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<title>
Entry
- *600571 - RE1-SILENCING TRANSCRIPTION FACTOR; REST
- OMIM
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<span class="h4">*600571</span>
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<strong>Table of Contents</strong>
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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">
<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Genome
</a>
</span>
</span>
</div>
<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000084093;t=ENST00000309042" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=5978" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600571" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
<span class="panel-title">
<span class="small">
<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> DNA
</a>
</span>
</span>
</div>
<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000084093;t=ENST00000309042" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001193508,NM_001363453,NM_005612,XM_017008527,XM_047416053" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005612" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600571" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
<span class="panel-title">
<span class="small">
<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9658;</span> Protein
</a>
</span>
</span>
</div>
<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://hprd.org/summary?hprd_id=08990&isoform_id=08990_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>
<div><a href="https://www.proteinatlas.org/search/REST" 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>
<div><a href="https://www.ncbi.nlm.nih.gov/protein/606944,606948,1621501,7385133,27370669,62089086,118142849,119625921,119625922,124376608,223460852,296452989,301897974,301897977,429336184,429336186,429336188,429336190,429336192,429336194,429336196,429336198,429336200,429336202,429336204,429336206,429336208,429336210,429336212,429336214,429336216,429336218,429336220,429336226,1034640898,1390157501,2217351731,2462598560,2462598562" 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>
<div><a href="https://www.uniprot.org/uniprotkb/Q13127" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
<span class="panel-title">
<span class="small">
<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Gene Info</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="http://biogps.org/#goto=genereport&id=5978" 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>
<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000084093;t=ENST00000309042" 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>
<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=REST" 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>
<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=REST" 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>
<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+5978" 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>
<dd><a href="http://v1.marrvel.org/search/gene/REST" 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>
<dd><a href="https://monarchinitiative.org/NCBIGene:5978" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
<div><a href="https://www.ncbi.nlm.nih.gov/gene/5978" 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>
<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr4&hgg_gene=ENST00000309042.12&hgg_start=56907900&hgg_end=56935844&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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
<span class="panel-title">
<span class="small">
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600571[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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
<span class="panel-title">
<span class="small">
<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">&#9660;</span> Variation
</a>
</span>
</span>
</div>
<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600571[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>
<div><a href="https://www.deciphergenomics.org/gene/REST/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000084093" 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>
<div><a href="https://www.ebi.ac.uk/gwas/search?query=REST" 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&nbsp;</a></div>
<div><a href="https://www.gwascentral.org/search?q=REST" 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&nbsp;</a></div>
<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=REST" 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>
<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=REST&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>
<div><a href="https://www.pharmgkb.org/gene/PA34334" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/gene/HGNC:9966" 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>
<div><a href="https://www.mousephenotype.org/data/genes/MGI:104897" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
<div><a href="http://v1.marrvel.org/search/gene/REST#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>
<div><a href="http://www.informatics.jax.org/marker/MGI:104897" 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>
<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>
<div><a href="https://www.ncbi.nlm.nih.gov/gene/5978/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>
<div><a href="https://www.orthodb.org/?ncbi=5978" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
<div><a href="https://zfin.org/ZDB-GENE-080415-1" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
<span class="panel-title">
<span class="small">
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cellular Pathways</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5978" 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>
<div><a href="https://reactome.org/content/query?q=REST&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>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<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">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
&nbsp;
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Gene description">
<span class="text-danger"><strong>*</strong></span>
600571
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
RE1-SILENCING TRANSCRIPTION FACTOR; REST
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
NEURON-RESTRICTIVE SILENCER FACTOR; NRSF
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<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=REST" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">REST</a></em></strong>
</span>
</p>
</div>
<div>
<a id="cytogeneticLocation" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: <a href="/geneMap/4/243?start=-3&limit=10&highlight=243">4q12</a>
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:56907900-56935844&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'})">4:56,907,900-56,935,844</a> </span>
</em>
</strong>
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
</span>
</p>
</div>
<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=616806,612431,617626" 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="3">
<span class="mim-font">
<a href="/geneMap/4/243?start=-3&limit=10&highlight=243">
4q12
</a>
</span>
</td>
<td>
<span class="mim-font">
{Wilms tumor 6, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/616806"> 616806 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
Deafness, autosomal dominant 27
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/612431"> 612431 </a>
</span>
</td>
<td>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Fibromatosis, gingival, 5
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<a href="/entry/617626"> 617626 </a>
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<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<strong>TEXT</strong>
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<a id="description" class="mim-anchor"></a>
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<strong>Description</strong>
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<p>REST is a transcriptional repressor that regulates gene expression throughout the body. It binds 21-bp repressor element-1 (RE1) sites, also called neuron-restrictive silencer elements (NRSEs), through its 8 C2H2 zinc fingers. REST mediates gene repression by acting as a hub for the recruitment of multiple chromatin-modifying enzymes (<a href="#21" class="mim-tip-reference" title="Ooi, L., Wood, I. C. &lt;strong&gt;Chromatin crosstalk in development and disease: lessons from REST.&lt;/strong&gt; Nature Rev. Genet. 8: 544-554, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17572692/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17572692&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nrg2100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17572692">Ooi and Wood, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17572692" 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 id="cloning" class="mim-anchor"></a>
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<strong>Cloning and Expression</strong>
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<p><a href="#25" class="mim-tip-reference" title="Schoenherr, C. J., Anderson, D. J. &lt;strong&gt;The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.&lt;/strong&gt; Science 267: 1360-1363, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7871435/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7871435&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.7871435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7871435">Schoenherr and Anderson (1995)</a> cloned a transcription factor, which they termed NRSF, that bound the NRSE present in the 5-prime regulatory region of SCG10 (<a href="/entry/600621">600621</a>), a neuron-specific gene. The NRSF cDNA was cloned from a HeLa cell library. The longest cDNA was predicted to encode 8 zinc fingers of the C2H2 class, with interfinger sequences that placed NRSE within the GLI (see <a href="/entry/165220">165220</a>)-Kruppel family of zinc finger proteins. Northern blot analysis detected a NRSF transcript of 7 to 8 kb. Expression of NRSF mRNA was detected in most nonneuronal progenitor cells, but it was absent in differentiated neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7871435" 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>Independently, <a href="#7" class="mim-tip-reference" title="Chong, J. A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J. J., Zheng, Y., Boutros, M. C., Altshuller, Y. M., Frohman, M. A., Kraner, S. D., Mandel, G. &lt;strong&gt;REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.&lt;/strong&gt; Cell 80: 949-957, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7697725/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7697725&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(95)90298-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7697725">Chong et al. (1995)</a> cloned REST from a HeLa cell cDNA library. The deduced 1,097-amino acid protein has a calculated molecular mass of 121 kD. REST has 8 N-terminal C2H2-type zinc fingers, followed by a basic region, 6 repeats of a proline-rich sequence, and a C-terminal zinc finger. It also has a nuclear localization signal. In situ hybridization of mouse embryos detected abundant Rest expression in nonneuronal tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697725" 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="#29" class="mim-tip-reference" title="Thiel, G., Lietz, M., Cramer, M. &lt;strong&gt;Biological activity and modulator structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes.&lt;/strong&gt; J. Biol. Chem. 273: 26891-26899, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9756936/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9756936&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.273.41.26891&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9756936">Thiel et al. (1998)</a> determined that REST contains 2 repressor domains, one located at the N terminus and the other at the C terminus, and an N-terminal zinc finger cluster which functions as the DNA-binding domain for neuronal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9756936" 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="#22" class="mim-tip-reference" title="Palm, K., Metsis, M., Timmusk, T. &lt;strong&gt;Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat.&lt;/strong&gt; Molec. Brain Res. 72: 30-39, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10521596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10521596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0169-328x(99)00196-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10521596">Palm et al. (1999)</a> identified several REST variants that arise from alternative splicing of an exon that they designated exon N. The splice variants produce insertions that generate in-frame stop codons and encode truncated proteins with an N-terminal repressor domain and weakened DNA-binding activity. The expression levels of these variants differ in human neuroblastoma and glial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521596" 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 id="geneStructure" class="mim-anchor"></a>
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<strong>Gene Structure</strong>
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<p><a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> stated that the REST gene has 4 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686854" 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 id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Mapping</strong>
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<p><a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> stated that the REST gene maps to chromosome 4q12. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686854" 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="#25" class="mim-tip-reference" title="Schoenherr, C. J., Anderson, D. J. &lt;strong&gt;The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.&lt;/strong&gt; Science 267: 1360-1363, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7871435/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7871435&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.7871435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7871435">Schoenherr and Anderson (1995)</a> showed that NRSF bound the NRSE DNA sequence in the 5-prime region of SCG10. They noted that the SCG10 regulatory region contains both activation and repression (i.e., silencer) domains and that similar NRSE-like sequence elements have been identified in other neuron-specific genes. <a href="#25" class="mim-tip-reference" title="Schoenherr, C. J., Anderson, D. J. &lt;strong&gt;The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.&lt;/strong&gt; Science 267: 1360-1363, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7871435/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7871435&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.7871435&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7871435">Schoenherr and Anderson (1995)</a> proposed that NRSF may function as a master negative regulator of neurogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7871435" 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>By transfecting rat myocyte and pheochromocytoma cell lines, <a href="#7" class="mim-tip-reference" title="Chong, J. A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J. J., Zheng, Y., Boutros, M. C., Altshuller, Y. M., Frohman, M. A., Kraner, S. D., Mandel, G. &lt;strong&gt;REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.&lt;/strong&gt; Cell 80: 949-957, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7697725/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7697725&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0092-8674(95)90298-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7697725">Chong et al. (1995)</a> showed that human REST downregulated expression of the type II voltage-dependent sodium channel (see <a href="/entry/182390">182390</a>). They proposed that REST suppresses expression of the channel in nonneuronal tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697725" 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="#29" class="mim-tip-reference" title="Thiel, G., Lietz, M., Cramer, M. &lt;strong&gt;Biological activity and modulator structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes.&lt;/strong&gt; J. Biol. Chem. 273: 26891-26899, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9756936/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9756936&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.273.41.26891&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9756936">Thiel et al. (1998)</a> noted that the REST binding sites of several neuron-specific genes, such as those encoding synapsin I (<a href="/entry/313440">313440</a>), SCG10 (<a href="/entry/600621">600621</a>), A1-glycine receptor (<a href="/entry/138491">138491</a>), the B2 subunit of the nicotinic acetylcholine receptor (<a href="/entry/118507">118507</a>), and the M4-subunit of the muscarinic acetylcholine receptor, are found at various positions within the sequence. By transfecting these sequences in reporter constructs together with REST, <a href="#29" class="mim-tip-reference" title="Thiel, G., Lietz, M., Cramer, M. &lt;strong&gt;Biological activity and modulator structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes.&lt;/strong&gt; J. Biol. Chem. 273: 26891-26899, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9756936/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9756936&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.273.41.26891&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9756936">Thiel et al. (1998)</a> found that REST blocks transcription of a gene irrespective of whether the NRSE is located upstream or downstream of the open reading frame in either orientation and in both a distance- and a gene-independent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9756936" 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="#1" class="mim-tip-reference" title="Abderrahmani, A., Steinmann, M., Plaisance, V., Niederhauser, G., Haefliger, J.-A., Mooser, V., Bonny, C., Nicod, P., Waeber, G. &lt;strong&gt;The transcriptional repressor REST determines the cell-specific expression of the human MAPK8IP1 gene encoding IB1 (JIP-1).&lt;/strong&gt; Molec. Cell. Biol. 21: 7256-7627, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11585908/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11585908&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=11585908[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1128/MCB.21.21.7256-7267.2001&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11585908">Abderrahmani et al. (2001)</a> identified an NRSE sequence in the promoter region of MAPK8PI1 (<a href="/entry/604641">604641</a>), which is expressed exclusively in neuronal tissue and pancreatic B cells. They confirmed that REST binds to the NRSE element of MAPK8PI1 and found that transfection and expression of REST in a B-cell line represses MAPK8PI1 transcription. Conversely, the introduction of a mutated NRSE into the MAPK8PI1 promoter allowed MAPK8PI1 expression in non-B-cell and nonneuronal cell lines. REST-mediated repression was found to be dependent on histone deacetylase (see <a href="/entry/601241">601241</a>) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11585908" 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="#16" class="mim-tip-reference" title="Lunyak, V. V., Burgess, R., Prefontaine, G. G., Nelson, C., Sze, S.-H., Chenoweth, J., Schwartz, P., Pevzner, P. A., Glass, C., Mandel, G., Rosenfeld, M. G. &lt;strong&gt;Corepressor-dependent silencing of chromosomal regions encoding neuronal genes.&lt;/strong&gt; Science 298: 1747-1752, 2002. Note: Erratum: Science 299: 1663 only, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12399542/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12399542&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1076469&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12399542">Lunyak et al. (2002)</a> reported that the zinc finger gene-specific repressor element REST can mediate extraneuronal restriction by imposing either active repression via histone deacetylase recruitment or long-term gene silencing using a distinct functional complex. Silencing of neuronal-specific genes requires the recruitment of an associated corepressor, COREST (<a href="/entry/607675">607675</a>), that serves as a functional molecular beacon for recruitment of molecular machinery that imposes silencing across a chromosomal interval, including transcriptional units that do not themselves contain REST/NRSF response elements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12399542" 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>Using indexing-based differential display PCR on neuronal precursor cells to study gene expression in Down syndrome (<a href="/entry/190685">190685</a>), <a href="#2" class="mim-tip-reference" title="Bahn, S., Mimmack, M., Ryan, M., Caldwell, M. A., Jauniaux, E., Starkey, M., Svendsen, C. N., Emson, P. &lt;strong&gt;Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down&#x27;s syndrome: a gene expression study.&lt;/strong&gt; Lancet 359: 310-315, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11830198/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11830198&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(02)07497-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11830198">Bahn et al. (2002)</a> found that genes regulated by the REST transcription factor were selectively repressed. One of these genes, SCG10, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. In cell culture, the Down syndrome cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830198" 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>The huntingtin gene (HTT; <a href="/entry/613004">613004</a>) is mutated in Huntington disease (HD; <a href="/entry/143100">143100</a>). <a href="#34" class="mim-tip-reference" title="Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E. &lt;strong&gt;Loss of huntingtin-mediated BDNF gene transcription in Huntington&#x27;s disease.&lt;/strong&gt; Science 293: 493-498, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11408619/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11408619&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1059581&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11408619">Zuccato et al. (2001)</a> reported that wildtype but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>). <a href="#35" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. &lt;strong&gt;Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.&lt;/strong&gt; Nature Genet. 