title: 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 +/- 2.0 versus 2.19 +/- 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 +/- 2.5 versus 2.76 +/- 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.
authors.affiliation: Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy. gennari@unisi.it
authors.forename: Luigi
authors.initials: L
authors.lastname: Gennari
authors.forename: Fernando
authors.initials: F
authors.lastname: Gianfrancesco
authors.forename: Marco
authors.initials: M
authors.lastname: Di Stefano
authors.forename: Domenico
authors.initials: D
authors.lastname: Rendina
authors.forename: Daniela
authors.initials: D
authors.lastname: Merlotti
authors.forename: Teresa
authors.initials: T
authors.lastname: Esposito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Gallone
authors.forename: Pina
authors.initials: P
authors.lastname: Fusco
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.forename: Pierpaola
authors.initials: P
authors.lastname: Fenoglio
authors.forename: Maria
authors.initials: M
authors.lastname: Mancini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Martini
authors.forename: Simona
authors.initials: S
authors.lastname: Bergui
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: De Filippo
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Isaia
authors.forename: Pasquale
authors.initials: P
authors.lastname: Strazzullo
authors.forename: Ranuccio
authors.initials: R
authors.lastname: Nuti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mossetti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004777:Environment; D005260:Female; D005843:Geography; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010001:Osteitis Deformans / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein