SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

Abstract

Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 AE 2.0 versus 2.19 AE 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 AE 2.5 versus 2.76 AE 2.2, p < .05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity. ß

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

“…Of interest, current and previous (9,17) candidate gene analysis in this pedigree excluded the presence of mutations in all the major genes associated with PDB or PDB-related syndromes, suggesting that a different genetic defect is associated with PDB and potentially GCT. In keeping with our observation, a recent study in a North-American cohort of PDB patients excluded the presence of SQSTM1 mutations in three cases of Italian origin who developed GCT.…”

“…In previous analysis, all the affected members of the pedigree were screened for mutations in the entire coding regions of SQSTM1 and TNFRSF11A genes, failing to detect any genetic alteration. (9,17) In the current candidate gene analysis, we now excluded the presence of mutations in five additional genes: OPTN encoding for optineurin, TNFSF11A encoding for RANKL (the ligand of RANK), CSF1 encoding for M-CSF, TNFRSF11B encoding for OPG (the decoy receptor of RANKL), and VCP encoding for valosin-containing protein.…”

“…(8) This gene encodes the p62/ sequestosome 1 protein, which acts as a scaffold protein in the NF-kB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins. Even though patients with SQSTM1 mutations generally show an increased disease severity than SQSTM1-negative patients, (9,10) we recently identified SQSTM1-negative patients with a severe phenotype and the presence of peculiar phenotypic characteristics, including the occurrence of giant cell tumors (GCT) originating from affected skeletal sites. (9,11,12) This complication represents a very uncommon clinical feature of PDB (described in less than 100 cases worldwide), and mainly occurs in patients with severe polyostotic PDB.…”

“…Even though patients with SQSTM1 mutations generally show an increased disease severity than SQSTM1-negative patients, (9,10) we recently identified SQSTM1-negative patients with a severe phenotype and the presence of peculiar phenotypic characteristics, including the occurrence of giant cell tumors (GCT) originating from affected skeletal sites. (9,11,12) This complication represents a very uncommon clinical feature of PDB (described in less than 100 cases worldwide), and mainly occurs in patients with severe polyostotic PDB. (11)(12)(13)(14)(15) GCTs may be multifocal and aggressive, leading to increased morbidity and mortality of patients.…”

“…(16) We recently characterized a large Italian pedigree with 14 affected members of whom four developed GCT, which despite the early onset and the severe phenotype were negative for the presence of SQSTM1 and TNFRSF11A mutations. (9,17) The high number of affected subjects across multiple generations (clinically followed from 1977 to date) allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. A mutation screening of other candidate genes encoding for components of the RANKL/OPG/RANK/NF-kB signaling pathway (namely TNFSF11A and TNFRSF11B genes) or previously associated with PDB-related syndromes (namely VCP, encoding for valosin containing protein) or classical PDB in SQSTM -negative patients (OPTN gene, encoding for optineurin, and CSF1, encoding for MCSF-1) was also performed.…”