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

Chung, Pui Yan Jenny; Beyens, Greet; Riches, Philip L.; Wesenbeeck, Liesbeth Van; Freitas, Fenna de; Jennes, Karen; Daroszewska, Anna; Fransén, Erik; Boonen, Steven; Geusens, Piet; Vanhoenacker, Filip; Verbruggen, Leon; Offel, Jan Van; Goemaere, Stefan; Zmierczak, Hans‐Georg; Westhovens, René; Karperien, Marcel; Papapoulos, Socrates E.; Ralston, Stuart H.; Devogelaer, Jean‐Pierre; Hul, Wim Van

doi:10.1002/jbmr.162

Cited by 41 publications

(40 citation statements)

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“…Two common polymorphisms have been described in the protein coding region of RANK [88] which are evolutionarily conserved [91]; these are a histidine to tyrosine amino acid change at codon 141 (H141Y) and an alanine to valine at codon 192 (A192V). Functional analyses of these polymorphisms have yielded mixed results; in one study no effect of these polymorphisms on RANK-induced NFkB activation was found in reporter assays [90], whereas in another study the alanine variant at codon 192 was reported to cause activation of RANK signaling in both the presence and the absence of the SQSTM1 P392L mutation [91]. Further studies will be required to confirm these observations and to determine if the A192V variant is fully responsible for the robust association that has been observed between PDB and common variants at the TNFRSF11A locus [4,49,90,93].…”

Section: Tnfrsf11amentioning

confidence: 95%

“…Mutations have not been detected in the exons or intronexon boundaries of TNFRSF11A in classical PDB [88,89], but there is evidence from candidate gene studies and genomewide association studies that common variants at the TNFRFS11A locus predispose to PDB [4,49,90]. Two common polymorphisms have been described in the protein coding region of RANK [88] which are evolutionarily conserved [91]; these are a histidine to tyrosine amino acid change at codon 141 (H141Y) and an alanine to valine at codon 192 (A192V).…”

Section: Tnfrsf11amentioning

confidence: 99%

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Pathogenesis of Paget Disease of Bone

2012

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Paget disease of bone (PDB) is a common disease characterized by focal areas of increased and disorganized bone turnover. Some patients are asymptomatic, whereas others develop complications such as pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes. PDB is primarily caused by dysregulation of osteoclast differentiation and function, and there is increasing evidence that this is due, in part, to genetic factors. One of the most important predisposing genes is SQSTM1, which harbors mutations that cause osteoclast activation in 5-20 % of PDB patients. Seven additional susceptibility loci for PDB have been identified by genomewide association studies on chromosomes 1p13, 7q33, 8q22, 10p13, 14q32, 15q24, and 18q21. Although the causal variants remain to be discovered, three of these loci contain CSF1, TNFRSF11A, and TM7SF4, genes that are known to play a critical role in osteoclast differentiation and function. Environmental factors are also important in the pathogenesis of PDB, as reflected by the fact that in many countries the disease has become less common and less severe over recent years. The most widely studied environmental trigger is paramyxovirus infection, but attempts to detect viral transcripts in tissues from patients with PDB have yielded mixed results. Although our understanding of the pathophysiology of PDB has advanced tremendously over the past 10 years, many questions remain unanswered, such as the mechanisms responsible for the focal nature of the disease and the recent changes in prevalence and severity.

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Section: Tnfrsf11amentioning

confidence: 95%

Section: Tnfrsf11amentioning

confidence: 99%

Pathogenesis of Paget Disease of Bone

2012

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“…The Belgian study population was described as previously (Chung et al 2010), but enlarged to 247 sporadic PDB patients, recruited from different clinical centres in Belgium. Diagnosis of PDB was based on alkaline phosphatase measurements and radiographic/scintigraphic examinations.…”

Section: Belgian Populationmentioning

confidence: 99%

“…DNA was extracted in a standard manner, using the salting out method (Miller et al 1988). No indication of population stratification was observed as described in our previous study (Chung et al 2010).…”

Section: Study Populationmentioning

confidence: 99%

“…Until recently our knowledge about these genetic risk factors was very limited. Association studies using a candidate gene approach revealed the role for variants in the TNFRSF11B gene encoding osteoprotegerin (OPG) (Beyens et al 2007;Daroszewska et al 2004;Wuyts et al 2001) and the TNFRSF11A gene encoding receptor activator of nuclear factor kappa-B (RANK) (Chung et al 2009(Chung et al , 2010. Both are receptors for the RANKL and therefore play a major role in the regulation of osteoclastogenesis via NFjB signalling.…”

Section: Introductionmentioning

confidence: 99%

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The majority of the genetic risk for Paget’s disease of bone is explained by genetic variants close to the CSF1, OPTN, TM7SF4, and TNFRSF11A genes

et al. 2010

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Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 × 10(-4) to 3.8 × 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 × 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 × 10(-4) and 8.8 × 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes.

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

Cited by 41 publications

References 90 publications

Pathogenesis of Paget Disease of Bone

Pathogenesis of Paget Disease of Bone

The majority of the genetic risk for Paget’s disease of bone is explained by genetic variants close to the CSF1, OPTN, TM7SF4, and TNFRSF11A genes

Molecular Genetics of Paget's Disease of Bone

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