Molecular effect of an OPTN common variant associated to Paget's disease of bone

PloS One
Iris A L SilvaLaëtitia Michou

Abstract

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 rs156157...Continue Reading

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Citations

Sep 4, 2019·Muscle & Nerve·Stefan Nicolau, Teerin Liewluck
Jan 17, 2021·Journal of Cellular Physiology·Yi-Fan GuoXiang-Hang Luo
Nov 5, 2020·Muscle & Nerve·Manisha K KorbTahseen Mozaffar

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Methods Mentioned

BETA
ubiquitination
density gradient centrifugation
ChIP-seq

Software Mentioned

ImageJ
GraphPad Prism
ENCODE
Methprimer
Volocity

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