title: Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).
abstract: PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder.
  
  
  BACKGROUND
  Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area.
  
  
  METHODS
  To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases.
  
  
  RESULTS
  We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without.
  
  
  CONCLUSIONS
  Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.
authors.affiliation: Department of Internal Medicine, Azienda Ospedaliera Careggi, Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Falchetti
authors.forename: Marco
authors.initials: M
authors.lastname: Di Stefano
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.forename: Francesca
authors.initials: F
authors.lastname: Del Monte
authors.forename: Carmelo
authors.initials: C
authors.lastname: Mavilia
authors.forename: Debora
authors.initials: D
authors.lastname: Strigoli
authors.forename: Maria L
authors.initials: ML
authors.lastname: De Feo
authors.forename: Giovan
authors.initials: G
authors.lastname: Isaia
authors.forename: Laura
authors.initials: L
authors.lastname: Masi
authors.forename: Antonietta
authors.initials: A
authors.lastname: Amedei
authors.forename: Federica
authors.initials: F
authors.lastname: Cioppi
authors.forename: Valentina
authors.initials: V
authors.lastname: Ghinoi
authors.forename: Susanna Maddali
authors.initials: SM
authors.lastname: Bongi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Fede
authors.forename: Carmela
authors.initials: C
authors.lastname: Sferrazza
authors.forename: Giovan B
authors.initials: GB
authors.lastname: Rini
authors.forename: Daniela
authors.initials: D
authors.lastname: Melchiorre
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.forename: Maria L
authors.initials: ML
authors.lastname: Brandi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D017931:DNA Primers; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein