A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype

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dc.contributor.authorCundy, T.
dc.contributor.authorHegde, M.
dc.contributor.authorNaot, D.
dc.contributor.authorChong, B.
dc.contributor.authorKing, A.
dc.contributor.authorWallace, R.
dc.contributor.authorMulley, J.
dc.contributor.authorLove, D.
dc.contributor.authorSeidel, J.
dc.contributor.authorFawkner, M.
dc.contributor.authorBanovic, T.
dc.contributor.authorCallon, K.
dc.contributor.authorGrey, A.
dc.contributor.authorReid, I.
dc.contributor.authorMiddleton-Hardie, C.
dc.contributor.authorCornish, J.
dc.date.issued2002
dc.descriptionCopyright © 2002 Oxford University Press
dc.description.abstractIdiopathic hyperphosphatasia is an autosomal recessive bone disease characterized by deformities of long bones, kyphosis and acetabular protrusion, increasing in severity as affected children pass through adolescence. Biochemical and histological evidence indicate that there is extremely rapid bone turnover, with indices of both bone resorption and formation greatly increased. 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). The gene TNFRSF11B encoding osteoprotegerin (OPG), which lies within this locus, was an obvious candidate, given the critical role of OPG in regulating osteoclast development. All three affected siblings were homozygous for a 3 bp inframe deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue. Their parents (who were first cousins) were heterozygous for the mutation. Recombinant wild-type and mutant OPG cDNAs were expressed in human epithelial kidney cells, and secreted OPG was collected from the conditioned medium. In vitro measurements of bone resorption showed that wild-type OPG suppressed bone resorption, whereas the mutant form did not, confirming this to be an inactivating mutation. This description of abnormal OPG function in humans expands the spectrum of genetic bone diseases arising from perturbations of the OPG/RANK-L/RANK system that regulates osteoclastogenesis.
dc.description.statementofresponsibilityTim Cundy, Madhuri Hegde, Dorit Naot, Belinda Chong, Alan King, Robyn Wallace, John Mulley, Donald R. Love, Joerg Seidel, Matthew Fawkner, Tatjana Banovic, Karen E. Callon, Andrew B. Grey, Ian R. Reid, Catherine A. Middleton-Hardie and Jillian Cornish
dc.identifier.citationHuman Molecular Genetics, 2002; 11(18):2119-2127
dc.identifier.doi10.1093/hmg/11.18.2119
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.urihttp://hdl.handle.net/2440/28131
dc.language.isoen
dc.publisherOxford Univ Press
dc.source.urihttp://hmg.oxfordjournals.org/cgi/content/abstract/11/18/2119
dc.subjectBone and Bones
dc.subjectHumans
dc.subjectOsteitis Deformans
dc.subjectGlycoproteins
dc.subjectReceptors, Tumor Necrosis Factor
dc.subjectReceptors, Cytoplasmic and Nuclear
dc.subjectPedigree
dc.subjectGenes, Recessive
dc.subjectMutation
dc.subjectAdolescent
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectFemale
dc.subjectMale
dc.subjectOsteoprotegerin
dc.titleA mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype
dc.typeJournal article
pubs.publication-statusPublished

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