Can zebrafish be a valid model to study Paget's disease of bone?

Paget's disease of bone (PDB) is the second most frequent metabolic bone disease after osteoporosis. Genetic factors play an important role in PDB, but to date the only PDB causal gene identified is the Sequestosome 1 (SQSTM1) gene. Because the zebrafish has been validated as a model for human genetic diseases, the objective was to investigate if the gene structure and chromosomal environment of the SQSTM1 were similar between zebrafish and humans, thus providing a basis for developing a mutant fish capable of modeling PDB. Through a comparative in silico analysis, we confirmed that zebrafish sqstm1 shares not only the same gene structure as its fish and mammalian orthologs, but they also present, within their promoter regions, similar putative binding sites for common transcriptional factors known to affect bone metabolism. The synteny of SQSTM1 was also determined and results indicate that the cluster of surrounding genes was conserved throughout evolution. The protein comparison revealed a high degree of conservation, particularly in the functional domains of the protein. The most common mutation in PDB patients is p.Pro392Leu and the residue Pro392 was found to be 100% conserved in all species analyzed, including zebrafish, confirming its known functional relevance. In conclusion, this study demonstrated that SQSTM1 is well conserved throughout evolution and therefore fish models such as the zebrafish could be an interesting tool to further investigate the biological role of SQSTM1 in PDB and in bone development.