RESUMO
Paget's disease of bone (PDB) is a skeletal disorder whose molecular basis is not fully elucidated. However, 10% of patients show a familial PDB and 35% of them carry mutations in the SQSTM1 gene. We recently reported a founder mutation (p.Pro937Arg) in the ZNF687 gene, underlying PDB complicated by giant cell tumor (GCT/PDB) and rarely occurring in PDB patients without neoplastic degeneration. Since 80% of Italian GCT/PDB patients derive from Avellino, we hypothesized that ZNF687 mutation rate was higher in this region than elsewhere. Interestingly, our molecular analysis on 30 PDB patients showed that 33% hosted ZNF687 mutations, with the p.Pro937Arg identified in 8 familial cases. Two novel ZNF687 mutations (p.Pro665Leu and p.Gln784Glu) were detected in 2 sporadic patients. Only 2 subjects were positive for the p.Pro392Leu mutation in SQSTM1. ZNF687-mutated patients showed a severe PDB, with a remarkable number of affected sites. in vitro studies revealed that the ZNF687-mutant osteoclasts appeared as giant sized with up to 150 nuclei, never described in PDB. Finally, we also confirmed the causality of the p.Pro937Arg mutation in 4 additional GCT/PDB cases deriving from the same geographic area, indicating that PDB and GCT/PDB represent 2 sides of the same coin.