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https://hdl.handle.net/2440/28131
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Type: | Journal article |
Title: | A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype |
Author: | Cundy, T. Hegde, M. Naot, D. Chong, B. King, A. Wallace, R. Mulley, J. Love, D. Seidel, J. Fawkner, M. Banovic, T. Callon, K. Grey, A. Reid, I. Middleton-Hardie, C. Cornish, J. |
Citation: | Human Molecular Genetics, 2002; 11(18):2119-2127 |
Publisher: | Oxford Univ Press |
Issue Date: | 2002 |
ISSN: | 0964-6906 1460-2083 |
Statement of Responsibility: | Tim 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 |
Abstract: | Idiopathic 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. |
Keywords: | Bone and Bones Humans Osteitis Deformans Glycoproteins Receptors, Tumor Necrosis Factor Receptors, Cytoplasmic and Nuclear Pedigree Genes, Recessive Mutation Adolescent Adult Middle Aged Child Child, Preschool Female Male Osteoprotegerin |
Description: | Copyright © 2002 Oxford University Press |
DOI: | 10.1093/hmg/11.18.2119 |
Published version: | http://hmg.oxfordjournals.org/cgi/content/abstract/11/18/2119 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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