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Abstract
Bone remodelling perturbation could promote skeletal disorders (e.g. Paget’s disease of bone,
PDB), but also neoplastic degenerations (e.g. Giant Cell Tumor, GCT) as a consequence of
uncontrolled proliferation of mesenchymal stromal cells. Recently, we studied a large pedigree with
a severe PDB phenotype characterized by 14 PDB patients, 4 of whom developed GCT at pagetic
sites. Through whole exome sequencing approach, we identified a germline missense mutation
(P937R) in the Zinc Finger Protein 687 (ZNF687) gene. The same mutation was also identified in 7
additional PDB/GCT unrelated cases showing a common genetic background (same haplotype),
supporting a founder effect. Preliminary results showed that ZNF687 was upregulated during
osteoclasts and osteoblasts differentiation, confirming its role in bone biology.
Immunohistochemistry assay and real-time PCR revealed that this gene was also strongly
upregulated in PDB/GCT tumour tissues. Cellular protein fractionation analysis suggested that
P937R mutation alters ZNF687 cytoplasm localization, improving its import in the nucleus and
resulting in the upregulation of Fibroblast Growth Factor Receptor 2 gene, as supported by
ZNF687 knock-down. Further studies are ongoing to disclose the pathological mechanism
responsible for this mesenchymal bone sarcoma and to understand similarities and differencies with
other skeletal degenerations (e.g. Osteosarcoma).
Giuseppina Divisato