Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: Genotype phenotype correlation, functional analysis, and structural consequences

Hocking, Lynne J., Lucas, Gavin J. A., Daroszewska, Anna, Cundy, Tim, Nicholson, Geoff C., Donath, Judit, Walsh, John P., Finlayson, Catriona, Cavey, James R., Ciani, Barbara, Sheppard, Paul W., Layfield, Robert and Ralston, Stuart H. (2004) Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: Genotype phenotype correlation, functional analysis, and structural consequences. Journal of Bone and Mineral Research, 19 7: 1122-1127. doi:10.1359/JBMR.0403015


Author Hocking, Lynne J.
Lucas, Gavin J. A.
Daroszewska, Anna
Cundy, Tim
Nicholson, Geoff C.
Donath, Judit
Walsh, John P.
Finlayson, Catriona
Cavey, James R.
Ciani, Barbara
Sheppard, Paul W.
Layfield, Robert
Ralston, Stuart H.
Title Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: Genotype phenotype correlation, functional analysis, and structural consequences
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
ISSN 0884-0431
1523-4681
Publication date 2004-07
Sub-type Article (original research)
DOI 10.1359/JBMR.0403015
Volume 19
Issue 7
Start page 1122
End page 1127
Total pages 6
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell
Language eng
Formatted abstract
Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin-binding properties of the mutant UBA domain peptides. Introduction: Mutations affecting the ubiquitin-associated (UBA) domain of Sequestosome 1 (SQSTM1) gene have recently been identified as a common cause of familial Paget's disease of bone (PDB), but the mechanisms responsible are unclear. We identified three novel SQSTM1 mutations in PDB, conducted functional and structural analyses of all PDB-causing mutations, and studied the relationship between genotype and phenotype. Materials and Methods: Mutation screening of the SQSTM1 gene was conducted in 70 kindreds with familial PDB. We characterized the effect of the mutations on structure of the UBA domain by protein NMR, studied the effects of the mutant UBA domains on ubiquitin binding, and looked at genotype-phenotype correlations. Results and Conclusions: Three novel missense mutations affecting the SQSTM1 UBA domain were identified, including a missense mutation at codon 411 (G411S), a missense mutation at codon 404 (M404V), and a missense mutation at codon 425 (G425R). We also identified a deletion leading to a premature stop codon at 394 (L394X). None of the mutations were found in controls. Structural analysis showed that M404V and G425R involved residues on the hydrophobic surface patch implicated in ubiquitin binding, and consistent with this, the G425R and M404V mutants abolished the ability of mutant UBA domains to bind polyubiquitin chains. In contrast, the G411S and P392L mutants bound polyubiquitin chains normally. Genotype-phenotype analysis showed that patients with truncating mutations had more extensive PDB than those with missense mutations (bones involved = 6.05 ± 2.71 versus 3.45 ± 2.46; p < 0.0001). This work confirms the importance of UBA domain mutations of SQSTM1 as a cause of PDB but shows that there is no correlation between the ubiquitin-binding properties of the different mutant UBA domains and disease occurrence or extent. This indicates that the mechanism of action most probably involves an interaction between SQSTM1 and a hitherto unidentified protein that modulates bone turnover.
Keyword Paget's disease of bone
SQSTM1
Ubiquitin
p62
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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