Identification of the familial cylindromatosis tumour-suppressor gene

Abstract

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

Mutations in the NF-κB signaling pathway: implications for human disease

“…Cylindromatosis Cylindromatosis (OMIM#132700) is a rare, recessive genetic disease characterized by the formation of benign tumors, called cylindromas, in hairy parts of the body, mostly the scalp (Bignell et al, 2000). Cylindromas are considered as originating from a transformation event specifically affecting the folliculo-sebaceous unit that produces hair and its associated glands.…”

“…Cylindromas are considered as originating from a transformation event specifically affecting the folliculo-sebaceous unit that produces hair and its associated glands. The mutated gene, CYLD, encodes a tumor suppressor protein (Bignell et al, 2000) that can negatively regulate NF-kB activation (Brummelkamp et al, 2003;Kovalenko et al, 2003;Regamey et al, 2003;Trompouki et al, 2003). CYLD is a member of the deubiquitinase family of enzymes that can specifically hydrolyse poly-ubiquitin chains of the 'K63' type.…”

“…Most CYLD mutations identified in cylindromatosis are frameshift or nonsense mutations that remove all or part of the catalytic domain of CYLD (Bignell et al, 2000;Poblete-Gutie´rrez et al, 2002;Hu et al, 2003;Scheinfeld et al, 2003;Tobin et al, 2003;Bowen et al, 2005;Heinritz et al, 2006) (Figure 2). In addition, a few missense mutations have been identified, but how they affect CYLD function is unclear .…”

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

“…CYLD negatively regulates NF-kB activation, and mutations that inactivate the carboxyl-terminal deubiquitinating domain of CYLD deregulate the NF-kB activity, underlying the development of skin appendage tumors in humans (Brummelkamp et al, 2003;Kovalenko et al, 2003;Trompouki et al, 2003). CYLD was originally identified as a gene mutated in familial cylindromatosis (FC), a genetic condition that predisposes patients for the development of cylindromas, benign tumors that typically appear on the scalp (Bignell et al, 2000). Cylindromatosis patients carry heterozygous germ-line mutations in the carboxyl-terminal end of the CYLD gene, but the wild-type CYLD allele undergoes loss of heterozygosity, indicating that CYLD appears as a tumor-suppressor gene (Bignell et al, 2000).…”

“…CYLD was originally identified as a gene mutated in familial cylindromatosis (FC), a genetic condition that predisposes patients for the development of cylindromas, benign tumors that typically appear on the scalp (Bignell et al, 2000). Cylindromatosis patients carry heterozygous germ-line mutations in the carboxyl-terminal end of the CYLD gene, but the wild-type CYLD allele undergoes loss of heterozygosity, indicating that CYLD appears as a tumor-suppressor gene (Bignell et al, 2000). Cylindromas are usually benign, although occasionally they can malignize (Durani et al, 2001;De Francesco et al, 2005).…”