Germ-line mutations in CYLD are found in patients with familial skin appendage tumours. The protein product functions as a deubiquitinase enzyme, which negatively regulates NF-kappaB and c-Jun N-terminal kinase signalling. Brooke-Spiegler syndrome (BSS) is characterised by cylindromas, trichoepitheliomas and spiradenomas, whereas in familial cylindromatosis (FC) patients present with cylindromas and in multiple familial trichoepitheliomas (MFT) with trichoepitheliomas as the only skin tumour type. Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity.
To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations.
25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene.
In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BSS, 100% for FC, and 44% for MFT. The majority of the mutations were insertions, deletions or nonsense mutations leading to formation of truncated proteins. All mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal a correlation between the types of mutations and their location within the gene and the patients' phenotypes and disease severity.
This study provides further evidence on the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas, trichoepitheliomas and/or spiradenomas, but the molecular mechanisms of CYLD in skin tumorigenesis and the reasons for phenotypic variability remain to be explored.
"CYLD encodes a ubiquitin hydrolase that cleaves lysine 63 (K63) linked ubiquitin chains (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003), the specificity of which depends on the presence of a B-box domain within the CYLD protein (Komander et al., 2008). In patients with germline CYLD mutations, the majority (94%) of mutations result in premature termination codons and predict translated truncated proteins that have reduced catalytic activity (Saggar et al., 2008) which in turn is thought to perturb regulation of the NFκB pathway. CYLD substrates including TRAF2, TRAF6 and NEMO which regulate canonical NFκB signalling are regulated by K63 ubiquitin tagging, and lack of functional CYLD results in constitutively active NFκB signalling (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin. Immunohistochemical analysis of a tumour microarray showed strong membranous TRKB and TRKC staining in cylindromas, as well as elevated levels of ERK phosphorylation and BCL2 expression. Membranous TRKC overexpression was also observed in 70% of sporadic BCCs. RNA interference-mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours. These results suggest that TRK inhibition could be used as a strategy to treat tumours with loss of functional CYLD.
[Show abstract][Hide abstract] ABSTRACT: Brooke-Spiegler syndrome is an autosomal dominant tumor predisposition disorder. The disease is characterized by the occurrence of multiple skin appendage tumors, including cylindroma, trichoepithelioma, and spiradenoma. In some patients, tumors cover the entire head circumference, thereby causing disfigurement and other complications. Here, we report on a man with multiple cylindroma that were distributed in a turban tumor-like fashion. One of these neoplasms arose in the meatus externus of the right ear leading to unilateral hearing loss, a complication that has been documented only on few occasions in this disease.
International journal of dermatology 12/2008; 47 Suppl 1(Suppl 1):56-9. DOI:10.1111/j.1365-4632.2008.03963.x · 1.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The NF-kappaB (nuclear factor kappaB) family of transcription factors are involved in a myriad of activities, including the regulation of immune responses, maturation of immune cells, development of secondary lymphoid organs and osteoclastogenesis. Fine tuning by positive and negative regulators keeps the NF-kappaB signalling pathway in check. Microbial products and genetic alterations in NF-kappaB and other signalling pathway components can lead to deregulation of NF-kappaB signalling in several human diseases, including cancers and chronic inflammatory disorders. NF-kappaB-pathway-specific therapies are being actively investigated, and these hold promises as interventions of NF-kappaB-related ailments.
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