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

Giuseppina Divisato, Daniela Formicola, Teresa Esposito, Daniela Merlotti, Laura Pazzaglia, Andrea Del Fattore, Ethel S. Siris, Philippe Orcel, Jacques P. Brown, R. Nuti, Pasquale Strazzullo, Maria Serena Benassi, M. Leonor Cancela, Laetitia Michou, Domenico Rendina, L. Gennari, Fernando Gianfrancesco

Research output: Contribution to journalArticle

Abstract

Paget 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.

Original languageEnglish
Pages (from-to)275-286
Number of pages12
JournalAmerican Journal of Human Genetics
Volume98
Issue number2
DOIs
Publication statusPublished - Feb 4 2016

Fingerprint

Osteitis Deformans
Giant Cell Tumors
Zinc Fingers
Giant Cell Tumor of Bone
Mutation
Proteins
Founder Effect
Exome
Hematologic Diseases
Bone Remodeling
Osteosarcoma
Missense Mutation
Osteogenesis
Skeleton
Transcription Factors
Biomarkers
Phenotype
Bone and Bones

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor. / Divisato, Giuseppina; Formicola, Daniela; Esposito, Teresa; Merlotti, Daniela; Pazzaglia, Laura; Del Fattore, Andrea; Siris, Ethel S.; Orcel, Philippe; Brown, Jacques P.; Nuti, R.; Strazzullo, Pasquale; Benassi, Maria Serena; Cancela, M. Leonor; Michou, Laetitia; Rendina, Domenico; Gennari, L.; Gianfrancesco, Fernando.

In: American Journal of Human Genetics, Vol. 98, No. 2, 04.02.2016, p. 275-286.

Research output: Contribution to journalArticle

Divisato, G, Formicola, D, Esposito, T, Merlotti, D, Pazzaglia, L, Del Fattore, A, Siris, ES, Orcel, P, Brown, JP, Nuti, R, Strazzullo, P, Benassi, MS, Cancela, ML, Michou, L, Rendina, D, Gennari, L & Gianfrancesco, F 2016, 'ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor', American Journal of Human Genetics, vol. 98, no. 2, pp. 275-286. https://doi.org/10.1016/j.ajhg.2015.12.016
Divisato, Giuseppina ; Formicola, Daniela ; Esposito, Teresa ; Merlotti, Daniela ; Pazzaglia, Laura ; Del Fattore, Andrea ; Siris, Ethel S. ; Orcel, Philippe ; Brown, Jacques P. ; Nuti, R. ; Strazzullo, Pasquale ; Benassi, Maria Serena ; Cancela, M. Leonor ; Michou, Laetitia ; Rendina, Domenico ; Gennari, L. ; Gianfrancesco, Fernando. / ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 2. pp. 275-286.
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AU - Pazzaglia, Laura

AU - Del Fattore, Andrea

AU - Siris, Ethel S.

AU - Orcel, Philippe

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