Diverse phenotype of Brooke–Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene

Zhang, Guolong; Huang, Yijin; Yan, Kai-Lin; Li, Wei; Fan, Xing; Liang, Yanhua; Sun, Liangdan; Li, Hui; Zhang, Shumei; Gao, Min; Du, Wenhui; Yang, Sen; Liu, Jing; Zhang, Xuejun

doi:10.1111/j.1600-0625.2006.00501.x

Cited by 27 publications

(35 citation statements)

References 19 publications

(31 reference statements)

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“…All three clinical variants exhibit variable expression among and within affected families; however, the most extreme differences in the manifested phenotypes have been reported for BSS [Bowen et al, 2005;Zhang et al, 2006;Nagy et al, 2013]. The penetrance is high for all three clinical variants and increases with age.…”

Section: Clinical and Diagnostic Relevancementioning

confidence: 97%

“…It is of interest to note that 25% of the identified nonsense mutations 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 9 affect glutamine amino acid residues within the CYLD protein, replacing them with stop codons [Sima et al, 2010;Bignell et al, 2000;Grossmann et al, 2013;Zheng et al, 2004;Chen et al, 2011;Almeida et al, 2008]. Nearly half of the nonsense mutations (40%) are recurrent [Sima et al, 2010;Bignell et al, 2000;Oranje et al, 2008;Bowen et al, 2005;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;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;…”

Section: Variants Of the Cyld Genementioning

confidence: 99%

“…Nearly half of the nonsense mutations (40%) are recurrent [Sima et al, 2010;Bignell et al, 2000;Oranje et al, 2008;Bowen et al, 2005;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;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013;Zheng et al, 2004;Chen et al, 2011]. In general, nonsense mutations -even the same mutation in different individuals -lead to the development of the different clinical variants; thus, nonsense mutations have been associated with the highest phenotypic diversity (Figure 4) [Bignell et al, 2000;Bowen et al, 2005;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;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013].…”

Section: Variants Of the Cyld Genementioning

confidence: 99%

“…BSS, FC and MFT1 were originally described as distinct clinical entities, but due to their overlapping clinical symptoms and their manifestation within the same families, they are now considered as a clinical variants that represent a phenotypic spectrum of a single entity Welch et al, 1968;Young et al, 2006;Oranje et al, 2008]. [Bignell et al, 2000;Bowen et al, 2005;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;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013]. Therefore, it has been hypothesized that BSS, FC and MFT1 are not different disease entities, but represent a phenotypic spectrum of the same disease.…”

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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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Section: Clinical and Diagnostic Relevancementioning

confidence: 97%

Section: Variants Of the Cyld Genementioning

confidence: 99%

Section: Variants Of the Cyld Genementioning

confidence: 99%

mentioning

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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“…Naturally occurring mutations are found in the USP and CAP regions (9). Several nonsynonymous mutations in the coding region of this gene have been linked to familial cylindromatosis (also termed "turban syndrome") as well as to the sporadic Brooke-Spiegler syndrome (5,10,11). CYLD controls chronic inflammation during tumor progression, and its expression is downregulated in melanoma, hepatocellular carcinoma, and colon cancer (12,13).…”

mentioning

confidence: 99%

Tumor Suppressor Cylindromatosis (CYLD) Controls HIV Transcription in an NF-κB-Dependent Manner

Manganaro

Pache

Herrmann

et al. 2014

J Virol

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Characterizing the cellular factors that play a role in the HIV replication cycle is fundamental to fully understanding mechanisms of viral replication and pathogenesis. Whole-genome small interfering RNA (siRNA) screens have identified positive and negative regulators of HIV replication, providing starting points for investigating new cellular factors. We report here that silencing of the deubiquitinase cylindromatosis protein (CYLD), increases HIV infection by enhancing HIV long terminal repeat (LTR)-driven transcription via the NF-B pathway. CYLD is highly expressed in CD4؉ T lymphocytes, monocyte-derived macrophages, and dendritic cells. We found that CYLD silencing increases HIV replication in T cell lines. We confirmed the positive role of CYLD silencing in HIV infection in primary human CD4 ؉ T cells, in which CYLD protein was partially processed upon activation. Lastly, Jurkat T cells latently infected with HIV (JLat cells) were more responsive to phorbol 12-myristate 13-acetate (PMA) reactivation in the absence of CYLD, indicating that CYLD activity could play a role in HIV reactivation from latency. In summary, we show that CYLD acts as a potent negative regulator of HIV mRNA expression by specifically inhibiting NF-Bdriven transcription. These findings suggest a function for this protein in modulating productive viral replication as well as in viral reactivation. IMPORTANCEHIV transcription is regulated by a number of host cell factors. Here we report that silencing of the lysine 63 deubiquitinase CYLD increases HIV transcription in an NF-B-dependent manner. We show that CYLD is expressed in HIV target cells and that its silencing increases HIV infection in transformed T cell lines as well as primary CD4 ؉ T cells. Similarly, reactivation of latent provirus was facilitated in the absence of CYLD. These data suggest that CYLD, which is highly expressed in CD4 ؉ T cells, can control HIV transcription in productive infection as well as during reactivation from latency.

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Tumor Mapping in 2 Large Multigenerational Families With CYLD Mutations

Rajan¹,

Langtry²,

Ashworth³

et al. 2009

Arch Dermatol

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Objective To comprehensively ascertain the extent and severity of clinical features in multiple affected individuals from two large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the three appendageal tumor predisposition syndromes, familial cylindromatosis (FC), Brooke-Spiegler syndrome (BSS), and multiple familial trichoepitheliomas (MFT) known to be associated with such germline mutations. Design Inter- and intra-familial observational study. Setting Tertiary genetic and dermatology referral centre. Participants 32 individuals were recruited from two large multigenerational families with CYLD mutations. Clinical details, history and tumor maps were obtained from all participants whilst 18 were further corroborated with detailed clinical examination. Main outcome measures Severity of tumor density, distribution and histology, associated medical conditions, patient symptoms and impact of disease on quality of life. Results We demonstrate a wide variation in clinical presentation seen in individuals from the same family. In addition, we provide clinical evidence that correlates with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction. Conclusion In view of our findings, we propose that the burden of disease at sites other than the head and neck is underreported in the literature, but impacts greatly on quality of life. The differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counselling even within individuals from the same family. Thus, we suggest an encompassing diagnosis of “CYLD cutaneous syndrome”. Finally, our results relating to the clinical distribution of tumors suggest hormonal factors may play an important role in tumor induction in these patients.

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Diverse phenotype of Brooke–Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene

Cited by 27 publications

References 19 publications

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

Tumor Suppressor Cylindromatosis (CYLD) Controls HIV Transcription in an NF-κB-Dependent Manner

Tumor Mapping in 2 Large Multigenerational Families With CYLD Mutations

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