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ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget's disease of bone.
- Source :
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Clinical genetics [Clin Genet] 2018 Jun; Vol. 93 (6), pp. 1240-1244. Date of Electronic Publication: 2018 Apr 11. - Publication Year :
- 2018
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Abstract
- 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.<br /> (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Subjects :
- Amino Acid Sequence
Base Sequence
Cell Differentiation
Female
Geography
Giant Cell Tumors genetics
Humans
Italy
Male
Osteoclasts pathology
Pedigree
Sequestosome-1 Protein genetics
Transcription Factors chemistry
Transcription Factors metabolism
DNA-Binding Proteins genetics
Mutation genetics
Osteitis Deformans genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1399-0004
- Volume :
- 93
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29493781
- Full Text :
- https://doi.org/10.1111/cge.13247