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CYLD gene

CYLD lysine 63 deubiquitinase
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Normal Function

The CYLD gene provides instructions for making a protein that helps regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related proteins that help protect cells from self-destruction (apoptosis) in response to certain signals. In regulating the action of nuclear factor-kappa-B, the CYLD protein allows cells to respond properly to signals to self-destruct when appropriate, such as when the cells become abnormal. By this mechanism, the CYLD protein acts as a tumor suppressor, which means that it helps prevent cells from growing and dividing too fast or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Brooke-Spiegler syndrome

At least 20 CYLD gene mutations have been identified in individuals with Brooke-Spiegler syndrome. This condition is characterized by multiple noncancerous (benign) tumors that develop in structures associated with the skin (skin appendages), such as sweat glands and hair follicles. People with Brooke-Spiegler syndrome may develop several types of skin appendage tumors, including growths called spiradenomas, trichoepitheliomas, and cylindromas. Spiradenomas are tumors of the sweat glands. Trichoepitheliomas arise from the hair follicles. While previously thought to derive from sweat glands, cylindromas are now generally believed to begin in hair follicles.

People with Brooke-Spiegler syndrome are born with a mutation in one of the two copies of the CYLD gene in each cell. This mutation prevents the cell from making functional CYLD protein from the altered copy of the gene. However, enough protein is usually produced from the other, normal copy of the gene to regulate cell growth effectively. For tumors to develop, a second mutation or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's lifetime. These genetic changes are called somatic mutations and are not inherited.

When both copies of the CYLD gene are mutated in a particular cell, that cell cannot produce any functional CYLD protein. The loss of this protein impairs the regulation of nuclear factor-kappa-B, allowing the cell to grow and divide in an uncontrolled way to form a tumor. In people with Brooke-Spiegler syndrome, second CYLD mutations typically occur in different types of cells in the skin over an affected person's lifetime, leading to the growth of multiple types of skin appendage tumors.

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Familial cylindromatosis

More than 30 CYLD gene mutations have been identified in individuals with familial cylindromatosis. People with this disorder typically develop large numbers of cylindromas.

As in Brooke-Spiegler syndrome, people with familial cylindromatosis are born with one mutated copy of the CYLD gene in each cell, and a second mutation or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's lifetime.

When both copies of the CYLD gene are mutated in particular hair follicle cells, those cells cannot produce any functional CYLD protein. The loss of this protein allows the cells to grow and divide in an uncontrolled way to form cylindromas.

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Multiple familial trichoepithelioma

At least 22 mutations in the CYLD gene have been identified in individuals with multiple familial trichoepithelioma. People with this disorder typically develop large numbers of trichoepitheliomas.

As in Brooke-Spiegler syndrome and familial cylindromatosis, people with CYLD-related multiple familial trichoepithelioma are born with one mutated copy of the CYLD gene in each cell, and a second mutation or deletion of genetic material involving the other copy of the CYLD gene must occur in certain cells during a person's lifetime.

When both copies of the CYLD gene are mutated in particular hair follicle cells, those cells cannot produce any functional CYLD protein. The loss of this protein allows the cells to grow and divide in an uncontrolled way to form trichoepitheliomas.

Some researchers consider familial cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome to be different forms of the same disorder. It is unclear why mutations in the CYLD gene cause different types of skin appendage tumors in each of these conditions, or why the tumors are generally confined to the skin in these disorders.

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Cancers

Somatic mutations and reduced activity (expression) of the CYLD gene have also been identified in certain cancerous tumors. These cancers include multiple myeloma, which starts in cells of the bone marrow, and cancers of the kidney, liver, uterus, and colon. These genetic changes likely impair the tumor suppressor function of the CYLD protein, allowing cells to grow and divide in an uncontrolled way and become cancerous.

Other Names for This Gene

  • BRSS
  • CDMT
  • CYLD1
  • CYLD_HUMAN
  • CYLDI
  • cylindromatosis (turban tumor syndrome)
  • EAC
  • HSPC057
  • KIAA0849
  • MFT
  • MFT1
  • SBS
  • TEM
  • USPL2

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Alameda JP, Fernández-Aceñero MJ, Moreno-Maldonado R, Navarro M, Quintana R, Page A, Ramírez A, Bravo A, Casanova ML. CYLD regulates keratinocyte differentiation and skin cancer progression in humans. Cell Death Dis. 2011 Sep 8;2:e208. doi: 10.1038/cddis.2011.82. Citation on PubMed or Free article on PubMed Central
  • Almeida S, Maillard C, Itin P, Hohl D, Huber M. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol. 2008 Mar;128(3):587-93. Epub 2007 Sep 13. Citation on PubMed
  • Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Rasmussen S. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet. 2000 Jun;25(2):160-5. Citation on PubMed
  • Blake PW, Toro JR. Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat. 2009 Jul;30(7):1025-36. doi: 10.1002/humu.21024. Review. Citation on PubMed or Free article on PubMed Central
  • Dubois A, Rajan N. CYLD Cutaneous Syndrome. 2020 Apr 16. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK555820/ Citation on PubMed
  • Lee DA, Grossman ME, Schneiderman P, Celebi JT. Genetics of skin appendage neoplasms and related syndromes. J Med Genet. 2005 Nov;42(11):811-9. Review. Citation on PubMed or Free article on PubMed Central
  • Massoumi R, Paus R. Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control. Bioessays. 2007 Dec;29(12):1203-14. Review. Citation on PubMed
  • Massoumi R. CYLD: a deubiquitination enzyme with multiple roles in cancer. Future Oncol. 2011 Feb;7(2):285-97. doi: 10.2217/fon.10.187. Review. Citation on PubMed
  • Massoumi R. Ubiquitin chain cleavage: CYLD at work. Trends Biochem Sci. 2010 Jul;35(7):392-9. doi: 10.1016/j.tibs.2010.02.007. Epub 2010 Mar 26. Review. Citation on PubMed
  • Saggar S, Chernoff KA, Lodha S, Horev L, Kohl S, Honjo RS, Brandt HR, Hartmann K, Celebi JT. CYLD mutations in familial skin appendage tumours. J Med Genet. 2008 May;45(5):298-302. doi: 10.1136/jmg.2007.056127. Epub 2008 Jan 30. Citation on PubMed
  • Sun SC. CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell Death Differ. 2010 Jan;17(1):25-34. doi: 10.1038/cdd.2009.43. Review. Citation on PubMed
  • Young AL, Kellermayer R, Szigeti R, Tészás A, Azmi S, Celebi JT. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006 Sep;70(3):246-9. Citation on PubMed
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