09Z
dc.date.available2017-04-07T15:57:09Z
dc.date.issued2016-02
dc.description.abstractPaget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.
dc.identifier.doihttps://dx.doi.org/10.1016/j.ajhg.2015.12.016
dc.identifier.issn0002-9297
dc.identifier.urihttp://hdl.handle.net/10400.1/9627
dc.language.isoeng
dc.peerreviewedyes
dc.relation.isbasedonWOS:000370502300004
dc.titleZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage286
oaire.citation.issue2
oaire.citation.startPage275
oaire.citation.titleAmerican Journal of Human Genetics
oaire.citation.volume98
person.familyNameCancela
person.givenNameM. Leonor
person.identifier.orcid0000-0003-3114-6662
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublicationb9bbfe32-3dfe-4131-ad14-a4394008447f
relation.isAuthorOfPublication.latestForDiscoveryb9bbfe32-3dfe-4131-ad14-a4394008447f

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