Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

Michou, Laëtitia; Conceição, Natércia; Morissette, Jean; Gagnon, Édith; Miltenberger-Miltényi, Gábriel; Siris, Ethel S.; Brown, Jacques P.; Cancela, M. Leonor

doi:10.1016/j.bone.2012.06.028

Cited by 20 publications

(21 citation statements)

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“…A genome-wide scan in British families with PDB has shown a linkage to the 10p13 ( PDB6 ) locus [ 9 , 10 ] and reanalysis of data from this genome-wide scan confirmed this genetic association [ 11 ], namely to the common variant rs1561570 (hg19, chr10:g.13155726 T>C) in the Optineurin ( OPTN ) gene. Our group has also replicated the strong, statistically significant, genetic association of rs1561570 ( p -value = 5.65×10 −7 ) with PDB in the French-Canadian population [ 12 ]. OPTN gene has been previously linked to glaucoma [ 13 ] and neurodegenerative diseases, like Alzheimer’s, Parkinson’s or amyotrophic lateral sclerosis [ 14 ].…”

Section: Introductionsupporting

confidence: 64%

“…Since our previous study has shown a strong association between rs1561570 (located in OPTN intron 7) and PDB [ 12 ], we determined the functional effect of rs1561570 in that disease by employing the splice site prediction algorithm, and showed that the allele harbouring a C was likely to create a potential new acceptor site for splicing and disrupt a potential branch point (consensus value for mutant sequence = 69.7%) ( S2 Table ). To validate this finding, we performed RT-PCR and qPCR using cDNA samples from patients and healthy controls with the three genotypes.…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we investigated the functional role of the most significantly PDB associated genetic variant of OPTN - rs1561570 (C>T). Previously, we reported that the C allele was more frequent in controls in the French-Canadian population ( C allele frequency = 52%, T allele frequency = 48%) while the T allele was more frequent in PDB patients ( C allele frequency = 36%, T allele frequency = 64%) [ 12 ]. Using in silico tools, we found that the rs1561570 T allele was predicted to cause the loss of a methylation site.…”

Section: Discussionmentioning

confidence: 99%

“…In order to test if the most strongly PDB associated OPTN variant had an impact on its gene expression, we performed qPCR as previously described [ 12 ]. The details of this analysis are provided in the S1 File .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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“…Subsequent studies indicated that that OPTN mutations are relatively more 77 common in Asian populations[15-19], and more rare in Caucasian ALS patients[20-78 23]. Mutations in OPTN are also linked to primary open-angle glaucoma[24] and 79Paget's disease of bone [25][26][27], suggesting that OPTN itself is a key driver of toxicity. 80Compared to other ALS-linked proteins, there is relatively little research focused on 81 OPTN-ALS.…”

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confidence: 99%

A multi-omic analysis of optineurin proteinopathy in a yeast model suggests the involvement of lipid metabolism in Amyotrophic Lateral Sclerosis

