A positional cloning effort in French Canadian families with Paget's disease of bone (PDB) resulted in the identification of a mutation in the sequestosome1 (SQSTM1) gene in a subset of both familial and sporadic PDB cases. This was confirmed in samples of mainly United Kingdom (UK) origin. In this study, we performed both mutation analysis and association studies in order to evaluate the role of this gene in a collection of isolated Belgian PDB patients. A mutation in the SQSTM1 gene was found in only 6 of 111 patients (5.4%). In all cases it involves the P392L mutation, previously shown to be common in both familial and sporadic cases. To perform association studies, we selected 8 single nucleotide polymorphisms (SNPs) and looked for linkage disequilibrium (LD) between these. Haplotype analysis indicated that typing of 3 Tag SNPs (IVS1 + 633A/C, IVS5 - 23A/G, and 976A/G) enables us to identify the most common haplotypes. Association studies for the 3 selected SNPs, based on 105 PDB cases without a SQSTM1 mutation and 159 control individuals, did not support a possible influence of natural variants in the SQSTM1 gene either on the pathogenesis of PDB or on the disease severity. In conclusion, our study confirms that the P392L mutation is a recurrent mutation causing PDB in different populations. We were not able to show an association between SQSTM1 polymorphisms and PDB in our population but this clearly needs to be extended to other populations. The presented identification of haplotype Tag SNPs will be of major help for such studies.
We studied the role of TNFRSF11B polymorphisms on the risk to develop Paget's disease of bone in a Belgian study population. We observed no association in men, but a highly significant association was found in women, and this was confirmed in a population from the United Kingdom.Introduction: Juvenile Paget's disease has been shown to be caused by mutations in TNFRSF11B encoding osteoprotegerin. Although mutations in this gene have never been found in patients with typical Paget's disease of bone (PDB), there are indications that polymorphisms in TNFRSF11B might contribute to the risk of developing PDB. Materials and Methods:We recruited a population of 131 Belgian patients with sporadic PDB and 171 Belgian controls. By means of the HapMap, we selected 17 SNPs that, in combination with four multimarker tests, contain most information on common genetic variation in TNFRSF11B. To replicate the findings observed in the Belgian study population, genotyping data of SNPs generated in a UK population were reanalyzed. Results: In our Belgian study population, associations were found for two SNPs (rs11573871, rs1485286) and for one multimarker test involving rs1032129. When subsequently analyzing men and women separately, these associations turned out to be driven by women (56 cases, 78 controls). In addition, three other tagSNPs turned out to be associated in women only. These were rs2073617 (C950T), rs6415470, and rs11573869. Reanalysis of genotyping data from a UK study population indicated that the associations found for C950T and C1181G were also exclusively driven by women (146 cases, 216 controls). Meta-analysis provided evidence for risk increasing effects of the T allele of C950T and the G allele of C1181G in the female population (p ס 0.002 and 0.003, respectively). The haplotypes formed by the SNPs associated in the Belgian population were also distributed differentially between female cases and controls. Conclusions: We showed for the first time that SNPs influencing the risk to develop PDB could be sex-specific. Further research is necessary to identify the causative variants in TNFRSF11B and to elucidate the molecular pathogenic mechanism.
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.
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
Paget's Disease of Bone (PDB) is one of the most frequent metabolic bone diseases, affecting 1-5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4-9.3% of nonfamilial PDB cases, with the 1215C-->T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch (n = 82), and Spanish (n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients (7.3%), three Dutch patients without a family history (3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms (SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG (H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.
Paget's disease of bone (PDB) is a common late-onset bone disorder characterized by focal areas of abnormal bone remodeling. Positional cloning efforts resulted in the identification of seven genetic loci (PDB1-7) with putative involvement in the pathogenesis of PDB. Meanwhile, the PDB-causing gene from the PDB3 region on chromosome 5q35 has been identified as the SQSTM1 gene. All mutations identified in this gene so far are located in or close to the ubiquitin-associated (UBA) domain of the protein. In 2001, we reported genotyping results of genetic markers located in the PDB3 region in an extended American family, indicating the involvement of the PDB3 locus. Here, we report the identification of a novel mutation (G1205C) in the SQSTM1 gene in this family. The G1205C mutation is located in the splice donor site of intron 7 and reverse-transcription polymerase chain reaction experiments showed that the presence of the C allele results in the production of two abnormal mRNA transcripts. Translation of the first transcript would result in a protein that lacks amino acids 351-388, including 26 amino acids of the second PEST domain in addition to two amino acids of the UBA domain. The second mutant mRNA transcript could result in a truncated protein (390X) that lacks almost the complete UBA domain. PDB mutations that disrupt the function of the PEST domain of SQSTM1 have not been reported before, so probably the pathogenic effect of both transcripts resides in the disruption of the ubiquitin-binding properties of the protein.
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