35: 76-83, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12881722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12881722&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1219&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12881722">Zuccato et al. (2003)</a> showed that the NRSE is the target of wildtype huntingtin activity on BDNF promoter II. Wildtype huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. <a href="#35" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. &lt;strong&gt;Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.&lt;/strong&gt; Nature Genet. 35: 76-83, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12881722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12881722&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1219&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12881722">Zuccato et al. (2003)</a> showed that this effect occurs through cytoplasmic sequestering of REST/NRSF, the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus was present in Huntington disease. They showed that wildtype huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. They also reported that wildtype huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes was shown in cells, mice, and human brain with Huntington disease. <a href="#35" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. &lt;strong&gt;Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.&lt;/strong&gt; Nature Genet. 35: 76-83, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12881722/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12881722&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1219&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12881722">Zuccato et al. (2003)</a> concluded that wildtype huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identified a novel mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11408619+12881722" 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="#11" class="mim-tip-reference" title="Kemp, D. M., Lin, J. C., Habener, J. F. &lt;strong&gt;Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor.&lt;/strong&gt; J. Biol. Chem. 278: 35057-35062, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12829700/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12829700&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M305891200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12829700">Kemp et al. (2003)</a> identified NRSE-like motifs in several genes involved in pancreas development, including a highly conserved NRSE-like motif in the upstream promoter of PAX4 (<a href="/entry/167413">167413</a>), a gene implicated in differentiation of the insulin-producing beta-cell lineage. Using mammalian cell lines, they found that the NRSE in the upstream promoter of Pax4 formed a DNA-protein complex with Nrsf and conferred Nrsf-dependent transcriptional repression on a reporter gene promoter and the native Pax4 gene promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12829700" 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>Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts. <a href="#12" class="mim-tip-reference" title="Kuwahara, K., Saito, Y., Takano, M., Arai, Y., Yasuno, S., Nakagawa, Y., Takahashi, N., Adachi, Y., Takemura, G., Horie, M., Miyamoto, Y., Morisaki, T., and 12 others. &lt;strong&gt;NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.&lt;/strong&gt; EMBO J. 22: 6310-6321, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14633990/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14633990&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=14633990[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/emboj/cdg601&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14633990">Kuwahara et al. (2003)</a> showed that Nrsf selectively regulated expression of multiple fetal cardiac genes and played a role in reexpression of these genes in rat neonatal ventricular myocytes. Transgenic mice expressing a dominant-negative Nrsf mutant in their hearts exhibited dilated cardiomyopathy, high susceptibility to arrhythmias, and sudden death. Genes encoding 2 ion channels that carry the fetal cardiac currents I(f) and I(Ca,T), which were induced in Nrsf-transgenic mice and were potentially responsible for both the cardiac dysfunction and arrhythmogenesis, were regulated by Nrsf. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14633990" 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>Neuronal gene transcription is repressed in nonneuronal cells by the REST/NRSF complex. To understand how this silencing is achieved, <a href="#32" class="mim-tip-reference" title="Yeo, M., Lee, S.-K., Lee, B., Ruiz, E. C., Pfaff, S. L., Gill, G. N. &lt;strong&gt;Small CTD phosphatases function in silencing neuronal gene expression.&lt;/strong&gt; Science 307: 596-600, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15681389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15681389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1100801&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15681389">Yeo et al. (2005)</a> examined CTDSP1 (<a href="/entry/605323">605323</a>), CTDSP2 (<a href="/entry/608711">608711</a>), and CTDSPL (<a href="/entry/608592">608592</a>), the small CTD phosphatases (SCP), whose expression is restricted to nonneuronal tissues. <a href="#32" class="mim-tip-reference" title="Yeo, M., Lee, S.-K., Lee, B., Ruiz, E. C., Pfaff, S. L., Gill, G. N. &lt;strong&gt;Small CTD phosphatases function in silencing neuronal gene expression.&lt;/strong&gt; Science 307: 596-600, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15681389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15681389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1100801&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15681389">Yeo et al. (2005)</a> showed that REST/NRSF recruits SCPs to neuronal genes that contain RE1 elements, leading to neuronal gene silencing in nonneuronal cells. Phosphatase-inactive forms of SCP interfere with REST/NRSF function and promote neuronal differentiation of P19 stem cells. Likewise, small interfering RNA directed to the single Drosophila SCP unmasks neuronal gene expression in S2 cells. Thus, <a href="#32" class="mim-tip-reference" title="Yeo, M., Lee, S.-K., Lee, B., Ruiz, E. C., Pfaff, S. L., Gill, G. N. &lt;strong&gt;Small CTD phosphatases function in silencing neuronal gene expression.&lt;/strong&gt; Science 307: 596-600, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15681389/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15681389&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1100801&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15681389">Yeo et al. (2005)</a> concluded that SCP activity is an evolutionarily conserved transcriptional regulator that acts globally to silence neuronal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15681389" 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="#6" class="mim-tip-reference" title="Cheong, A., Bingham, A. J., Li, J., Kumar, B., Sukumar, P., Munsch, C., Buckley, N. J., Neylon, C. B., Porter, K. E., Beech, D. J., Wood, I. C. &lt;strong&gt;Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation.&lt;/strong&gt; Molec. Cell 20: 45-52, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16209944/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16209944&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.molcel.2005.08.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16209944">Cheong et al. (2005)</a> identified a functional REST-binding sequence in the promoter region of the KCNN4 gene (<a href="/entry/602754">602754</a>). REST was expressed in the nuclei of human vascular smooth muscle cells (SMCs), and it downregulated KCNN4 expression in mouse and human vascular SMCs. Downregulated REST and upregulated KCNN4 were evident in SMCs of human neointimal hyperplasia grown in organ culture, and exogenous REST reduced the functional impact of KCNN4. <a href="#6" class="mim-tip-reference" title="Cheong, A., Bingham, A. J., Li, J., Kumar, B., Sukumar, P., Munsch, C., Buckley, N. J., Neylon, C. B., Porter, K. E., Beech, D. J., Wood, I. C. &lt;strong&gt;Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation.&lt;/strong&gt; Molec. Cell 20: 45-52, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16209944/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16209944&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.molcel.2005.08.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16209944">Cheong et al. (2005)</a> concluded that REST acts as a switch to regulate potassium channel expression and consequently the phenotype of vascular smooth muscle cells and human vascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16209944" 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="#24" class="mim-tip-reference" title="Plaisance, V., Niederhauser, G., Azzouz, F., Lenain, V., Haefliger, J.-A., Waeber, G., Abderrahmani, A. &lt;strong&gt;The repressor element silencing transcription factor (REST)-mediated transcriptional repression requires the inhibition of Sp1.&lt;/strong&gt; J. Biol. Chem. 280: 401-407, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15528196/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15528196&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M411825200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15528196">Plaisance et al. (2005)</a> showed that the transcriptional factor Sp1 (<a href="/entry/189906">189906</a>) was required for expression of most Rest target genes in mouse insulin-secreting cells and rat neuronal-like cells where Rest is absent. Inhibition of REST in HeLa cells and in mouse beta cells restored the transcriptional activity of Sp1. Coimmunoprecipitation and transfection assays indicated that the C-terminal repressor domain of REST was required for interaction with Sp1 and inhibited its activity. Silencing of Sp1 by REST required histone deacetylase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15528196" 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="#28" class="mim-tip-reference" title="Tahiliani, M., Mei, P., Fang, R., Leonor, T., Rutenberg, M., Shimizu, F., Li, J., Rao, A., Shi, Y. &lt;strong&gt;The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.&lt;/strong&gt; Nature 447: 601-605, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17468742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17468742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05823&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17468742">Tahiliani et al. (2007)</a> showed that JARID1C/SMCX (<a href="/entry/314690">314690</a>), a JmjC domain-containing protein implicated in X-linked mental retardation and epilepsy, possesses H3K4 tridemethylase activity and functions as a transcriptional repressor. An SMCX complex isolated from HeLa cells contained additional chromatin modifiers (the histone deacetylases HDAC1 (<a href="/entry/601241">601241</a>) and HDAC2 (<a href="/entry/605164">605164</a>), and the histone H3K9 methyltransferase G9a (<a href="/entry/604599">604599</a>)) and the transcriptional repressor REST, suggesting a direct role for SMCX in chromatin dynamics and REST-mediated repression. Chromatin immunoprecipitation revealed that SMCX and REST co-occupy the neuron-restrictive silencing elements in the promoters of a subset of REST target genes. RNA interference-mediated depletion of SMCX derepressed several of these targets and simultaneously increased H3K4 trimethylation at the sodium channel type 2A (SCN2A; <a href="/entry/182390">182390</a>) and synapsin I (SYN1; <a href="/entry/313440">313440</a>) promoters. <a href="#28" class="mim-tip-reference" title="Tahiliani, M., Mei, P., Fang, R., Leonor, T., Rutenberg, M., Shimizu, F., Li, J., Rao, A., Shi, Y. &lt;strong&gt;The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.&lt;/strong&gt; Nature 447: 601-605, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17468742/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17468742&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature05823&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17468742">Tahiliani et al. (2007)</a> proposed that loss of SMCX activity impairs REST-mediated neuronal gene regulation, thereby contributing to SMCX-associated X-linked mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17468742" 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="#9" class="mim-tip-reference" title="Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G. &lt;strong&gt;Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.&lt;/strong&gt; Molec. Cell 31: 347-359, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18691967/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18691967&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18691967[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.molcel.2008.05.023&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18691967">Ding et al. (2008)</a> found that purified HeLa cell mediator complexes that included MED12 (<a href="/entry/300188">300188</a>) interacted directly with the G9A and REST. Endogenous REST in HEK293 cells suppressed expression of a reporter gene bearing RE1 sites, and knockdown of either MED12 or G9A abrogated the suppression. Depletion of MED12 significantly reduced the association of G9A with RE1 elements and decreased the level of H3K9 dimethylation by G9A without influencing RE1 site occupancy by REST. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18691967" 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>Using an unbiased screen, <a href="#10" class="mim-tip-reference" title="Guardavaccaro, D., Frescas, D., Dorrello, N. V., Peschiaroli, A., Multani, A. S., Cardozo, T., Lasorella, A., Iavarone, A., Chang, S., Hernando, E., Pagano, M. &lt;strong&gt;Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.&lt;/strong&gt; Nature 452: 365-369, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18354482/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18354482&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18354482[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06641&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18354482">Guardavaccaro et al. (2008)</a> demonstrated that REST is an interactor with the F-box protein beta-TRCP (<a href="/entry/603482">603482</a>). REST is degraded by means of the ubiquitin beta-TRCP during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2 (<a href="/entry/601467">601467</a>), an essential component of the spindle assembly checkpoint. The expression in cultured cells of a stable REST mutant, which is unable to bind beta-TRCP, inhibited Mad2 expression and resulted in a phenotype analogous to that observed in Mad2 heterozygous cells. In particular, <a href="#10" class="mim-tip-reference" title="Guardavaccaro, D., Frescas, D., Dorrello, N. V., Peschiaroli, A., Multani, A. S., Cardozo, T., Lasorella, A., Iavarone, A., Chang, S., Hernando, E., Pagano, M. &lt;strong&gt;Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.&lt;/strong&gt; Nature 452: 365-369, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18354482/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18354482&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18354482[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06641&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18354482">Guardavaccaro et al. (2008)</a> observed defects that were consistent with faulty activation of the spindle checkpoint, such as shortened mitosis, premature sister-chromatid separation, chromosome bridges and missegregation in anaphase, tetraploidy, and a faster mitotic slippage in the presence of a spindle inhibitor. An indistinguishable phenotype was observed by expressing the oncogenic REST-FS mutant, which does not bind beta-TRCP. Thus, beta-TRCP-dependent degradation of REST during G2 permits the optimal activation of the spindle checkpoint, and consequently it is required for the fidelity of mitosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18354482" 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="#30" class="mim-tip-reference" title="Westbrook, T. F., Hu, G., Ang, X. L., Mulligan, P., Pavlova, N. N., Liang, A., Leng, Y., Maehr, R., Shi, Y., Harper, J. W., Elledge, S. J. &lt;strong&gt;SCF-(beta-TRCP) controls oncogenic transformation and neural differentiation through REST degradation.&lt;/strong&gt; Nature 452: 370-374, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18354483/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18354483&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18354483[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06780&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18354483">Westbrook et al. (2008)</a> showed that REST is regulated by ubiquitin-mediated proteolysis, and used an RNA interference screen to identify a Skp1-Cul1-F-box protein complex containing the F-box protein beta-TRCP as an E3 ubiquitin ligase responsible for REST degradation. Beta-TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron. During neural differentiation, REST is degraded in a beta-TRCP-dependent manner. Beta-TRCP is required for proper neural differentiation only in the presence of REST, indicating that beta-TRCP facilitates this process through degradation of REST. Conversely, failure to degrade REST attenuates differentiation. Furthermore, <a href="#30" class="mim-tip-reference" title="Westbrook, T. F., Hu, G., Ang, X. L., Mulligan, P., Pavlova, N. N., Liang, A., Leng, Y., Maehr, R., Shi, Y., Harper, J. W., Elledge, S. J. &lt;strong&gt;SCF-(beta-TRCP) controls oncogenic transformation and neural differentiation through REST degradation.&lt;/strong&gt; Nature 452: 370-374, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18354483/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18354483&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18354483[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06780&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18354483">Westbrook et al. (2008)</a> found that beta-TRCP overexpression, which is common in human epithelial cancers, causes oncogenic transformation of human mammary epithelial cells and that this pathogenic function requires REST degradation. Thus, <a href="#30" class="mim-tip-reference" title="Westbrook, T. F., Hu, G., Ang, X. L., Mulligan, P., Pavlova, N. N., Liang, A., Leng, Y., Maehr, R., Shi, Y., Harper, J. W., Elledge, S. J. &lt;strong&gt;SCF-(beta-TRCP) controls oncogenic transformation and neural differentiation through REST degradation.&lt;/strong&gt; Nature 452: 370-374, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18354483/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18354483&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18354483[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06780&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18354483">Westbrook et al. (2008)</a> concluded that REST is a key target in beta-TRCP-driven transformation and that the beta-TRCP-REST axis is a new regulatory pathway controlling neurogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18354483" 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="#27" class="mim-tip-reference" title="Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H., Majumder, S. &lt;strong&gt;REST maintains self-renewal and pluripotency of embryonic stem cells.&lt;/strong&gt; Nature 453: 223-227, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18362916/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18362916&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18362916[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06863&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18362916">Singh et al. (2008)</a> demonstrated that REST maintains self-renewal and pluripotency in mouse ES cells through suppression of the microRNA miR21 (<a href="/entry/611020">611020</a>). The authors found that, as with known self-renewal markers, the level of REST expression is much higher in self-renewing mouse embryonic stem (ES) cells than in differentiating mouse ES (embryoid body, EB) cells. Heterozygous deletion of Rest and its short interfering RNA (siRNA)-mediated knockdown in mouse ES cells caused a loss of self-renewal--even when these cells were grown under self-renewal conditions--and led to the expression of markers specific for multiple lineages. Conversely, exogenously added REST maintained self-renewal in mouse EB cells. Furthermore, Rest heterozygous mouse ES cells cultured under self-renewal conditions expressed substantially reduced levels of several self-renewal regulators, including Oct4 (<a href="/entry/164177">164177</a>), Nanog (<a href="/entry/607937">607937</a>), Sox2 (<a href="/entry/184429">184429</a>), and c-Myc (<a href="/entry/190080">190080</a>), and exogenously added Rest in mouse EB cells maintained the self-renewal phenotypes and expression of these self-renewal regulators. <a href="#27" class="mim-tip-reference" title="Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H., Majumder, S. &lt;strong&gt;REST maintains self-renewal and pluripotency of embryonic stem cells.&lt;/strong&gt; Nature 453: 223-227, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18362916/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18362916&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18362916[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06863&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18362916">Singh et al. (2008)</a> also demonstrated that in mouse ES cells, Rest is bound to the gene chromatin of a set of miRNAs that potentially target self-renewal genes. Whereas mouse ES cells and mouse EB cells containing exogenously added Rest expressed lower levels of these miRNAs, EB cells, Rest heterozygous ES cells, and ES cells treated with siRNA targeting Rest expressed higher levels of these miRNAs. At least one of these REST-regulated miRNAs, miR21, specifically suppressed the self-renewal of mouse ES cells, corresponding to the decreased expression of Oct4, Nanog, Sox2, and c-Myc. Thus, <a href="#27" class="mim-tip-reference" title="Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H., Majumder, S. &lt;strong&gt;REST maintains self-renewal and pluripotency of embryonic stem cells.&lt;/strong&gt; Nature 453: 223-227, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18362916/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18362916&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18362916[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06863&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18362916">Singh et al. (2008)</a> concluded that REST is an element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mouse ES cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18362916" 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>Using a transchromosomic mouse model of Down syndrome, <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> showed that a 30 to 60% reduced expression of Nrsf/Rest, a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 (see <a href="/entry/190685">190685</a>) from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic ES cells, <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A (<a href="/entry/600855">600855</a>). The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (<a href="/entry/607937">607937</a>) and Sox2 (<a href="/entry/184429">184429</a>), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (<a href="/entry/600576">600576</a>) and a strongly reduced neuroectodermal progenitor compartment. <a href="#4" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and new rationales for therapeutic approaches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18771760" 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>Using yeast 2-hybrid and immunoprecipitation analyses, <a href="#26" class="mim-tip-reference" title="Shimojo, M. &lt;strong&gt;Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150-Glued.