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Molecular effect of an OPTN common variant associated to Paget's disease of bone
Paget’s disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains se...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962077/ https://www.ncbi.nlm.nih.gov/pubmed/29782529 http://dx.doi.org/10.1371/journal.pone.0197543 |
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author | Silva, Iris A. L. Conceição, Natércia Gagnon, Édith Brown, Jacques P. Cancela, M. Leonor Michou, Laëtitia |
author_facet | Silva, Iris A. L. Conceição, Natércia Gagnon, Édith Brown, Jacques P. Cancela, M. Leonor Michou, Laëtitia |
author_sort | Silva, Iris A. L. |
collection | PubMed |
description | Paget’s disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its T allele results in the loss of a methylation site in patients’ DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients’ osteoclasts. This increase in OPTN expression leads to higher levels of NF-κB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis. |
format | Online Article Text |
id | pubmed-5962077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-59620772018-06-02 Molecular effect of an OPTN common variant associated to Paget's disease of bone Silva, Iris A. L. Conceição, Natércia Gagnon, Édith Brown, Jacques P. Cancela, M. Leonor Michou, Laëtitia PLoS One Research Article Paget’s disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its T allele results in the loss of a methylation site in patients’ DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients’ osteoclasts. This increase in OPTN expression leads to higher levels of NF-κB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis. Public Library of Science 2018-05-21 /pmc/articles/PMC5962077/ /pubmed/29782529 http://dx.doi.org/10.1371/journal.pone.0197543 Text en © 2018 Silva et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Silva, Iris A. L. Conceição, Natércia Gagnon, Édith Brown, Jacques P. Cancela, M. Leonor Michou, Laëtitia Molecular effect of an OPTN common variant associated to Paget's disease of bone |
title | Molecular effect of an OPTN common variant associated to Paget's disease of bone |
title_full | Molecular effect of an OPTN common variant associated to Paget's disease of bone |
title_fullStr | Molecular effect of an OPTN common variant associated to Paget's disease of bone |
title_full_unstemmed | Molecular effect of an OPTN common variant associated to Paget's disease of bone |
title_short | Molecular effect of an OPTN common variant associated to Paget's disease of bone |
title_sort | molecular effect of an optn common variant associated to paget's disease of bone |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962077/ https://www.ncbi.nlm.nih.gov/pubmed/29782529 http://dx.doi.org/10.1371/journal.pone.0197543 |
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