A Novel Missense Mutation in the CYLD Gene in a Spanish Family With Multiple Familial Trichoepithelioma

España, A.; García-Amigot, Fermín; Aguado, Leyre; García‐Foncillas, Jesús

doi:10.1001/archderm.143.9.1209

Cited by 20 publications

(12 citation statements)

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“…[11][12][13][14][15][16] There are more than 20 germline CYLD mutations reported in MFT. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] An earlier study however suggested the role of another genetic locus on chromosome 9p21 in the etiopathogenesis of MFT. 26 Additionally, occasional studies focused on the PTCH gene 27 on chromosome 9q22.3, inasmuch as PTCH abnormalities had been recorded in sporadic basal cell carcinoma (BCC), the nevoid BCC syndrome, and trichoblastomas (including trichoepitheliomas).…”

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confidence: 99%

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients

Kazakov

Vaněček²,

Zelger³

et al. 2011

The American Journal of Dermatopathology

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Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.

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confidence: 99%

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients

Kazakov

Vaněček²,

Zelger³

et al. 2011

The American Journal of Dermatopathology

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“…Seven families with MFT phenotype that harbour germ-line mutations in CYLD have been reported in the literature. These consist of four missense,11 18 21 22 one insertion,19 one deletion16 and one nonsense2 mutation. In this study, we describe nine additional families with the MFT phenotype in which four were found to have CYLD mutations.…”

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confidence: 99%

CYLD mutations in familial skin appendage tumours

Saggar

Chernoff

Lodha

et al. 2008

Journal of Medical Genetics

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“…Only a quarter (27%) of these are recurrent mutations [Sima et al, 2010;Hu et al, 2003;Grossmann et al, 2013;Saggar et al, 2008;Kazakov et al, 2009]. In general, missense mutations of the CYLD gene have been associated with less phenotypic diversity that other kinds of mutations: three quarters (73%) have been reported in MFT1 only (Figure 4) [Nagy et al, 2012;Zheng et al, 2004;Almeida et al, 2008;Espana et al, 2007;Wang et al, 2010;Zuo et al, 2007]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 Splice-site mutations account for 11% of all mutations (Figure 2).…”

Section: Variants Of the Cyld Genementioning

confidence: 99%

“…Missense mutations of the CYLD gene are more frequently associated only with MFT1 (73%) than the other types of mutations [Sima et al, 2010;Hu et al, 2003;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Kazakov et al, 2009;Nagy et al, 2012;Zheng et al, 2004;Almeida et al, 2008;Espana et al, 2007;Wang et al, 2010;Zuo et al, 2007]. Missense mutations also lead to the development of milder phenotype [Nagy et al, 2012].…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

“…This observation might be explained by the fact that missense mutations are distributed differently than the other types 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 16 of mutations: they are located only between exons 12-20 and not at all in the 5' end. In general, missense mutations are associated with low phenotypic diversity, as the majority of missense mutations result in the MFT1 phenotype [Nagy et al, 2012;Zheng et al, 2004;Almeida et al, 2008;Espana et al, 2007;Wang et al, 2010;Zuo et al, 2007]. Moreover, only 12% of missense mutations are recurrent [Sima et al, 2010;Hu et al, 2003;Grossmann et al, 2013;Saggar et al, 2008;Kazakov et al, 2009].…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

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Phenotype–genotype correlations for clinical variants caused by CYLD mutations

Nagy

Farkas

Kemény

et al. 2015

European Journal of Medical Genetics

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Brooke-Spiegler syndrome (BSS; OMIM 605041) is an autosomal dominant condition characterized by skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. In 1996, the gene locus for BSS was mapped to 16q12-13, and, in 2000, mutations in the cylindromatosis (CYLD) gene were determined to cause BSS, familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma type 1 (MFT1; OMIM 601606). The CYLD gene encodes an enzyme with deubiquitinase activity. To date, a total of 95 different diseases-causing mutations have been published for the CYLD gene. A summary of mutations identified in Hungarian patients and a review of previously published mutations are presented in this update. The majority of the sequence changes are frameshift (48%), nonsense (27%), missense (12%) and splice-site (11%) mutations; however, two in-frame deletions have also been reported Most mutations are located in exons 9-20. Analysis of the identified CYLD gene mutations and the observed BSS, FC and MFT1 clinical phenotypes of the patients revealed significant genotype-phenotype correlations. Elucidation of these genotype-phenotype correlations is critical for the diagnosis of these rare monogenic skin diseases. In addition, characterized correlations may promote the understanding of their mechanisms and may hopefully contribute to the development of future therapeutic modalities.

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A Novel Missense Mutation in the CYLD Gene in a Spanish Family With Multiple Familial Trichoepithelioma

Cited by 20 publications

References 5 publications

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients

Multiple (Familial) Trichoepitheliomas: A Clinicopathological and Molecular Biological Study, Including CYLD and PTCH Gene Analysis, of a Series of 16 Patients

CYLD mutations in familial skin appendage tumours

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

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