A nonsynonymous TNFRSF11A variation increases NFkB activity and the severity of Paget's disease (Articolo in rivista)

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  • A nonsynonymous TNFRSF11A variation increases NFkB activity and the severity of Paget's disease (Articolo in rivista) (literal)
Anno
  • 2012-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1002/jbmr.542 (literal)
Alternative label
  • Gianfrancesco F; Rendina D; Di Stefano M; Mingione A; Esposito T; Merlotti D; Gallone S; Magliocca S; Goode A; Formicola D; Morello G; Layfield R; Frattini A; De Filippo G; Nuti R; Searle M; Strazzullo P; Isaia GC; Mossetti G; Gennari L A (2012)
    A nonsynonymous TNFRSF11A variation increases NFkB activity and the severity of Paget's disease
    in Journal of bone and mineral research
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Gianfrancesco F; Rendina D; Di Stefano M; Mingione A; Esposito T; Merlotti D; Gallone S; Magliocca S; Goode A; Formicola D; Morello G; Layfield R; Frattini A; De Filippo G; Nuti R; Searle M; Strazzullo P; Isaia GC; Mossetti G; Gennari L A (literal)
Pagina inizio
  • 443 (literal)
Pagina fine
  • 452 (literal)
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  • 27 (literal)
Rivista
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  • PMID: 21987421 (literal)
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  • 2 (literal)
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  • Pubblicazione (literal)
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  • ISI Web of Science (WOS) (literal)
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  • 1. Natl Res Council Italy, Inst Genet & Biophys Adriano Buzzati Traverso, I-80131 Naples, Italy 2. Univ Naples Federico 2, Sch Med, Dept Clin & Expt Med, Naples, Italy 3. Univ Turin, Dept Internal Med, Turin, Italy 4. Univ Siena, Dept Internal Med Endocrine Metab Sci & Biochem, I-53100 Siena, Italy 5. Univ Turin, Dept Neurosci, Turin, Italy 6. Univ Nottingham, Sch Med, Queens Med Ctr, Sch Biomed Sci, Nottingham, England 7. CNR, Inst Biomed Technol, I-20133 Milan, Italy 8. Sch Chem, Ctr Biomol Sci, Nottingham, England (literal)
Titolo
  • A nonsynonymous TNFRSF11A variation increases NFkB activity and the severity of Paget's disease (literal)
Abstract
  • Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for the T575C variant, yielding an odds ratio of 1.29 (p=0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p=0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p=0.01), as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p=0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11AA192 produced a level of activation of NF?B signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11AV192, confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations. (C) 2012 American Society for Bone and Mineral Research (literal)
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