It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants.
Hepatosplenomegaly, pneumopathy, bone changes and fronto-temporal dementia: Niemann-Pick type B and SQSTM1-associated Paget's disease in the same individual.
Recessive, loss-of-function mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB and here the bone disease is due to unopposed activation of RANK by RANKL.
SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation.
The incidence of new Paget's disease in SQSTM1 positive subjects was 7.1% and no mutation-negative subject developed the disease within 16 years of follow-up.
Paget's disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus.
The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis.
Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687.
Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP.
Amongst the 6 family members analyzed, the p.P392LSQSTM1 mutation segregated as expected with PDB, whereas the C9orf72 expansion segregated with frontal cognitive impairment or dementia in all but one carrier.
Bivariate and multivariate logistic regression models with adjustment for age and sex were fitted to search for a combination of SNPs and/or bone biomarkers that could best detect PDB in patient non-carriers of SQSTM1 mutations.
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.
The goal of this study is to compare the background history and phenotype of patients with PDB carrying the SQSTM1P392L mutation to those patients without.
Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD).
A large number of mutations in SQSTM1 (which encodes sequestosome-1; also known as ubiquitin-binding protein p62) seem to account for the susceptibility to develop Paget's disease in some families; the involvement of other genes is currently under investigation.
This mutation is the most common SQSTM1 mutation found in ALS to date, and a likely pathogenicity is supported by having an established causal role in PDB.
Mutations in the SQSTM1/p62 gene have been reported in Paget's disease of bone (PDB), but they are not sufficient to induce the pagetic osteoclast (OC) phenotype.