PDB (Paget's disease of bone) is a common condition characterized by focal increases in bone turnover affecting one or more sites throughout the skeleton. Genetic factors are important in the pathogenesis of PDB and many families have been described where PDB is inherited in an autosomal-dominant fashion. 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 [receptor activator of NF-κB (nuclear factor-κB)]/NF-κB signalling pathway play an important role in the pathogenesis of this group of diseases. Insertion mutations in the TNFRSF11A gene encoding RANK have been identified as the cause of familial expansile osteolysis, some cases of early onset PDB and expansile skeletal hyperphosphatasia. Inactivating mutations in the TNFRSF11B gene that encodes OPG (osteoprotegerin) have been found to cause the syndrome of juvenile PDB. Polymorphisms in OPG also appear to increase the risk of developing PDB. The most important causal gene for classical PDB is Sequestosome 1 (SQSTM1), which is a scaffold protein in the NF-κB signalling pathway, and mutations affecting the UBA (ubiquitin-associated) domain of this protein occur in between 20–50% of familial and 10–20% of sporadic PDB cases. The rare syndrome of IBMPFD (inclusion body myopathy, PDB and fronto-temporal dementia) is due to mutations in the VCP gene and these also cluster in the domain of VCP that interacts with ubiquitin, suggesting a common disease mechanism with SQSTM1-mediated PDB.
Skip Nav Destination
Article navigation
September 2005
-
Cover Image
Cover Image
- PDF Icon PDF LinkTable of Contents
Review Article|
August 24 2005
Genetics of Paget's disease of bone
Anna Daroszewska;
Anna Daroszewska
*Institute of Medical Sciences, University of Aberdeen Medical School, Aberdeen AB25 2ZD, U.K.
Search for other works by this author on:
Stuart H. Ralston
†Rheumatic Diseases Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, U.K.
Correspondence: Professor Stuart H. Ralston (email [email protected]).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
February 04 2005
Revision Received:
March 14 2005
Accepted:
April 07 2005
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society
2005
Clin Sci (Lond) (2005) 109 (3): 257–263.
Article history
Received:
February 04 2005
Revision Received:
March 14 2005
Accepted:
April 07 2005
Citation
Anna Daroszewska, Stuart H. Ralston; Genetics of Paget's disease of bone. Clin Sci (Lond) 1 September 2005; 109 (3): 257–263. doi: https://doi.org/10.1042/CS20050053
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |