Browsing by Author "Gagnon, Edith"
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- Effect of genetic variants of OPTN in the pathophysiology of Paget's disease of bonePublication . Silva, Iris; Conceição, Natércia; Gagnon, Edith; Caiado, Helena; Brown, Jacques P.; Gianfrancesco, Fernando; Michou, Laëtitia; Cancela, LeonorPaget'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 PDB causing mutations were identified only in the Sequestosome 1 gene at the PDB3 locus. OPTN has been recently associated with PDB, however little is known about the effect of genetic variants in this gene in PDB pathophysiology. By sequencing OPTN in SQSTM1 non-carriers PDB patients we found 16 SNPs in regulatory, coding and non-coding regions. One of those was found to be associated with PDB in our cohort - rs2234968. Our results show that rs2238968 effect may be explained by a change in OPTN splicing that give rise to a predicted truncated protein. We also performed functional studies on the variants located in OPTN promoter - rs3829923 and the rare variant -9906 - to investigate putative regulators of OPTN. Our results show that OPTN expression seems to be regulated by SP1, RXR, E47, and the E2F family. In conclusion, our work suggests a potential pathophysiological role of SNPs in OPTN, giving a new perspective about the regulatory mechanisms of this gene. Ultimately we discovered a new variant associated with PDB in OPTN, reinforcing the relevance of this gene for the development of this bone disease.
- Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bonePublication . Michou, Laetitia; Conceicao, Natercia; Morissette, Jean; Gagnon, Edith; Miltenberger-Miltenyi, Gabriel; Siris, Ethel S.; Brown, Jacques P.; Leonor Cancela, M.We performed a genetic association study of rare variants and single nucleotide polymorphisms (SNPs) of UCMA/GRP and OPTN genes, in French-Canadian patients with Paget's disease of bone (PDB) and in healthy controls from the same population. We reproduced the variant found in the UCMA/GRP basal promoter and tested its functionality using in vitro transient transfection assays. Interestingly, this SNP rs17152980 appears to affect the transcription level of UCMA/GRP. In addition, we have identified five rare genetic variants in UCMA/GRP gene, four of them being population-specific, although none were found to be associated with PDB. Six Tag SNPs of UCMA/GRP gene were associated with PDB, particularly the SNP rs17152980 (uncorrected P = 3.8 x 10(-3)), although not significant after Bonferroni's correction. More importantly, we replicated the strong and statistically significant genetic association of two SNPs of the OPTN gene, the rs1561570 (uncorrected P = 5.7 x 10(-7)) and the rs2095388 (uncorrected P = 4.9 x 10(-3)), With PDB. In addition, we identified a very rare variant found to be located close to the basal promoter of the OPTN gene, at -232 bp from its distal transcription start site. Furthermore, depending on the type of allele present (G or A), the binding of several important nuclear factors such as the vitamin D or the retinoic acid receptors is predicted to be altered at this position, suggesting a significant effect in the regulation of transcription of the OPTN gene. In conclusion, we identified a functional SNP located in the basal promoter of the UCMA/GRP gene which provided a weak genetic association with PDB. In addition, we replicated the strong genetic association of two already known SNPs of the OPTN gene, with PDB in a founder effect population. We also identified a very rare variant in the promoter of OPTN, and through bioinformatic analysis, identified putative transcription factor binding sites likely to affect OPTN gene transcription. (C) 2012 Elsevier Inc. All rights reserved.
- Molecular effect of an OPTN common variant associated to Paget's disease of bonePublication . Silva, Iris; Conceição, Natércia; Gagnon, Edith; Brown, Jacques P.; Cancela, M. Leonor; Michou, LaetitiaPaget'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 Tallele 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-KB 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.