Functional significance of Sequestosome 1 (SQSTM1/p62) mutations in Paget's disease of bone

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    [Truncated abstract] Paget's disease of bone (PDB) is a common bone disorder. Recently, mutations within the Sequestosome 1(SQSTM1) gene have been identified in many patients, such that they are now acknowledged to be a common predisposing factor for the disease. This study determined the SQSTM1 mutation prevalence in Western Australian PDB patients to be approximately 25% for familial patients and 5% in sporadic cases. Two novel mutations were identified, one truncating (K378X) in a patient with a severe disease phenotype and one missense (P364S) in a patient with mild disease. Genotype-phenotype correlations were performed; mutation presence was associated with increased disease severity, however the disease severity of patients with truncating compared with missense mutations was not significantly different. Pagetic osteoclasts are large, contain many nuclei and are overactive. AP-1 and NF-B are important mediators of osteoclastogenesis; the effect of expressing SQSTM1 mutant proteins on NF-B and AP-1 activity were investigated. Expression of SQSTM1 mutant proteins increase, whilst over-expression of the wild type protein attenuates, NF-B activation. Additionally, mutant proteins increase RANKL-induced AP-1 activation compared with the wild-type protein. Accordingly, expression of mutant proteins increased osteoclast formation from murine precursors. Monocytic precursors from a patient with the K378X mutation formed more osteoclasts with more nuclei and greater bone-resorbing activity than cells from an age and sex-matched control. As signalling was increased in cells expressing mutant proteins, it seemed plausible that cell proliferation might also be increased. However, no significant difference was observed. The mechanisms underlying increased NF-B and AP-1 activity were investigated. Ubiquitin modification of signalling pathway intermediates is an important regulatory mechanism and SQSTM1 regulates ubiquitinated proteins. Therefore, the effect of
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2010

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