title: CYLD mutations in familial skin appendage tumours.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations.
  
  
  METHODS
  25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, Columbia University, New York, NY 10032, USA.
authors.forename: S
authors.initials: S
authors.lastname: Saggar
authors.forename: K A
authors.initials: KA
authors.lastname: Chernoff
authors.forename: S
authors.initials: S
authors.lastname: Lodha
authors.forename: L
authors.initials: L
authors.lastname: Horev
authors.forename: S
authors.initials: S
authors.lastname: Kohl
authors.forename: R S
authors.initials: RS
authors.lastname: Honjo
authors.forename: H R C
authors.initials: HR
authors.lastname: Brandt
authors.forename: K
authors.initials: K
authors.lastname: Hartmann
authors.forename: J T
authors.initials: JT
authors.lastname: Celebi
mesh_terms: D018280:Carcinoma, Skin Appendage / Q000235:genetics* / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D005091:Exons; D005190:Family; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD