4709 lines
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Entry
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- *605018 - CYLD LYSINE-63 DEUBIQUITINASE; CYLD
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605018</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605018">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
|
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000083799;t=ENST00000427738" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=1540" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=605018" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000083799;t=ENST00000427738" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001042355,NM_001042412,NM_001378743,NM_001378744,NM_001378745,NM_001378746,NM_001378747,NM_001378748,NM_001378749,NM_001378750,NM_001378751,NM_001378752,NM_001378753,NM_001378754,NM_001378755,NM_015247,NR_166071,XM_047433656,XM_047433658,XM_047433659,XM_047433660,XM_047433661,XM_047433662,XM_047433663,XM_047433664,XR_007064858" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001378743" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=605018" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05427&isoform_id=05427_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/CYLD" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/6841352,8250236,14165258,15214434,50833762,51316104,109637774,109637776,119603174,119603175,119603176,119603177,119603178,119603179,158259411,193785836,193786510,296062662,296062664,300862796,300862797,1819229346,1819229353,1819229355,1819229358,1819229360,1819229367,1819229369,1819229371,1819229373,1819229382,1819229387,1819291721,1819291724,2217304784,2217304786,2217304788,2217304790,2217304792,2217304794,2217304796,2217304798,2462547721,2462547723,2462547725,2462547727,2462547729,2462547731,2462547733,2462547735" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q9NQC7" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Gene Info</div>
|
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</div>
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=1540" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000083799;t=ENST00000427738" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=CYLD" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=CYLD" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+1540" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/CYLD" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:1540" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1540" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000427738.8&hgg_start=50742086&hgg_end=50801935&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:2584" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2584" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cyld" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605018[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605018[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000083799" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=CYLD" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=CYLD" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CYLD" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CYLD&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA27084" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:2584" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0032210.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1921506" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/CYLD#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1921506" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1540/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1540" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00009594;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-061108-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1540" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=CYLD&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 211710004, 403825008, 703531009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
605018
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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CYLD LYSINE-63 DEUBIQUITINASE; CYLD
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CYLD GENE<br />
|
|
CYLD1<br />
|
|
KIAA0849
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CYLD" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CYLD</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/16/430?start=-3&limit=10&highlight=430">16q12.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:50742086-50801935&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:50,742,086-50,801,935</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=619132,605041,132700,601606" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/430?start=-3&limit=10&highlight=430">
|
|
16q12.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619132"> 619132 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</span>
|
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The tumor suppressor CYLD is a deubiquitinating enzyme that removes lys63-linked ubiquitin chains and acts as a negative regulator of NF-kappa-B (see <a href="/entry/164011">164011</a>) signaling. CYLD deubiquitinates several NF-kappa-B regulators, including TRAF2 (<a href="/entry/601895">601895</a>), TRAF6 (<a href="/entry/602355">602355</a>), and NEMO (IKBKG; <a href="/entry/300248">300248</a>), as well as BCL3 (<a href="/entry/109560">109560</a>), a member of the NF-kappa-B family of transcription factors (<a href="#8" class="mim-tip-reference" title="Hutti, J. E., Shen, R. R., Abbott, D. W., Zhou, A. Y., Sprott, K. M., Asara, J. M., Hahn, W. C., Cantley, L. C. <strong>Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon promotes cell transformation.</strong> Molec. Cell 34: 461-472, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19481526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19481526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19481526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2009.04.031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19481526">Hutti et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19481526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By positional cloning, <a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> isolated a gene on chromosome 16q, termed CYLD, responsible for familial cylindromatosis (<a href="/entry/132700">132700</a>). The full-length cDNA encodes a deduced 956-amino acid protein, and a splice variant lacking exon 7 encodes a deduced 953-amino acid protein. Likely orthologs were identified in Drosophila melanogaster and C. elegans. The CYLD protein has 3 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 (see <a href="/entry/603090">603090</a>). RT-PCR detected expression of CYLD in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary, and lung. The splice variant lacking exon 7 was found in all tissues in which CYLD was expressed except kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Brummelkamp, T. R., Nijman, S. M. B., Dirac, A. M. G., Bernards, R. <strong>Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappa-B.</strong> Nature 424: 797-801, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917690</a>] [<a href="https://doi.org/10.1038/nature01811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12917690">Brummelkamp et al. (2003)</a> designed a collection of RNA interference vectors to suppress 50 human deubiquitinating enzymes and used these vectors to identify deubiquitinating enzymes in cancer-relevant pathways. They demonstrated that inhibition of CYLD enhances activation of the transcription factor NF-kappa-B. They showed that CYLD binds to the NEMO component of the I-kappa-B kinase (IKK) complex, and appears to regulate its activity through deubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increased resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. <a href="#4" class="mim-tip-reference" title="Brummelkamp, T. R., Nijman, S. M. B., Dirac, A. M. G., Bernards, R. <strong>Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappa-B.</strong> Nature 424: 797-801, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917690</a>] [<a href="https://doi.org/10.1038/nature01811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12917690">Brummelkamp et al. (2003)</a> further demonstrated that this effect can be relieved by aspirin derivatives that inhibit NF-kappa-B activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12917690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#21" class="mim-tip-reference" title="Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G. <strong>CYLD is a deubiquitinating enzyme that negatively regulates NF-kappa-B activation by TNFR family members.</strong> Nature 424: 793-796, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917689</a>] [<a href="https://doi.org/10.1038/nature01803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12917689">Trompouki et al. (2003)</a> identified CYLD as a deubiquitinating enzyme that negatively regulates activation of NF-kappa-B by specific tumor necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlated with tumorigenesis. CYLD inhibits activation of NF-kappa-B by the TNFR family members CD40 (<a href="/entry/109535">109535</a>), XEDAR (<a href="/entry/300276">300276</a>), and EDAR (<a href="/entry/604095">604095</a>) in a manner that depends on deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappa-B. The inhibition of NF-kappa-B activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6. <a href="#21" class="mim-tip-reference" title="Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G. <strong>CYLD is a deubiquitinating enzyme that negatively regulates NF-kappa-B activation by TNFR family members.</strong> Nature 424: 793-796, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917689</a>] [<a href="https://doi.org/10.1038/nature01803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12917689">Trompouki et al. (2003)</a> concluded that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappa-B that is required for appropriate cellular homeostasis of skin appendages. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12917689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Kovalenko, A., Chable-Bessia, C., Cantarella, G., Israel, A., Wallach, D., Courtois, G. <strong>The tumour suppressor CYLD negatively regulates NF-kappa-B signalling by deubiquitination.</strong> Nature 424: 801-805, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917691</a>] [<a href="https://doi.org/10.1038/nature01802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12917691">Kovalenko et al. (2003)</a> showed that CYLD interacts with NEMO and TRAF2. CYLD has a deubiquitinating activity that is directed toward the non-lys48-linked polyubiquitin chains and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12917691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By yeast 2-hybrid screening with CYLD as bait, followed by far Western blot and coimmunoprecipitation analyses, <a href="#16" class="mim-tip-reference" title="Regamey, A., Hohl, D., Liu, J. W., Roger, T., Kogerman, P., Toftgard, R., Huber, M. <strong>The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappa-B activation by tumor necrosis factor.</strong> J. Exp. Med. 198: 1959-1964, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676304</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14676304[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20031187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676304">Regamey et al. (2003)</a> found that the C terminus of TRIP (<a href="/entry/605958">605958</a>) interacted with the central domain of CYLD. CYLD downregulated TNF (<a href="/entry/191160">191160</a>)-induced NFKB activation, and this downregulation was dependent on CYLD-TRIP interaction and the deubiquitinating activity of CYLD. <a href="#16" class="mim-tip-reference" title="Regamey, A., Hohl, D., Liu, J. W., Roger, T., Kogerman, P., Toftgard, R., Huber, M. <strong>The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappa-B activation by tumor necrosis factor.</strong> J. Exp. Med. 198: 1959-1964, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676304</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14676304[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20031187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14676304">Regamey et al. (2003)</a> suggested that cylindromas might arise through constitutive NFKB activation leading to hyperproliferation and tumor growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A., Fassler, R. <strong>Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappa-B signaling.</strong> Cell 125: 665-677, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713561</a>] [<a href="https://doi.org/10.1016/j.cell.2006.03.041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713561">Massoumi et al. (2006)</a> found that mice lacking Cyld were prone to chemically-induced skin tumors. They showed that Cyld inhibited tumor formation and keratinocyte proliferation by removing lys63-linked polyubiquitin chains from Bcl3, which resulted in retention of Bcl3 in the cytoplasm. In Cyld-deficient keratinocytes, Bcl3 accumulated in the nucleus, activated the NF-kappa-B subunits p50 (NFKB1; <a href="/entry/164011">164011</a>) and p52 (NFKB2; <a href="/entry/164012">164012</a>), and induced transcription of NF-kappa-B target genes, such as cyclin D1 (CCND1; <a href="/entry/168461">168461</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#20" class="mim-tip-reference" title="Stegmeier, F., Sowa, M. E., Nalepa, G., Gygi, S. P., Harper, J. W., Elledge, S. J. <strong>The tumor suppressor CYLD regulates entry into mitosis.</strong> Proc. Nat. Acad. Sci. 104: 8869-8874, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17495026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17495026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17495026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0703268104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17495026">Stegmeier et al. (2007)</a> showed that CYLD was required for timely entry into mitosis in human cell lines. CYLD localized to microtubules in interphase and to the midbody during telophase, and its level decreased as cells exited mitosis. <a href="#20" class="mim-tip-reference" title="Stegmeier, F., Sowa, M. E., Nalepa, G., Gygi, S. P., Harper, J. W., Elledge, S. J. <strong>The tumor suppressor CYLD regulates entry into mitosis.</strong> Proc. Nat. Acad. Sci. 104: 8869-8874, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17495026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17495026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17495026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0703268104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17495026">Stegmeier et al. (2007)</a> identified the protein kinase PLK1 (<a href="/entry/602098">602098</a>) as a potential target of CYLD in the regulation of mitotic entry based on their physical interaction and similar loss-of-function and overexpression phenotypes. They concluded that, in addition to suppressing tumor formation through apoptosis regulation, CYLD can promote tumor formation by enhancing mitotic entry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17495026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a proteomic and bioinformatic approach, <a href="#8" class="mim-tip-reference" title="Hutti, J. E., Shen, R. R., Abbott, D. W., Zhou, A. Y., Sprott, K. M., Asara, J. M., Hahn, W. C., Cantley, L. C. <strong>Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon promotes cell transformation.</strong> Molec. Cell 34: 461-472, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19481526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19481526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19481526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2009.04.031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19481526">Hutti et al. (2009)</a> identified a number of putative substrates for phosphorylation by IKK-epsilon (IKBKE; <a href="/entry/605048">605048</a>), including ser418 of CYLD. CYLD was phosphorylated by IKK-epsilon on ser418 in vitro and in vivo. Phosphorylation of CYLD at ser418 decreased its deubiquitinase activity and was necessary for IKK-epsilon-dependent transformation in NIH-3T3 mouse fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19481526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="O'Donnell, M. A., Perez-Jimenez, E., Oberst, A., Ng, A., Massoumi, R., Xavier, R., Green, D. R., Ting, A. T. <strong>Caspase 8 inhibits programmed necrosis by processing CYLD.</strong> Nature Cell Biol. 13: 1437-1442, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22037414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22037414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22037414[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ncb2362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22037414">O'Donnell et al. (2011)</a> identified CYLD as the key substrate for CASP8 (<a href="/entry/601763">601763</a>) to inhibit programmed necrosis. Analysis with mouse embryonic fibroblasts (MEFs) showed that Cyld was essential for necrotic cell death. Upon TNF stimulation, CASP8 proteolytically cleaved CYLD at the carboxyl end of asp215 to generate a survival signal and block necrosis in various cell types. In contrast, loss of CASP8 blocked proteolytic degradation of CYLD and triggered programmed necrosis. Mutation of asp215 was sufficient to convert the prosurvival response to TNF-induced necrosis, even in the presence of CASP8. Cleavage by CASP8 removed the deubiquitinase domain of CYLD and prevented CYLD from deubiquitinating downstream molecules, such as RIPK1 (<a href="/entry/603453">603453</a>), thereby affecting its interactions with signaling partners and resulting in a switch from a prosurvival NEMO-RIPK1 complex to a pronecrotic RIPK1-FADD (<a href="/entry/602457">602457</a>) complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22037414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p>By database analysis, <a href="#22" class="mim-tip-reference" title="Yang, S., Yu, F., Yang, M., Ni, H., Bu, W., Yin, H., Yang, J., Wang, W., Zhai, D., Wu, X., Ma, N., Li, T., and 9 others. <strong>CYLD maintains retinal homeostasis by deubiquitinating ENKD1 and promoting the phagocytosis of photoreceptor outer segments.</strong> Adv. Sci. (Weinh) 11: e2404067, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39373352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39373352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39373352[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/advs.202404067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39373352">Yang et al. (2024)</a> showed that the level of CYLD in human retina declined with age. Analysis of Cyld -/- mice, which displayed age-related retinal degeneration, revealed that Cyld played a crucial role in retinal homeostasis by enhancing the phagocytic activity of RPE cells. Analysis of primary RPE cells isolated from Cyld -/- mouse retina showed that Cyld promoted RPE-mediated photoreceptor outer segment (POS) phagocytosis in a deubiquitinase-dependent manner. Cyld interacted with Enkd1 (<a href="/entry/621119">621119</a>), and the interaction was mediated by the ubiquitin-specific protease (USP) domain of Cyld and the amino acids 91 to 250 of Enkd1. Enkd1 was also required for POS phagocytosis, and interaction with Cyld deubiquitinated Enkd1 at lys141 and lys242. Knockdown analysis revealed that Cyld was required for formation of microvilli in RPE cells, as Cyld deubiquitinated Enkd1 at lys141 and lys242 and promoted Enkd1 interaction with Ezrin (EZR; <a href="/entry/123900">123900</a>), leading to enhanced Ezrin microvillar localization and POS phagocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39373352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p><a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> demonstrated that the CYLD gene contains 20 exons (the smallest being 9 bp), of which the first 3 are untranslated, and extends over approximately 56 kb of genomic DNA. Exon 3 (in the 5-prime untranslated region) and the 9-bp exon 7 (which is coding) show alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> mapped the CYLD gene to chromosome 16q12-q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Cylindromatosis, Trichoepithelioma, and Brooke-Spiegler Syndrome</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> detected 21 different germline mutations in the CYLD gene in 21 families with familial cylindromatosis (<a href="/entry/132700">132700</a>), and 6 different somatic mutations in 1 patient with sporadic disease and 5 patients with familial disease (see, e.g., <a href="#0001">605018.0001</a>-<a href="#0002">605018.0002</a>). All the mutations predicted truncated proteins: 9 caused translational frameshifts due to small insertions or deletions; 9 were base substitutions that directly generated translational termination codons; and 3 altered splice sites. <a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> noted that approximately 70% of familial cylindromas have exhibited loss of heterozygosity (LOH) in the 16q region and that the allele lost was always the wildtype allele. This pattern of loss is characteristic of a tumor suppressor gene, i.e., a recessive oncogene. Loss of heterozygosity on chromosome 16q has also been found in many sporadic cylindromas (<a href="#1" class="mim-tip-reference" title="Biggs, P. J., Chapman, P., Lakhani, S. R., Burn, J., Stratton, M. R. <strong>The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas.</strong> Oncogene 12: 1375-1377, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8649842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8649842</a>]" pmid="8649842">Biggs et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10835629+8649842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 67-year-old man with Brooke-Spiegler syndrome (BRSS; <a href="/entry/605041">605041</a>), <a href="#19" class="mim-tip-reference" title="Scheinfeld, N., Hu, G., Gill, M., Austin, C., Celebi, J. T. <strong>Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome.</strong> Clin. Exp. Dermatol. 28: 539-541, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12950348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12950348</a>] [<a href="https://doi.org/10.1046/j.1365-2230.2003.01344.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12950348">Scheinfeld et al. (2003)</a> identified a heterozygous frameshift mutation in the CYLD gene (<a href="#0004">605018.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12950348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 2 unrelated Chinese families with multiple familial trichoepithelioma-1 (MFT1; <a href="/entry/601606">601606</a>), <a href="#11" class="mim-tip-reference" title="Liang, Y. H., Gao, M., Sun, L. D., Liu, L. J., Cui, Y., Yang, S., Fan, X., Wang, J., Xiao, F. L., Zhang, X. J. <strong>Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China.</strong> Brit. J. Derm. 153: 1213-1215, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16307661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16307661</a>] [<a href="https://doi.org/10.1111/j.1365-2133.2005.06960.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16307661">Liang et al. (2005)</a> identified 2 different heterozygous mutations in the CYLD gene (<a href="#0005">605018.0005</a> and <a href="#0006">605018.0006</a>, respectively). One was a frameshift and the other a splice site, suggesting a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16307661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a Turkish family with multiple familial trichoepithelioma, <a href="#7" class="mim-tip-reference" title="Hu, G., Onder, M., Gill, M., Aksakal, B., Oztas, M., Gurer, M. A., Celebi, J. T. <strong>A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome.</strong> J. Invest. Derm. 121: 732-734, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14632188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14632188</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2003.12514.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14632188">Hu et al. (2003)</a> identified a heterozygous missense mutation in the CYLD gene (E747G; <a href="#0007">605018.0007</a>). <a href="#7" class="mim-tip-reference" title="Hu, G., Onder, M., Gill, M., Aksakal, B., Oztas, M., Gurer, M. A., Celebi, J. T. <strong>A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome.</strong> J. Invest. Derm. 121: 732-734, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14632188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14632188</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2003.12514.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14632188">Hu et al. (2003)</a> noted that the phenotype of most of the affected individuals in this family resembled MFT1, but 1 patient had cylindromas, suggesting BRSS. The findings suggested that BRSS and MFT1 represent phenotypic variability of a single entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14632188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Young, A. L., Kellermayer, R., Szigeti, R., Teszas, A., Azmi, S., Celebi, J. T. <strong>CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes.</strong> Clin. Genet. 70: 246-249, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922728</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00667.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922728">Young et al. (2006)</a> identified a heterozygous nonsense mutation in the CYLD gene (R936X; <a href="#0008">605018.0008</a>) in a 73-year-old man with cylindromatosis and turban tumor syndrome and in his 2 children with multiple familial trichoepithelioma without cylindromas. The findings suggested that the 2 disorders represent phenotypic variation of a single genetic defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Saggar, S., Chernoff, K. A., Lodha, S., Horev, L., Kohl, S., Honjo, R. S., Brandt, H. R. C., Hartmann, K., Celebi, J. T. <strong>CYLD mutations in familial skin appendage tumours. (Letter)</strong> J. Med. Genet. 45: 298-302, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234730</a>] [<a href="https://doi.org/10.1136/jmg.2007.056127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234730">Saggar et al. (2008)</a> performed genetic analysis of 25 probands with familial skin appendage tumors. In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BRSS, 100% for FC, and 44% for MFT1. The majority of the mutations resulted in truncated proteins, and all mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal any correlations. <a href="#18" class="mim-tip-reference" title="Saggar, S., Chernoff, K. A., Lodha, S., Horev, L., Kohl, S., Honjo, R. S., Brandt, H. R. C., Hartmann, K., Celebi, J. T. <strong>CYLD mutations in familial skin appendage tumours. (Letter)</strong> J. Med. Genet. 45: 298-302, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234730</a>] [<a href="https://doi.org/10.1136/jmg.2007.056127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234730">Saggar et al. (2008)</a> concluded that the 3 disorders represent phenotypic variation of a single disease entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18234730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Nasti, S., Pastorino, L., Bruno, W., Gargiulo, S., Battistuzzi, L., Zavattaro, E., Leigheb, G., De Francesco, V., Tulli, A., Mari, F., Biancheri Scarra, G., Ghiorzo, P. <strong>Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. (Letter)</strong> Clin. Genet. 76: 481-485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807742</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01259.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19807742">Nasti et al. (2009)</a> identified 5 different truncating or splice site mutations in the CYLD gene (see, e.g., <a href="#0009">605018.0009</a>-<a href="#0011">605018.0011</a>) in 5 Italian probands with cylindromatosis or Brooke-Spiegler syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 8</em></strong></p><p>
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In 5 affected individuals from a large multigenerational family of European Australian descent (Aus-12) with frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8; <a href="/entry/619132">619132</a>), <a href="#6" class="mim-tip-reference" title="Dobson-Stone, C., Luty, A. A., Thompson, E. M., Blumbergs, P., Brooks, W. S., Short, C. L., Field, C. D., Panegyres, P. K., Hecker, J., Solski, J. A., Blair, I. P., Fullerton, J. M., Halliday, G. M., Schofield, P. R., Kwok, J. B. J. <strong>Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.</strong> Acta Neuropath. 125: 523-533, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23338750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23338750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23338750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-013-1078-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23338750">Dobson-Stone et al. (2013)</a> and <a href="#5" class="mim-tip-reference" title="Dobson-Stone, C., Hallupp, M., Shahheydari, H., Ragagnin, A. M. G., Chatterton, Z., Carew-Jones, F., Shepherd, C. E., Stefen, H., Paric, E., Fath, T., Thompson, E. M., Blumbergs, P., and 28 others. <strong>CYLD is a causative gene for frontotemporal dementia-amyotrophic lateral sclerosis.</strong> Brain 143: 783-799, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32185393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32185393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32185393[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32185393">Dobson-Stone et al. (2020)</a> identified a heterozygous missense mutation in the CYLD gene (M719V; <a href="#0012">605018.0012</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. It was not present in several public databases, including gnomAD. Transfection of primary mouse cortical neurons with mutant M719V CYLD resulted in an increased proportion of neurons with cytoplasmic TDP43 (<a href="/entry/605078">605078</a>) staining (55%) compared to cells transfected with wildtype CYLD (34%). The mutation also altered axonal morphology, leading to a decrease in axonal length. Additional in vitro cellular studies showed that the M719V mutation resulted in increased K63 deubiquitinase activity, enhanced inhibition of NFKB, and impaired autophagosome fusion with lysosomes compared to wildtype, indicating a gain-of-function effect. The authors noted that other disorders associated the CYLD mutations result in a loss of function. CYLD was found to directly interact with TBK1 (<a href="/entry/604834">604834</a>), OPTN (<a href="/entry/602432">602432</a>), and SQSTM1 (<a href="/entry/601530">601530</a>), all of which are implicated in autophagy and, when mutated, are causative of FTD or ALS. The report thus identified another molecular mechanism by which impaired autophagy can result in a neurodegenerative disorder. CYLD mutations were not found in several cohorts of ALS and FTD patients comprising several thousand individuals, suggesting that it is a rare cause of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23338750+32185393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#17" class="mim-tip-reference" title="Reiley, W. W., Zhang, M., Jin, W., Losiewicz, M., Donohue, K. B., Norbury, C. C., Sun, S.-C. <strong>Regulation of T cell development by the deubiquitinating enzyme CYLD.</strong> Nature Immun. 7: 411-417, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501569</a>] [<a href="https://doi.org/10.1038/ni1315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501569">Reiley et al. (2006)</a> generated Cyld -/- mice. Activation of Nfkb through Toll-like receptors (e.g., TLR4; <a href="/entry/603030">603030</a>) and Tnf receptors was normal in Cyld -/- mice, but thymocyte development was impaired. Immunoblot analysis showed defective tyrosine phosphorylation of Zap70 (<a href="/entry/176947">176947</a>) and Lat (<a href="/entry/602354">602354</a>) in Cyld -/- thymocytes. Cyld failed to physically interact with Lck (<a href="/entry/153390">153390</a>) in Cyld -/- thymocytes, and Lck was not recruited to Zap70. Catalytically inactive CYLD failed to deubiquitinate LCK in human embryonic kidney cells. <a href="#17" class="mim-tip-reference" title="Reiley, W. W., Zhang, M., Jin, W., Losiewicz, M., Donohue, K. B., Norbury, C. C., Sun, S.-C. <strong>Regulation of T cell development by the deubiquitinating enzyme CYLD.</strong> Nature Immun. 7: 411-417, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501569</a>] [<a href="https://doi.org/10.1038/ni1315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501569">Reiley et al. (2006)</a> concluded that CYLD physically interacts with LCK, promotes its recruitment to ZAP70, removes polyubiquitin chains from LCK, and regulates maturation of CD4-positive and CD8-positive single-positive thymocytes and peripheral T cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16501569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Jin, W., Chang, M., Paul, E. M., Babu, G., Lee, A. J., Reiley, W., Wright, A., Zhang, M., You, J., Sun, S.-C. <strong>Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.</strong> J. Clin. Invest. 118: 1858-1866, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18382763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18382763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18382763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI34257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18382763">Jin et al. (2008)</a> observed that Cyld -/- mice developed severe osteoporosis, which was due to aberrant osteoclast differentiation. Cultured osteoclast precursors derived from Cyld -/- mice were hyperresponsive to Rankl (TNFSF11; <a href="/entry/602642">602642</a>)-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. In wildtype preosteoclasts, Cyld was upregulated during Rankl-induced differentiation, and Cyld negatively regulated Rank (TNFRSF11A; <a href="/entry/603499">603499</a>) signaling by inhibiting Traf6 ubiquitination and downstream signaling events. Cyld interacted physically with the signaling adaptor p62 (SQSTM1; <a href="/entry/601530">601530</a>) and thereby was recruited to Traf6. <a href="#9" class="mim-tip-reference" title="Jin, W., Chang, M., Paul, E. M., Babu, G., Lee, A. J., Reiley, W., Wright, A., Zhang, M., You, J., Sun, S.-C. <strong>Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.</strong> J. Clin. Invest. 118: 1858-1866, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18382763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18382763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18382763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI34257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18382763">Jin et al. (2008)</a> concluded that CYLD is a negative regulator of osteoclastogenesis via the p62/TRAF6 signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18382763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="mim-changed mim-change"><p><a href="#22" class="mim-tip-reference" title="Yang, S., Yu, F., Yang, M., Ni, H., Bu, W., Yin, H., Yang, J., Wang, W., Zhai, D., Wu, X., Ma, N., Li, T., and 9 others. <strong>CYLD maintains retinal homeostasis by deubiquitinating ENKD1 and promoting the phagocytosis of photoreceptor outer segments.</strong> Adv. Sci. (Weinh) 11: e2404067, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39373352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39373352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39373352[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/advs.202404067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="39373352">Yang et al. (2024)</a> found that Cyld -/- mice displayed age-related retinal degeneration. Analysis of primary RPE cells isolated from Cyld -/- mouse retina showed that Cyld promoted RPE-mediated photoreceptor outer segment phagocytosis in a deubiquitinase-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39373352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p></div>
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<p>In affected members of 2 presumably unrelated families with cylindromatosis (<a href="/entry/132700">132700</a>), <a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> identified a heterozygous G-to-A transition in the CYLD gene in the first position of a canonical splice donor site. Haplotype analysis indicated a common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908388 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908388;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005565 OR RCV000120624 OR RCV002281697" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005565, RCV000120624, RCV002281697" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005565...</a>
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<p>In 2 unrelated families with cylindromatosis (<a href="/entry/132700">132700</a>), <a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> identified a heterozygous 2272C-T transition in the CYLD gene, resulting in an arg758-to-ter (R758X) substitution. These were presumably independent mutations because the mutation was located on different haplotypes in the 2 families. The same R758X mutation was found as the 'second hit' (somatic mutation) in a familial cylindroma. Therefore, this mutation, which is at a CpG dinucleotide, appeared to have arisen on 3 separate occasions, whereas all other CYLD mutations detected by <a href="#2" class="mim-tip-reference" title="Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others. <strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong> Nature Genet. 25: 160-165, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835629</a>] [<a href="https://doi.org/10.1038/76006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835629">Bignell et al. (2000)</a> had arisen only once. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 CYLINDROMATOSIS, FAMILIAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597088499 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597088499;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597088499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597088499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005566 OR RCV000005567" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005566, RCV000005567" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005566...</a>
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<p>In affected members of a German family with familial cylindromatosis (<a href="/entry/132700">132700</a>), <a href="#15" class="mim-tip-reference" title="Poblete Gutierrez, P. P., Eggermann, T., Holler, D., Jugert, F. K., Beermann, T., Grussendorf-Conen, E.-I., Zerres, K., Merk, H. F., Frank, J. <strong>Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages.</strong> J. Invest. Derm. 119: 527-531, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12190880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12190880</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2002.01839.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12190880">Poblete Gutierrez et al. (2002)</a> identified a heterozygous 1-bp deletion (2253delG) in the CYLD gene, resulting in a frameshift and premature termination. Two individuals had cylindromas, whereas a third had both cylindromas and trichoepitheliomas, suggesting Brooke-Spiegler syndrome (<a href="/entry/605041">605041</a>) and demonstrating intrafamilial and intraindividual phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12190880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 BROOKE-SPIEGLER SYNDROME</strong>
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CYLD, 1-BP DEL, 2172A
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005568" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005568" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005568</a>
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<p>In a 67-year-old man with Brooke-Spiegler syndrome (<a href="/entry/605041">605041</a>), <a href="#19" class="mim-tip-reference" title="Scheinfeld, N., Hu, G., Gill, M., Austin, C., Celebi, J. T. <strong>Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome.</strong> Clin. Exp. Dermatol. 28: 539-541, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12950348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12950348</a>] [<a href="https://doi.org/10.1046/j.1365-2230.2003.01344.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12950348">Scheinfeld et al. (2003)</a> identified a heterozygous 1-bp deletion (2172delA) in exon 16 of the CYLD gene, resulting in a frameshift and premature termination. The patient had multiple disfiguring facial papules and painful scalp nodules histologically classified predominantly as cylindromas and spiradenomas, but also including epidermoid inclusion cyst, and basal cell carcinoma. His father and sister were similarly affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12950348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1</strong>
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CYLD, 2-BP DEL, 2241AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597085967 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597085967;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597085967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597085967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005569</a>
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<p>In affected members of a large Chinese family with multiple trichoepithelioma-1 (<a href="/entry/601606">601606</a>), <a href="#11" class="mim-tip-reference" title="Liang, Y. H., Gao, M., Sun, L. D., Liu, L. J., Cui, Y., Yang, S., Fan, X., Wang, J., Xiao, F. L., Zhang, X. J. <strong>Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China.</strong> Brit. J. Derm. 153: 1213-1215, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16307661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16307661</a>] [<a href="https://doi.org/10.1111/j.1365-2133.2005.06960.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16307661">Liang et al. (2005)</a> identified a heterozygous 2-bp deletion (2241delAG) in the CYLD gene, resulting in a frameshift and premature termination of the protein at codon 763 prior to a catalytic domain of ubiquitin C-terminal hydrolase. None of the patients had cylindromas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16307661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1</strong>
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CYLD, IVS12AS, T-G, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597058708 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597058708;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597058708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597058708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005570" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005570" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005570</a>
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<p>In affected members of a large Chinese family with multiple trichoepithelioma-1 (<a href="/entry/601606">601606</a>), <a href="#11" class="mim-tip-reference" title="Liang, Y. H., Gao, M., Sun, L. D., Liu, L. J., Cui, Y., Yang, S., Fan, X., Wang, J., Xiao, F. L., Zhang, X. J. <strong>Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China.</strong> Brit. J. Derm. 153: 1213-1215, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16307661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16307661</a>] [<a href="https://doi.org/10.1111/j.1365-2133.2005.06960.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16307661">Liang et al. (2005)</a> identified a heterozygous T-to-G transversion in intron 12, thus preventing proper splicing of the transcript. None of the patients had cylindromas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16307661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1</strong>
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BROOKE-SPIEGLER SYNDROME, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908389;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005571 OR RCV000005572" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005571, RCV000005572" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005571...</a>
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<p>In affected members of a Turkish family with multiple trichoepithelioma-1 (<a href="/entry/601606">601606</a>), <a href="#7" class="mim-tip-reference" title="Hu, G., Onder, M., Gill, M., Aksakal, B., Oztas, M., Gurer, M. A., Celebi, J. T. <strong>A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome.</strong> J. Invest. Derm. 121: 732-734, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14632188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14632188</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2003.12514.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14632188">Hu et al. (2003)</a> identified a heterozygous 2240A-G transition in exon 16 of the CYLD gene, resulting in a glu474-to-gly (E747G) substitution. All of the affected individuals presented with multiple trichoepitheliomas, except for 1 patient who had cylindromas on the scalp, suggesting Brooke-Spiegler syndrome (<a href="/entry/605041">605041</a>). The findings indicated that MFT1 and BRSS may be variable manifestations of a single disease entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14632188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908390 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908390;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908390?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005573 OR RCV000005574 OR RCV000005575 OR RCV002496269 OR RCV005089180" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005573, RCV000005574, RCV000005575, RCV002496269, RCV005089180" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005573...</a>
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<p>In a 73-year-old man with cylindromatosis and turban tumor syndrome (<a href="/entry/132700">132700</a>), <a href="#23" class="mim-tip-reference" title="Young, A. L., Kellermayer, R., Szigeti, R., Teszas, A., Azmi, S., Celebi, J. T. <strong>CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes.</strong> Clin. Genet. 70: 246-249, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922728</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00667.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922728">Young et al. (2006)</a> identified a heterozygous 2806C-T transition in the CYLD gene, resulting in an arg936-to-ter (R936X) substitution. His 2 children, who also carried the mutation, had multiple familial trichoepithelioma-1 (<a href="/entry/601606">601606</a>) without cylindromas. The findings suggested that the 2 disorders represent phenotypic variation of a single genetic defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bowen, S., Gill, M., Lee, D. A., Fisher, G., Geronemus, R. G., Vazquez, M. E., Celebi, J. T., Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma. <strong>lack of genotype-phenotype correlation.</strong> J. Invest. Derm. 124: 919-920, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15854031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15854031</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2005.23688.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15854031">Bowen et al. (2005)</a> identified a heterozygous R936X mutation in a Canadian woman with Brooke-Spiegler syndrome (<a href="/entry/605041">605041</a>) who had both cylindroma and trichoepithelioma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15854031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1596971597 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1596971597;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1596971597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1596971597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005576" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005576" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005576</a>
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<p>In a 46-year-old Italian man with a mild form of cylindromatosis (<a href="/entry/132700">132700</a>), <a href="#13" class="mim-tip-reference" title="Nasti, S., Pastorino, L., Bruno, W., Gargiulo, S., Battistuzzi, L., Zavattaro, E., Leigheb, G., De Francesco, V., Tulli, A., Mari, F., Biancheri Scarra, G., Ghiorzo, P. <strong>Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. (Letter)</strong> Clin. Genet. 76: 481-485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807742</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01259.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19807742">Nasti et al. (2009)</a> identified a heterozygous 1-bp duplication (561dupT) in exon 5 of the CYLD gene, predicted to result in a frameshift and premature termination. The mutation occurred toward the N terminus of the protein in the first cytoskeleton-associated protein glycine-rich (CAP-GLY) domain, which is responsible for the interaction of CYLD with microtubules. He began developing numerous small nodules on his scalp and thorax starting at the age of 42. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 BROOKE-SPIEGLER SYNDROME</strong>
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CYLD, 1-BP DUP, 1392T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1597052041 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1597052041;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1597052041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1597052041" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005577</a>
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<p>In an Italian mother and son with Brooke-Spiegler syndrome (BRSS; <a href="/entry/605041">605041</a>), <a href="#13" class="mim-tip-reference" title="Nasti, S., Pastorino, L., Bruno, W., Gargiulo, S., Battistuzzi, L., Zavattaro, E., Leigheb, G., De Francesco, V., Tulli, A., Mari, F., Biancheri Scarra, G., Ghiorzo, P. <strong>Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. (Letter)</strong> Clin. Genet. 76: 481-485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807742</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01259.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19807742">Nasti et al. (2009)</a> identified a heterozygous 1-bp duplication (1392dupT) in exon 10 of the CYLD gene, predicted to result in a frameshift and premature termination. The 79-year-old mother began developing skin lesions at age 16. She had severe scalp involvement. Most were cylindromas, some with combined features of cylindroma and spiradenoma, and many smaller nodules were trichoepitheliomas. She also had a cutaneous carcinosarcoma on the trunk; these features were consistent with BRSS. Her 54-year-old son had 7 cylindromas and 6 basal cell carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2151015263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2151015263;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2151015263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs2151015263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005578" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005578" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005578</a>
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<p>In a 52-year-old Italian man with cylindromatosis (<a href="/entry/132700">132700</a>), <a href="#13" class="mim-tip-reference" title="Nasti, S., Pastorino, L., Bruno, W., Gargiulo, S., Battistuzzi, L., Zavattaro, E., Leigheb, G., De Francesco, V., Tulli, A., Mari, F., Biancheri Scarra, G., Ghiorzo, P. <strong>Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. (Letter)</strong> Clin. Genet. 76: 481-485, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807742</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01259.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19807742">Nasti et al. (2009)</a> identified a heterozygous 4-bp deletion (1950-1delGATA) in the acceptor splice site of exon 14 of the CYLD gene. He developed several cylindromas on his scalp starting at age 20, and reported that his deceased mother had developed a small nodule on her scalp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 8 (1 family)</strong>
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CYLD, MET719VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1971438573 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1971438573;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1971438573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1971438573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001281091" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001281091" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001281091</a>
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<p>In 5 affected individuals from a large multigenerational family of European Australian descent (Aus-12) with frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8; <a href="/entry/619132">619132</a>), <a href="#6" class="mim-tip-reference" title="Dobson-Stone, C., Luty, A. A., Thompson, E. M., Blumbergs, P., Brooks, W. S., Short, C. L., Field, C. D., Panegyres, P. K., Hecker, J., Solski, J. A., Blair, I. P., Fullerton, J. M., Halliday, G. M., Schofield, P. R., Kwok, J. B. J. <strong>Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.</strong> Acta Neuropath. 125: 523-533, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23338750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23338750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23338750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-013-1078-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23338750">Dobson-Stone et al. (2013)</a> and <a href="#5" class="mim-tip-reference" title="Dobson-Stone, C., Hallupp, M., Shahheydari, H., Ragagnin, A. M. G., Chatterton, Z., Carew-Jones, F., Shepherd, C. E., Stefen, H., Paric, E., Fath, T., Thompson, E. M., Blumbergs, P., and 28 others. <strong>CYLD is a causative gene for frontotemporal dementia-amyotrophic lateral sclerosis.</strong> Brain 143: 783-799, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32185393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32185393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32185393[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32185393">Dobson-Stone et al. (2020)</a> identified a heterozygous c.2155A-G transition in the CYLD gene (chr16.50,825,515A-G, GRCh37), resulting in a met719-to-val (M719V) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. It was not present in several public databases, including gnomAD. <a href="#6" class="mim-tip-reference" title="Dobson-Stone, C., Luty, A. A., Thompson, E. M., Blumbergs, P., Brooks, W. S., Short, C. L., Field, C. D., Panegyres, P. K., Hecker, J., Solski, J. A., Blair, I. P., Fullerton, J. M., Halliday, G. M., Schofield, P. R., Kwok, J. B. J. <strong>Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.</strong> Acta Neuropath. 125: 523-533, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23338750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23338750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23338750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00401-013-1078-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23338750">Dobson-Stone et al. (2013)</a> noted that in silico analysis predicted that the mutation was not likely to be pathogenic; however, <a href="#5" class="mim-tip-reference" title="Dobson-Stone, C., Hallupp, M., Shahheydari, H., Ragagnin, A. M. G., Chatterton, Z., Carew-Jones, F., Shepherd, C. E., Stefen, H., Paric, E., Fath, T., Thompson, E. M., Blumbergs, P., and 28 others. <strong>CYLD is a causative gene for frontotemporal dementia-amyotrophic lateral sclerosis.</strong> Brain 143: 783-799, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32185393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32185393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32185393[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awaa039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32185393">Dobson-Stone et al. (2020)</a> provided evidence that the M719V mutation was in fact pathogenic. Transfection of primary mouse cortical neurons with mutant M719V CYLD resulted in an increased proportion of neurons with cytoplasmic TDP43 staining (55%) compared to cells transfected with wildtype CYLD (34%). The mutation also altered axonal morphology, leading to a decrease in axonal length. Additional in vitro cellular studies showed that the M719V mutation resulted in increased K63 deubiquitinase activity, enhanced inhibition of NFKB, and impaired autophagosome fusion with lysosomes compared to wildtype, indicating a gain-of-function effect. Neuropathologic analysis of postmortem brain tissue of 2 affected individuals showed widespread glial CYLD immunoreactivity that was not present in other patients with sporadic FTD. There were also patchy areas of diffuse neuronal cytoplasmic CYLD staining in the hippocampus and frontal cortex, as well as CYLD immunoreactivity in the nuclei of pyknotic neurons. CYLD did not colocalize with either tau or TDP43 inclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23338750+32185393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1111/j.0022-202X.2005.23688.x" target="_blank">Full Text</a>]
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Dobson-Stone, C., Hallupp, M., Shahheydari, H., Ragagnin, A. M. G., Chatterton, Z., Carew-Jones, F., Shepherd, C. E., Stefen, H., Paric, E., Fath, T., Thompson, E. M., Blumbergs, P., and 28 others.
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<strong>CYLD is a causative gene for frontotemporal dementia-amyotrophic lateral sclerosis.</strong>
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Brain 143: 783-799, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32185393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32185393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32185393[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32185393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awaa039" target="_blank">Full Text</a>]
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Dobson-Stone, C., Luty, A. A., Thompson, E. M., Blumbergs, P., Brooks, W. S., Short, C. L., Field, C. D., Panegyres, P. K., Hecker, J., Solski, J. A., Blair, I. P., Fullerton, J. M., Halliday, G. M., Schofield, P. R., Kwok, J. B. J.
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<strong>Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.</strong>
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Acta Neuropath. 125: 523-533, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23338750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23338750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23338750[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23338750" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00401-013-1078-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1046/j.1523-1747.2003.12514.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19481526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19481526</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19481526[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19481526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2009.04.031" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18382763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18382763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18382763[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18382763" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI34257" target="_blank">Full Text</a>]
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Kovalenko, A., Chable-Bessia, C., Cantarella, G., Israel, A., Wallach, D., Courtois, G.
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<strong>The tumour suppressor CYLD negatively regulates NF-kappa-B signalling by deubiquitination.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917691</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12917691" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature01802" target="_blank">Full Text</a>]
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Liang, Y. H., Gao, M., Sun, L. D., Liu, L. J., Cui, Y., Yang, S., Fan, X., Wang, J., Xiao, F. L., Zhang, X. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16307661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16307661</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16307661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2133.2005.06960.x" target="_blank">Full Text</a>]
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<a id="Massoumi2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A., Fassler, R.
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<strong>Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappa-B signaling.</strong>
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Cell 125: 665-677, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713561</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2006.03.041" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Nasti2009" class="mim-anchor"></a>
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<div class="">
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Nasti, S., Pastorino, L., Bruno, W., Gargiulo, S., Battistuzzi, L., Zavattaro, E., Leigheb, G., De Francesco, V., Tulli, A., Mari, F., Biancheri Scarra, G., Ghiorzo, P.
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<strong>Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. (Letter)</strong>
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Clin. Genet. 76: 481-485, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19807742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19807742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19807742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2009.01259.x" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="O'Donnell2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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O'Donnell, M. A., Perez-Jimenez, E., Oberst, A., Ng, A., Massoumi, R., Xavier, R., Green, D. R., Ting, A. T.
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<strong>Caspase 8 inhibits programmed necrosis by processing CYLD.</strong>
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Nature Cell Biol. 13: 1437-1442, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22037414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22037414</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22037414[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22037414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncb2362" target="_blank">Full Text</a>]
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</p>
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<a id="15" class="mim-anchor"></a>
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<a id="Poblete Gutierrez2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Poblete Gutierrez, P. P., Eggermann, T., Holler, D., Jugert, F. K., Beermann, T., Grussendorf-Conen, E.-I., Zerres, K., Merk, H. F., Frank, J.
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<strong>Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages.</strong>
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J. Invest. Derm. 119: 527-531, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12190880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12190880</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12190880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1046/j.1523-1747.2002.01839.x" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Regamey2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Regamey, A., Hohl, D., Liu, J. W., Roger, T., Kogerman, P., Toftgard, R., Huber, M.
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<strong>The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappa-B activation by tumor necrosis factor.</strong>
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J. Exp. Med. 198: 1959-1964, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14676304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14676304</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14676304[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14676304" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1084/jem.20031187" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Reiley2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Reiley, W. W., Zhang, M., Jin, W., Losiewicz, M., Donohue, K. B., Norbury, C. C., Sun, S.-C.
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<strong>Regulation of T cell development by the deubiquitinating enzyme CYLD.</strong>
|
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Nature Immun. 7: 411-417, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501569</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16501569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ni1315" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Saggar2008" class="mim-anchor"></a>
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<div class="">
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Saggar, S., Chernoff, K. A., Lodha, S., Horev, L., Kohl, S., Honjo, R. S., Brandt, H. R. C., Hartmann, K., Celebi, J. T.
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<strong>CYLD mutations in familial skin appendage tumours. (Letter)</strong>
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J. Med. Genet. 45: 298-302, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234730</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18234730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2007.056127" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Scheinfeld2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Scheinfeld, N., Hu, G., Gill, M., Austin, C., Celebi, J. T.
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<strong>Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome.</strong>
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Clin. Exp. Dermatol. 28: 539-541, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12950348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12950348</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12950348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1046/j.1365-2230.2003.01344.x" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Stegmeier2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stegmeier, F., Sowa, M. E., Nalepa, G., Gygi, S. P., Harper, J. W., Elledge, S. J.
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<strong>The tumor suppressor CYLD regulates entry into mitosis.</strong>
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Proc. Nat. Acad. Sci. 104: 8869-8874, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17495026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17495026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17495026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17495026" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0703268104" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Trompouki2003" class="mim-anchor"></a>
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<div class="">
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Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G.
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<strong>CYLD is a deubiquitinating enzyme that negatively regulates NF-kappa-B activation by TNFR family members.</strong>
|
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Nature 424: 793-796, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12917689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12917689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12917689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature01803" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Yang2024" class="mim-anchor"></a>
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Yang, S., Yu, F., Yang, M., Ni, H., Bu, W., Yin, H., Yang, J., Wang, W., Zhai, D., Wu, X., Ma, N., Li, T., and 9 others.
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<strong>CYLD maintains retinal homeostasis by deubiquitinating ENKD1 and promoting the phagocytosis of photoreceptor outer segments.</strong>
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Adv. Sci. (Weinh) 11: e2404067, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/39373352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">39373352</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=39373352[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=39373352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/advs.202404067" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Young2006" class="mim-anchor"></a>
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Young, A. L., Kellermayer, R., Szigeti, R., Teszas, A., Azmi, S., Celebi, J. T.
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<strong>CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes.</strong>
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Clin. Genet. 70: 246-249, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922728</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2006.00667.x" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 02/28/2025
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Bao Lige - updated : 05/05/2021<br>Cassandra L. Kniffin - updated : 12/30/2020<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Matthew B. Gross - updated : 10/29/2009<br>Patricia A. Hartz - updated : 10/20/2009<br>Patricia A. Hartz - updated : 1/14/2009<br>Cassandra L. Kniffin - updated : 6/16/2008<br>Patricia A. Hartz - updated : 1/16/2008<br>Paul J. Converse - updated : 2/15/2007<br>Paul J. Converse - updated : 3/13/2006<br>Ada Hamosh - updated : 8/26/2003<br>Gary A. Bellus - updated : 5/13/2003
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Victor A. McKusick : 5/26/2000
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carol : 03/03/2025
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mgross : 02/28/2025<br>mgross : 05/05/2021<br>carol : 01/06/2021<br>ckniffin : 12/30/2020<br>carol : 03/14/2020<br>carol : 09/16/2019<br>carol : 08/21/2017<br>carol : 09/13/2013<br>carol : 7/26/2011<br>wwang : 1/26/2010<br>ckniffin : 12/21/2009<br>mgross : 10/29/2009<br>terry : 10/20/2009<br>mgross : 1/14/2009<br>wwang : 6/26/2008<br>carol : 6/17/2008<br>ckniffin : 6/16/2008<br>mgross : 1/25/2008<br>terry : 1/16/2008<br>alopez : 11/14/2007<br>mgross : 2/15/2007<br>joanna : 9/25/2006<br>mgross : 3/13/2006<br>mgross : 3/13/2006<br>alopez : 8/27/2003<br>terry : 8/26/2003<br>alopez : 5/13/2003<br>alopez : 5/27/2000
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<span class="mim-font">
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<strong>*</strong> 605018
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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CYLD LYSINE-63 DEUBIQUITINASE; CYLD
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</span>
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</h3>
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</div>
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<br />
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CYLD GENE<br />
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CYLD1<br />
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KIAA0849
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CYLD</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 211710004, 403825008, 703531009;
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</span>
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</p>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 16q12.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:50,742,086-50,801,935 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="4">
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<span class="mim-font">
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16q12.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
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</span>
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</td>
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<td>
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<span class="mim-font">
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619132
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Brooke-Spiegler syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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605041
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Cylindromatosis, familial
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</span>
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</td>
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<td>
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<span class="mim-font">
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132700
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Trichoepithelioma, multiple familial, 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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601606
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The tumor suppressor CYLD is a deubiquitinating enzyme that removes lys63-linked ubiquitin chains and acts as a negative regulator of NF-kappa-B (see 164011) signaling. CYLD deubiquitinates several NF-kappa-B regulators, including TRAF2 (601895), TRAF6 (602355), and NEMO (IKBKG; 300248), as well as BCL3 (109560), a member of the NF-kappa-B family of transcription factors (Hutti et al., 2009). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By positional cloning, Bignell et al. (2000) isolated a gene on chromosome 16q, termed CYLD, responsible for familial cylindromatosis (132700). The full-length cDNA encodes a deduced 956-amino acid protein, and a splice variant lacking exon 7 encodes a deduced 953-amino acid protein. Likely orthologs were identified in Drosophila melanogaster and C. elegans. The CYLD protein has 3 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 (see 603090). RT-PCR detected expression of CYLD in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary, and lung. The splice variant lacking exon 7 was found in all tissues in which CYLD was expressed except kidney. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Brummelkamp et al. (2003) designed a collection of RNA interference vectors to suppress 50 human deubiquitinating enzymes and used these vectors to identify deubiquitinating enzymes in cancer-relevant pathways. They demonstrated that inhibition of CYLD enhances activation of the transcription factor NF-kappa-B. They showed that CYLD binds to the NEMO component of the I-kappa-B kinase (IKK) complex, and appears to regulate its activity through deubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increased resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. Brummelkamp et al. (2003) further demonstrated that this effect can be relieved by aspirin derivatives that inhibit NF-kappa-B activity. </p><p>Trompouki et al. (2003) identified CYLD as a deubiquitinating enzyme that negatively regulates activation of NF-kappa-B by specific tumor necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlated with tumorigenesis. CYLD inhibits activation of NF-kappa-B by the TNFR family members CD40 (109535), XEDAR (300276), and EDAR (604095) in a manner that depends on deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-kappa-B. The inhibition of NF-kappa-B activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6. Trompouki et al. (2003) concluded that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappa-B that is required for appropriate cellular homeostasis of skin appendages. </p><p>Kovalenko et al. (2003) showed that CYLD interacts with NEMO and TRAF2. CYLD has a deubiquitinating activity that is directed toward the non-lys48-linked polyubiquitin chains and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. </p><p>By yeast 2-hybrid screening with CYLD as bait, followed by far Western blot and coimmunoprecipitation analyses, Regamey et al. (2003) found that the C terminus of TRIP (605958) interacted with the central domain of CYLD. CYLD downregulated TNF (191160)-induced NFKB activation, and this downregulation was dependent on CYLD-TRIP interaction and the deubiquitinating activity of CYLD. Regamey et al. (2003) suggested that cylindromas might arise through constitutive NFKB activation leading to hyperproliferation and tumor growth. </p><p>Massoumi et al. (2006) found that mice lacking Cyld were prone to chemically-induced skin tumors. They showed that Cyld inhibited tumor formation and keratinocyte proliferation by removing lys63-linked polyubiquitin chains from Bcl3, which resulted in retention of Bcl3 in the cytoplasm. In Cyld-deficient keratinocytes, Bcl3 accumulated in the nucleus, activated the NF-kappa-B subunits p50 (NFKB1; 164011) and p52 (NFKB2; 164012), and induced transcription of NF-kappa-B target genes, such as cyclin D1 (CCND1; 168461). </p><p>Stegmeier et al. (2007) showed that CYLD was required for timely entry into mitosis in human cell lines. CYLD localized to microtubules in interphase and to the midbody during telophase, and its level decreased as cells exited mitosis. Stegmeier et al. (2007) identified the protein kinase PLK1 (602098) as a potential target of CYLD in the regulation of mitotic entry based on their physical interaction and similar loss-of-function and overexpression phenotypes. They concluded that, in addition to suppressing tumor formation through apoptosis regulation, CYLD can promote tumor formation by enhancing mitotic entry. </p><p>Using a proteomic and bioinformatic approach, Hutti et al. (2009) identified a number of putative substrates for phosphorylation by IKK-epsilon (IKBKE; 605048), including ser418 of CYLD. CYLD was phosphorylated by IKK-epsilon on ser418 in vitro and in vivo. Phosphorylation of CYLD at ser418 decreased its deubiquitinase activity and was necessary for IKK-epsilon-dependent transformation in NIH-3T3 mouse fibroblasts. </p><p>O'Donnell et al. (2011) identified CYLD as the key substrate for CASP8 (601763) to inhibit programmed necrosis. Analysis with mouse embryonic fibroblasts (MEFs) showed that Cyld was essential for necrotic cell death. Upon TNF stimulation, CASP8 proteolytically cleaved CYLD at the carboxyl end of asp215 to generate a survival signal and block necrosis in various cell types. In contrast, loss of CASP8 blocked proteolytic degradation of CYLD and triggered programmed necrosis. Mutation of asp215 was sufficient to convert the prosurvival response to TNF-induced necrosis, even in the presence of CASP8. Cleavage by CASP8 removed the deubiquitinase domain of CYLD and prevented CYLD from deubiquitinating downstream molecules, such as RIPK1 (603453), thereby affecting its interactions with signaling partners and resulting in a switch from a prosurvival NEMO-RIPK1 complex to a pronecrotic RIPK1-FADD (602457) complex. </p><p>By database analysis, Yang et al. (2024) showed that the level of CYLD in human retina declined with age. Analysis of Cyld -/- mice, which displayed age-related retinal degeneration, revealed that Cyld played a crucial role in retinal homeostasis by enhancing the phagocytic activity of RPE cells. Analysis of primary RPE cells isolated from Cyld -/- mouse retina showed that Cyld promoted RPE-mediated photoreceptor outer segment (POS) phagocytosis in a deubiquitinase-dependent manner. Cyld interacted with Enkd1 (621119), and the interaction was mediated by the ubiquitin-specific protease (USP) domain of Cyld and the amino acids 91 to 250 of Enkd1. Enkd1 was also required for POS phagocytosis, and interaction with Cyld deubiquitinated Enkd1 at lys141 and lys242. Knockdown analysis revealed that Cyld was required for formation of microvilli in RPE cells, as Cyld deubiquitinated Enkd1 at lys141 and lys242 and promoted Enkd1 interaction with Ezrin (EZR; 123900), leading to enhanced Ezrin microvillar localization and POS phagocytosis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bignell et al. (2000) demonstrated that the CYLD gene contains 20 exons (the smallest being 9 bp), of which the first 3 are untranslated, and extends over approximately 56 kb of genomic DNA. Exon 3 (in the 5-prime untranslated region) and the 9-bp exon 7 (which is coding) show alternative splicing. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bignell et al. (2000) mapped the CYLD gene to chromosome 16q12-q13. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cylindromatosis, Trichoepithelioma, and Brooke-Spiegler Syndrome</em></strong></p><p>
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Bignell et al. (2000) detected 21 different germline mutations in the CYLD gene in 21 families with familial cylindromatosis (132700), and 6 different somatic mutations in 1 patient with sporadic disease and 5 patients with familial disease (see, e.g., 605018.0001-605018.0002). All the mutations predicted truncated proteins: 9 caused translational frameshifts due to small insertions or deletions; 9 were base substitutions that directly generated translational termination codons; and 3 altered splice sites. Bignell et al. (2000) noted that approximately 70% of familial cylindromas have exhibited loss of heterozygosity (LOH) in the 16q region and that the allele lost was always the wildtype allele. This pattern of loss is characteristic of a tumor suppressor gene, i.e., a recessive oncogene. Loss of heterozygosity on chromosome 16q has also been found in many sporadic cylindromas (Biggs et al., 1996). </p><p>In a 67-year-old man with Brooke-Spiegler syndrome (BRSS; 605041), Scheinfeld et al. (2003) identified a heterozygous frameshift mutation in the CYLD gene (605018.0004). </p><p>In affected members of 2 unrelated Chinese families with multiple familial trichoepithelioma-1 (MFT1; 601606), Liang et al. (2005) identified 2 different heterozygous mutations in the CYLD gene (605018.0005 and 605018.0006, respectively). One was a frameshift and the other a splice site, suggesting a loss-of-function effect. </p><p>In affected members of a Turkish family with multiple familial trichoepithelioma, Hu et al. (2003) identified a heterozygous missense mutation in the CYLD gene (E747G; 605018.0007). Hu et al. (2003) noted that the phenotype of most of the affected individuals in this family resembled MFT1, but 1 patient had cylindromas, suggesting BRSS. The findings suggested that BRSS and MFT1 represent phenotypic variability of a single entity. </p><p>Young et al. (2006) identified a heterozygous nonsense mutation in the CYLD gene (R936X; 605018.0008) in a 73-year-old man with cylindromatosis and turban tumor syndrome and in his 2 children with multiple familial trichoepithelioma without cylindromas. The findings suggested that the 2 disorders represent phenotypic variation of a single genetic defect. </p><p>Saggar et al. (2008) performed genetic analysis of 25 probands with familial skin appendage tumors. In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BRSS, 100% for FC, and 44% for MFT1. The majority of the mutations resulted in truncated proteins, and all mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal any correlations. Saggar et al. (2008) concluded that the 3 disorders represent phenotypic variation of a single disease entity. </p><p>Nasti et al. (2009) identified 5 different truncating or splice site mutations in the CYLD gene (see, e.g., 605018.0009-605018.0011) in 5 Italian probands with cylindromatosis or Brooke-Spiegler syndrome. </p><p><strong><em>Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 8</em></strong></p><p>
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In 5 affected individuals from a large multigenerational family of European Australian descent (Aus-12) with frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8; 619132), Dobson-Stone et al. (2013) and Dobson-Stone et al. (2020) identified a heterozygous missense mutation in the CYLD gene (M719V; 605018.0012). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. It was not present in several public databases, including gnomAD. Transfection of primary mouse cortical neurons with mutant M719V CYLD resulted in an increased proportion of neurons with cytoplasmic TDP43 (605078) staining (55%) compared to cells transfected with wildtype CYLD (34%). The mutation also altered axonal morphology, leading to a decrease in axonal length. Additional in vitro cellular studies showed that the M719V mutation resulted in increased K63 deubiquitinase activity, enhanced inhibition of NFKB, and impaired autophagosome fusion with lysosomes compared to wildtype, indicating a gain-of-function effect. The authors noted that other disorders associated the CYLD mutations result in a loss of function. CYLD was found to directly interact with TBK1 (604834), OPTN (602432), and SQSTM1 (601530), all of which are implicated in autophagy and, when mutated, are causative of FTD or ALS. The report thus identified another molecular mechanism by which impaired autophagy can result in a neurodegenerative disorder. CYLD mutations were not found in several cohorts of ALS and FTD patients comprising several thousand individuals, suggesting that it is a rare cause of the disorder. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Reiley et al. (2006) generated Cyld -/- mice. Activation of Nfkb through Toll-like receptors (e.g., TLR4; 603030) and Tnf receptors was normal in Cyld -/- mice, but thymocyte development was impaired. Immunoblot analysis showed defective tyrosine phosphorylation of Zap70 (176947) and Lat (602354) in Cyld -/- thymocytes. Cyld failed to physically interact with Lck (153390) in Cyld -/- thymocytes, and Lck was not recruited to Zap70. Catalytically inactive CYLD failed to deubiquitinate LCK in human embryonic kidney cells. Reiley et al. (2006) concluded that CYLD physically interacts with LCK, promotes its recruitment to ZAP70, removes polyubiquitin chains from LCK, and regulates maturation of CD4-positive and CD8-positive single-positive thymocytes and peripheral T cells. </p><p>Jin et al. (2008) observed that Cyld -/- mice developed severe osteoporosis, which was due to aberrant osteoclast differentiation. Cultured osteoclast precursors derived from Cyld -/- mice were hyperresponsive to Rankl (TNFSF11; 602642)-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. In wildtype preosteoclasts, Cyld was upregulated during Rankl-induced differentiation, and Cyld negatively regulated Rank (TNFRSF11A; 603499) signaling by inhibiting Traf6 ubiquitination and downstream signaling events. Cyld interacted physically with the signaling adaptor p62 (SQSTM1; 601530) and thereby was recruited to Traf6. Jin et al. (2008) concluded that CYLD is a negative regulator of osteoclastogenesis via the p62/TRAF6 signaling pathway. </p><p>Yang et al. (2024) found that Cyld -/- mice displayed age-related retinal degeneration. Analysis of primary RPE cells isolated from Cyld -/- mouse retina showed that Cyld promoted RPE-mediated photoreceptor outer segment phagocytosis in a deubiquitinase-dependent manner. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>12 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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|
<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CYLINDROMATOSIS, FAMILIAL</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
CYLD, NT2469, G-A, +1
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|
<br />
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|
|
SNP: rs1597091470,
|
|
|
|
|
|
|
|
ClinVar: RCV000005564
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of 2 presumably unrelated families with cylindromatosis (132700), Bignell et al. (2000) identified a heterozygous G-to-A transition in the CYLD gene in the first position of a canonical splice donor site. Haplotype analysis indicated a common ancestor. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
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</div>
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</div>
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|
<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CYLINDROMATOSIS, FAMILIAL</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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CYLD, ARG758TER
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<br />
|
|
|
|
SNP: rs121908388,
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|
|
|
|
ClinVar: RCV000005565, RCV000120624, RCV002281697
|
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|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated families with cylindromatosis (132700), Bignell et al. (2000) identified a heterozygous 2272C-T transition in the CYLD gene, resulting in an arg758-to-ter (R758X) substitution. These were presumably independent mutations because the mutation was located on different haplotypes in the 2 families. The same R758X mutation was found as the 'second hit' (somatic mutation) in a familial cylindroma. Therefore, this mutation, which is at a CpG dinucleotide, appeared to have arisen on 3 separate occasions, whereas all other CYLD mutations detected by Bignell et al. (2000) had arisen only once. </p>
|
|
</span>
|
|
</div>
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|
<div>
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|
<br />
|
|
</div>
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|
</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CYLINDROMATOSIS, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BROOKE-SPIEGLER SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, 1-BP DEL, 2253G
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1597088499,
|
|
|
|
|
|
|
|
ClinVar: RCV000005566, RCV000005567
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a German family with familial cylindromatosis (132700), Poblete Gutierrez et al. (2002) identified a heterozygous 1-bp deletion (2253delG) in the CYLD gene, resulting in a frameshift and premature termination. Two individuals had cylindromas, whereas a third had both cylindromas and trichoepitheliomas, suggesting Brooke-Spiegler syndrome (605041) and demonstrating intrafamilial and intraindividual phenotypic variability. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 BROOKE-SPIEGLER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, 1-BP DEL, 2172A
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000005568
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 67-year-old man with Brooke-Spiegler syndrome (605041), Scheinfeld et al. (2003) identified a heterozygous 1-bp deletion (2172delA) in exon 16 of the CYLD gene, resulting in a frameshift and premature termination. The patient had multiple disfiguring facial papules and painful scalp nodules histologically classified predominantly as cylindromas and spiradenomas, but also including epidermoid inclusion cyst, and basal cell carcinoma. His father and sister were similarly affected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, 2-BP DEL, 2241AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1597085967,
|
|
|
|
|
|
|
|
ClinVar: RCV000005569
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large Chinese family with multiple trichoepithelioma-1 (601606), Liang et al. (2005) identified a heterozygous 2-bp deletion (2241delAG) in the CYLD gene, resulting in a frameshift and premature termination of the protein at codon 763 prior to a catalytic domain of ubiquitin C-terminal hydrolase. None of the patients had cylindromas. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, IVS12AS, T-G, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1597058708,
|
|
|
|
|
|
|
|
ClinVar: RCV000005570
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large Chinese family with multiple trichoepithelioma-1 (601606), Liang et al. (2005) identified a heterozygous T-to-G transversion in intron 12, thus preventing proper splicing of the transcript. None of the patients had cylindromas. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
BROOKE-SPIEGLER SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, GLU747GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908389,
|
|
|
|
|
|
|
|
ClinVar: RCV000005571, RCV000005572
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Turkish family with multiple trichoepithelioma-1 (601606), Hu et al. (2003) identified a heterozygous 2240A-G transition in exon 16 of the CYLD gene, resulting in a glu474-to-gly (E747G) substitution. All of the affected individuals presented with multiple trichoepitheliomas, except for 1 patient who had cylindromas on the scalp, suggesting Brooke-Spiegler syndrome (605041). The findings indicated that MFT1 and BRSS may be variable manifestations of a single disease entity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CYLINDROMATOSIS, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
TRICHOEPITHELIOMA, MULTIPLE FAMILIAL, 1, INCLUDED<br />
|
|
BROOKE-SPIEGLER SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, ARG936TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121908390,
|
|
|
|
|
|
gnomAD: rs121908390,
|
|
|
|
|
|
ClinVar: RCV000005573, RCV000005574, RCV000005575, RCV002496269, RCV005089180
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 73-year-old man with cylindromatosis and turban tumor syndrome (132700), Young et al. (2006) identified a heterozygous 2806C-T transition in the CYLD gene, resulting in an arg936-to-ter (R936X) substitution. His 2 children, who also carried the mutation, had multiple familial trichoepithelioma-1 (601606) without cylindromas. The findings suggested that the 2 disorders represent phenotypic variation of a single genetic defect. </p><p>Bowen et al. (2005) identified a heterozygous R936X mutation in a Canadian woman with Brooke-Spiegler syndrome (605041) who had both cylindroma and trichoepithelioma. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CYLINDROMATOSIS, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, 1-BP DUP, 561T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1596971597,
|
|
|
|
|
|
|
|
ClinVar: RCV000005576
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46-year-old Italian man with a mild form of cylindromatosis (132700), Nasti et al. (2009) identified a heterozygous 1-bp duplication (561dupT) in exon 5 of the CYLD gene, predicted to result in a frameshift and premature termination. The mutation occurred toward the N terminus of the protein in the first cytoskeleton-associated protein glycine-rich (CAP-GLY) domain, which is responsible for the interaction of CYLD with microtubules. He began developing numerous small nodules on his scalp and thorax starting at the age of 42. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 BROOKE-SPIEGLER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, 1-BP DUP, 1392T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1597052041,
|
|
|
|
|
|
|
|
ClinVar: RCV000005577
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian mother and son with Brooke-Spiegler syndrome (BRSS; 605041), Nasti et al. (2009) identified a heterozygous 1-bp duplication (1392dupT) in exon 10 of the CYLD gene, predicted to result in a frameshift and premature termination. The 79-year-old mother began developing skin lesions at age 16. She had severe scalp involvement. Most were cylindromas, some with combined features of cylindroma and spiradenoma, and many smaller nodules were trichoepitheliomas. She also had a cutaneous carcinosarcoma on the trunk; these features were consistent with BRSS. Her 54-year-old son had 7 cylindromas and 6 basal cell carcinomas. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CYLINDROMATOSIS, FAMILIAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, 4-BP DEL, 1950-1GATA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2151015263,
|
|
|
|
|
|
|
|
ClinVar: RCV000005578
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 52-year-old Italian man with cylindromatosis (132700), Nasti et al. (2009) identified a heterozygous 4-bp deletion (1950-1delGATA) in the acceptor splice site of exon 14 of the CYLD gene. He developed several cylindromas on his scalp starting at age 20, and reported that his deceased mother had developed a small nodule on her scalp. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 8 (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CYLD, MET719VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1971438573,
|
|
|
|
|
|
|
|
ClinVar: RCV001281091
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected individuals from a large multigenerational family of European Australian descent (Aus-12) with frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8; 619132), Dobson-Stone et al. (2013) and Dobson-Stone et al. (2020) identified a heterozygous c.2155A-G transition in the CYLD gene (chr16.50,825,515A-G, GRCh37), resulting in a met719-to-val (M719V) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. It was not present in several public databases, including gnomAD. Dobson-Stone et al. (2013) noted that in silico analysis predicted that the mutation was not likely to be pathogenic; however, Dobson-Stone et al. (2020) provided evidence that the M719V mutation was in fact pathogenic. Transfection of primary mouse cortical neurons with mutant M719V CYLD resulted in an increased proportion of neurons with cytoplasmic TDP43 staining (55%) compared to cells transfected with wildtype CYLD (34%). The mutation also altered axonal morphology, leading to a decrease in axonal length. Additional in vitro cellular studies showed that the M719V mutation resulted in increased K63 deubiquitinase activity, enhanced inhibition of NFKB, and impaired autophagosome fusion with lysosomes compared to wildtype, indicating a gain-of-function effect. Neuropathologic analysis of postmortem brain tissue of 2 affected individuals showed widespread glial CYLD immunoreactivity that was not present in other patients with sporadic FTD. There were also patchy areas of diffuse neuronal cytoplasmic CYLD staining in the hippocampus and frontal cortex, as well as CYLD immunoreactivity in the nuclei of pyknotic neurons. CYLD did not colocalize with either tau or TDP43 inclusions. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Biggs, P. J., Chapman, P., Lakhani, S. R., Burn, J., Stratton, M. R.
