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Cited by 131Bone Metabolism and DiseasesAlkaline Phosphatase Research StudiesBone Tumor Diagnosis and Treatments

A point mutation in the ubiquitin-associated domain of SQSMT1 is sufficient to cause a Paget's disease-like disorder in mice

Daroszewska, Anna, van 't Hof, Robert J., Rojas, Javier A., Layfield, Robert, Landao-Basonga, Euphemie, Rose, Lorraine, Rose, Ken, Ralston, Stuart H.·2011·Human Molecular Genetics
DOI 10.1093/hmg/ddr172
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Abstract

Mutations of SQSTM1 occur in about10% of patients with Paget's disease of bone (PDB), but it is unclear whether they play a causal role or regulate susceptibility to an environmental trigger. Here we show that mice with a proline to leucine mutation at codon 394 of mouse sqstm1 (P394L), equivalent to the P392L SQSTM1 mutation in humans, develop a bone disorder with remarkable similarity to PDB. The P394L mutant mice developed focal bone lesions with increasing age and by 12 months, 14/18 (77%) heterozygotes and 20/21 (95%) homozygotes had lesions, compared with 0/18 (0%) wild-type littermates (P< 0.001). Lesions predominantly affected the lower limbs in an asymmetric manner and were characterized by focal increases in bone turnover, with increased bone resorption and formation, disruption of the normal bone architecture and accumulation of woven bone. Osteoclasts within lesions were larger and more nucleated than normal and some contained nuclear inclusions similar to those observed in human PDB. Osteoclast precursors from P394L mutant mice had increased sensitivity to RANKL in vitro resulting in the generation of osteoclasts that were larger and more nucleated than those generated from wild-type littermates. There was increased expression of sqstm1, autophagy-related gene 5 (atg5) and light chain 3 gene (lc3) in osteoclast precursors and increased LC3-II protein levels in Bafilomycin-treated osteoclasts from P394L mutant mice compared with wild-type suggesting dysregulation of autophagy and enhanced autophagosome formation. These studies demonstrate that SQSTM1 mutations can cause a PDB-like skeletal disorder in the absence of an additional trigger and provide a new disease model for PDB.

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Crossref · 10.1093/hmg/ddr172

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  • Overexpression of SQSTM1 variants carrying disease-associated mutations in the UBA domain exhibits a PDB-like skeletal disorder and impaired spatial learning and long-term memory.

    “On the other hand, overexpression of SQSTM1 variants carrying disease-associated mutations in the UBA domain exhibit a PDB-like skeletal disorder [138,139] as well as impaired spatial learning and long-term memory [140].”

    From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [138]

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Authors
Daroszewska, A., van 't Hof, R. J., Rojas, J. A., Layfield, R., Landao-Basonga, E., Rose, L., Rose, K., & Ralston, S. H.
Affiliations
  • University of Edinburgh (GB)
  • University of Nottingham (GB)
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2011-04-21
Volume
20
Issue
14
Pages
2734-2744
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddr172
OpenAlex
W2133860741
Cited by
131
References
43
Citations by year
2026: 2 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 13 · 2020: 6 · 2019: 11 · 2018: 10 · 2017: 7 · 2016: 13 · 2015: 14 · 2014: 10 · 2013: 9 · 2012: 12
FWCI
4.54
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Versus Arthritis (18865, 13724)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
  • Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
Keywords
p62, Paget's disease of bone, ubiquitin-associated domain, mouse model, bone lesions, bone turnover, bone resorption, osteoclasts, autophagy, LC3, ATG5, pathogenic variants
MeSH terms
Autophagy-Related Protein 5, Sequestosome-1 Protein, Animals, Autophagy, Bone Resorption, Disease Models, Animal, Heat-Shock Proteins, Humans, Mice, Mutant Strains, Microtubule-Associated Proteins, Osteitis Deformans, Osteoclasts, Osteogenesis, Point Mutation, Amino Acid Substitution, Adaptor Proteins, Signal Transducing, Mice, RANK Ligand

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