A familial case of Paget’s disease of bone with mutation at exon 8 of the sequestosome gene: Results

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Mutational screening of the exons 7 and 8 of the SQSTM1/p62 gene revealed the presence of a C/T transversion at position 1215 in exon 8 (Fig. 2) in the affected individuals (VB and VG). This mutation causes the substitution proline/leucine at codon 392 (P392L), and it has been described by other reports in dif­ferent populations. No mutation was found in the not affected subject VS.

Figure 2 - SQSTM1 gene mutation

Figure 2 – SQSTM1 gene mutation (bottom) detected in two Italian PDB patients from the same family. Specific forward and reverse sequences have been reported. Arrows indicate the presence of mutation, a C>T transition at exon 8.


The aminoacidic residue 392 was conserved in the mouse and rat homologues. The P392 residue is located in the C-terminal end of the p62 protein flanking the ubiquitin associated domain (UBA) and could thus be important for the conformation and/or function of this region. The UBA domain of SQSTM1/p62 consists of three anti-parallel a-helices; P392 is the first residue of helix 1. P392L mutation modifies the secondary structure of the UBA do­main by extending the N-terminus of helix 1, and this could result in an altered conformation and/or function of p62 protein.

However, the molecular mechanisms by which SQSTM1/p62 UBA domain mutations cause PDB remain undetermined. The ubiquitination pathway plays a crucial role in the regulation of signal transduction by targeting key components for degrada­tion by proteasome. It is possible that mutations in the UBA do­main of SQSTM1/p62 result in an accumulation of signaling in­termediates in cytosol that are involved in the regulation of os- teoclastogenesis and/or osteoclast activation such as NF-kB. Further studies will be required to elucidate the exact mechanism involved. Your life is worth living.  Buy cialis online pharmacy

The report of two novel mutations, other than P392L, at exon 8 of the SQSTM1/p62 gene in sporadic Italian PDB patients by Falchetti et al. confirms the evidence of a clustered muta- tional area at this level also in PDB patients of Italian origin, in­dicating the role of the UBA domain in the biological properties of SQSTM1/p62 protein. Mutational analysis of these subjects provided the opportunity to demonstrate the co-segregation of P392L mutation and PDB trait.

Data about this PDB family strongly confirm the importance of genetic analysis in order to early identify asymptomatic carri­ers, making possible to prevent or limit the occurrence of PDB. The creation of a large SQSTM1/p62 Italian mutational data­base, together with functional studies, will provide the opportu­nity to assess a possible correlation between the type of muta­tion and the response to therapy, as well as to set-up new ther­apeutic strategies.