title: Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.
abstract: Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 germline CYLD mutations have been reported, occurring in exons 9-20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma (MFT). CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the nuclear factor (NF)-kappaB and c-Jun N-terminal kinase (JNK) pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked Ub chains but has been shown to act on K48-linked Ub chains as well. In 2008, the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD's unique specificity for K63-linked Ub chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation.
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Rockville, Maryland 20892-4562, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Blake
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Toro
mesh_terms: D000818:Animals; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D054875:Ubiquitination
chemical_list: D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD