Evaluation of the Role of the SQSTM1 Gene in Sporadic Belgian Patients with Paget’s Disease

Beyens, Greet; Hul, Els Van; Driessche, K. Van; Fransén, Erik; Devogelaer, Jean‐Pierre; Vanhoenacker, Filip; Offel, Jan Van; Verbruggen, Leon; Clerck, L. De; Westhovens, René; Hul, Wim Van

doi:10.1007/s00223-004-0244-4

Cited by 50 publications

(48 citation statements)

References 37 publications

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“…p62, as noted earlier, is an adaptor protein that binds ubiquitin and plays an important role in regulating NFjB signaling [69] as well as autophagy [70][71][72]. Current evidence suggests that mutations of SQSTM1 occur in 40-50 % of patients with a familial history of PDB and 2.5-10 % of ''sporadic'' PDB cases [60,65,66,73,74]. Virtually all of the PDB-causing mutations cluster in the UBA domain, and most prevent or A427D Yes Gennari et al [16] a Two different mutations were reported at the genomic level, which both resulted in the same amino acid change.…”

Section: Sqstm1mentioning

confidence: 92%

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: Sqstm1mentioning

confidence: 92%

Pathogenesis of Paget Disease of Bone

2012

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“…Both are receptors for the RANKL and therefore play a major role in the regulation of osteoclastogenesis via NFjB signalling. On the other hand, no evidence could be obtained for the presence of genetic variants within the SQSTM1 gene influencing the risk for PDB (Beyens et al 2004). Very recently, Albagha et al (2010) performed a genome-wide association study (GWAS) mainly on the British population and found strong evidence for genetic risk factors around the CSF1 (colony stimulating factor 1) and OPTN (optineurin) genes and confirmed involvement of the TNFRSF11A gene.…”

Section: Introductionmentioning

confidence: 95%

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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“…(72,74) Diagnosis of PDB was based both on alkaline phosphatase measurements and radiologic/scintigraphic examinations. All patients were of Belgian origin.…”

Section: Belgian Populationmentioning

confidence: 99%

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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Evaluation of the Role of the SQSTM1 Gene in Sporadic Belgian Patients with Paget’s Disease

Cited by 50 publications

References 37 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

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

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