Abstract
Multiple familial trichoepithelioma (MFT) (OMIM: 601606) is an autosomal dominantly inherited disorder characterized by numerous, skin-colored papules and nodules with pilar differentiation. Recently, several mutations in the cylindromatosis (CYLD) gene have been reported in MFT. In this study, a mutation analysis of the CYLD was conducted in a Chinese pedigree of typical MFT. Affected individuals were identified through probands from Shanxi Province, China. Lesional skin biopsy of the proband revealed the typical histopathological characteristics of trichoepithelioma. Individuals belonging to five consecutive generations were similarly affected, which indicated an autosomal dominant inheritance pattern. Genomic DNA was extracted from peripheral blood lymphocytes using standard phenol/chloroform extraction method. All the coding exons (4–20) and exon–intron boundaries of the CYLD gene were amplified by polymerase chain reaction (PCR). Direct sequencing of all PCR products amplified from the complete coding regions of the CYLD gene was performed to identify mutations. Sequencing of the CYLD gene was performed in a further 100 unrelated, unaffected control individuals to exclude the possibility of polymorphism. A novel heterozygous frameshift mutation c.1169_1170delCA (p.Thr390Argfs) was identified in exon 10 of the CYLD gene in the affected family members. This mutation was also detected in unaffected family members, but not in the unrelated, healthy individuals who were also analyzed. Our study expands the database on the CYLD gene mutations in MFT and should be useful in providing genetic counseling and prenatal diagnosis for families affected by MFT.
This is a preview of subscription content, log in via an institution to check access.
References
Almeida S, Maillard C, Itin P, Hohl D, Huber M (2008) Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol 128:587–593
Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR et al (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25:160–165
Bowen S, Gill M, Lee DA, Fisher G, Geronemus RG, Vazquez ME, Celebi JT (2005) Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol 124:919–920
Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424:797–801
Chen M, Liu H, Fu X, Yu Y, Yu G, Liu H, Tian H, Zhou G, Zhang D, Wang G et al (2011) Mutation analysis of the CYLD gene in two Chinese families with multiple familial Trichoepithelioma. Australas J Dermatol 52:146–147
Duparc A, Lasek-Duriez A, Wiart T, Duban-Bedu B, Gosset P, Modiano P (2013) Multiple familial trichoepithelioma: a new CYLD gene mutation. Ann Dermatol Venereol 140:274–277
Espana A, Garcia-Amigot F, Aguado L, Garcia-Foncillas J (2007) A novel missense mutation in the CYLD gene in a Spanish family with multiple familial trichoepithelioma. Arch Dermatol 143:1209–1210
Kazakov DV, Vanecek T, Zelger B, Carlson JA, Spagnolo DV, Schaller J, Nemcova J, Kacerovska D, Vazmitel M, Sangueza M et al (2011) Multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including CYLD and PTCH gene analysis, of a series of 16 patients. Am J Dermatopathol 33:251–265
Liang YH, Gao M, Sun LD, Liu LJ, Cui Y, Yang S, Fan X, Wang J, Xiao FL, Zhang XJ (2005) Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol 153:1213–1215
Regamey A, Hohl D, Liu JW, Roger T, Kogerman P, Toftgard R, Huber M (2003) The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. J Exp Med 198:1959–1964
Reuven B, Margarita I, Dov H, Ziad K (2013) Multiple trichoepitheliomas associated with a novel heterozygous mutation in the CYLD gene as an adjunct to the histopathological diagnosis. Am J Dermatopathol 35:445–447
Salhi A, Bornholdt D, Oeffner F, Malik S, Heid E, Happle R, Grzeschik KH (2004) Multiple familial trichoepithelioma caused by mutations in the cylindromatosis tumor suppressor gene. Cancer Res 64:5113–5117
Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424:793–796
Wang FX, Yang LJ, Li M, Zhang SL, Zhu XH (2010) A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma. Arch Dermatol Res 302:67–70
Ying ZX, Ma HQ, Liu Y, Xiao SX, Wang YX, Wang GX (2012) A novel mutation of CYLD in a Chinese family with multiple familial trichoepithelioma. J Eur Acad Dermatol Venereol 26:1420–1423
Zhang XJ, Liang YH, He PP, Yang S, Wang HY, Chen JJ, Yuan WT, Xu SJ, Cui, Huang W (2004) Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma. J Invest Dermatol 122:658–664
Zuo YG, Xu Y, Wang B, Liu YH, Qu T, Fang K, Ho MG (2007) A novel mutation of CYLD in a Chinese family with multiple familial trichoepithelioma and no CYLD protein expression in the tumour tissue. Br J Dermatol 157:818–821
Acknowledgments
We are grateful to the patients, their families and volunteers for providing blood samples.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wu, J.W., Xiao, S.X., Huo, J. et al. A novel frameshift mutation in the cylindromatosis (CYLD) gene in a Chinese family with multiple familial trichoepithelioma. Arch Dermatol Res 306, 857–860 (2014). https://doi.org/10.1007/s00403-014-1499-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-014-1499-x