&lt;/strong&gt; J. Biol. Chem. 283: 34880-34886, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18922795/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18922795&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18922795[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1074/jbc.M804183200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18922795">Shimojo (2008)</a> showed that human RILP (PRICKLE1; <a href="/entry/608500">608500</a>) and huntingtin interacted directly with dynactin-1 (DCTN1; <a href="/entry/601143">601143</a>) to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in nonneuronal cells. In neuronal cells, the complex also contained HAP1 (<a href="/entry/600947">600947</a>), which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18922795" 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>At the point of mitotic exit within the vertebrate nervous system, when cells lose multipotency and begin to develop stable connections that will persist over life, a switch in ATP-dependent chromatin-remodeling mechanisms occurs. This switch involves the exchange of the BAF53A and BAF45A (PHF10; <a href="/entry/613069">613069</a>) subunits within Swi/Snf-like neural progenitor-specific BAF (npBAF) complexes for the homologous BAF53B (ACTL6B; <a href="/entry/612458">612458</a>) and BAF45B (DPF1; <a href="/entry/601670">601670</a>) subunits within neuron-specific BAF (nBAF) complexes in postmitotic neurons. The subunits of the npBAF complex are essential for neural progenitor proliferation, and mice with reduced dosage for the genes encoding its subunits have defects in neural tube closure similar to those in human spina bifida. In contrast, BAF53B and the nBAF complex are essential for an evolutionarily conserved program of postmitotic neural development and dendritic morphogenesis. <a href="#33" class="mim-tip-reference" title="Yoo, A. S., Staahl, B. T., Chen, L., Crabtree, G. R. &lt;strong&gt;MicroRNA-mediated switching of chromatin-remodelling complexes in neural development.&lt;/strong&gt; Nature 460: 642-646, 2009. Note: Erratum: Nature 461: 296 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19561591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19561591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19561591[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature08139&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19561591">Yoo et al. (2009)</a> showed that this essential transition is mediated by repression of BAF53A by miR9* (an miRNA processed from the opposite arm of the miR9 (<a href="/entry/611186">611186</a>) stem-loop precursor) and miR124 (<a href="/entry/609327">609327</a>). They found that BAF53a repression is mediated by sequences in the 3-prime untranslated region corresponding to the recognition sites for miR9* and miR124, which are selectively expressed in postmitotic neurons. Mutation of these sites led to persistent expression of BAF53A and defective activity-dependent dendritic outgrowth in neurons. In addition, overexpression of miR9* and miR124 in neural progenitors caused reduced proliferation. miR9* and miR124 are repressed by REST. <a href="#33" class="mim-tip-reference" title="Yoo, A. S., Staahl, B. T., Chen, L., Crabtree, G. R. &lt;strong&gt;MicroRNA-mediated switching of chromatin-remodelling complexes in neural development.&lt;/strong&gt; Nature 460: 642-646, 2009. Note: Erratum: Nature 461: 296 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19561591/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19561591&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19561591[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature08139&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19561591">Yoo et al. (2009)</a> showed that expression of REST in postmitotic neurons led to derepression of BAF53A, indicating that REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19561591" 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="#14" class="mim-tip-reference" title="Loe-Mie, Y., Lepagnol-Bestel, A.-M., Maussion, G., Doron-Faigenboim, A., Imbeaud, S., Delacroix, H., Aggerbeck, L., Pupko, T., Gorwood, P., Simonneau, M., Moalic, J.-M. &lt;strong&gt;SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.&lt;/strong&gt; Hum. Molec. Genet. 19: 2841-2857, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20457675/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20457675&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq184&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20457675">Loe-Mie et al. (2010)</a> showed that an SWI/SNF-centered network including the Smarca2 gene (<a href="/entry/600014">600014</a>) was modified by the downregulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF downregulation also modified the levels of Smarce1 (<a href="/entry/603111">603111</a>), Smarcd3 (<a href="/entry/601737">601737</a>), and SWI/SNF interactors (Hdac1, <a href="/entry/601241">601241</a>; RcoR, <a href="/entry/607675">607675</a>; and Mecp2, <a href="/entry/300005">300005</a>). Smarca2 downregulation generated an abnormal dendritic spine morphology that was an intermediate phenotype of schizophrenia (see <a href="/entry/181500">181500</a>). The authors noted that 8 genomewide-supported schizophrenia-associated genes (SMARCA2; CSF2RA, <a href="/entry/306250">306250</a>; HIST1H2BJ, <a href="/entry/615044">615044</a>; NOTCH4, <a href="/entry/164951">164951</a>; NRGN, <a href="/entry/602350">602350</a>; SHOX, <a href="/entry/312865">312865</a>; TCF4, <a href="/entry/602272">602272</a>; and ZNF804A, <a href="/entry/612282">612282</a>) are part of an interacting network; 5 of the 8, including SMARCA2, encode transcription regulators, and 3 (TCF4, SMARCA2, and CSF2RA) were modified at the level of expression when the REST/NRSF-SWI/SNF chromatin remodeling complex was experimentally manipulated in mouse cell lines and in transgenic mouse models. REST/NRSF-SWI/SNF deregulation also resulted in the differential expression of genes that are clustered in chromosomes, suggesting the induction of genomewide epigenetic changes. <a href="#14" class="mim-tip-reference" title="Loe-Mie, Y., Lepagnol-Bestel, A.-M., Maussion, G., Doron-Faigenboim, A., Imbeaud, S., Delacroix, H., Aggerbeck, L., Pupko, T., Gorwood, P., Simonneau, M., Moalic, J.-M. &lt;strong&gt;SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.&lt;/strong&gt; Hum. Molec. Genet. 19: 2841-2857, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20457675/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20457675&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq184&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20457675">Loe-Mie et al. (2010)</a> concluded that the SWI/SNF chromatin remodeling complex is a key component of the genetic architecture of schizophrenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20457675" 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="#31" class="mim-tip-reference" title="Yang, Y. J., Baltus, A. E., Mathew, R. S., Murphy, E. A., Evrony, G. D., Gonzalez, D. M., Wang, E. P., Marshall-Walker, C. A., Barry, B. J., Murn, J., Tatarakis, A., Mahajan, M. A., Samuels, H. H., Shi, Y., Golden, J. A., Mahajnah, M., Shenhav, R., Walsh, C. A. &lt;strong&gt;Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.&lt;/strong&gt; Cell 151: 1097-1112, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23178126/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23178126&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23178126[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2012.10.043&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23178126">Yang et al. (2012)</a> demonstrated that ZNF335 (<a href="/entry/610827">610827</a>) acts upstream of REST and regulates its expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23178126" 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="#8" class="mim-tip-reference" title="Das, C. M., Taylor, P., Gireud, M., Singh, A., Lee, D., Fuller, G., Ji, L., Fangusaro, J., Rajaram, V., Goldman, S., Eberhart, C., Gopalakrishnan, V. &lt;strong&gt;The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.&lt;/strong&gt; Oncogene 32: 1691-1701, 2013. Note: Erratum: Oncogene 35: 6153-6154, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22665064/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22665064&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22665064[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/onc.2012.182&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22665064">Das et al. (2013)</a> found that knockdown of REST resulted in a decline in medulloblastoma cell proliferation and accumulation of p27 (CDKN1B; <a href="/entry/600778">600778</a>). In vitro analysis showed that REST and p27 expression were reciprocally correlated in human medulloblastoma samples. REST repressed expression of USP37 (<a href="/entry/620226">620226</a>), and USP37 expression promoted p27 deubiquitination. USP37 interacted with p27 to promote its deubiquitination and stabilization, thereby blocking cell proliferation. The authors concluded that REST regulates p27 stability and cell proliferation by controlling USP37. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22665064" 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="#15" class="mim-tip-reference" title="Lu, T., Aron, L., Zullo, J., Pan, Y., Kim, H., Chen, Y., Yang, T.-H., Kim, H.-M., Drake, D., Liu, X. S., Bennett, D. A., Colaiacovo, M. P., Yankner, B. A. &lt;strong&gt;REST and stress resistance in ageing and Alzheimer&#x27;s disease.&lt;/strong&gt; Nature 507: 448-454, 2014. Note: Erratum: Nature 540: 470 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24670762/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24670762&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24670762[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature13163&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24670762">Lu et al. (2014)</a> demonstrated that induction of REST is a universal feature of normal aging in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer disease (AD; <a href="/entry/104300">104300</a>). Chromatin immunoprecipitation with deep sequencing and expression analysis showed that REST represses genes that promote cell death and AD pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and beta-amyloid (see <a href="/entry/104760">104760</a>) protein toxicity, and conditional deletion of Rest in the mouse brain leads to age-related neurodegeneration. A functional ortholog of REST, C. elegans Spr4, also protects against oxidative stress and beta-amyloid protein toxicity. During normal aging, REST is induced in part by cell-nonautonomous Wnt signaling. However, in Alzheimer disease, frontotemporal dementia (FTD; <a href="/entry/600274">600274</a>), and dementia with Lewy bodies (DLB; <a href="/entry/127750">127750</a>), REST is lost from the nucleus and appears in autophagosomes together with pathologic misfolded proteins. Finally, REST levels during aging are closely correlated with cognitive preservation and longevity. <a href="#15" class="mim-tip-reference" title="Lu, T., Aron, L., Zullo, J., Pan, Y., Kim, H., Chen, Y., Yang, T.-H., Kim, H.-M., Drake, D., Liu, X. S., Bennett, D. A., Colaiacovo, M. P., Yankner, B. A. &lt;strong&gt;REST and stress resistance in ageing and Alzheimer&#x27;s disease.&lt;/strong&gt; Nature 507: 448-454, 2014. Note: Erratum: Nature 540: 470 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24670762/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24670762&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24670762[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature13163&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24670762">Lu et al. (2014)</a> therefore concluded that the activation state of REST may distinguish neuroprotection from neurodegeneration in the aging brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24670762" 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="#36" class="mim-tip-reference" title="Zullo, J. M., Drake, D., Aron, L., O&#x27;Hern, P., Dhamne, S. C., Davidsohn, N., Mao, C.-A., Klein, W. H., Rotenberg, A., Bennett, D. A., Church, G. M., Colaiacovo, M. P., Yankner, B. A. &lt;strong&gt;Regulation of lifespan by neural excitation and REST.&lt;/strong&gt; Nature 574: 359-364, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31619788/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31619788&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31619788[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1647-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31619788">Zullo et al. (2019)</a> showed that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In C. elegans, neural excitation increases with age, and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, Rest-deficient mice exhibit increased cortical activity and neuronal excitability during aging. Similarly, loss-of-function mutations in the C. elegans REST ortholog genes spr3 and spr4 elevate neural excitation and reduce the lifespan of long-lived daf2 mutants. In wildtype worms, overexpression of spr4 suppresses excitation and extends lifespan. REST, spr3, spr4, and reduced excitation activated the longevity-associated transcription factors FOXO1 (<a href="/entry/136533">136533</a>) and daf16 in mammals and worms, respectively. <a href="#36" class="mim-tip-reference" title="Zullo, J. M., Drake, D., Aron, L., O&#x27;Hern, P., Dhamne, S. C., Davidsohn, N., Mao, C.-A., Klein, W. H., Rotenberg, A., Bennett, D. A., Church, G. M., Colaiacovo, M. P., Yankner, B. A. &lt;strong&gt;Regulation of lifespan by neural excitation and REST.&lt;/strong&gt; Nature 574: 359-364, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31619788/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31619788&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=31619788[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/s41586-019-1647-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31619788">Zullo et al. (2019)</a> concluded that their findings revealed a conserved mechanism of aging that is mediated by neural circuit activity and regulated by REST. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31619788" 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 id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Wilms Tumor 6</em></strong></p><p>
<a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> identified 11 different REST mutations (see, e.g., <a href="#0001">600571.0001</a>-<a href="#0003">600571.0003</a>) in 16 individuals from 4 families and 9 nonfamilial Wilms tumor (WT6; <a href="/entry/616806">616806</a>) pedigrees. Ten of the 11 different mutations, including all of the nonsynonymous mutations, clustered in the DNA binding domain of REST. In 4 cases for whom parental DNA was available, 1 mutation had occurred de novo and 3 had been inherited, confirming incomplete penetrance. None was present in ICR1000 exome series of 993 or in the 61,312 individuals in the ExAC browser. All tested variants showed abrogation of REST function. <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> concluded that their data established REST as a Wilms tumor predisposition gene accounting for approximately 2% of Wilms tumors, and recommended screening of REST in all familial cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26551668" 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>Gingival Fibromatosis 5</em></strong></p><p>
In a 11 patients from 3 unrelated Turkish families with gingival fibromatosis-5 (GINGF5; <a href="/entry/617626">617626</a>), <a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> identified 3 different heterozygous truncating mutations in the REST gene (<a href="#0004">600571.0004</a>-<a href="#0006">600571.0006</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in 2 families; the mutation in the proband of the third family occurred de novo. A mildly affected father in 1 of the families was mosaic for the mutation. All mutations occurred in the final exon of the gene, which may result in escape from nonsense-mediated mRNA decay, suggesting that the alleles may act through a dominant-negative or gain-of-function effect. <a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> noted that studies have suggested that the disorder results from excessive accumulation of extracellular matrix components, particularly collagen type I, which may be due to abnormal expression of TGF-beta (TGFB1; <a href="/entry/190180">190180</a>) and IL6 (<a href="/entry/147620">147620</a>). The mutant transcripts may reduce the repressor function of REST on the collagen synthesis pathway, resulting in the accumulation of collagen in gingiva. However, functional studies of the REST variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686854" 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 4 affected members of a Brazilian family with mild gingival overgrowth, <a href="#17" class="mim-tip-reference" title="Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H. &lt;strong&gt;New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.&lt;/strong&gt; J. Periodont. 94: 108-118, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35665929/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35665929&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/JPER.22-0219&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35665929">Machado et al. (2023)</a> identified heterozygosity for a 2-bp deletion in the REST gene (<a href="#0009">600571.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35665929" 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>Autosomal Dominant Deafness 27</em></strong></p><p>
In a 3-generation family with autosomal dominant hearing loss mapping to chromosome 4q12-q13.1 (DFNA27; <a href="/entry/612431">612431</a>), <a href="#20" class="mim-tip-reference" title="Nakano, Y., Kelly, M. C., Rehman, A. U., Boger, E. T., Morell, R. J., Kelley, M. W., Friedman, T. B., Banfi, B. &lt;strong&gt;Defects in the alternative splicing-dependent regulation of REST cause deafness.&lt;/strong&gt; Cell 174: 536-548, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29961578/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29961578&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29961578[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2018.06.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29961578">Nakano et al. (2018)</a> identified heterozygosity for an intronic variant in the REST gene (<a href="#0007">600571.0007</a>) that segregated fully with deafness in the family and was not found in public variant databases. Functional analysis revealed that the DFNA27-associated REST variant causes gain or loss of function depending on the cellular context: in cells lacking the splicing factor SRRM4 (<a href="/entry/613103">613103</a>), it causes REST inactivation (loss of function), whereas in cells expressing SRRM4, such as neurons and mechanosensory hair cells of the ear, the variant prevents REST inactivation by alternative splicing (gain of function), thus abrogating its normal downregulation in differentiating neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29961578" 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 South African Xhosa mother and son with progressive prelingual sensorineural hearing loss, <a href="#19" class="mim-tip-reference" title="Manyisa, N., Schrauwen, I., Alves de Souza Rios, L., Mowla, S., Tekendo-Ngongang, C., Popel, K., Esoh, K., Bharadwaj, T., Nouel-Saied, L. M., Acharya, A., Nasir, A., Wonkam-Tingang, E., de Kock, C., Dandara C., Leal, S. M., Wonkam, A. &lt;strong&gt;A monoallelic variant in REST is associated with non-syndromic autosomal dominant hearing impairment in a South African family.&lt;/strong&gt; Genes 12: 1765, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34828371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34828371&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=34828371[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3390/genes12111765&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34828371">Manyisa et al. (2021)</a> identified heterozygosity for a missense mutation in the REST gene (C415S; <a href="#0008">600571.0008</a>) that segregated with disease in the family and was not found in controls or in public variant databases. Functional analysis revealed perturbation of cellular localization and loss of function with the mutant compared to wildtype REST. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34828371" 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="#5" class="mim-tip-reference" title="Chen, Z.-F., Paquette, A. J., Anderson, D. J. &lt;strong&gt;NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis.&lt;/strong&gt; Nature Genet. 20: 136-142, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9771705/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9771705&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/2431&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9771705">Chen et al. (1998)</a> disrupted the Rest gene in mice by gene targeting in mouse embryonic stem cells. As a result, derepression of neuron-specific tubulin (<a href="/entry/602529">602529</a>) in a subset of nonneural tissues resulted and embryonic lethality ensued. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771705" 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="Lepagnol-Bestel, A.-M., Zvara, A., Maussion, G., Quignon, F., Ngimbous, B., Ramoz, N., Imbeaud, S., Loe-Mie, Y., Benihoud, K., Agier, N., Salin, P. A., Cardona, A., and 11 others. &lt;strong&gt;DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.&lt;/strong&gt; Hum. Molec. Genet. 18: 1405-1414, 2009. Note: Erratum: Hum. Molec. Genet. 31: 2106-2107, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19218269/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19218269&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19218269">Lepagnol-Bestel et al. (2009)</a> used the transgenic 152F7 mouse model of Down syndrome (<a href="/entry/190685">190685</a>) to show that the DYRK1A (<a href="/entry/600855">600855</a>) gene dosage imbalance deregulated chromosomal clusters of genes located near REST/NRSF binding sites. Dyrk1a bound the SWI/SNF complex (see <a href="/entry/603111">603111</a>), which is known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam (<a href="/entry/308840">308840</a>) modified the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbed Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. In transgenic embryonic brain subregions, the authors identified a coordinated deregulation of multiple genes that responsible for dendritic growth impairment. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. <a href="#13" class="mim-tip-reference" title="Lepagnol-Bestel, A.-M., Zvara, A., Maussion, G., Quignon, F., Ngimbous, B., Ramoz, N., Imbeaud, S., Loe-Mie, Y., Benihoud, K., Agier, N., Salin, P. A., Cardona, A., and 11 others. &lt;strong&gt;DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.&lt;/strong&gt; Hum. Molec. Genet. 18: 1405-1414, 2009. Note: Erratum: Hum. Molec. Genet. 31: 2106-2107, 2022.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19218269/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19218269&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp047&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19218269">Lepagnol-Bestel et al. (2009)</a> proposed that both the DYRK1A overexpression-related neuronal gene deregulation (via disturbance of REST/NRSF levels) and the REST/NRSF-SWI/SNF chromatin remodeling complex significantly contribute to the neural phenotypic changes that characterize Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19218269" 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="#20" class="mim-tip-reference" title="Nakano, Y., Kelly, M. C., Rehman, A. U., Boger, E. T., Morell, R. J., Kelley, M. W., Friedman, T. B., Banfi, B. &lt;strong&gt;Defects in the alternative splicing-dependent regulation of REST cause deafness.&lt;/strong&gt; Cell 174: 536-548, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29961578/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29961578&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29961578[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2018.06.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29961578">Nakano et al. (2018)</a> found that heterozygous deletion of exon 4 of mouse Rest activated the apoptotic pathway and caused hair cell death in a cell-autonomous manner, resulting in balance defects and deafness. Single-cell quantitative RT-PCR revealed that alternative splicing of Rest exon 4 regulated gene expression specifically in hair cells. As a result, lack of exon 4-dependent alternative splicing in mutant mice reduced expression of many hearing-related genes, especially genes critical for development and function of hair cells, causing defects in cilia of utricles. In vitro studies demonstrated that HDAC inhibitors increased expression of many Rest target genes and prevented degeneration of outer hair cells of mutant mice in organ cultures. The HDAC inhibitor SAHA (Vorinostat) rescued hair cells and hearing of Rest mutant mice in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29961578" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>9 Selected Examples</a>):</strong>
