Role of SQSTM1 in Paget's Disease of Bone and the regulation of normal bone turnover

Lead Research Organisation: University of Edinburgh
Department Name: Edinburgh Research and Innovation


The principal applicant is advisor to the National Association for Relief of Pagets disease (a patient self-help group) and has lectured widely to medical and lay audiences on Pagets disease and related disorders. The bone research group web site also contains information relevant to public understanding of the disease.

Technical Summary

Paget‘s disease of bone (PDB) is a common disorder, which affects about 3% of individuals over the age of 55 years in the UK. The disease is characterised by focal abnormalities of bone turnover, which disrupt normal bone architecture, causing bone pain, bone deformity, deafness, osteoarthritis and pathological fractures. Genetic factors are important in PDB and we recently identified mutations in the sequestosome 1 (SQSTM1) gene as a common cause of both familial and sporadic PDB. The aims of this programme are to define the molecular mechanism by which SQSTM1 gene mutations affect bone cell function and to develop an animal model for PDB, by knock-in of representative mutations to transgenic mice. This will allow us to explore the factors that determine when, where and why bone lesions develop in patients with SQSTM1 mutations. The research programme is important, not only for understanding the pathogenesis of PDB, but also for understanding the basic mechanisms by which the SQSTM1 gene product regulates normal bone turnover and links bone resorption to bone formation.


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Albagha OM (2013) Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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Corral-Gudino L (2013) Secular changes in Paget's disease: contrasting changes in the number of new referrals and in disease severity in two neighboring regions of Spain. in Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA

Description MRC Models of Disease
Amount £464,415 (GBP)
Funding ID G0800933 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2009 
End 01/2012
Description Medical Research Council Charity, John Wheale Bequest
Amount £15,390 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2007 
End 08/2010
Description Programme Grant
Amount £400,000 (GBP)
Funding ID 19799 
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2012 
End 08/2016
Title SQSTM1 P394L mutant mouse 
Description This is a mouse model of SQSTM1 mediated Paget's which recapitulates many features of the disease 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact We have presented data on the phenotype of this model at several meetings including ASBMR where the presenter won a "young investigator" award. A paper has been published describing the phenotype of the mouse. 
Description SQSTM1 mutations and disease severity in PDB 
Organisation University of Nottingham
Department School of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We are supplying the clinical data
Collaborator Contribution Our collaborator is Dr Rob Layfield who has devised methods to assess the effect of different SQSTM1 mutations on binding affinity for Ubiquitin. We are using this data to determine if the clinical severity of PDB is related to the affect of different mutations on ubiquitin binding affinity
Impact This research will help to clarify if the type of mutation is related to clinical severity of Paget's disease
Start Year 2007
Description NARPD Members Day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact I have presented the result of our ongoing research to the "members day" of the National Association for relief of Paget's disease (NARPD) a patient organisation

This has raised awareness of the important of genetic factors in Paget's and helped us enroll patients into the MRC-funded ZIPP study
Year(s) Of Engagement Activity 2007,2009