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).
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References
Abenoza, P. & Ackerman, A.B. Neoplasms with Eccrine Differentiation (Lea and Febiger, Philadelphia, 1990).
van Balkom, I.D. & Hennekam, R.C. Dermal eccrine cylindromatosis. J. Med. Genet. 31, 321–324 (1994)
Gerretsen, A.L., Beemer, F.A., Deenstra, W., Hennekam, F.A. & van Vloten, W.A. Familial cutaneous cylindromas: investigations in five generations of a family. J. Am. Acad. Dermatol. 33, 199–206 (1995).
Biggs, P.J. et al. Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12–q13: evidence for its role as a tumour suppressor gene. Nature Genet. 11, 441–443 (1995).
Verhoef, S. et al. Familial cylindromatosis mimicking tuberous sclerosis complex and confirmation of the cylindromatosis locus, CYLD1, in a large family. J. Med. Genet. 35, 841–845 (1998).
Thomson, S.A., Rasmussen, S.A., Zhang, J. & Wallace, M.R. A new hereditary cylindromatosis family associated with CYLD1 on chromosome 16. Hum. Genet. 105, 171–173 (1999).
Takahashi, M. et al. Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12–q13. Hum. Genet. 106, 58–65 (2000).
Biggs, P.J., Chapman, P., Lakhani, S.R., Burn, J. & Stratton, M.R. The cylindromatosis gene (CYLD) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas. Oncogene 12, 1375–1377 (1996).
Ioannou, P.A. et al. A new bacteriophage P1-derived vector for the propagation of large human DNA fragments. Nature Genet. 6, 84–89 (1994).
Futreal, A. et al. Isolation of a diverged homeobox gene, MOX1, from the BRCA1 region on 17q21 by solution hybrid capture. Hum. Mol. Genet. 3, 1359–1364 (1994).
Ganguly, A., Rock, M.J. & Prockop, D.J. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc. Natl Acad. Sci. USA 90, 10325–10329 (1993).
Chase, D.S. et al. The North Cumbria Community Genetics Project. J. Med. Genet. 35, 413–416 (1998)
Nagase, T. et al. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5, 355–364 (1998).
Riehemann, K. & Sorg, C. Sequence homologies between four cytoskeleton-associated proteins. Trends Biochem. Sci. 18, 82–83 (1993).
Feng, S., Chen, J.K., Yu, H., Simon, J.A. & Schreiber, S.L. Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Science 266, 1241–1247 (1994)
D'Andrea, A. & Pellman, D. Deubiquitinating enzymes: a new class of biological regulators. Crit. Rev. Biochem. Mol. Biol. 33, 337–352 (1998).
Pierre, P., Scheel, J., Rickard, J.E. & Kreis, T.E. CLIP-170 links endocytic vesicles to microtubules. Cell 70, 887–900 (1992).
Bilbe, G. et al. Restin: a novel intermediate filament-associated protein highly expressed in the Reed-Sternberg cells of Hodgkin's disease. EMBO J. 11, 2103–2113 (1992).
Waterman-Storer, C.M. & Holzbaur, E.L. The product of the Drosophila gene, Glued, is the functional homologue of the p150Glued component of the vertebrate dynactin complex. J. Biol. Chem. 271, 1153–1159 (1996).
Berlin, V., Styles, C.A. & Fink, G.R. BIK1, a protein required for microtubule function during mating and mitosis in Saccharomyces cerevisiae, colocalizes with tubulin. J. Cell Biol. 111, 2573–2586 (1990).
Pellman, D., Bagget, M., Tu, Y.H. & Fink, G.R. Two microtubule-associated proteins required for anaphase spindle movement in Saccharomyces cerevisiae. J. Cell Biol. 130, 1373–1385 (1995)
Pierre, P., Pepperkok, R. & Kreis, T.E. Molecular characterization of two functional domains of CLIP-170 in vivo. J. Cell. Sci. 107, 1909–1920 (1994).
Karki, S. & Holzbaur, E.L. Cytoplasmic dynein and dynactin in cell division and intracellular transport. Curr. Opin. Cell Biol. 11, 45–53 (1999).
Dujardin, D. et al. Evidence for a role of CLIP-170 in the establishment of metaphase chromosome alignment. J. Cell Biol. 141, 849–862 (1998).
Kahana, J.A. et al. The yeast dynactin complex is involved in partitioning the mitotic spindle between mother and daughter cells during anaphase B. Mol. Biol. Cell 9, 1741–1756 (1998).
Hershko, A. Roles of ubiquitin-mediated proteolysis in cell cycle control. Curr. Opin. Cell Biol. 9, 788–799 (1997).
Antonarakis, S.E. Recommendations for a nomenclature system for human gene mutations. Hum. Mutat. 11, 1–3 (1998)
Acknowledgements
We thank the families for cooperation; the Institute of Cancer Research Gene Cloning Laboratory and R. Warren for assistance; D. Cooke, P. Itin, D. Schorderet and the many other clinicians for ascertaining families; HGMP for provision of PAC library filters; North Cumbria Community Genetics Project for control DNA samples; and E. Peacock for help in preparing the manuscript. G.T., P.C. and J.B. are members of the ICRF Clinical Genetics Network. The work was supported by the Cancer Research Campaign.
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Bignell, G., Warren, W., Seal, S. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25, 160–165 (2000). https://doi.org/10.1038/76006
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DOI: https://doi.org/10.1038/76006
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