Two Novel Mutations at Exon 8 of the <i>Sequestosome 1</i> (<i>SQSTM1</i>) Gene in an Italian Series of Patients Affected by Paget's Disease of Bone (PDB)

Falchetti, Alberto; Stefano, Marco Di; Marini, Francesca; Monte, Francesca Del; Mavilia, Carmelo; Strigoli, Debora; Feo, Maria Laura De; Isaia, Giovan; Masi, Laura; Amedei, Antonietta; Cioppi, Federica; Ghinoi, Valentina; Bongi, Susanna Maddali; Fede, Giuseppina Di; Sferrazza, Carmela; Rini, Giovan Battista; Melchiorre, Daniela; Matucci‐Cerinic, Marco; Brandi, Maria Luisa

doi:10.1359/jbmr.040203

Cited by 75 publications

(74 citation statements)

References 31 publications

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“…The cohort of PDB patients from Turin partially overlapped (54 of 186 patients) with a cohort examined in two previous studies on SQSTM1 mutations. (13,29) The patients having a previous report of at least one other family member affected with PDB were defined as familial cases. If the presence of relatives with suspected clinical features of PDB (ie, focal bone pain and/or bone deformity or deafness) was referred, these relatives were invited to undergo a specific diagnostic test for PDB.…”

Section: Subjectsmentioning

confidence: 99%

“…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%

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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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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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“…Mice that are deficient in p62 show no obvious skeletal phenotype under normal conditions but exhibit defective osteoclastogenesis when challenged with bone-resorbing factors (4). Moreover, mutations affecting p62 are a common cause of Paget disease of bone (PDB), a condition associated with increased osteoclast and osteoblast activity (5)(6)(7)(8). PDB is characterized by excessive bone turnover leading to bone expansion, structural weakness, deformity, and pain (9,10).…”

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Ubiquitin Recognition by the Ubiquitin-associated Domain of p62 Involves a Novel Conformational Switch

Long

Gallagher

Cavey

et al. 2008

Journal of Biological Chemistry

132

149

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The p62 protein functions as a scaffold in signaling pathways that lead to activation of NF-B and is an important regulator of osteoclastogenesis. Mutations affecting the receptor activator of NF-B signaling axis can result in human skeletal disorders, including those identified in the C-terminal ubiquitin-associated (UBA) domain of p62 in patients with Paget disease of bone. These observations suggest that the disease may involve a common mechanism related to alterations in the ubiquitin-binding properties of p62. The structural basis for ubiquitin recognition by the UBA domain of p62 has been investigated using NMR and reveals a novel binding mechanism involving a slow exchange structural reorganization of the UBA domain to a "bound" noncanonical UBA conformation that is not significantly populated in the absence of ubiquitin. The repacking of the three-helix bundle generates a binding surface localized around the conserved Xaa-Gly-Phe-Xaa loop that appears to optimize both hydrophobic and electrostatic surface complementarity with ubiquitin. NMR titration analysis shows that the p62-UBA binds to Lys 48 -linked di-ubiquitin with ϳ4-fold lower affinity than to mono-ubiquitin, suggesting preferential binding of the p62-UBA to single ubiquitin units, consistent with the apparent in vivo preference of the p62 protein for Lys 63 -linked polyubiquitin chains (which adopt a more open and extended structure). The conformational switch observed on binding may represent a novel mechanism that underlies specificity in regulating signalinduced protein recognition events.The p62 protein (encoded by the sequestosome 1 (SQSTM1) gene) functions as a scaffold in signaling pathways downstream of the interleukin-1, tumor necrosis factor-␣, nerve growth factor, and receptor activator of NF-B 3 receptors, which ultimately lead to activation of the NF-B transcription factor, with receptor activator of NF-B signaling being a critical determinant in the regulation of osteoclast formation (1-3). Mice that are deficient in p62 show no obvious skeletal phenotype under normal conditions but exhibit defective osteoclastogenesis when challenged with bone-resorbing factors (4). Moreover, mutations affecting p62 are a common cause of Paget disease of bone (PDB), a condition associated with increased osteoclast and osteoblast activity (5-8). PDB is characterized by excessive bone turnover leading to bone expansion, structural weakness, deformity, and pain (9, 10).The p62 protein has a domain structure consistent with its participation in multiple signaling complexes, although p62 also appears to be multifunctional, not least in controlling protein recruitment to endosomes (3) and proteasomal proteolysis (11). Within the p62 sequence, an N-terminal PB1 domain has been identified that binds atypical protein kinase C. In addition, a ZZ motif is evident, a binding site for the RING finger protein TRAF6, and two PEST sequences that lie adjacent to the C-terminal ubiquitin-associated (UBA) domain (Fig. 1), a motif that occurs in enzymes of the ubiq...

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“…(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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Two Novel Mutations at Exon 8 of the Sequestosome 1 (SQSTM1) Gene in an Italian Series of Patients Affected by Paget's Disease of Bone (PDB)

Cited by 75 publications

References 31 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

Ubiquitin Recognition by the Ubiquitin-associated Domain of p62 Involves a Novel Conformational Switch

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

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