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      A novel large deletion of the CYLD gene causes CYLD cutaneous syndrome in a Chinese family

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          Abstract

          Background

          CYLD cutaneous syndrome (CCS; syn. Brooke‐Spiegler syndrome) is a rare autosomal dominant hereditary disease characterized by multiple adnexal skin tumors including cylindromas, spiradenomas, and trichoepitheliomas. More than 100 germline mutations of the cylindromatosis ( CYLD) gene have been reported in CCS and most of them are frameshift mutations or small alterations.

          Methods

          We identified a large, three‐generation Chinese family with CCS, which consisted of 18 living family members, including six affected individuals. To explore the molecular biology of this family, we carried out targeted next‐generation sequencing and Affymetrix CytoScan HD SNP array to analyze the mutation in the CYLD gene.

          Results

          A novel large deletion mutation, NC_000016.9:g.(50826498_50827517)_(50963389‐50967346)del was found in the proband of this family. This deletion results in the loss of a nearly 140 kb fragment of the CYLD gene, spanning exons 17 ~ 20, which represent the coding regions of the ubiquitin‐specific protease domain. Further quantitative polymerase chain reaction proved that all patients and two proband‐related family members carried this large deletion.

          Conclusions

          Our study expands the types of mutations in CCS and will undoubtedly provide valuable information for genetic counseling for families affected by the condition.

          Abstract

          A large, three‐generation Chinese family with CCS, which consisted of 18 living family members, including six affected individuals was identified. We carried out targeted next‐generation sequencing and Affymetrix CytoScan HD SNP array to analyze the mutation in the CYLD gene and a novel large deletion mutation was found.

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          Most cited references18

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          Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB.

          Protein modification by the conjugation of ubiquitin moieties--ubiquitination--plays a major part in many biological processes, including cell cycle and apoptosis. The enzymes that mediate ubiquitin-conjugation have been well-studied, but much less is known about the ubiquitin-specific proteases that mediate de-ubiquitination of cellular substrates. To study this gene family, we designed a collection of RNA interference vectors to suppress 50 human de-ubiquitinating enzymes, and used these vectors to identify de-ubiquitinating enzymes in cancer-relevant pathways. We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD), having no known function, enhances activation of the transcription factor NF-kappaB. We show that CYLD binds to the NEMO (also known as IKKgamma) component of the IkappaB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. We show that this effect can be relieved by aspirin derivatives that inhibit NF-kappaB activity, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.
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            Identification of the familial cylindromatosis tumour-suppressor gene.

            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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              LncRNA GMDS‐AS1 inhibits lung adenocarcinoma development by regulating miR‐96‐5p/CYLD signaling

              Abstract According to the global cancer statistic, lung cancer is one of the most dangerous tumors, which poses a serious threat to human health. Exploration the mechanism of lung cancer and new targeted therapeutic measures is always the hot topic. Long noncoding RNA (lncRNA) is an important factor affecting the development of tumors. However, the research on the mechanism of lncRNA in the progress of lung cancer needs to be further expanded. In this study, we found that the expression of lncRNA GMDS‐AS1 was significantly reduced in lung adenocarcinoma (LUAD) tissues and cells. Upregulated GMDS‐AS1 can significantly inhibit the proliferation of LUAD cells and promote cell apoptosis in vitro and in vivo. The results indicate that GMDS‐AS1 acts as a tumor suppressor gene to affect the development of LUAD. Further studies revealed that GMDS‐AS1 is a target gene of miR‐96‐5p, and GMDS‐AS1 regulates proliferation and apoptosis of LUAD cells in association with miR‐96‐5p. In addition, we also confirmed that CYLD lysine 63 deubiquitinase (CYLD) is also a target gene of miR‐96‐5p. Through various validations, we confirmed that GMDS‐AS1 can act as a ceRNA to upregulate the expression of CYLD by sponging miR‐96‐5p. Moreover, the intervention of GMDS‐AS1/miR‐96‐5p/CYLD network can regulate the proliferation and apoptosis of LUAD cells. In this study, we revealed that the GMDS‐AS1/miR‐96‐5p/CYLD network based on ceRNA mechanism plays an important role in the development of LUAD and provides a new direction and theoretical basis for targeted therapy of LUAD.
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                Author and article information

                Contributors
                lyqdoctor@163.com
                baiyun@chgc.sh.cn
                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                11 August 2020
                October 2020
                : 8
                : 10 ( doiID: 10.1002/mgg3.v8.10 )
                : e1441
                Affiliations
                [ 1 ] Shanghai Skin Disease Hospital Tongji University School of Medicine Shanghai China
                [ 2 ] Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine Wenzhou City China
                Author notes
                [*] [* ] Correspondence

                Yun Bai and Yeqiang Liu, Shanghai Skin Disease Hospital, Tongji University School of Medicine, No. 1278 Baode Road, Shanghai 200443, China.

                Email: baiyun@ 123456chgc.sh.cn (Y. B.) and lyqdoctor@ 123456163.com (Y. L.)

                Author information
                https://orcid.org/0000-0001-9564-8712
                https://orcid.org/0000-0001-8755-2737
                Article
                MGG31441
                10.1002/mgg3.1441
                7549610
                32783365
                07eca40c-38dc-40a4-a3b2-5d2e98205639
                © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 May 2020
                : 05 June 2020
                : 02 July 2020
                Page count
                Figures: 4, Tables: 0, Pages: 7, Words: 7402
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:12.10.2020

                cyld cutaneous syndrome,cyld gene,large deletion,multiple familial trichoepithelioma,mutation

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