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 533/608 consecutive PDB subjects 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, A427D) were observed in 34/92 (37%) and 43/441 (10%) of familial and sporadic PDB cases, respectively. All the 5 subjects with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations was observed in Southern Italy (showing 9 of the 11 mutations), than in central and Northern Italy. Genotype-phenotype analysis showed only a modest reduction of age of diagnosis in subjects with truncating vs. missense mutations, while the number of affected skeletal sites did not significantly differ. Patients from Campania had the highest prevalence of animal contacts (i.e. working or living in a farm or pet ownership) without any difference between subjects with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutation. 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 +/- 2.0 vs. 2.19 +/- 1.9; p < 0.05;) than patients without animal contacts. This difference was also evidenced in the sub-group of patients with SQSTM1 mutations (3.84 +/- 2.5 vs. 2.76 +/- 2.2; p < 0.05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutation influencing disease severity.
SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone
RAINERO, Innocenzo;ISAIA, Giovanni Carlo;
2010-01-01
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 533/608 consecutive PDB subjects 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, A427D) were observed in 34/92 (37%) and 43/441 (10%) of familial and sporadic PDB cases, respectively. All the 5 subjects with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations was observed in Southern Italy (showing 9 of the 11 mutations), than in central and Northern Italy. Genotype-phenotype analysis showed only a modest reduction of age of diagnosis in subjects with truncating vs. missense mutations, while the number of affected skeletal sites did not significantly differ. Patients from Campania had the highest prevalence of animal contacts (i.e. working or living in a farm or pet ownership) without any difference between subjects with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutation. 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 +/- 2.0 vs. 2.19 +/- 1.9; p < 0.05;) than patients without animal contacts. This difference was also evidenced in the sub-group of patients with SQSTM1 mutations (3.84 +/- 2.5 vs. 2.76 +/- 2.2; p < 0.05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutation influencing disease severity.File | Dimensione | Formato | |
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