Evaluation of the role of RANK and OPG genes in Paget’s disease of bone

Wuyts, Wim; Wesenbeeck, Liesbeth Van; Morales‐Piga, Antonio; Ralston, Stuart H.; Hocking, Lynne J.; Vanhoenacker, Filip; Westhovens, René; Verbruggen, Leon; Anderson, D; Hughes, Anne E.; Hul, Wim Van

doi:10.1016/s8756-3282(00)00411-7

Cited by 100 publications

(92 citation statements)

References 16 publications

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“…(83) Finally, mutations in the TNFRSF11B gene (encoding OPG) also give rise to juvenile Paget's disease, (84,85) and we and others were able to show that genetic variants in TNFRSF11B do have an influence on the susceptibility to PDB in sporadic female patients. (38,71,72) Therefore, it seems very possible that polymorphisms in the TNFRSF11A gene contribute to the susceptibility for the sporadic form of PDB despite the fact that mutations have not been found in typical PDB patients. (38)(39)(40) This study was initiated in the Belgian study population with a power of 75% to find an association with an OR of 1.5 for an SNP with an MAF of 25%.…”

Section: Discussionmentioning

confidence: 99%

“…(38,71,72) Therefore, it seems very possible that polymorphisms in the TNFRSF11A gene contribute to the susceptibility for the sporadic form of PDB despite the fact that mutations have not been found in typical PDB patients. (38)(39)(40) This study was initiated in the Belgian study population with a power of 75% to find an association with an OR of 1.5 for an SNP with an MAF of 25%. Furthermore, the availability of two populations for replication studies increased the power and together delivered a chance of 94% to find an OR of 1.5 for an SNP with an MAF of 25%.…”

Section: Discussionmentioning

confidence: 99%

“…(70) However, no TNFRSF11A mutations were reported in PDB patients. (38)(39)(40) We and others reported association between sporadic PDB and polymorphisms in the TNFRSF11B gene encoding osteoprotegerin (OPG; MIM 602643), a decoy receptor for RANKL, indicating that variation in the OPG/RANKL/RANK-NFkB pathway influences the risk to develop PDB. (38,71,72) In this study we evaluated whether polymorphisms in the TNFRSF11A gene encoding RANK contribute to the development of PDB in three different European populations of sporadic PDB patients.…”

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confidence: 99%

“…(29)(30)(31)(32)(33)(34)(35) However, several of these loci are currently assumed to be falsepositive results. (36)(37)(38)(39)(40)(41) Until now, only one PDB-causing gene has been identified: the sequestosome1 gene (SQSTM1; MIM 601530), located in the PDB3 region on chromosome 5q35. (34,42,43) To date, 23 SQSTM1 mutations have been found in 28.3% of patients with familial PDB and 7.5% of those with sporadic PDB.…”

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confidence: 99%

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Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

Chung

Beyens

Riches

et al. 2010

Journal of Bone and Mineral Research

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RANK (receptor activator of nuclear factor-kB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 Â 10 À4 , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction ( p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 Â 10 À5 in both populations. Meta-analysis over three populations resulted in p ¼ .002 for rs35211496 and p ¼ 1.27 Â 10 À8 for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A. ß

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

Chung

Beyens

Riches

et al. 2010

Journal of Bone and Mineral Research

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“…(5,6) However, further screening in different populations excluded mutations in TNFRSF11A as a common cause of PDB. (7) Of interest, since 2002 mutations in a different gene, SQSTM1, have been identified in up to 10% and 40% of sporadic and familial PDB cases, respectively. (8) This gene encodes the p62/ sequestosome 1 protein, which acts as a scaffold protein in the NF-kB pathway as well as an intermediate protein in the proteosomal degradation of polyubiquitinated proteins.…”

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Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Gianfrancesco¹,

Rendina²,

Merlotti³

et al. 2012

Journal of Bone and Mineral Research

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Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. ß

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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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Evaluation of the role of RANK and OPG genes in Paget’s disease of bone

Cited by 100 publications

References 16 publications

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Molecular Genetics of Paget's Disease of Bone

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