Hnatova

Mülleder

et al. 2019

Preprint

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27Amyotrophic Lateral Sclerosis (ALS) is an incurable fatal neurodegenerative disease for 28 which the precise mechanisms of toxicity remain unclear despite some significant 29 advances in our understanding of the underlying genetic basis. A holistic, integrated 30 view of cellular changes will be critical to understanding the processes of 31 neurodegeneration and the development of effective treatments. Mutant forms of 32 optineurin (a ubiquitin-binding protein involved in autophagy, membrane trafficking, 33 and NF-kB activation) are found associated with cytoplasmic inclusions containing 34 TDP43 or SOD1 in some ALS patients. We have taken a multi-omics approach to 35 understand the cellular response to OPTN overexpression in a yeast model of ALS. We 36 found that genetic interaction screens and metabolomics provided parallel, highly 37 complementary data on OPTN toxicity. Genetic enhancers of OPTN toxicity in yeast 38 relate directly to the native function of OPTN in vesicular trafficking and intracellular 39 transport, suggesting the human OPTN protein is functional when expressed in yeast 40 even though there is no yeast ortholog. Crucially, we find that the genetic modifiers and 41 the metabolic response are distinct for different ALS-linked genes expressed in yeast. 42This lends strong support to the use of yeast as a model system and omics platform to 43 study ALS. 44 45 46 47 48 Keywords 49 ALS; Systems Biology; Metabolomics 50 51 52 Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease for which 53 there is no effective treatment available. ALS has been divided into familial (FALS) and 54 sporadic (SALS) forms on the basis of family history, with FALS patients accounting 55 for 5% of all ALS cases overall, but this dichotomy is now questioned[1]. Despite our 56 incomplete picture of the genetic landscape of ALS, it is considered a genetic disease. 57 Associated genetic variants, particularly the hexanucleotide repeat expansion of 58 C9orf72[2,3] and mutations in SOD1[4], TDP43[5,6] and FUS[7,8], are the basis for 59 experimental models of ALS in most model systems. Genetic variants and model 60 organism studies implicate a wide range of cellular pathways in the neurodegenerative 61 processes occurring in ALS, including oxidative stress, RNA metabolism, protein 62 aggregation and degradation (autophagy, and the ubiquitin-proteasome system), and 63 intracellular trafficking[9]. The hallmark histopathological feature of ALS is the 64 presence of intracellular protein aggregates. In most cases, these aggregates contain the 65 TDP43 protein, even though mutations in the TDP43 gene are only a rare cause of ALS. 66 A notable exception is patients with SOD1 mutations, where intracellular aggregates 67 contain the SOD1 protein, but not TDP43. With such a complex pathology 68 underpinning ALS, it is vital to develop multi-omics approaches to understand how the 69 interaction of multiple pathways is driving disease progression. 70 71 The OPTN gene encodes Optineurin, a ubiquitin-binding protein ...

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Molecular Genetics of Paget's Disease of Bone

Gennari

Gianfrancesco

Rendina

et al. 2014

Encyclopedia of Life Sciences

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Paget's disease of bone (PDB) is a chronic disorder of bone metabolism, which typically results in enlarged and deformed bones in one or more regions of the skeleton. The aetiology of PDB has remained unknown for several decades, but either environmental or genetic factors have been implicated. The former mainly concern the presence of a slow‐acting viral infection, a condition that may be present for many years before symptoms appear. However, there are also several data supporting a hereditary hypothesis, since in up to 40% of patients the disease may appear in more than one family member. The genetic architecture of PDB is incompletely understood, but recent evidence suggests that the disease may be caused by a combination of rare variants in genes such as SQSTM 1 (detected in up to 50% of familial cases of PDB) and more common variants (i.e. polymorphisms) in genes such as CSF1 , TNFRSF11A , OPTN and TM7SF4 . Key Concepts: Paget's disease of bone (PDB) is a focal disorder of bone metabolism characterised by enlarged and deformed bones in one (monostotic form) or more regions (polyostotic form) of the skeleton. Over the last two decades there have been major advances in our understanding of the genetic basis of the disorder. Mutations in 3 genes have been detected in rare syndromes related to PDB and mutations in SQSTM1 gene have been associated with the classical form of PDB in up to 50% of familial cases. SQSTM1 gene encodes for the p62/sequestosome 1 protein, which acts as a scaffold protein in the NFκB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins. To date the exact molecular mechanisms leading to the development of pagetic lesions in SQSTM1 mutation carriers remain to be defined. Indeed, recent experimental evidence suggests that additional contribution from environmental factors (i.e. a viral infection with paramyxovirus) or other genetic factors (i.e. polymorphisms) may be required to induce the full pagetic phenotype in the presence of SQSTM1 mutation. The genetic cause of PDB in familial cases negative for SQSTM1 mutations remains to be determined in more detail.

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Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone

Cited by 20 publications

References 34 publications

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

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

A multi-omic analysis of optineurin proteinopathy in a yeast model suggests the involvement of lipid metabolism in Amyotrophic Lateral Sclerosis

Molecular Genetics of Paget's Disease of Bone

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