A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma

Abstract

Multiple familial trichoepithelioma (MFT, OMIM 601606) is an autosomal dominantly inherited disease characterized by numerous, skin-colored papules with pilar differentiation. The skin tumors usually occur on the face, especially around the nasolabial folds, and more commonly found in females between the first and second decade of the life. Mutations in the CYLD gene on chromosome 16q12-q13 have been identified as the molecular basis of MFT [ [1] Zhang X.J. Liang Y.H. He P.P. Yang S. Wang H.Y. Chen J.J. et al. Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma. J Invest Dermatol. 2004; 122: 658-664 Crossref PubMed Scopus (86) Google Scholar ], which is also responsible for familial cylindromatosia (FC, cylindromas only) [ [2] Bignell G.R. Warren W. Seal S. Takahashi M. Rapley E. Barfoot R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet. 2000; 25: 160-165 Crossref PubMed Scopus (578) Google Scholar ], and Brooke-Spiegler syndrome (BSS, a combination of cylindromas, trichoepitheliomas and spiradenomas) [ [3] Scheinfeld N. Hu G. Gill M. Austin C. Celebi J.T. Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome. Clin Exp Dermatol. 2003; 28: 539-541 Crossref PubMed Scopus (26) Google Scholar ]. CYLD gene functions as a tumor suppressor, while CYLD protein is a deubiquitinating enzyme, which negatively regulates activation of the transcription factor NF-κB by removing lysine-63-linked ubiquitin chains from TRAF2 (tumor necrosis factor receptor-associated factor 2), TRAF6 and NEMO (NF-κB essential modulator, also known as IκB kinase γ, Ikkγ) [ 4 Trompouki E. Hatzivassiliou E. Tsichritzis T. Farmer H. Ashworth A. Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003; 424: 793-796 Crossref PubMed Scopus (788) Google Scholar , 5 Jono H. Lim J.H. Chen L.F. Xu H. Trompouki E. Pan Z.K. et al. NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. J Biol Chem. 2004; 279: 36171-36174 Crossref PubMed Scopus (156) Google Scholar , 6 Regamey A. Hohl D. Liu J.W. Roger T. Kogerman P. Toftgard R. et al. The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. J Exp Med. 2003; 198: 1959-1964 Crossref PubMed Scopus (100) Google Scholar ]. Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis.