Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone

Lucas, Gavin J. A., Mehta, Sarju G., Hocking, Lynne J., Stewart, Tracey L., Cundy, Tim, Nicholson, Geoffrey C., Walsh, John P., Fraser, William D., Watts, Giles D. J., Ralston, Stuart H. and Kimonis, Virginia E. (2006) Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone. Bone, 38 2: 280-285. doi:10.1016/j.bone.2005.07.014


Author Lucas, Gavin J. A.
Mehta, Sarju G.
Hocking, Lynne J.
Stewart, Tracey L.
Cundy, Tim
Nicholson, Geoffrey C.
Walsh, John P.
Fraser, William D.
Watts, Giles D. J.
Ralston, Stuart H.
Kimonis, Virginia E.
Title Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone
Journal name Bone   Check publisher's open access policy
ISSN 8756-3282
1873-2763
Publication date 2006-02-01
Year available 2006
Sub-type Article (original research)
DOI 10.1016/j.bone.2005.07.014
Open Access Status Not Open Access
Volume 38
Issue 2
Start page 280
End page 285
Total pages 6
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Abstract Paget's disease of bone (PDB) is a common metabolic bone disease of late onset with a strong genetic component. Rarely, PDB can occur as part of a syndrome in which the disease is accompanied by inclusion body myopathy and frontotemporal dementia (inclusion body myopathy, Paget's disease and frontotemporal dementia, IBMPFD). Recently, IBMPFD has been shown to be caused by mutations in Valosin-containing Protein (VCP), which is required for the proteasomal degradation of phosphorylated IκB-α, a necessary step in the activation of the transcription factor NF-κB. Here, we evaluated the role of VCP in the pathogenesis of typical PDB. We conducted mutation screening of VCP in 44 kindreds with familial Paget's disease recruited mainly through clinic referrals in the UK, Australia and New Zealand. We also performed an association study of VCP haplotypes in patients with PDB who did not have a family history of the disease (sporadic PDB). No mutations were found in VCP in three PDB families where there was evidence of allele sharing between affected subjects in the VCP critical region on chromosome 9p13. We failed to detect disease-associated mutations in any of the three exons previously reported to contain IBMPFD mutations in a further 41 PDB families. We found no evidence of allelic association between common VCP haplotypes in a case-control study of 179 sporadic PDB patients and 172 age- and sex-matched controls. Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia.
Keyword Paget's disease
Ubiquitin
VCP genetic
NF-kappa B
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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