Identification of the familial cylindromatosis tumour-suppressor gene

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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Figure 1: Familial cylindromatosis.
Figure 2: Contig of PACs for the minimum linked interval between markers CDRP39 and CDRP21.
Figure 3: CSGE shifts of the first 13 germline mutations detected.
Figure 4: Alignment of CYLD with putative
Figure 5: Duplicate RT–PCR analyses of CYLD in a range of tissues using primers in exons 6 and 9.

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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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Correspondence to Michael R. Stratton.

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