Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees

Good, David A.; Busfield, Frances; Fletcher, Barbara H.; Lovelock, Paul K.; Duffy, David L.; Kesting, Janine; Andersen, John Roger; Shaw, Joanne T.E.

doi:10.1016/j.bone.2004.01.010

Cited by 58 publications

(62 citation statements)

References 26 publications

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“…The same P392L mutation was identified subsequently in familial and sporadic PDB subjects from different countries. (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) Currently, at least 20 further mutations in the SQSTM1 gene have been identified, all of which are clustered within or near the ubiquitin-associated (UBA) domain of the protein and lead to increased NFkB signaling and enhanced bone resorption. In some but not all patient samples, truncating mutations (where all or part of the UBA domain is deleted) were associated with a more severe phenotype than missense mutations.…”

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confidence: 99%

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

Gennari

Gianfrancesco

Stefano

et al. 2010

Journal of Bone and Mineral Research

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Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 AE 2.0 versus 2.19 AE 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 AE 2.5 versus 2.76 AE 2.2, p < .05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity. ß

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SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

Gennari

Gianfrancesco

Stefano

et al. 2010

Journal of Bone and Mineral Research

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“…(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%

“…(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. (37,42,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60) Furthermore, in most cases, the same missense mutation was identified (C1215T, P392L). This missense mutation turned out to be due to a founder effect over several populations.…”

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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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“…The SQSTM1 gene encodes p62 which is a scaffold protein that plays an important role in regulating NFκB signaling downstream of the IL-1 receptor, TNF receptor, RANK receptor and nerve growth factor receptor [9]. Mutation screening of families previously reported to have linkage to the PDB2 region [2] and the PDB7 region [5] has shown that most affected subjects carried mutations in the SQSTM1 gene. Studies in mice with targeted inactivation of SQSTM1 have shown impaired osteoclastogenesis in response to PTHrP injection in vivo, indicating that p62 play a role in regulating osteoclast function and activity in response to bone resorbing stimuli [4].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Variations of SQSTM1 Gene are Associated with Bone Density in the Korean Population

Jin¹,

Eom

2010

Journal of Life Science

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Osteoporosis is a complex systemic skeletal disease and a major public health concern worldwide. It is a heritable disorder characterized mainly by low bone density and/or low trauma osteoporotic fractures, both of which have strong genetic determination. However, the specific genetic variants determining risk for low bone density are still largely unknown. Here, we performed association analysis to elucidate the possible relationship between genetic polymorphisms in the SQSTM1 gene and low bone density. By examining a total of 7225 (men: 3622, women: 3603) subjects from the Korean population in the Korean Association REsource (KARE) study, we discovered that SQSTM1 gene polymorphisms were associated with bone density. The results of the BD-RT (bone density estimated by T-score at distal radius) showed that three SNPs (rs513235, rs3734007, and rs11249661) within the SQSTM1 gene were significantly associated with bone density. The results of the BD-TT (bone density estimated by T-score at midshaft tibia) showed that four SNPs (rs513235, rs3734007, rs2241349, and rs11249661) were significantly associated with bone density. The three SNPs (rs513235, rs3734007, and rs11249661) had common significance in both BD-RT and BD-TT. In summary, we found statistically significant SNPs in the SQSTM1 gene that are associated with bone density traits. Therefore, our findings suggest SQSTM1 gene could be related to pathogenesis of osteoporosis.

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Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees

Cited by 58 publications

References 26 publications

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

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

The Genetic Variations of SQSTM1 Gene are Associated with Bone Density in the Korean Population

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