Paget's Disease of Bone and Genetic Disorders of RANKL/OPG/RANK/NF‐κB Signaling

@article{Whyte2006PagetsDO,
  title={Paget's Disease of Bone and Genetic Disorders of RANKL/OPG/RANK/NF‐$\kappa$B Signaling},
  author={Michael P Whyte},
  journal={Annals of the New York Academy of Sciences},
  year={2006},
  volume={1068}
}
  • M. Whyte
  • Published 1 April 2006
  • Biology
  • Annals of the New York Academy of Sciences
Abstract:  Identification of the RANKL/OPG/RANK/NF‐kB (receptor activator of nuclear factor κ‐B ligand / osteoprotegerin) signaling pathway as the major regulatory system for osteoclastogenesis began with discovery of these ligands and receptors in the tumor necrosis factor (TNF) superfamily. Subsequently, genetically altered mice revealed physiologic roles for these proteins in bone biology. However, full appreciation of their significance for the human skeleton came from clinical… Expand
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TLDR
Mutation screening of the TNFRSF11A gene in patients with familial and sporadic Paget's disease as well as DNA extracted from Pagetic bone lesions, an osteosarcoma arising in PageticBone and six osteosARcoma cell lines indicate that TNFRL11A mutations contribute neither to the vast majority of cases of sporadic or familial PDB, nor to the development of osteosArcoma. Expand
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Several candidate loci for susceptibility to PDB and related syndromes have been identified by genome-wide scans and recent evidence suggests that mutations in genes that encode components of the RANK/NF-kappaB signalling pathway play an important role in the pathogenesis of this group of diseases. Expand
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The heritable disorders identified to date that directly involve the RANKL/OPG/RANK signaling pathway in humans include PDB, which can be inherited as an autosomal dominant trait with focal osteolytic disease, and increasingly associated with mutations, but in other genes. Expand
Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis
TLDR
Two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone caused an increase in RANK-mediated nuclear factor-κB signalling in vitro, consistent with the presence of an activating mutation. Expand
Identification of a Novel Tandem Duplication in Exon 1 of the TNFRSF11A Gene in Two Unrelated Patients With Familial Expansile Osteolysis
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Genetics of Paget's disease of bone
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Phenotypic Characterization of Early Onset Paget's Disease of Bone Caused by a 27‐bp Duplication in the TNFRSF11A Gene
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TLDR
It is concluded that the 75dup27 mutation of RANK causes a Paget's disease of bone‐like phenotype that is distinct from, but which overlaps with, FEO and ESH. Expand
A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype.
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A genome-wide search in a family with three children affected by idiopathic hyperphosphatasia suggested linkage to a locus on the long arm of chromosome 8 (8q24), and the gene TNFRSF11B encoding osteoprotegerin (OPG), which lies within this locus, was an obvious candidate. Expand
Linkage of Paget disease of bone to a novel region on human chromosome 18q23.
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The data are consistent with genetic heterogeneity within the pedigree and indicate that 18q23 harbors a novel susceptibility gene for PDB. Expand
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