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URL of this page: https://medlineplus.gov/genetics/gene/sqstm1/

SQSTM1 gene

sequestosome 1

Normal Function

The SQSTM1 gene provides instructions for making a protein called sequestosome-1. This protein helps regulate bone remodeling, a normal process in which old bone is broken down and replaced by new bone. Sequestosome-1 is involved in a chemical signaling pathway that promotes the formation and activity of bone cells called osteoclasts, which are specialized cells that break down bone tissue during bone remodeling.

In addition to its role in bone remodeling, sequestosome-1 may have other functions, although these are less well-defined. Sequestosome-1 may be involved in recycling worn-out cell parts and unneeded proteins (autophagy), the self-destruction of cells when they are no longer needed (apoptosis), and the body's immune responses and inflammatory reactions.

Health Conditions Related to Genetic Changes

Paget disease of bone

Variants (also called mutations) in the SQSTM1 gene have been associated with Paget disease of bone. This disorder causes one or more bones to be larger than normal, misshapen, and easily broken (fractured). Many SQSTM1 gene variants lead to the substitution of one protein building block (amino acid) for another in sequestosome-1. 

Through a mechanism that is not well understood, SQSTM1 gene variants lead to an increase (overactivation) in the chemical signaling pathway that promotes osteoclast formation. This increase in signaling stimulates the production of too many osteoclasts and triggers the breakdown of bone. In people with Paget disease of bone, affected bone is broken down by osteoclasts and replaced by bone cells called osteoblasts much faster than usual. As a result, the new bone tissue is less organized and weaker than normal bone. These problems with bone remodeling cause certain bones to become unusually large, misshapen, and prone to fracture. 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 sclerosis

More About This Health Condition

Other disorders

Variants in the SQSTM1 gene can also cause frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language.  FTD is often considered to be part of the same disease spectrum as amyotrophic lateral sclerosis (ALS). Variants in the SQSTM1 gene cause cells to produce a version of the sequestome-1 protein that does not function properly. As a result, cell signaling pathways that influence important cellular processes, such as autophagy and apoptosis, are disrupted. These changes can lead to FTD, ALS, or a combination of both diseases.

Variants in the SQSTM1 gene have been found in a few individuals with a muscle disorder called distal myopathy with rimmed vacuoles (DMRV). Affected individuals have muscle weakness (myopathy) that typically begins in adulthood. This muscle weakness primarily affects movement in the shoulder muscles and movement in the muscles that are furthest from the center of the body (distal muscles), such as the muscles in the hands and feet. People with DMRV may also have difficulty walking. Researchers are still investigating how variants in the SQSTM1 gene cause DMRV.

Variants in the SQSTM1 gene have also been associated with a condition called NADGP. NADGP is an acronym that stands for the key features of the condition, which include a decline in cognitive function (neurodegeneration), poor coordination and balance (ataxia), involuntary tensing of the muscles (dystonia), and difficulty following movements with the eyes (gaze palsy). The signs and symptoms of NADGP typically begin in childhood or adolescence. Affected individuals may require wheelchair assistance as young adults. The variants in the SQSTM1 gene that cause NADGP lead to the production of a protein that does not function properly. As a result, autophagy is impaired, resulting in the buildup of various abnormal proteins in the cells of the brain. This buildup of proteins contributes to the neurodegeneration and the other features seen in people with NADGP. 

Other Names for This Gene

  • A170
  • autophagy receptor p62
  • OSIL
  • p60
  • p62
  • p62B
  • PDB3
  • ubiquitin-binding protein p62
  • ZIP3

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Banaganapalli B, Fallatah I, Alsubhi F, Shetty PJ, Awan Z, Elango R, Shaik NA. Paget's disease: a review of the epidemiology, etiology, genetics, and treatment. Front Genet. 2023 Apr 26;14:1131182. doi: 10.3389/fgene.2023.1131182. eCollection 2023. Citation on PubMed
  • Bucelli RC, Arhzaouy K, Pestronk A, Pittman SK, Rojas L, Sue CM, Evila A, Hackman P, Udd B, Harms MB, Weihl CC. SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology. 2015 Aug 25;85(8):665-74. doi: 10.1212/WNL.0000000000001864. Epub 2015 Jul 24. Citation on PubMed
  • 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
  • Davidson JM, Chung RS, Lee A. The converging roles of sequestosome-1/p62 in the molecular pathways of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurobiol Dis. 2022 May;166:105653. doi: 10.1016/j.nbd.2022.105653. Epub 2022 Feb 7. 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
  • Muto V, Flex E, Kupchinsky Z, Primiano G, Galehdari H, Dehghani M, Cecchetti S, Carpentieri G, Rizza T, Mazaheri N, Sedaghat A, Vahidi Mehrjardi MY, Traversa A, Di Nottia M, Kousi MM, Jamshidi Y, Ciolfi A, Caputo V, Malamiri RA, Pantaleoni F, Martinelli S, Jeffries AR, Zeighami J, Sherafat A, Di Giuda D, Shariati GR, Carrozzo R, Katsanis N, Maroofian R, Servidei S, Tartaglia M. Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. Neurology. 2018 Jul 24;91(4):e319-e330. doi: 10.1212/WNL.0000000000005869. Epub 2018 Jun 29. 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
  • Rendina D, Falchetti A, Diacinti D, Bertoldo F, Merlotti D, Giannini S, Cianferotti L, Girasole G, Di Monaco M, Gonnelli S, Malavolta N, Minisola S, Vescini F, Rossini M, Frediani B, Chiodini I, Asciutti F, Gennari L. Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS). J Endocrinol Invest. 2024 Jun;47(6):1335-1360. doi: 10.1007/s40618-024-02318-1. Epub 2024 Mar 15. Citation on PubMed
  • Salari M, Etemadifar M, Neshat Ghalibaf M, Azizi F, Davoodi M, Asadi S. Neurodegeneration, Ataxia, Dystonia, and Gaze Palsy (NADGP) Syndrome with Nocturnal Paroxysmal Head Tremor. Mov Disord Clin Pract. 2023 Apr 20;10(5):835-838. doi: 10.1002/mdc3.13697. eCollection 2023 May. No abstract available. Citation on PubMed

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