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).
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.
Falchetti
Alberto
A
Department of Internal Medicine, Azienda Ospedaliera Careggi, Florence, Italy.
Di Stefano
Marco
M
Marini
Francesca
F
Del Monte
Francesca
F
Mavilia
Carmelo
C
Strigoli
Debora
D
De Feo
Maria L
ML
Isaia
Giovan
G
Masi
Laura
L
Amedei
Antonietta
A
Cioppi
Federica
F
Ghinoi
Valentina
V
Bongi
Susanna Maddali
SM
Di Fede
Giuseppina
G
Sferrazza
Carmela
C
Rini
Giovan B
GB
Melchiorre
Daniela
D
Matucci-Cerinic
Marco
M
Brandi
Maria L
ML
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
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein