The SQSTM1 gene provides instructions for making a protein called p62. This protein plays an important role in bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it. The p62 protein helps regulate this process through its role in a chemical signaling pathway that promotes the formation of osteoclasts. Osteoclasts are specialized cells that break down bone tissue during bone remodeling.
Studies suggest that p62 may have other functions in addition to its role in bone remodeling. It may be involved in recycling worn-out cell parts and unneeded proteins (autophagy), the self-destruction of cells (apoptosis), and the body's immune responses and inflammatory reactions.
Health Conditions Related to Genetic Changes
Paget disease of bone
More than 20 mutations in the SQSTM1 gene have been found to cause Paget disease of bone. Many SQSTM1 gene mutations change single protein building blocks (amino acids) in the p62 protein. The most common mutation replaces the amino acid proline with the amino acid leucine at protein position 392 (written as Pro392Leu or P392L).
Through a mechanism that is not well understood, SQSTM1 gene mutations appear to overactivate the chemical signaling pathway that promotes osteoclast formation. The increased signaling stimulates the production of too many osteoclasts and triggers these cells to break down bone abnormally. In people with Paget disease of bone, affected bone is broken down and replaced much faster than usual. When the new bone tissue grows, it is weaker and less organized than normal bone. These problems with bone remodeling cause certain bones to become unusually large, misshapen, and easily broken (fractured). It is unclear why the disease affects some bones but not others.More About This Health Condition
Amyotrophic lateral sclerosis
MedlinePlus Genetics provides information about Amyotrophic lateral sclerosisMore About This Health Condition
Other Names for This Gene
- EBI3-associated protein p60
- oxidative stress induced like
- phosphotyrosine independent ligand for the Lck SH2 domain p62
- ubiquitin-binding protein p62
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Cavey JR, Ralston SH, Hocking LJ, Sheppard PW, Ciani B, Searle MS, Layfield R. Loss of ubiquitin-binding associated with Paget's disease of bone p62 (SQSTM1) mutations. J Bone Miner Res. 2005 Apr;20(4):619-24. doi: 10.1359/JBMR.041205. Epub 2004 Dec 6. Citation on PubMed
- Goode A, Layfield R. Recent advances in understanding the molecular basis of Paget disease of bone. J Clin Pathol. 2010 Mar;63(3):199-203. doi: 10.1136/jcp.2009.064428. Epub 2009 Oct 26. Citation on PubMed
- Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet. 2002 Oct 15;11(22):2735-9. doi: 10.1093/hmg/11.22.2735. Citation on PubMed
- Laurin N, Brown JP, Morissette J, Raymond V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002 Jun;70(6):1582-8. doi: 10.1086/340731. Epub 2002 Apr 30. Citation on PubMed or Free article on PubMed Central
- Morissette J, Laurin N, Brown JP. Sequestosome 1: mutation frequencies, haplotypes, and phenotypes in familial Paget's disease of bone. J Bone Miner Res. 2006 Dec;21 Suppl 2:P38-44. doi: 10.1359/jbmr.06s207. Citation on PubMed
- Rea SL, Walsh JP, Ward L, Magno AL, Ward BK, Shaw B, Layfield R, Kent GN, Xu J, Ratajczak T. Sequestosome 1 mutations in Paget's disease of bone in Australia: prevalence, genotype/phenotype correlation, and a novel non-UBA domain mutation (P364S) associated with increased NF-kappaB signaling without loss of ubiquitin binding. J Bone Miner Res. 2009 Jul;24(7):1216-23. doi: 10.1359/jbmr.090214. Citation on PubMed
- Vadlamudi RK, Joung I, Strominger JL, Shin J. p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J Biol Chem. 1996 Aug 23;271(34):20235-7. doi: 10.1074/jbc.271.34.20235. Citation on PubMed
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