|
|
<strong>The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas.</strong>
|
|
Oncogene 12: 1375-1377, 1996.
|
|
|
|
|
|
[PubMed: 8649842]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bignell, G. R., Warren, W., Seal, S., Takahashi, M., Rapley, E., Barfoot, R., Green, H., Brown, C., Biggs, P. J., Lakhani, S. R., Jones, C., Hansen, J., and 29 others.
|
|
<strong>Identification of the familial cylindromatosis tumour-suppressor gene.</strong>
|
|
Nature Genet. 25: 160-165, 2000.
|
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[PubMed: 10835629]
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[Full Text: https://doi.org/10.1038/76006]
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Bowen, S., Gill, M., Lee, D. A., Fisher, G., Geronemus, R. G., Vazquez, M. E., Celebi, J. T., Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma.
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<strong>lack of genotype-phenotype correlation.</strong>
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J. Invest. Derm. 124: 919-920, 2005.
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[PubMed: 15854031]
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[Full Text: https://doi.org/10.1111/j.0022-202X.2005.23688.x]
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</p>
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Brummelkamp, T. R., Nijman, S. M. B., Dirac, A. M. G., Bernards, R.
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<strong>Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappa-B.</strong>
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Nature 424: 797-801, 2003.
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[PubMed: 12917690]
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[Full Text: https://doi.org/10.1038/nature01811]
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</p>
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Dobson-Stone, C., Hallupp, M., Shahheydari, H., Ragagnin, A. M. G., Chatterton, Z., Carew-Jones, F., Shepherd, C. E., Stefen, H., Paric, E., Fath, T., Thompson, E. M., Blumbergs, P., and 28 others.
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<strong>CYLD is a causative gene for frontotemporal dementia-amyotrophic lateral sclerosis.</strong>
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Brain 143: 783-799, 2020.
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[PubMed: 32185393]
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[Full Text: https://doi.org/10.1093/brain/awaa039]
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</p>
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Dobson-Stone, C., Luty, A. A., Thompson, E. M., Blumbergs, P., Brooks, W. S., Short, C. L., Field, C. D., Panegyres, P. K., Hecker, J., Solski, J. A., Blair, I. P., Fullerton, J. M., Halliday, G. M., Schofield, P. R., Kwok, J. B. J.
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<strong>Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.</strong>
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Acta Neuropath. 125: 523-533, 2013.
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[PubMed: 23338750]
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[Full Text: https://doi.org/10.1007/s00401-013-1078-9]
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</p>
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</li>
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<li>
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Hu, G., Onder, M., Gill, M., Aksakal, B., Oztas, M., Gurer, M. A., Celebi, J. T.
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<strong>A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome.</strong>
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J. Invest. Derm. 121: 732-734, 2003.
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[PubMed: 14632188]
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[Full Text: https://doi.org/10.1046/j.1523-1747.2003.12514.x]
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</p>
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</li>
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<li>
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Hutti, J. E., Shen, R. R., Abbott, D. W., Zhou, A. Y., Sprott, K. M., Asara, J. M., Hahn, W. C., Cantley, L. C.
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<strong>Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKK-epsilon promotes cell transformation.</strong>
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Molec. Cell 34: 461-472, 2009.
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[PubMed: 19481526]
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[Full Text: https://doi.org/10.1016/j.molcel.2009.04.031]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jin, W., Chang, M., Paul, E. M., Babu, G., Lee, A. J., Reiley, W., Wright, A., Zhang, M., You, J., Sun, S.-C.
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<strong>Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.</strong>
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J. Clin. Invest. 118: 1858-1866, 2008.
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[PubMed: 18382763]
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[Full Text: https://doi.org/10.1172/JCI34257]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kovalenko, A., Chable-Bessia, C., Cantarella, G., Israel, A., Wallach, D., Courtois, G.
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<strong>The tumour suppressor CYLD negatively regulates NF-kappa-B signalling by deubiquitination.</strong>
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Nature 424: 801-805, 2003.
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[PubMed: 12917691]
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[Full Text: https://doi.org/10.1038/nature01802]
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</p>
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</li>
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<li>
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Liang, Y. H., Gao, M., Sun, L. D., Liu, L. J., Cui, Y., Yang, S., Fan, X., Wang, J., Xiao, F. L., Zhang, X. J.
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<strong>Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China.</strong>
|
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Brit. J. Derm. 153: 1213-1215, 2005.
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[PubMed: 16307661]
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[Full Text: https://doi.org/10.1111/j.1365-2133.2005.06960.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A., Fassler, R.
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<strong>Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappa-B signaling.</strong>
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Cell 125: 665-677, 2006.
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[PubMed: 16713561]
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[Full Text: https://doi.org/10.1016/j.cell.2006.03.041]
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Nasti, S., Pastorino, L., Bruno, W., Gargiulo, S., Battistuzzi, L., Zavattaro, E., Leigheb, G., De Francesco, V., Tulli, A., Mari, F., Biancheri Scarra, G., Ghiorzo, P.
|
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<strong>Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas. (Letter)</strong>
|
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Clin. Genet. 76: 481-485, 2009.
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[PubMed: 19807742]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2009.01259.x]
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</li>
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<li>
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O'Donnell, M. A., Perez-Jimenez, E., Oberst, A., Ng, A., Massoumi, R., Xavier, R., Green, D. R., Ting, A. T.
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<strong>Caspase 8 inhibits programmed necrosis by processing CYLD.</strong>
|
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Nature Cell Biol. 13: 1437-1442, 2011.
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[PubMed: 22037414]
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[Full Text: https://doi.org/10.1038/ncb2362]
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<li>
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Poblete Gutierrez, P. P., Eggermann, T., Holler, D., Jugert, F. K., Beermann, T., Grussendorf-Conen, E.-I., Zerres, K., Merk, H. F., Frank, J.
|
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<strong>Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages.</strong>
|
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J. Invest. Derm. 119: 527-531, 2002.
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[PubMed: 12190880]
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[Full Text: https://doi.org/10.1046/j.1523-1747.2002.01839.x]
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<li>
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Regamey, A., Hohl, D., Liu, J. W., Roger, T., Kogerman, P., Toftgard, R., Huber, M.
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<strong>The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappa-B activation by tumor necrosis factor.</strong>
|
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J. Exp. Med. 198: 1959-1964, 2003.
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[PubMed: 14676304]
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[Full Text: https://doi.org/10.1084/jem.20031187]
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Reiley, W. W., Zhang, M., Jin, W., Losiewicz, M., Donohue, K. B., Norbury, C. C., Sun, S.-C.
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<strong>Regulation of T cell development by the deubiquitinating enzyme CYLD.</strong>
|
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Nature Immun. 7: 411-417, 2006.
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[PubMed: 16501569]
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[Full Text: https://doi.org/10.1038/ni1315]
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Saggar, S., Chernoff, K. A., Lodha, S., Horev, L., Kohl, S., Honjo, R. S., Brandt, H. R. C., Hartmann, K., Celebi, J. T.
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<strong>CYLD mutations in familial skin appendage tumours. (Letter)</strong>
|
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J. Med. Genet. 45: 298-302, 2008.
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[PubMed: 18234730]
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[Full Text: https://doi.org/10.1136/jmg.2007.056127]
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<p class="mim-text-font">
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Scheinfeld, N., Hu, G., Gill, M., Austin, C., Celebi, J. T.
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<strong>Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome.</strong>
|
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Clin. Exp. Dermatol. 28: 539-541, 2003.
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[PubMed: 12950348]
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[Full Text: https://doi.org/10.1046/j.1365-2230.2003.01344.x]
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Stegmeier, F., Sowa, M. E., Nalepa, G., Gygi, S. P., Harper, J. W., Elledge, S. J.
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<strong>The tumor suppressor CYLD regulates entry into mitosis.</strong>
|
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Proc. Nat. Acad. Sci. 104: 8869-8874, 2007.
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[PubMed: 17495026]
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[Full Text: https://doi.org/10.1073/pnas.0703268104]
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Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., Mosialos, G.
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<strong>CYLD is a deubiquitinating enzyme that negatively regulates NF-kappa-B activation by TNFR family members.</strong>
|
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Nature 424: 793-796, 2003.
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[PubMed: 12917689]
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[Full Text: https://doi.org/10.1038/nature01803]
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Yang, S., Yu, F., Yang, M., Ni, H., Bu, W., Yin, H., Yang, J., Wang, W., Zhai, D., Wu, X., Ma, N., Li, T., and 9 others.
|
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<strong>CYLD maintains retinal homeostasis by deubiquitinating ENKD1 and promoting the phagocytosis of photoreceptor outer segments.</strong>
|
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Adv. Sci. (Weinh) 11: e2404067, 2024.
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[PubMed: 39373352]
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[Full Text: https://doi.org/10.1002/advs.202404067]
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Young, A. L., Kellermayer, R., Szigeti, R., Teszas, A., Azmi, S., Celebi, J. T.
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<strong>CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes.</strong>
|
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Clin. Genet. 70: 246-249, 2006.
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[PubMed: 16922728]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00667.x]
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To ensure long-term funding for the OMIM project, we have diversified
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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