Paget's disease of bone (PDB) is a bone disorder characterized by an increase in bone turnover in a disorganized way with a large increase in bone resorption followed by bone formation. The most important known genetic factor predisposing to PDB is mutation in Sequestosome1 (SQSTM1) gene. We have studied the prevalence of SQSTM1 mutations and examined genotype-phenotype correlations in a Spanish cohort of PDB patients. Also, we have characterized three PDB patients that carry the c.961C>T SQSTM1 gene mutation that it is localized in exon 6 of SQSTM1 gene and it causes the p. R321C mutation. This mutation has been reported in patients with amyotrophic lateral sclerosis and frontotemporal dementia but in our knowledge this is the first time that p62 p. R321C mutation is associated to PDB. We show that p62 p.R321C mutation could induce blockage of autophagy and cell proliferation through NF-kB pathway. These results reinforce the hypothesis of autophagy involvement in Paget's disease of bone.
Keywords: Autophagy; Mutation; NF-kB pathway; Paget's disease of bone; SQSTM1; Sequestosome1; p62.
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