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The concept of CYLD cutaneous syndrome was proposed by Rajan et al. in 2009 (Rajan et al., 2009). The syndrome represents an uncommon autosomal dominant disease caused by a germline mutation in the cylindromatosis gene (CYLD) (Biggs PJ, et al. 1995). CYLD cutaneous syndrome is characterized by the development of multiple neoplasms originating from the skin appendages (Rajan et al., 2009). It includes three appendageal tumor predisposition syndromes; familial cylindromatosis (FC, MIM 132700), Brooke-Spiegler syndrome (BSS, MIM 605041), and multiple familial trichoepithelioma (MFT, MIM 601606) (Rajan et al., 2009). BSS is characterized by multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. FC is typified by multiple cylindromas and MFT by multiple trichoepitheliomas. Here, we summarize current clinical and genetic recognition in CYLD cutaneous syndrome.
A genome search using two FC families identified strong evidence for linkage to the locus on chromosome 16q12-q13 (Biggs et al., 1995). Subsequently, germline mutations in the tumor suppressor CYLD gene were identified in individuals having FC (Bignell et al. 2000). A combination of genetic linkage analysis and loss of heterozygosity in 15 FC families showed only the linkage to the locus, providing no evidence for genetic heterogeneity (Takahashi et al. 2000). The germline mutations were then detected in individuals with BSS (HU et al., 2003; Poblete Gutiérrez et al., 2002) and MFT (Salhi et al., 2004; Zhang et al., 2004; Zheng et al., 2004). Affected family members with the same germline mutation in CYLD showed FC, BSS or MFT phenotypes, indicating the absence of genotype-phenotype relationship (Fenske et al., 2000; Rajan et al., 2009; Young et al., 2006). The phenotypic diversity from mild type to severe turban tumor is present in the affected family members with CYLD cutaneous syndrome (Biggs et al., 1995; Oiso et al., 2004; Rajan et al., 2009; Young et al., 2006). Bowen et al. suggested that FC, BSS, and MTF represent phenotypic variation of a single entity (Bowen et al., 2005). Rajan et al. proposed the term, CYLD cutaneous syndrome, for unifying three skin appendage-associated disorders (Rajan et al., 2009).
In 2003, CYLD was shown as a deubiquitinating enzyme that negatively regulates nuclear factor-kappa B (NF-κB) activation (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003; Wilkinson, 2003). NF-κB is involved in controlling inflammation, the immune response, and apoptosis (Pasparakis, 2002). Nowadays, many different cellular functions have been ascribed to CYLD such as proliferation and cell cycle, Ca2+ channel signaling, survival and apoptosis, inflammation, T-cell development and activation, antiviral response, and spermatogenesis (Pasparakis, 2002).
CYLD contains three cytoskeleton-associated protein-glycine-rich (CAP-Gly) domains, two proline-rich motifs, a tumor necrosis factor-alpha (TNF-α) receptor-associated factor 2 (TRAF2) binding site, and ubiquitin-specific proteases (USP) domain responsible for its deubiquitinases (DUB) activity (Harhaj et al., 2011; Pasparakis, 2002). The first two CAP-Gly domains mediate binding to microtubules (Gao et al., 2008; Wickström et al., 2010), and the third CAP-Gly domain regulates NEMO interactions. NEMO (also known as IκB kinase gamma (IKKγ)) is the regulatory subunit of the IκB kinase (IKK) (Yoshida et al., 2011). IKK plays crucial role in activating NF-κB in response to various inflammatory stimuli (Zheng et al., 2011). TRAF2 regulates activation of the c-Jun N-terminal kinase (JNK)/c-Jun and the inhibitor of IKK/ NF-κB signaling cascades in response to TNF-α stimulation (Zhang et al., 2011).
CYLD cutaneous syndrome represents familial cylindromatosis, Brooke-Spiegler syndrome, and multiple familial trichoepithelioma. Further studies for elucidating the function of CYLD will focus on defining the multifunctional activities including tumor suppression for neoplasms from the skin appendages.
References
1.BiggsP. JWoosterRFordDet alFamilial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor geneNat Genet 19951144413
2.BignellG. RWarrenWSealSet alIdentification of the familial cylindromatosis tumour-suppressor gene.Nat Genet 20002521605
3.BowenSGillMLeeD. Aet alMutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlationJ Invest Dermatol 2005124591920
4.BrummelkampT. RNijmanS. MDiracA. Met alLoss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB.Nature20034246950797801
5.FenskeCBanerjeePHoldenCet alBrooke-Spiegler syndrome locus assigned to 16q12-q13.J Invest Dermatol 2000114510578
6.GaoJHuoLSunXet alThe tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migrationJ Biol Chem 20082831488029
7.HarhajE. WDixitV. MDeubiquitinases in the regulation of NF-κB signaling. Cell Res 20112112239
8.HuGOnderMGillMet alA novel missense mutation in CYLD in a family with Brooke-Spiegler syndromeJ Invest Dermatol 200312147324
10.MassoumiRUbiquitin chain cleavage: CYLD at work. Trends Biochem Sci 20103573929
11.OisoNMizunoNFukaiKet alMild phenotype of familial cylindromatosis associated with an R758X nonsense mutation in the CYLD tumour suppressor gene. Br J Dermatol 2004151510846
12.PasparakisMCourtoisGHafnerMet alTNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2.Nature200241768918616
13.Poblete Gutiérrez PEggermann T, Höller D, et al. Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendagesJ Invest Dermatol 2002119252731
14.RajanNLangtryJ. AAshworthAet alTumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction. Arch Dermatol 200914511127784
15.SalhiABornholdtDOeffnerFet alMultiple familial trichoepithelioma caused by mutations in the cylindromatosis tumor suppressor gene.Cancer Res 2004641551137
16.TakahashiMRapleyEBiggsP. Jet alLinkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.Hum Genet 200010615865
17.TrompoukiEHatzivassiliouETsichritzisTet alCYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members.Nature200342469507936
18.WickströmS. AMasoumiK. CKhochbinSet alCYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin EMBO J 201029113144
19.WilkinsonK. DSignal transduction: aspirin, ubiquitin and cancer. Nature 200342469507389
20.YoshidaMOisoNKimuraMet alSkin ulcer mimicking pyoderma gangrenosum in a patient with incontinentia pigmenti.J Dermatol 20113810101921
23.ZhangX. JLiangY. HHeP. Pet alIdentification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepitheliomaJ Invest Dermatol 2004122365864
24.ZhengCYinQWuHStructural studies of NF-κB signaling. Cell Res 201121118395
25.ZhengGHuLHuangWet alCYLD mutation causes multiple familial trichoepithelioma in three Chinese families.Hum Mutat 2004400 EOF
Written By
Takahiro Kurimoto, Naoki Oiso, Muneharu Miyake and Akira Kawada
Submitted: September 14th, 2012Published: February 6th, 2013
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