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&nbsp;&nbsp;<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600571[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<strong>.0001&nbsp;WILMS TUMOR 6, SUSCEPTIBILITY TO</strong>
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REST, 2-BP DEL, 831AT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025310 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025310;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=rs869025310" 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=rs869025310" 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=RCV000207462 OR RCV001230375" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207462, RCV001230375" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207462...</a>
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<p>In 2 sisters (FAM0482) and an unrelated individual (FAM00250) with Wilms tumor (WT6; <a href="/entry/616806">616806</a>), <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> identified a heterozygous 2-bp deletion (c.831_832delAT, ENST00000309042) in the DNA binding domain of the REST gene resulting in frameshift. The mutation was inherited from the mother by the sisters and from the father by the unrelated individual. Age at diagnosis was 3.7 and 6.0 years in the sisters, and 3.2 years in the unrelated individual. Histology of the sisters' tumors showed triphasic (blastemal, epithelial, and stromal) elements. <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> noted that this mutation was not identified in the ICR1000 UK exome series or in the ExAC browser. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26551668" 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>.0002&nbsp;WILMS TUMOR 6, SUSCEPTIBILITY TO</strong>
</span>
</h4>
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REST, 4-BP DEL, 772GTGA
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</span>
&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025311 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025311;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=rs869025311" 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=rs869025311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000207468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207468</a>
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<p>In 2 first cousins once removed (FAM0509) with Wilms tumor (WT6; <a href="/entry/616806">616806</a>), <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> identified a heterozygous 4-bp deletion (c.772_775delGTGA, ENST00000309042) in the DNA binding domain of the REST gene. In one cousin the mutation was inherited from the mother, age at diagnosis was 2.6 years, and the tumor sample showed triphasic histology. In the other cousin the mutation was inherited from the father, age at diagnosis was 0.8 years, and tumor histology was predominantly blastemal. <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> noted that this mutation was not identified in the ICR1000 UK exome series or in the ExAC browser. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26551668" 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>
<a id="0003" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>.0003&nbsp;WILMS TUMOR 6, SUSCEPTIBILITY TO</strong>
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REST, HIS322ARG
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025312 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025312;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=rs869025312" 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=rs869025312" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000207458" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207458" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207458</a>
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<p>In 2 cousins (FAM0481) and in an unrelated individual (FAM1324) with Wilms tumor (WT6; <a href="/entry/616806">616806</a>), <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> detected a heterozygous c.965A-G transition (c.965A-G, ENST00000309042) in the zinc finger DNA-binding domain of the REST gene, resulting in a his322-to-arg (H322R) substitution. The mutation was paternally inherited in the female cousin and maternally inherited in the male cousin. Age of onset was 3 years in female patient and 0.5 years in the male patient. Inheritance was unknown in the unrelated individual; Wilms tumor developed at 0.5 years of age and was of triphasic histology. Functional studies showed that this variant was unable to repress REST target gene expression, supporting pathogenicity. <a href="#18" class="mim-tip-reference" title="Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others. &lt;strong&gt;Mutations in the transcriptional repressor REST predispose to Wilms tumor.&lt;/strong&gt; Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26551668/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26551668&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng.3440&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26551668">Mahamdallie et al. (2015)</a> noted that this mutation was not identified in the ICR1000 UK exome series or in the ExAC browser. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26551668" 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 id="0004" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>.0004&nbsp;FIBROMATOSIS, GINGIVAL, 5</strong>
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</h4>
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<div style="float: left;">
REST, 2-BP DEL, 2865AA (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000579327" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000579327</a>)
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553904481 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553904481;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=rs1553904481" 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=rs1553904481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000497680 OR RCV000516014 OR RCV001851328" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000497680, RCV000516014, RCV001851328" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000497680...</a>
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<span class="mim-text-font">
<p>In 2 Turkish brothers with gingival fibromatosis-5 (GINGF5; <a href="/entry/617626">617626</a>), <a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> identified a heterozygous 2-bp deletion (c.2865_2866delAA, NM_005612.4) in the last exon (exon 4) of the REST gene, resulting in a frameshift and premature termination (Asn958SerfsTer9). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of more than 6,500 exomes. The father, who had a mild form of the disorder, was mosaic for the mutation. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686854" 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 id="0005" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>.0005&nbsp;FIBROMATOSIS, GINGIVAL, 5</strong>
</span>
</h4>
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<span class="mim-text-font">
<div style="float: left;">
REST, LEU437TER (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000579328" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000579328</a>)
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553904077 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553904077;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=rs1553904077" 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=rs1553904077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000498225 OR RCV000516150" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000498225, RCV000516150" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000498225...</a>
</span>
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<span class="mim-text-font">
<p>In 5 members of a Turkish family with gingival fibromatosis-5 (GINGF5; <a href="/entry/617626">617626</a>), <a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> identified a heterozygous c.1310T-A transversion (c.1310T-A, NM_005612.4) in the last exon (exon 4) of the REST gene, resulting in a leu437-to-ter (L437X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of more than 6,500 exomes. The family was originally reported by <a href="#23" class="mim-tip-reference" title="Pehlivan, D., Abe, S., Ozturk, S., Kayhan, K. B., Gunduz, E., Cefle, K., Bayrak, A., Ark, N., Gunduz, M., Palanduz, S. &lt;strong&gt;Cytogenetic analysis and examination of SOS1 gene mutation in a Turkish family with hereditary gingival fibromatosis.&lt;/strong&gt; J. Hard Tissue Biol. 18: 131-134, 2009."None>Pehlivan et al. (2009)</a>. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686854" 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 id="0006" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>.0006&nbsp;FIBROMATOSIS, GINGIVAL, 5</strong>
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</h4>
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<span class="mim-text-font">
<div style="float: left;">
REST, 1-BP DEL, 2413C (<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=SCV000579329" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ClinVar\', \'domain\': \'ncbi.nlm.nih.gov\'})">SCV000579329</a>)
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&nbsp;&nbsp;
<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553904346 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553904346;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=rs1553904346" 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=rs1553904346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
<span class="mim-text-font">
<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000498949 OR RCV000515908" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000498949, RCV000515908" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000498949...</a>
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<p>In a 9-year-old Turkish girl with gingival fibromatosis-5 (GINGF5; <a href="/entry/617626">617626</a>), <a href="#3" class="mim-tip-reference" title="Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others. &lt;strong&gt;REST final-exon-truncating mutations cause hereditary gingival fibromatosis.&lt;/strong&gt; Am. J. Hum. Genet. 101: 149-156, 2017.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/28686854/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;28686854&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2017.06.006&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="28686854">Bayram et al. (2017)</a> identified a de novo heterozygous 1-bp deletion (c.2413delC, NM_005612.4) in the last exon (exon 4) of the REST gene, resulting in a frameshift and premature termination (Leu805PhefsTer38). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of more than 6,500 exomes. The patient was identified through the GeneMatcher database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28686854" 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&nbsp;DEAFNESS, AUTOSOMAL DOMINANT 27</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">rs1720770872 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1720770872;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=rs1720770872" 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=rs1720770872" 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=RCV000855719" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000855719" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000855719</a>
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<p>In a 3-generation family (LMG2) with autosomal dominant hearing loss (DFNA27; <a href="/entry/612431">612431</a>), <a href="#20" class="mim-tip-reference" title="Nakano, Y., Kelly, M. C., Rehman, A. U., Boger, E. T., Morell, R. J., Kelley, M. W., Friedman, T. B., Banfi, B. &lt;strong&gt;Defects in the alternative splicing-dependent regulation of REST cause deafness.&lt;/strong&gt; Cell 174: 536-548, 2018.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/29961578/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;29961578&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=29961578[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2018.06.004&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="29961578">Nakano et al. (2018)</a> identified heterozygosity for a C-to-G transversion (chr4.56,927,594C-G, GRCh38) at a conserved nucleotide in intron 3, 21 bp upstream of exon 4a/b of the REST gene. The mutation segregated fully with deafness in the family and was not found in 400 control DNA samples or in the gnomAD database. RT-PCR in patient and control blood cells showed that the C-G variant causes truncation of the coding region of REST by generating a novel splice acceptor site for exon 4a. The authors noted that splicing of exon 4 into REST mRNA is normally tissue-specific and requires SRRM4 (<a href="/entry/613103">613103</a>), which is selectively expressed in neurons and mechanosensory hair cells of the ear. Using minigenes transfected into HEK293 cells, they observed that DFNA27-associated aberrant splicing results in a novel splice form containing a 24-nucleotide variant of exon 4b, and splicing of this variant exon 4b requires both the C-G variant-dependent relocation of the splice acceptor site as well as an SRRM4-dependent shift in the splice donor site. Analysis of luciferase activity of isoforms generated in the presence or absence of SRRM4 suggested that the C-G DFNA27-associated variant has opposing effects on REST depending on whether SRRM4 is present. In cells that do not express SRRM4, the C-G variant aberrantly inactivates REST by creating a novel acceptor site for constitutive splicing upstream of exon 4a/b. Conversely, in cells that do express SRRM4, the C-G variant aberrantly results in production of active REST that cannot be inactivated by SRRM4-directed alternative splicing of exon 4, thus abrogating the normal downregulation of REST that occurs in differentiating neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29961578" 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>.0008&nbsp;DEAFNESS, AUTOSOMAL DOMINANT 27</strong>
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REST, CYS415SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2109573013 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2109573013;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=rs2109573013" 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=rs2109573013" 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=RCV002248339 OR RCV004809799" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002248339, RCV004809799" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002248339...</a>
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<p>In a South African Xhosa mother and son with progressive prelingual sensorineural hearing loss (DFNA27; <a href="/entry/612431">612431</a>), <a href="#19" class="mim-tip-reference" title="Manyisa, N., Schrauwen, I., Alves de Souza Rios, L., Mowla, S., Tekendo-Ngongang, C., Popel, K., Esoh, K., Bharadwaj, T., Nouel-Saied, L. M., Acharya, A., Nasir, A., Wonkam-Tingang, E., de Kock, C., Dandara C., Leal, S. M., Wonkam, A. &lt;strong&gt;A monoallelic variant in REST is associated with non-syndromic autosomal dominant hearing impairment in a South African family.&lt;/strong&gt; Genes 12: 1765, 2021.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/34828371/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;34828371&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=34828371[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3390/genes12111765&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="34828371">Manyisa et al. (2021)</a> identified heterozygosity for a c.1244G-C transversion (c.1244G-C, NM_005612.5) in exon 4 of the REST gene, resulting in a cys415-to-ser (C415S) substitution at a highly conserved residue. The mutation was not found in the proband's unaffected half-brother or unaffected maternal grandmother, in 103 black South African controls or 52 sporadic South African probands of black or mixed ancestry with nonsyndromic hearing impairment, or in the gnomAD, UK10K, Greater Middle East Variome (GME), or dbSNP databases. Experiments using GFP tagging in HEK293 cells showed that the wildtype REST protein is located exclusively within the nucleus, whereas the mutant showed localization throughout the cell, indicating loss of exclusive nuclear shuttling/localization. In addition, wildtype REST competently repressed transcription of the known REST target AF1Q (<a href="/entry/604684">604684</a>) in transiently transfected HEK293 cells, whereas transcriptional repression was lost in cells expressing the mutant REST protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34828371" 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>.0009&nbsp;FIBROMATOSIS, GINGIVAL, 5</strong>
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REST, 2-BP DEL, 1901AG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV004776464" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV004776464" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV004776464</a>
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<p>In 2 Brazilian brothers and their 2 affected daughters (family C) with mild gingival overgrowth (GINGF5; <a href="/entry/617626">617626</a>), <a href="#17" class="mim-tip-reference" title="Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H. &lt;strong&gt;New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.&lt;/strong&gt; J. Periodont. 94: 108-118, 2023.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/35665929/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;35665929&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/JPER.22-0219&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="35665929">Machado et al. (2023)</a> identified heterozygosity for a 2-bp deletion (c.1491_1492delAG) in the REST gene, causing a frameshift predicted to result in a premature termination codon (Glu498GlyfsTer). Sanger sequencing confirmed the deletion, which was not found in 3 unaffected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35665929" 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>REFERENCES</strong>
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<a id="Abderrahmani2001" class="mim-anchor"></a>
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Abderrahmani, A., Steinmann, M., Plaisance, V., Niederhauser, G., Haefliger, J.-A., Mooser, V., Bonny, C., Nicod, P., Waeber, G.
<strong>The transcriptional repressor REST determines the cell-specific expression of the human MAPK8IP1 gene encoding IB1 (JIP-1).</strong>
Molec. Cell. Biol. 21: 7256-7627, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11585908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11585908</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11585908[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=11585908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1128/MCB.21.21.7256-7267.2001" target="_blank">Full Text</a>]
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<a id="Bahn2002" class="mim-anchor"></a>
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Bahn, S., Mimmack, M., Ryan, M., Caldwell, M. A., Jauniaux, E., Starkey, M., Svendsen, C. N., Emson, P.
<strong>Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study.</strong>
Lancet 359: 310-315, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11830198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11830198</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/S0140-6736(02)07497-4" target="_blank">Full Text</a>]
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<a id="Bayram2017" class="mim-anchor"></a>
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Bayram, Y., White, J. J., Elcioglu, N., Cho, M. T., Zadeh, N., Gedikbasi, A., Palanduz, S., Ozturk, S., Cefle, K., Kasapcopur, O., Akdemir, Z. C., Pehlivan, D., and 11 others.
<strong>REST final-exon-truncating mutations cause hereditary gingival fibromatosis.</strong>
Am. J. Hum. Genet. 101: 149-156, 2017.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28686854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28686854</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28686854[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=28686854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2017.06.006" target="_blank">Full Text</a>]
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<a id="Canzonetta2008" class="mim-anchor"></a>
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Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O'Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others.
<strong>DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.</strong>
Am. J. Hum. Genet. 83: 388-400, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18771760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18771760</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[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=18771760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2008.08.012" target="_blank">Full Text</a>]
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<a id="Chen1998" class="mim-anchor"></a>
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Chen, Z.-F., Paquette, A. J., Anderson, D. J.
<strong>NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis.</strong>
Nature Genet. 20: 136-142, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9771705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9771705</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9771705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/2431" target="_blank">Full Text</a>]
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<a id="Cheong2005" class="mim-anchor"></a>
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Cheong, A., Bingham, A. J., Li, J., Kumar, B., Sukumar, P., Munsch, C., Buckley, N. J., Neylon, C. B., Porter, K. E., Beech, D. J., Wood, I. C.
<strong>Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation.</strong>
Molec. Cell 20: 45-52, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16209944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16209944</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16209944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.molcel.2005.08.030" target="_blank">Full Text</a>]
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<a id="Chong1995" class="mim-anchor"></a>
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Chong, J. A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J. J., Zheng, Y., Boutros, M. C., Altshuller, Y. M., Frohman, M. A., Kraner, S. D., Mandel, G.
<strong>REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.</strong>
Cell 80: 949-957, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697725</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0092-8674(95)90298-8" target="_blank">Full Text</a>]
</p>
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<a id="Das2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Das, C. M., Taylor, P., Gireud, M., Singh, A., Lee, D., Fuller, G., Ji, L., Fangusaro, J., Rajaram, V., Goldman, S., Eberhart, C., Gopalakrishnan, V.
<strong>The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.</strong>
Oncogene 32: 1691-1701, 2013. Note: Erratum: Oncogene 35: 6153-6154, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22665064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22665064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22665064[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=22665064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/onc.2012.182" target="_blank">Full Text</a>]
</p>
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<a id="Ding2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G.
<strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong>
Molec. Cell 31: 347-359, 2008.
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[<a href="https://doi.org/10.1016/j.molcel.2008.05.023" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Guardavaccaro2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Guardavaccaro, D., Frescas, D., Dorrello, N. V., Peschiaroli, A., Multani, A. S., Cardozo, T., Lasorella, A., Iavarone, A., Chang, S., Hernando, E., Pagano, M.
<strong>Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.</strong>
Nature 452: 365-369, 2008.
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[<a href="https://doi.org/10.1038/nature06641" target="_blank">Full Text</a>]
</p>
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<a id="Kemp2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kemp, D. M., Lin, J. C., Habener, J. F.
<strong>Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor.</strong>
J. Biol. Chem. 278: 35057-35062, 2003.
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[<a href="https://doi.org/10.1074/jbc.M305891200" target="_blank">Full Text</a>]
</p>
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<a id="Kuwahara2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Kuwahara, K., Saito, Y., Takano, M., Arai, Y., Yasuno, S., Nakagawa, Y., Takahashi, N., Adachi, Y., Takemura, G., Horie, M., Miyamoto, Y., Morisaki, T., and 12 others.
<strong>NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.</strong>
EMBO J. 22: 6310-6321, 2003.
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[<a href="https://doi.org/10.1093/emboj/cdg601" target="_blank">Full Text</a>]
</p>
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<a id="Lepagnol-Bestel2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lepagnol-Bestel, A.-M., Zvara, A., Maussion, G., Quignon, F., Ngimbous, B., Ramoz, N., Imbeaud, S., Loe-Mie, Y., Benihoud, K., Agier, N., Salin, P. A., Cardona, A., and 11 others.
<strong>DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.</strong>
Hum. Molec. Genet. 18: 1405-1414, 2009. Note: Erratum: Hum. Molec. Genet. 31: 2106-2107, 2022.
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[<a href="https://doi.org/10.1093/hmg/ddp047" target="_blank">Full Text</a>]
</p>
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<a id="Loe-Mie2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Loe-Mie, Y., Lepagnol-Bestel, A.-M., Maussion, G., Doron-Faigenboim, A., Imbeaud, S., Delacroix, H., Aggerbeck, L., Pupko, T., Gorwood, P., Simonneau, M., Moalic, J.-M.
<strong>SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.</strong>
Hum. Molec. Genet. 19: 2841-2857, 2010.
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[<a href="https://doi.org/10.1093/hmg/ddq184" target="_blank">Full Text</a>]
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<a id="Lu2014" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lu, T., Aron, L., Zullo, J., Pan, Y., Kim, H., Chen, Y., Yang, T.-H., Kim, H.-M., Drake, D., Liu, X. S., Bennett, D. A., Colaiacovo, M. P., Yankner, B. A.
<strong>REST and stress resistance in ageing and Alzheimer's disease.</strong>
Nature 507: 448-454, 2014. Note: Erratum: Nature 540: 470 only, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24670762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24670762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24670762[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=24670762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature13163" target="_blank">Full Text</a>]
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<a id="Lunyak2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Lunyak, V. V., Burgess, R., Prefontaine, G. G., Nelson, C., Sze, S.-H., Chenoweth, J., Schwartz, P., Pevzner, P. A., Glass, C., Mandel, G., Rosenfeld, M. G.
<strong>Corepressor-dependent silencing of chromosomal regions encoding neuronal genes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12399542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12399542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12399542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1076469" target="_blank">Full Text</a>]
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<a id="Machado2023" class="mim-anchor"></a>
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<p class="mim-text-font">
Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H.
<strong>New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.</strong>
J. Periodont. 94: 108-118, 2023.
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[<a href="https://doi.org/10.1002/JPER.22-0219" target="_blank">Full Text</a>]
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<a id="Mahamdallie2015" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others.
<strong>Mutations in the transcriptional repressor REST predispose to Wilms tumor.</strong>
Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26551668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26551668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26551668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng.3440" target="_blank">Full Text</a>]
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<a id="Manyisa2021" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Manyisa, N., Schrauwen, I., Alves de Souza Rios, L., Mowla, S., Tekendo-Ngongang, C., Popel, K., Esoh, K., Bharadwaj, T., Nouel-Saied, L. M., Acharya, A., Nasir, A., Wonkam-Tingang, E., de Kock, C., Dandara C., Leal, S. M., Wonkam, A.
<strong>A monoallelic variant in REST is associated with non-syndromic autosomal dominant hearing impairment in a South African family.</strong>
Genes 12: 1765, 2021.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34828371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34828371</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34828371[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=34828371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.3390/genes12111765" target="_blank">Full Text</a>]
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<a id="Nakano2018" class="mim-anchor"></a>
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Nakano, Y., Kelly, M. C., Rehman, A. U., Boger, E. T., Morell, R. J., Kelley, M. W., Friedman, T. B., Banfi, B.
<strong>Defects in the alternative splicing-dependent regulation of REST cause deafness.</strong>
Cell 174: 536-548, 2018.
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[<a href="https://doi.org/10.1016/j.cell.2018.06.004" target="_blank">Full Text</a>]
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Ooi, L., Wood, I. C.
<strong>Chromatin crosstalk in development and disease: lessons from REST.</strong>
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[<a href="https://doi.org/10.1038/nrg2100" target="_blank">Full Text</a>]
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Palm, K., Metsis, M., Timmusk, T.
<strong>Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat.</strong>
Molec. Brain Res. 72: 30-39, 1999.
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[<a href="https://doi.org/10.1016/s0169-328x(99)00196-5" target="_blank">Full Text</a>]
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Pehlivan, D., Abe, S., Ozturk, S., Kayhan, K. B., Gunduz, E., Cefle, K., Bayrak, A., Ark, N., Gunduz, M., Palanduz, S.
<strong>Cytogenetic analysis and examination of SOS1 gene mutation in a Turkish family with hereditary gingival fibromatosis.</strong>
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Plaisance, V., Niederhauser, G., Azzouz, F., Lenain, V., Haefliger, J.-A., Waeber, G., Abderrahmani, A.
<strong>The repressor element silencing transcription factor (REST)-mediated transcriptional repression requires the inhibition of Sp1.</strong>
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[<a href="https://doi.org/10.1074/jbc.M411825200" target="_blank">Full Text</a>]
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<strong>The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7871435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7871435</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7871435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.7871435" target="_blank">Full Text</a>]
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Shimojo, M.
<strong>Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150-Glued.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18922795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18922795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18922795[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=18922795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1074/jbc.M804183200" target="_blank">Full Text</a>]
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<a id="Singh2008" class="mim-anchor"></a>
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Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H., Majumder, S.
<strong>REST maintains self-renewal and pluripotency of embryonic stem cells.</strong>
Nature 453: 223-227, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18362916/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18362916</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18362916[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=18362916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature06863" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="28" class="mim-anchor"></a>
<a id="Tahiliani2007" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tahiliani, M., Mei, P., Fang, R., Leonor, T., Rutenberg, M., Shimizu, F., Li, J., Rao, A., Shi, Y.
<strong>The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.</strong>
Nature 447: 601-605, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17468742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17468742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17468742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature05823" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="29" class="mim-anchor"></a>
<a id="Thiel1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Thiel, G., Lietz, M., Cramer, M.
<strong>Biological activity and modulator structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes.</strong>
J. Biol. Chem. 273: 26891-26899, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9756936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9756936</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9756936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1074/jbc.273.41.26891" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="30" class="mim-anchor"></a>
<a id="Westbrook2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Westbrook, T. F., Hu, G., Ang, X. L., Mulligan, P., Pavlova, N. N., Liang, A., Leng, Y., Maehr, R., Shi, Y., Harper, J. W., Elledge, S. J.
<strong>SCF-(beta-TRCP) controls oncogenic transformation and neural differentiation through REST degradation.</strong>
Nature 452: 370-374, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18354483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18354483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18354483[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=18354483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature06780" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="31" class="mim-anchor"></a>
<a id="Yang2012" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yang, Y. J., Baltus, A. E., Mathew, R. S., Murphy, E. A., Evrony, G. D., Gonzalez, D. M., Wang, E. P., Marshall-Walker, C. A., Barry, B. J., Murn, J., Tatarakis, A., Mahajan, M. A., Samuels, H. H., Shi, Y., Golden, J. A., Mahajnah, M., Shenhav, R., Walsh, C. A.
<strong>Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.</strong>
Cell 151: 1097-1112, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23178126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23178126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23178126[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=23178126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.cell.2012.10.043" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="32" class="mim-anchor"></a>
<a id="Yeo2005" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yeo, M., Lee, S.-K., Lee, B., Ruiz, E. C., Pfaff, S. L., Gill, G. N.
<strong>Small CTD phosphatases function in silencing neuronal gene expression.</strong>
Science 307: 596-600, 2005.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15681389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15681389</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15681389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1100801" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="33" class="mim-anchor"></a>
<a id="Yoo2009" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yoo, A. S., Staahl, B. T., Chen, L., Crabtree, G. R.
<strong>MicroRNA-mediated switching of chromatin-remodelling complexes in neural development.</strong>
Nature 460: 642-646, 2009. Note: Erratum: Nature 461: 296 only, 2009.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19561591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19561591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19561591[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=19561591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature08139" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="34" class="mim-anchor"></a>
<a id="Zuccato2001" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E.
<strong>Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.</strong>
Science 293: 493-498, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11408619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11408619</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11408619" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1059581" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="35" class="mim-anchor"></a>
<a id="Zuccato2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E.
<strong>Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.</strong>
Nature Genet. 35: 76-83, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881722</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12881722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng1219" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="36" class="mim-anchor"></a>
<a id="Zullo2019" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zullo, J. M., Drake, D., Aron, L., O'Hern, P., Dhamne, S. C., Davidsohn, N., Mao, C.-A., Klein, W. H., Rotenberg, A., Bennett, D. A., Church, G. M., Colaiacovo, M. P., Yankner, B. A.
<strong>Regulation of lifespan by neural excitation and REST.</strong>
Nature 574: 359-364, 2019.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31619788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31619788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31619788[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=31619788" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/s41586-019-1647-8" target="_blank">Full Text</a>]
</p>
</div>
</li>
</ol>
<div>
<br />
</div>
</div>
</div>
<div>
<a id="contributors" class="mim-anchor"></a>
<div class="row">
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="mim-text-font">
<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Marla J. F. O'Neill - updated : 10/31/2024
</span>
</div>
</div>
<div class="row collapse" id="mimCollapseContributors">
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Bao Lige - updated : 01/31/2023<br>Marla J. F. O'Neill - updated : 04/22/2022<br>Ada Hamosh - updated : 04/09/2020<br>Bao Lige - updated : 01/09/2020<br>Marla J. F. O'Neill - updated : 11/12/2019<br>Bao Lige - updated : 09/23/2019<br>Cassandra L. Kniffin - updated : 08/14/2017<br>Ada Hamosh - updated : 02/11/2016<br>Ada Hamosh - updated : 4/11/2014<br>George E. Tiller - updated : 8/27/2013<br>Cassandra L. Kniffin - updated : 2/25/2013<br>Patricia A. Hartz - updated : 4/13/2012<br>George E. Tiller - updated : 11/30/2009<br>Ada Hamosh - updated : 8/27/2009<br>Patricia A. Hartz - updated : 8/20/2009<br>Ada Hamosh - updated : 11/5/2008<br>Ada Hamosh - updated : 6/12/2008<br>Ada Hamosh - updated : 5/22/2008<br>Patricia A. Hartz - updated : 9/25/2007<br>Ada Hamosh - updated : 6/15/2007<br>Patricia A. Hartz - updated : 12/12/2005<br>Ada Hamosh - updated : 3/1/2005<br>Victor A. McKusick - updated : 8/15/2003<br>Cassandra L. Kniffin - updated : 6/23/2003<br>Ada Hamosh - updated : 4/3/2003<br>Patricia A. Hartz - updated : 6/13/2002<br>Victor A. McKusick - updated : 9/28/1998
</span>
</div>
</div>
</div>
<div>
<a id="creationDate" class="mim-anchor"></a>
<div class="row">
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="text-nowrap mim-text-font">
Creation Date:
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Alan F. Scott : 6/1/1995
</span>
</div>
</div>
</div>
<div>
<a id="editHistory" class="mim-anchor"></a>
<div class="row">
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
<span class="text-nowrap mim-text-font">
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
alopez : 10/31/2024
</span>
</div>
</div>
<div class="row collapse" id="mimCollapseEditHistory">
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
carol : 06/08/2023<br>mgross : 01/31/2023<br>alopez : 07/27/2022<br>carol : 04/22/2022<br>carol : 02/15/2022<br>carol : 07/17/2020<br>carol : 06/23/2020<br>alopez : 04/09/2020<br>mgross : 01/09/2020<br>carol : 11/13/2019<br>alopez : 11/12/2019<br>alopez : 11/12/2019<br>carol : 10/08/2019<br>mgross : 09/23/2019<br>carol : 08/24/2017<br>carol : 08/24/2017<br>carol : 08/15/2017<br>ckniffin : 08/14/2017<br>alopez : 02/11/2016<br>alopez : 4/11/2014<br>carol : 8/27/2013<br>tpirozzi : 8/27/2013<br>tpirozzi : 8/27/2013<br>carol : 2/25/2013<br>ckniffin : 2/25/2013<br>mgross : 5/18/2012<br>mgross : 5/18/2012<br>terry : 4/13/2012<br>wwang : 1/7/2010<br>terry : 11/30/2009<br>mgross : 10/5/2009<br>carol : 9/23/2009<br>carol : 9/15/2009<br>alopez : 9/4/2009<br>terry : 8/27/2009<br>mgross : 8/24/2009<br>terry : 8/20/2009<br>carol : 6/3/2009<br>alopez : 12/1/2008<br>terry : 11/5/2008<br>alopez : 6/17/2008<br>terry : 6/12/2008<br>alopez : 5/28/2008<br>alopez : 5/28/2008<br>terry : 5/22/2008<br>mgross : 10/2/2007<br>terry : 9/25/2007<br>alopez : 6/20/2007<br>terry : 6/15/2007<br>wwang : 12/12/2005<br>wwang : 3/7/2005<br>terry : 3/1/2005<br>alopez : 9/2/2003<br>alopez : 8/19/2003<br>alopez : 8/19/2003<br>terry : 8/15/2003<br>carol : 7/10/2003<br>carol : 7/9/2003<br>ckniffin : 6/23/2003<br>alopez : 4/3/2003<br>terry : 4/3/2003<br>carol : 6/20/2002<br>terry : 6/13/2002<br>alopez : 9/28/1998<br>joanna : 9/28/1998<br>mark : 3/6/1998<br>joanna : 12/6/1995<br>mark : 6/1/1995
</span>
</div>
</div>
</div>
</div>
</div>
</div>
<div class="container visible-print-block">
<div class="row">
<div class="col-md-8 col-md-offset-1">
<div>
<div>
<h3>
<span class="mim-font">
<strong>*</strong> 600571
</span>
</h3>
</div>
<div>
<h3>
<span class="mim-font">
RE1-SILENCING TRANSCRIPTION FACTOR; REST
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<div >
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
NEURON-RESTRICTIVE SILENCER FACTOR; NRSF
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<p>
<span class="mim-text-font">
<strong><em>HGNC Approved Gene Symbol: REST</em></strong>
</span>
</p>
</div>
<div>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: 4q12
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : 4:56,907,900-56,935,844 </span>
</em>
</strong>
<span class="small">(from NCBI)</span>
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Gene-Phenotype Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="3">
<span class="mim-font">
4q12
</span>
</td>
<td>
<span class="mim-font">
{Wilms tumor 6, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
616806
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
Deafness, autosomal dominant 27
</span>
</td>
<td>
<span class="mim-font">
612431
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
Fibromatosis, gingival, 5
</span>
</td>
<td>
<span class="mim-font">
617626
</span>
</td>
<td>
<span class="mim-font">
Autosomal dominant
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>REST is a transcriptional repressor that regulates gene expression throughout the body. It binds 21-bp repressor element-1 (RE1) sites, also called neuron-restrictive silencer elements (NRSEs), through its 8 C2H2 zinc fingers. REST mediates gene repression by acting as a hub for the recruitment of multiple chromatin-modifying enzymes (Ooi and Wood, 2007). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Cloning and Expression</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Schoenherr and Anderson (1995) cloned a transcription factor, which they termed NRSF, that bound the NRSE present in the 5-prime regulatory region of SCG10 (600621), a neuron-specific gene. The NRSF cDNA was cloned from a HeLa cell library. The longest cDNA was predicted to encode 8 zinc fingers of the C2H2 class, with interfinger sequences that placed NRSE within the GLI (see 165220)-Kruppel family of zinc finger proteins. Northern blot analysis detected a NRSF transcript of 7 to 8 kb. Expression of NRSF mRNA was detected in most nonneuronal progenitor cells, but it was absent in differentiated neurons. </p><p>Independently, Chong et al. (1995) cloned REST from a HeLa cell cDNA library. The deduced 1,097-amino acid protein has a calculated molecular mass of 121 kD. REST has 8 N-terminal C2H2-type zinc fingers, followed by a basic region, 6 repeats of a proline-rich sequence, and a C-terminal zinc finger. It also has a nuclear localization signal. In situ hybridization of mouse embryos detected abundant Rest expression in nonneuronal tissues. </p><p>Thiel et al. (1998) determined that REST contains 2 repressor domains, one located at the N terminus and the other at the C terminus, and an N-terminal zinc finger cluster which functions as the DNA-binding domain for neuronal genes. </p><p>Palm et al. (1999) identified several REST variants that arise from alternative splicing of an exon that they designated exon N. The splice variants produce insertions that generate in-frame stop codons and encode truncated proteins with an N-terminal repressor domain and weakened DNA-binding activity. The expression levels of these variants differ in human neuroblastoma and glial cells. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Gene Structure</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bayram et al. (2017) stated that the REST gene has 4 exons. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bayram et al. (2017) stated that the REST gene maps to chromosome 4q12. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Gene Function</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Schoenherr and Anderson (1995) showed that NRSF bound the NRSE DNA sequence in the 5-prime region of SCG10. They noted that the SCG10 regulatory region contains both activation and repression (i.e., silencer) domains and that similar NRSE-like sequence elements have been identified in other neuron-specific genes. Schoenherr and Anderson (1995) proposed that NRSF may function as a master negative regulator of neurogenesis. </p><p>By transfecting rat myocyte and pheochromocytoma cell lines, Chong et al. (1995) showed that human REST downregulated expression of the type II voltage-dependent sodium channel (see 182390). They proposed that REST suppresses expression of the channel in nonneuronal tissues. </p><p>Thiel et al. (1998) noted that the REST binding sites of several neuron-specific genes, such as those encoding synapsin I (313440), SCG10 (600621), A1-glycine receptor (138491), the B2 subunit of the nicotinic acetylcholine receptor (118507), and the M4-subunit of the muscarinic acetylcholine receptor, are found at various positions within the sequence. By transfecting these sequences in reporter constructs together with REST, Thiel et al. (1998) found that REST blocks transcription of a gene irrespective of whether the NRSE is located upstream or downstream of the open reading frame in either orientation and in both a distance- and a gene-independent manner. </p><p>Abderrahmani et al. (2001) identified an NRSE sequence in the promoter region of MAPK8PI1 (604641), which is expressed exclusively in neuronal tissue and pancreatic B cells. They confirmed that REST binds to the NRSE element of MAPK8PI1 and found that transfection and expression of REST in a B-cell line represses MAPK8PI1 transcription. Conversely, the introduction of a mutated NRSE into the MAPK8PI1 promoter allowed MAPK8PI1 expression in non-B-cell and nonneuronal cell lines. REST-mediated repression was found to be dependent on histone deacetylase (see 601241) activity. </p><p>Lunyak et al. (2002) reported that the zinc finger gene-specific repressor element REST can mediate extraneuronal restriction by imposing either active repression via histone deacetylase recruitment or long-term gene silencing using a distinct functional complex. Silencing of neuronal-specific genes requires the recruitment of an associated corepressor, COREST (607675), that serves as a functional molecular beacon for recruitment of molecular machinery that imposes silencing across a chromosomal interval, including transcriptional units that do not themselves contain REST/NRSF response elements. </p><p>Using indexing-based differential display PCR on neuronal precursor cells to study gene expression in Down syndrome (190685), Bahn et al. (2002) found that genes regulated by the REST transcription factor were selectively repressed. One of these genes, SCG10, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. In cell culture, the Down syndrome cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome. </p><p>The huntingtin gene (HTT; 613004) is mutated in Huntington disease (HD; 143100). Zuccato et al. (2001) reported that wildtype but not mutant huntingtin stimulates transcription of the gene encoding brain-derived neurotrophic factor (BDNF; 113505). Zuccato et al. (2003) showed that the NRSE is the target of wildtype huntingtin activity on BDNF promoter II. Wildtype huntingtin inhibits the silencing activity of NRSE, increasing transcription of BDNF. Zuccato et al. (2003) showed that this effect occurs through cytoplasmic sequestering of REST/NRSF, the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus was present in Huntington disease. They showed that wildtype huntingtin coimmunoprecipitates with REST/NRSF and that less immunoprecipitated material is found in brain tissue with Huntington disease. They also reported that wildtype huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes was shown in cells, mice, and human brain with Huntington disease. Zuccato et al. (2003) concluded that wildtype huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. These data identified a novel mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes. </p><p>Kemp et al. (2003) identified NRSE-like motifs in several genes involved in pancreas development, including a highly conserved NRSE-like motif in the upstream promoter of PAX4 (167413), a gene implicated in differentiation of the insulin-producing beta-cell lineage. Using mammalian cell lines, they found that the NRSE in the upstream promoter of Pax4 formed a DNA-protein complex with Nrsf and conferred Nrsf-dependent transcriptional repression on a reporter gene promoter and the native Pax4 gene promoter. </p><p>Reactivation of the fetal cardiac gene program is a characteristic feature of hypertrophied and failing hearts. Kuwahara et al. (2003) showed that Nrsf selectively regulated expression of multiple fetal cardiac genes and played a role in reexpression of these genes in rat neonatal ventricular myocytes. Transgenic mice expressing a dominant-negative Nrsf mutant in their hearts exhibited dilated cardiomyopathy, high susceptibility to arrhythmias, and sudden death. Genes encoding 2 ion channels that carry the fetal cardiac currents I(f) and I(Ca,T), which were induced in Nrsf-transgenic mice and were potentially responsible for both the cardiac dysfunction and arrhythmogenesis, were regulated by Nrsf. </p><p>Neuronal gene transcription is repressed in nonneuronal cells by the REST/NRSF complex. To understand how this silencing is achieved, Yeo et al. (2005) examined CTDSP1 (605323), CTDSP2 (608711), and CTDSPL (608592), the small CTD phosphatases (SCP), whose expression is restricted to nonneuronal tissues. Yeo et al. (2005) showed that REST/NRSF recruits SCPs to neuronal genes that contain RE1 elements, leading to neuronal gene silencing in nonneuronal cells. Phosphatase-inactive forms of SCP interfere with REST/NRSF function and promote neuronal differentiation of P19 stem cells. Likewise, small interfering RNA directed to the single Drosophila SCP unmasks neuronal gene expression in S2 cells. Thus, Yeo et al. (2005) concluded that SCP activity is an evolutionarily conserved transcriptional regulator that acts globally to silence neuronal genes. </p><p>Cheong et al. (2005) identified a functional REST-binding sequence in the promoter region of the KCNN4 gene (602754). REST was expressed in the nuclei of human vascular smooth muscle cells (SMCs), and it downregulated KCNN4 expression in mouse and human vascular SMCs. Downregulated REST and upregulated KCNN4 were evident in SMCs of human neointimal hyperplasia grown in organ culture, and exogenous REST reduced the functional impact of KCNN4. Cheong et al. (2005) concluded that REST acts as a switch to regulate potassium channel expression and consequently the phenotype of vascular smooth muscle cells and human vascular disease. </p><p>Plaisance et al. (2005) showed that the transcriptional factor Sp1 (189906) was required for expression of most Rest target genes in mouse insulin-secreting cells and rat neuronal-like cells where Rest is absent. Inhibition of REST in HeLa cells and in mouse beta cells restored the transcriptional activity of Sp1. Coimmunoprecipitation and transfection assays indicated that the C-terminal repressor domain of REST was required for interaction with Sp1 and inhibited its activity. Silencing of Sp1 by REST required histone deacetylase activity. </p><p>Tahiliani et al. (2007) showed that JARID1C/SMCX (314690), a JmjC domain-containing protein implicated in X-linked mental retardation and epilepsy, possesses H3K4 tridemethylase activity and functions as a transcriptional repressor. An SMCX complex isolated from HeLa cells contained additional chromatin modifiers (the histone deacetylases HDAC1 (601241) and HDAC2 (605164), and the histone H3K9 methyltransferase G9a (604599)) and the transcriptional repressor REST, suggesting a direct role for SMCX in chromatin dynamics and REST-mediated repression. Chromatin immunoprecipitation revealed that SMCX and REST co-occupy the neuron-restrictive silencing elements in the promoters of a subset of REST target genes. RNA interference-mediated depletion of SMCX derepressed several of these targets and simultaneously increased H3K4 trimethylation at the sodium channel type 2A (SCN2A; 182390) and synapsin I (SYN1; 313440) promoters. Tahiliani et al. (2007) proposed that loss of SMCX activity impairs REST-mediated neuronal gene regulation, thereby contributing to SMCX-associated X-linked mental retardation. </p><p>Ding et al. (2008) found that purified HeLa cell mediator complexes that included MED12 (300188) interacted directly with the G9A and REST. Endogenous REST in HEK293 cells suppressed expression of a reporter gene bearing RE1 sites, and knockdown of either MED12 or G9A abrogated the suppression. Depletion of MED12 significantly reduced the association of G9A with RE1 elements and decreased the level of H3K9 dimethylation by G9A without influencing RE1 site occupancy by REST. </p><p>Using an unbiased screen, Guardavaccaro et al. (2008) demonstrated that REST is an interactor with the F-box protein beta-TRCP (603482). REST is degraded by means of the ubiquitin beta-TRCP during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2 (601467), an essential component of the spindle assembly checkpoint. The expression in cultured cells of a stable REST mutant, which is unable to bind beta-TRCP, inhibited Mad2 expression and resulted in a phenotype analogous to that observed in Mad2 heterozygous cells. In particular, Guardavaccaro et al. (2008) observed defects that were consistent with faulty activation of the spindle checkpoint, such as shortened mitosis, premature sister-chromatid separation, chromosome bridges and missegregation in anaphase, tetraploidy, and a faster mitotic slippage in the presence of a spindle inhibitor. An indistinguishable phenotype was observed by expressing the oncogenic REST-FS mutant, which does not bind beta-TRCP. Thus, beta-TRCP-dependent degradation of REST during G2 permits the optimal activation of the spindle checkpoint, and consequently it is required for the fidelity of mitosis. </p><p>Westbrook et al. (2008) showed that REST is regulated by ubiquitin-mediated proteolysis, and used an RNA interference screen to identify a Skp1-Cul1-F-box protein complex containing the F-box protein beta-TRCP as an E3 ubiquitin ligase responsible for REST degradation. Beta-TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron. During neural differentiation, REST is degraded in a beta-TRCP-dependent manner. Beta-TRCP is required for proper neural differentiation only in the presence of REST, indicating that beta-TRCP facilitates this process through degradation of REST. Conversely, failure to degrade REST attenuates differentiation. Furthermore, Westbrook et al. (2008) found that beta-TRCP overexpression, which is common in human epithelial cancers, causes oncogenic transformation of human mammary epithelial cells and that this pathogenic function requires REST degradation. Thus, Westbrook et al. (2008) concluded that REST is a key target in beta-TRCP-driven transformation and that the beta-TRCP-REST axis is a new regulatory pathway controlling neurogenesis. </p><p>Singh et al. (2008) demonstrated that REST maintains self-renewal and pluripotency in mouse ES cells through suppression of the microRNA miR21 (611020). The authors found that, as with known self-renewal markers, the level of REST expression is much higher in self-renewing mouse embryonic stem (ES) cells than in differentiating mouse ES (embryoid body, EB) cells. Heterozygous deletion of Rest and its short interfering RNA (siRNA)-mediated knockdown in mouse ES cells caused a loss of self-renewal--even when these cells were grown under self-renewal conditions--and led to the expression of markers specific for multiple lineages. Conversely, exogenously added REST maintained self-renewal in mouse EB cells. Furthermore, Rest heterozygous mouse ES cells cultured under self-renewal conditions expressed substantially reduced levels of several self-renewal regulators, including Oct4 (164177), Nanog (607937), Sox2 (184429), and c-Myc (190080), and exogenously added Rest in mouse EB cells maintained the self-renewal phenotypes and expression of these self-renewal regulators. Singh et al. (2008) also demonstrated that in mouse ES cells, Rest is bound to the gene chromatin of a set of miRNAs that potentially target self-renewal genes. Whereas mouse ES cells and mouse EB cells containing exogenously added Rest expressed lower levels of these miRNAs, EB cells, Rest heterozygous ES cells, and ES cells treated with siRNA targeting Rest expressed higher levels of these miRNAs. At least one of these REST-regulated miRNAs, miR21, specifically suppressed the self-renewal of mouse ES cells, corresponding to the decreased expression of Oct4, Nanog, Sox2, and c-Myc. Thus, Singh et al. (2008) concluded that REST is an element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mouse ES cells. </p><p>Using a transchromosomic mouse model of Down syndrome, Canzonetta et al. (2008) showed that a 30 to 60% reduced expression of Nrsf/Rest, a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 (see 190685) from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic ES cells, Canzonetta et al. (2008) mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A (600855). The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. Canzonetta et al. (2008) found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (607937) and Sox2 (184429), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (600576) and a strongly reduced neuroectodermal progenitor compartment. Canzonetta et al. (2008) concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and new rationales for therapeutic approaches. </p><p>Using yeast 2-hybrid and immunoprecipitation analyses, Shimojo (2008) showed that human RILP (PRICKLE1; 608500) and huntingtin interacted directly with dynactin-1 (DCTN1; 601143) to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in nonneuronal cells. In neuronal cells, the complex also contained HAP1 (600947), which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity. </p><p>At the point of mitotic exit within the vertebrate nervous system, when cells lose multipotency and begin to develop stable connections that will persist over life, a switch in ATP-dependent chromatin-remodeling mechanisms occurs. This switch involves the exchange of the BAF53A and BAF45A (PHF10; 613069) subunits within Swi/Snf-like neural progenitor-specific BAF (npBAF) complexes for the homologous BAF53B (ACTL6B; 612458) and BAF45B (DPF1; 601670) subunits within neuron-specific BAF (nBAF) complexes in postmitotic neurons. The subunits of the npBAF complex are essential for neural progenitor proliferation, and mice with reduced dosage for the genes encoding its subunits have defects in neural tube closure similar to those in human spina bifida. In contrast, BAF53B and the nBAF complex are essential for an evolutionarily conserved program of postmitotic neural development and dendritic morphogenesis. Yoo et al. (2009) showed that this essential transition is mediated by repression of BAF53A by miR9* (an miRNA processed from the opposite arm of the miR9 (611186) stem-loop precursor) and miR124 (609327). They found that BAF53a repression is mediated by sequences in the 3-prime untranslated region corresponding to the recognition sites for miR9* and miR124, which are selectively expressed in postmitotic neurons. Mutation of these sites led to persistent expression of BAF53A and defective activity-dependent dendritic outgrowth in neurons. In addition, overexpression of miR9* and miR124 in neural progenitors caused reduced proliferation. miR9* and miR124 are repressed by REST. Yoo et al. (2009) showed that expression of REST in postmitotic neurons led to derepression of BAF53A, indicating that REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes. </p><p>Loe-Mie et al. (2010) showed that an SWI/SNF-centered network including the Smarca2 gene (600014) was modified by the downregulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF downregulation also modified the levels of Smarce1 (603111), Smarcd3 (601737), and SWI/SNF interactors (Hdac1, 601241; RcoR, 607675; and Mecp2, 300005). Smarca2 downregulation generated an abnormal dendritic spine morphology that was an intermediate phenotype of schizophrenia (see 181500). The authors noted that 8 genomewide-supported schizophrenia-associated genes (SMARCA2; CSF2RA, 306250; HIST1H2BJ, 615044; NOTCH4, 164951; NRGN, 602350; SHOX, 312865; TCF4, 602272; and ZNF804A, 612282) are part of an interacting network; 5 of the 8, including SMARCA2, encode transcription regulators, and 3 (TCF4, SMARCA2, and CSF2RA) were modified at the level of expression when the REST/NRSF-SWI/SNF chromatin remodeling complex was experimentally manipulated in mouse cell lines and in transgenic mouse models. REST/NRSF-SWI/SNF deregulation also resulted in the differential expression of genes that are clustered in chromosomes, suggesting the induction of genomewide epigenetic changes. Loe-Mie et al. (2010) concluded that the SWI/SNF chromatin remodeling complex is a key component of the genetic architecture of schizophrenia. </p><p>Yang et al. (2012) demonstrated that ZNF335 (610827) acts upstream of REST and regulates its expression. </p><p>Das et al. (2013) found that knockdown of REST resulted in a decline in medulloblastoma cell proliferation and accumulation of p27 (CDKN1B; 600778). In vitro analysis showed that REST and p27 expression were reciprocally correlated in human medulloblastoma samples. REST repressed expression of USP37 (620226), and USP37 expression promoted p27 deubiquitination. USP37 interacted with p27 to promote its deubiquitination and stabilization, thereby blocking cell proliferation. The authors concluded that REST regulates p27 stability and cell proliferation by controlling USP37. </p><p>Lu et al. (2014) demonstrated that induction of REST is a universal feature of normal aging in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer disease (AD; 104300). Chromatin immunoprecipitation with deep sequencing and expression analysis showed that REST represses genes that promote cell death and AD pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and beta-amyloid (see 104760) protein toxicity, and conditional deletion of Rest in the mouse brain leads to age-related neurodegeneration. A functional ortholog of REST, C. elegans Spr4, also protects against oxidative stress and beta-amyloid protein toxicity. During normal aging, REST is induced in part by cell-nonautonomous Wnt signaling. However, in Alzheimer disease, frontotemporal dementia (FTD; 600274), and dementia with Lewy bodies (DLB; 127750), REST is lost from the nucleus and appears in autophagosomes together with pathologic misfolded proteins. Finally, REST levels during aging are closely correlated with cognitive preservation and longevity. Lu et al. (2014) therefore concluded that the activation state of REST may distinguish neuroprotection from neurodegeneration in the aging brain. </p><p>Zullo et al. (2019) showed that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In C. elegans, neural excitation increases with age, and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, Rest-deficient mice exhibit increased cortical activity and neuronal excitability during aging. Similarly, loss-of-function mutations in the C. elegans REST ortholog genes spr3 and spr4 elevate neural excitation and reduce the lifespan of long-lived daf2 mutants. In wildtype worms, overexpression of spr4 suppresses excitation and extends lifespan. REST, spr3, spr4, and reduced excitation activated the longevity-associated transcription factors FOXO1 (136533) and daf16 in mammals and worms, respectively. Zullo et al. (2019) concluded that their findings revealed a conserved mechanism of aging that is mediated by neural circuit activity and regulated by REST. </p>
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<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
<p><strong><em>Wilms Tumor 6</em></strong></p><p>
Mahamdallie et al. (2015) identified 11 different REST mutations (see, e.g., 600571.0001-600571.0003) in 16 individuals from 4 families and 9 nonfamilial Wilms tumor (WT6; 616806) pedigrees. Ten of the 11 different mutations, including all of the nonsynonymous mutations, clustered in the DNA binding domain of REST. In 4 cases for whom parental DNA was available, 1 mutation had occurred de novo and 3 had been inherited, confirming incomplete penetrance. None was present in ICR1000 exome series of 993 or in the 61,312 individuals in the ExAC browser. All tested variants showed abrogation of REST function. Mahamdallie et al. (2015) concluded that their data established REST as a Wilms tumor predisposition gene accounting for approximately 2% of Wilms tumors, and recommended screening of REST in all familial cases. </p><p><strong><em>Gingival Fibromatosis 5</em></strong></p><p>
In a 11 patients from 3 unrelated Turkish families with gingival fibromatosis-5 (GINGF5; 617626), Bayram et al. (2017) identified 3 different heterozygous truncating mutations in the REST gene (600571.0004-600571.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in 2 families; the mutation in the proband of the third family occurred de novo. A mildly affected father in 1 of the families was mosaic for the mutation. All mutations occurred in the final exon of the gene, which may result in escape from nonsense-mediated mRNA decay, suggesting that the alleles may act through a dominant-negative or gain-of-function effect. Bayram et al. (2017) noted that studies have suggested that the disorder results from excessive accumulation of extracellular matrix components, particularly collagen type I, which may be due to abnormal expression of TGF-beta (TGFB1; 190180) and IL6 (147620). The mutant transcripts may reduce the repressor function of REST on the collagen synthesis pathway, resulting in the accumulation of collagen in gingiva. However, functional studies of the REST variants and studies of patient cells were not performed. </p><p>In 4 affected members of a Brazilian family with mild gingival overgrowth, Machado et al. (2023) identified heterozygosity for a 2-bp deletion in the REST gene (600571.0009). </p><p><strong><em>Autosomal Dominant Deafness 27</em></strong></p><p>
In a 3-generation family with autosomal dominant hearing loss mapping to chromosome 4q12-q13.1 (DFNA27; 612431), Nakano et al. (2018) identified heterozygosity for an intronic variant in the REST gene (600571.0007) that segregated fully with deafness in the family and was not found in public variant databases. Functional analysis revealed that the DFNA27-associated REST variant causes gain or loss of function depending on the cellular context: in cells lacking the splicing factor SRRM4 (613103), it causes REST inactivation (loss of function), whereas in cells expressing SRRM4, such as neurons and mechanosensory hair cells of the ear, the variant prevents REST inactivation by alternative splicing (gain of function), thus abrogating its normal downregulation in differentiating neurons. </p><p>In a South African Xhosa mother and son with progressive prelingual sensorineural hearing loss, Manyisa et al. (2021) identified heterozygosity for a missense mutation in the REST gene (C415S; 600571.0008) that segregated with disease in the family and was not found in controls or in public variant databases. Functional analysis revealed perturbation of cellular localization and loss of function with the mutant compared to wildtype REST. </p>
</span>
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<h4>
<span class="mim-font">
<strong>Animal Model</strong>
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</h4>
</div>
<span class="mim-text-font">
<p>Chen et al. (1998) disrupted the Rest gene in mice by gene targeting in mouse embryonic stem cells. As a result, derepression of neuron-specific tubulin (602529) in a subset of nonneural tissues resulted and embryonic lethality ensued. </p><p>Lepagnol-Bestel et al. (2009) used the transgenic 152F7 mouse model of Down syndrome (190685) to show that the DYRK1A (600855) gene dosage imbalance deregulated chromosomal clusters of genes located near REST/NRSF binding sites. Dyrk1a bound the SWI/SNF complex (see 603111), which is known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam (308840) modified the transcriptional effect of Dyrk1a-dosage imbalance on L1cam. Dyrk1a dosage imbalance perturbed Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. In transgenic embryonic brain subregions, the authors identified a coordinated deregulation of multiple genes that responsible for dendritic growth impairment. Similarly, Dyrk1a overexpression in primary mouse cortical neurons induced severe reduction of the dendritic growth and dendritic complexity. Lepagnol-Bestel et al. (2009) proposed that both the DYRK1A overexpression-related neuronal gene deregulation (via disturbance of REST/NRSF levels) and the REST/NRSF-SWI/SNF chromatin remodeling complex significantly contribute to the neural phenotypic changes that characterize Down syndrome. </p><p>Nakano et al. (2018) found that heterozygous deletion of exon 4 of mouse Rest activated the apoptotic pathway and caused hair cell death in a cell-autonomous manner, resulting in balance defects and deafness. Single-cell quantitative RT-PCR revealed that alternative splicing of Rest exon 4 regulated gene expression specifically in hair cells. As a result, lack of exon 4-dependent alternative splicing in mutant mice reduced expression of many hearing-related genes, especially genes critical for development and function of hair cells, causing defects in cilia of utricles. In vitro studies demonstrated that HDAC inhibitors increased expression of many Rest target genes and prevented degeneration of outer hair cells of mutant mice in organ cultures. The HDAC inhibitor SAHA (Vorinostat) rescued hair cells and hearing of Rest mutant mice in vivo. </p>
</span>
<div>
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</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>ALLELIC VARIANTS</strong>
</span>
<strong>9 Selected Examples):</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0001 &nbsp; WILMS TUMOR 6, SUSCEPTIBILITY TO</strong>
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</h4>
</div>
<div>
<span class="mim-text-font">
REST, 2-BP DEL, 831AT
<br />
SNP: rs869025310,
ClinVar: RCV000207462, RCV001230375
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 2 sisters (FAM0482) and an unrelated individual (FAM00250) with Wilms tumor (WT6; 616806), Mahamdallie et al. (2015) identified a heterozygous 2-bp deletion (c.831_832delAT, ENST00000309042) in the DNA binding domain of the REST gene resulting in frameshift. The mutation was inherited from the mother by the sisters and from the father by the unrelated individual. Age at diagnosis was 3.7 and 6.0 years in the sisters, and 3.2 years in the unrelated individual. Histology of the sisters' tumors showed triphasic (blastemal, epithelial, and stromal) elements. Mahamdallie et al. (2015) noted that this mutation was not identified in the ICR1000 UK exome series or in the ExAC browser. </p>
</span>
</div>
<div>
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</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0002 &nbsp; WILMS TUMOR 6, SUSCEPTIBILITY TO</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, 4-BP DEL, 772GTGA
<br />
SNP: rs869025311,
ClinVar: RCV000207468
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 2 first cousins once removed (FAM0509) with Wilms tumor (WT6; 616806), Mahamdallie et al. (2015) identified a heterozygous 4-bp deletion (c.772_775delGTGA, ENST00000309042) in the DNA binding domain of the REST gene. In one cousin the mutation was inherited from the mother, age at diagnosis was 2.6 years, and the tumor sample showed triphasic histology. In the other cousin the mutation was inherited from the father, age at diagnosis was 0.8 years, and tumor histology was predominantly blastemal. Mahamdallie et al. (2015) noted that this mutation was not identified in the ICR1000 UK exome series or in the ExAC browser. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0003 &nbsp; WILMS TUMOR 6, SUSCEPTIBILITY TO</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, HIS322ARG
<br />
SNP: rs869025312,
ClinVar: RCV000207458
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 2 cousins (FAM0481) and in an unrelated individual (FAM1324) with Wilms tumor (WT6; 616806), Mahamdallie et al. (2015) detected a heterozygous c.965A-G transition (c.965A-G, ENST00000309042) in the zinc finger DNA-binding domain of the REST gene, resulting in a his322-to-arg (H322R) substitution. The mutation was paternally inherited in the female cousin and maternally inherited in the male cousin. Age of onset was 3 years in female patient and 0.5 years in the male patient. Inheritance was unknown in the unrelated individual; Wilms tumor developed at 0.5 years of age and was of triphasic histology. Functional studies showed that this variant was unable to repress REST target gene expression, supporting pathogenicity. Mahamdallie et al. (2015) noted that this mutation was not identified in the ICR1000 UK exome series or in the ExAC browser. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0004 &nbsp; FIBROMATOSIS, GINGIVAL, 5</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, 2-BP DEL, 2865AA ({dbSNP SCV000579327})
<br />
SNP: rs1553904481,
ClinVar: RCV000497680, RCV000516014, RCV001851328
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 2 Turkish brothers with gingival fibromatosis-5 (GINGF5; 617626), Bayram et al. (2017) identified a heterozygous 2-bp deletion (c.2865_2866delAA, NM_005612.4) in the last exon (exon 4) of the REST gene, resulting in a frameshift and premature termination (Asn958SerfsTer9). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of more than 6,500 exomes. The father, who had a mild form of the disorder, was mosaic for the mutation. Functional studies of the variant and studies of patient cells were not performed. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0005 &nbsp; FIBROMATOSIS, GINGIVAL, 5</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, LEU437TER ({dbSNP SCV000579328})
<br />
SNP: rs1553904077,
ClinVar: RCV000498225, RCV000516150
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 5 members of a Turkish family with gingival fibromatosis-5 (GINGF5; 617626), Bayram et al. (2017) identified a heterozygous c.1310T-A transversion (c.1310T-A, NM_005612.4) in the last exon (exon 4) of the REST gene, resulting in a leu437-to-ter (L437X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of more than 6,500 exomes. The family was originally reported by Pehlivan et al. (2009). Functional studies of the variant and studies of patient cells were not performed. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0006 &nbsp; FIBROMATOSIS, GINGIVAL, 5</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, 1-BP DEL, 2413C ({dbSNP SCV000579329})
<br />
SNP: rs1553904346,
ClinVar: RCV000498949, RCV000515908
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 9-year-old Turkish girl with gingival fibromatosis-5 (GINGF5; 617626), Bayram et al. (2017) identified a de novo heterozygous 1-bp deletion (c.2413delC, NM_005612.4) in the last exon (exon 4) of the REST gene, resulting in a frameshift and premature termination (Leu805PhefsTer38). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in an in-house database of more than 6,500 exomes. The patient was identified through the GeneMatcher database. Functional studies of the variant and studies of patient cells were not performed. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0007 &nbsp; DEAFNESS, AUTOSOMAL DOMINANT 27</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, IVS3AS, C-G, -21
<br />
SNP: rs1720770872,
ClinVar: RCV000855719
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a 3-generation family (LMG2) with autosomal dominant hearing loss (DFNA27; 612431), Nakano et al. (2018) identified heterozygosity for a C-to-G transversion (chr4.56,927,594C-G, GRCh38) at a conserved nucleotide in intron 3, 21 bp upstream of exon 4a/b of the REST gene. The mutation segregated fully with deafness in the family and was not found in 400 control DNA samples or in the gnomAD database. RT-PCR in patient and control blood cells showed that the C-G variant causes truncation of the coding region of REST by generating a novel splice acceptor site for exon 4a. The authors noted that splicing of exon 4 into REST mRNA is normally tissue-specific and requires SRRM4 (613103), which is selectively expressed in neurons and mechanosensory hair cells of the ear. Using minigenes transfected into HEK293 cells, they observed that DFNA27-associated aberrant splicing results in a novel splice form containing a 24-nucleotide variant of exon 4b, and splicing of this variant exon 4b requires both the C-G variant-dependent relocation of the splice acceptor site as well as an SRRM4-dependent shift in the splice donor site. Analysis of luciferase activity of isoforms generated in the presence or absence of SRRM4 suggested that the C-G DFNA27-associated variant has opposing effects on REST depending on whether SRRM4 is present. In cells that do not express SRRM4, the C-G variant aberrantly inactivates REST by creating a novel acceptor site for constitutive splicing upstream of exon 4a/b. Conversely, in cells that do express SRRM4, the C-G variant aberrantly results in production of active REST that cannot be inactivated by SRRM4-directed alternative splicing of exon 4, thus abrogating the normal downregulation of REST that occurs in differentiating neurons. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0008 &nbsp; DEAFNESS, AUTOSOMAL DOMINANT 27</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, CYS415SER
<br />
SNP: rs2109573013,
ClinVar: RCV002248339, RCV004809799
</span>
</div>
<div>
<span class="mim-text-font">
<p>In a South African Xhosa mother and son with progressive prelingual sensorineural hearing loss (DFNA27; 612431), Manyisa et al. (2021) identified heterozygosity for a c.1244G-C transversion (c.1244G-C, NM_005612.5) in exon 4 of the REST gene, resulting in a cys415-to-ser (C415S) substitution at a highly conserved residue. The mutation was not found in the proband's unaffected half-brother or unaffected maternal grandmother, in 103 black South African controls or 52 sporadic South African probands of black or mixed ancestry with nonsyndromic hearing impairment, or in the gnomAD, UK10K, Greater Middle East Variome (GME), or dbSNP databases. Experiments using GFP tagging in HEK293 cells showed that the wildtype REST protein is located exclusively within the nucleus, whereas the mutant showed localization throughout the cell, indicating loss of exclusive nuclear shuttling/localization. In addition, wildtype REST competently repressed transcription of the known REST target AF1Q (604684) in transiently transfected HEK293 cells, whereas transcriptional repression was lost in cells expressing the mutant REST protein. </p>
</span>
</div>
<div>
<br />
</div>
</div>
<div>
<div>
<h4>
<span class="mim-font">
<strong>.0009 &nbsp; FIBROMATOSIS, GINGIVAL, 5</strong>
</span>
</h4>
</div>
<div>
<span class="mim-text-font">
REST, 2-BP DEL, 1901AG
<br />
ClinVar: RCV004776464
</span>
</div>
<div>
<span class="mim-text-font">
<p>In 2 Brazilian brothers and their 2 affected daughters (family C) with mild gingival overgrowth (GINGF5; 617626), Machado et al. (2023) identified heterozygosity for a 2-bp deletion (c.1491_1492delAG) in the REST gene, causing a frameshift predicted to result in a premature termination codon (Glu498GlyfsTer). Sanger sequencing confirmed the deletion, which was not found in 3 unaffected family members. </p>
</span>
</div>
<div>
<br />
</div>
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Abderrahmani, A., Steinmann, M., Plaisance, V., Niederhauser, G., Haefliger, J.-A., Mooser, V., Bonny, C., Nicod, P., Waeber, G.
<strong>The transcriptional repressor REST determines the cell-specific expression of the human MAPK8IP1 gene encoding IB1 (JIP-1).</strong>
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[PubMed: 11585908]
[Full Text: https://doi.org/10.1128/MCB.21.21.7256-7267.2001]
</p>
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<p class="mim-text-font">
Bahn, S., Mimmack, M., Ryan, M., Caldwell, M. A., Jauniaux, E., Starkey, M., Svendsen, C. N., Emson, P.
<strong>Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down&#x27;s syndrome: a gene expression study.</strong>
Lancet 359: 310-315, 2002.
[PubMed: 11830198]
[Full Text: https://doi.org/10.1016/S0140-6736(02)07497-4]
</p>
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<li>
<p class="mim-text-font">
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</p>
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<p class="mim-text-font">
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</p>
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<p class="mim-text-font">
Chen, Z.-F., Paquette, A. J., Anderson, D. J.
<strong>NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis.</strong>
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[PubMed: 9771705]
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</p>
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<p class="mim-text-font">
Cheong, A., Bingham, A. J., Li, J., Kumar, B., Sukumar, P., Munsch, C., Buckley, N. J., Neylon, C. B., Porter, K. E., Beech, D. J., Wood, I. C.
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</p>
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<li>
<p class="mim-text-font">
Chong, J. A., Tapia-Ramirez, J., Kim, S., Toledo-Aral, J. J., Zheng, Y., Boutros, M. C., Altshuller, Y. M., Frohman, M. A., Kraner, S. D., Mandel, G.
<strong>REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.</strong>
Cell 80: 949-957, 1995.
[PubMed: 7697725]
[Full Text: https://doi.org/10.1016/0092-8674(95)90298-8]
</p>
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<li>
<p class="mim-text-font">
Das, C. M., Taylor, P., Gireud, M., Singh, A., Lee, D., Fuller, G., Ji, L., Fangusaro, J., Rajaram, V., Goldman, S., Eberhart, C., Gopalakrishnan, V.
<strong>The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation.</strong>
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[PubMed: 22665064]
[Full Text: https://doi.org/10.1038/onc.2012.182]
</p>
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<li>
<p class="mim-text-font">
Ding, N., Zhou, H., Esteve, P.-O., Chin, H. G., Kim, S., Xu, X., Joseph, S. M., Friez, M. J., Schwartz, C. E., Pradhan, S., Boyer, T. G.
<strong>Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation.</strong>
Molec. Cell 31: 347-359, 2008.
[PubMed: 18691967]
[Full Text: https://doi.org/10.1016/j.molcel.2008.05.023]
</p>
</li>
<li>
<p class="mim-text-font">
Guardavaccaro, D., Frescas, D., Dorrello, N. V., Peschiaroli, A., Multani, A. S., Cardozo, T., Lasorella, A., Iavarone, A., Chang, S., Hernando, E., Pagano, M.
<strong>Control of chromosome stability by the beta-TrCP-REST-Mad2 axis.</strong>
Nature 452: 365-369, 2008.
[PubMed: 18354482]
[Full Text: https://doi.org/10.1038/nature06641]
</p>
</li>
<li>
<p class="mim-text-font">
Kemp, D. M., Lin, J. C., Habener, J. F.
<strong>Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor.</strong>
J. Biol. Chem. 278: 35057-35062, 2003.
[PubMed: 12829700]
[Full Text: https://doi.org/10.1074/jbc.M305891200]
</p>
</li>
<li>
<p class="mim-text-font">
Kuwahara, K., Saito, Y., Takano, M., Arai, Y., Yasuno, S., Nakagawa, Y., Takahashi, N., Adachi, Y., Takemura, G., Horie, M., Miyamoto, Y., Morisaki, T., and 12 others.
<strong>NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function.</strong>
EMBO J. 22: 6310-6321, 2003.
[PubMed: 14633990]
[Full Text: https://doi.org/10.1093/emboj/cdg601]
</p>
</li>
<li>
<p class="mim-text-font">
Lepagnol-Bestel, A.-M., Zvara, A., Maussion, G., Quignon, F., Ngimbous, B., Ramoz, N., Imbeaud, S., Loe-Mie, Y., Benihoud, K., Agier, N., Salin, P. A., Cardona, A., and 11 others.
<strong>DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome.</strong>
Hum. Molec. Genet. 18: 1405-1414, 2009. Note: Erratum: Hum. Molec. Genet. 31: 2106-2107, 2022.
[PubMed: 19218269]
[Full Text: https://doi.org/10.1093/hmg/ddp047]
</p>
</li>
<li>
<p class="mim-text-font">
Loe-Mie, Y., Lepagnol-Bestel, A.-M., Maussion, G., Doron-Faigenboim, A., Imbeaud, S., Delacroix, H., Aggerbeck, L., Pupko, T., Gorwood, P., Simonneau, M., Moalic, J.-M.
<strong>SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.</strong>
Hum. Molec. Genet. 19: 2841-2857, 2010.
[PubMed: 20457675]
[Full Text: https://doi.org/10.1093/hmg/ddq184]
</p>
</li>
<li>
<p class="mim-text-font">
Lu, T., Aron, L., Zullo, J., Pan, Y., Kim, H., Chen, Y., Yang, T.-H., Kim, H.-M., Drake, D., Liu, X. S., Bennett, D. A., Colaiacovo, M. P., Yankner, B. A.
<strong>REST and stress resistance in ageing and Alzheimer&#x27;s disease.</strong>
Nature 507: 448-454, 2014. Note: Erratum: Nature 540: 470 only, 2016.
[PubMed: 24670762]
[Full Text: https://doi.org/10.1038/nature13163]
</p>
</li>
<li>
<p class="mim-text-font">
Lunyak, V. V., Burgess, R., Prefontaine, G. G., Nelson, C., Sze, S.-H., Chenoweth, J., Schwartz, P., Pevzner, P. A., Glass, C., Mandel, G., Rosenfeld, M. G.
<strong>Corepressor-dependent silencing of chromosomal regions encoding neuronal genes.</strong>
Science 298: 1747-1752, 2002. Note: Erratum: Science 299: 1663 only, 2003.
[PubMed: 12399542]
[Full Text: https://doi.org/10.1126/science.1076469]
</p>
</li>
<li>
<p class="mim-text-font">
Machado, R. A., de Andrade, R. S., Pego, S. P. B., Krepischi, A. C. V., Coletta, R. D., Martelli-Junior, H.
<strong>New evidence of genetic heterogeneity causing hereditary gingival fibromatosis and ALK and CD36 as new candidate genes.</strong>
J. Periodont. 94: 108-118, 2023.
[PubMed: 35665929]
[Full Text: https://doi.org/10.1002/JPER.22-0219]
</p>
</li>
<li>
<p class="mim-text-font">
Mahamdallie, S. S., Hanks, S., Karlin, K. L., Zachariou, A., Perdeaux, E. R., Ruark, E., Shaw, C. A., Renwick, A., Ramsay, E., Yost, S., Elliott, A., Birch, J., and 13 others.
<strong>Mutations in the transcriptional repressor REST predispose to Wilms tumor.</strong>
Nature Genet. 47: 1471-1474, 2015. Note: Erratum: Nature Genet. 48: 473 only, 2016.
[PubMed: 26551668]
[Full Text: https://doi.org/10.1038/ng.3440]
</p>
</li>
<li>
<p class="mim-text-font">
Manyisa, N., Schrauwen, I., Alves de Souza Rios, L., Mowla, S., Tekendo-Ngongang, C., Popel, K., Esoh, K., Bharadwaj, T., Nouel-Saied, L. M., Acharya, A., Nasir, A., Wonkam-Tingang, E., de Kock, C., Dandara C., Leal, S. M., Wonkam, A.
<strong>A monoallelic variant in REST is associated with non-syndromic autosomal dominant hearing impairment in a South African family.</strong>
Genes 12: 1765, 2021.
[PubMed: 34828371]
[Full Text: https://doi.org/10.3390/genes12111765]
</p>
</li>
<li>
<p class="mim-text-font">
Nakano, Y., Kelly, M. C., Rehman, A. U., Boger, E. T., Morell, R. J., Kelley, M. W., Friedman, T. B., Banfi, B.
<strong>Defects in the alternative splicing-dependent regulation of REST cause deafness.</strong>
Cell 174: 536-548, 2018.
[PubMed: 29961578]
[Full Text: https://doi.org/10.1016/j.cell.2018.06.004]
</p>
</li>
<li>
<p class="mim-text-font">
Ooi, L., Wood, I. C.
<strong>Chromatin crosstalk in development and disease: lessons from REST.</strong>
Nature Rev. Genet. 8: 544-554, 2007.
[PubMed: 17572692]
[Full Text: https://doi.org/10.1038/nrg2100]
</p>
</li>
<li>
<p class="mim-text-font">
Palm, K., Metsis, M., Timmusk, T.
<strong>Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat.</strong>
Molec. Brain Res. 72: 30-39, 1999.
[PubMed: 10521596]
[Full Text: https://doi.org/10.1016/s0169-328x(99)00196-5]
</p>
</li>
<li>
<p class="mim-text-font">
Pehlivan, D., Abe, S., Ozturk, S., Kayhan, K. B., Gunduz, E., Cefle, K., Bayrak, A., Ark, N., Gunduz, M., Palanduz, S.
<strong>Cytogenetic analysis and examination of SOS1 gene mutation in a Turkish family with hereditary gingival fibromatosis.</strong>
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</p>
</li>
<li>
<p class="mim-text-font">
Plaisance, V., Niederhauser, G., Azzouz, F., Lenain, V., Haefliger, J.-A., Waeber, G., Abderrahmani, A.
<strong>The repressor element silencing transcription factor (REST)-mediated transcriptional repression requires the inhibition of Sp1.</strong>
J. Biol. Chem. 280: 401-407, 2005.
[PubMed: 15528196]
[Full Text: https://doi.org/10.1074/jbc.M411825200]
</p>
</li>
<li>
<p class="mim-text-font">
Schoenherr, C. J., Anderson, D. J.
<strong>The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes.</strong>
Science 267: 1360-1363, 1995.
[PubMed: 7871435]
[Full Text: https://doi.org/10.1126/science.7871435]
</p>
</li>
<li>
<p class="mim-text-font">
Shimojo, M.
<strong>Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150-Glued.</strong>
J. Biol. Chem. 283: 34880-34886, 2008.
[PubMed: 18922795]
[Full Text: https://doi.org/10.1074/jbc.M804183200]
</p>
</li>
<li>
<p class="mim-text-font">
Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H., Majumder, S.
<strong>REST maintains self-renewal and pluripotency of embryonic stem cells.</strong>
Nature 453: 223-227, 2008.
[PubMed: 18362916]
[Full Text: https://doi.org/10.1038/nature06863]
</p>
</li>
<li>
<p class="mim-text-font">
Tahiliani, M., Mei, P., Fang, R., Leonor, T., Rutenberg, M., Shimizu, F., Li, J., Rao, A., Shi, Y.
<strong>The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation.</strong>
Nature 447: 601-605, 2007.
[PubMed: 17468742]
[Full Text: https://doi.org/10.1038/nature05823]
</p>
</li>
<li>
<p class="mim-text-font">
Thiel, G., Lietz, M., Cramer, M.
<strong>Biological activity and modulator structure of RE-1-silencing transcription factor (REST), a repressor of neuronal genes.</strong>
J. Biol. Chem. 273: 26891-26899, 1998.
[PubMed: 9756936]
[Full Text: https://doi.org/10.1074/jbc.273.41.26891]
</p>
</li>
<li>
<p class="mim-text-font">
Westbrook, T. F., Hu, G., Ang, X. L., Mulligan, P., Pavlova, N. N., Liang, A., Leng, Y., Maehr, R., Shi, Y., Harper, J. W., Elledge, S. J.
<strong>SCF-(beta-TRCP) controls oncogenic transformation and neural differentiation through REST degradation.</strong>
Nature 452: 370-374, 2008.
[PubMed: 18354483]
[Full Text: https://doi.org/10.1038/nature06780]
</p>
</li>
<li>
<p class="mim-text-font">
Yang, Y. J., Baltus, A. E., Mathew, R. S., Murphy, E. A., Evrony, G. D., Gonzalez, D. M., Wang, E. P., Marshall-Walker, C. A., Barry, B. J., Murn, J., Tatarakis, A., Mahajan, M. A., Samuels, H. H., Shi, Y., Golden, J. A., Mahajnah, M., Shenhav, R., Walsh, C. A.
<strong>Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation.</strong>
Cell 151: 1097-1112, 2012.
[PubMed: 23178126]
[Full Text: https://doi.org/10.1016/j.cell.2012.10.043]
</p>
</li>
<li>
<p class="mim-text-font">
Yeo, M., Lee, S.-K., Lee, B., Ruiz, E. C., Pfaff, S. L., Gill, G. N.
<strong>Small CTD phosphatases function in silencing neuronal gene expression.</strong>
Science 307: 596-600, 2005.
[PubMed: 15681389]
[Full Text: https://doi.org/10.1126/science.1100801]
</p>
</li>
<li>
<p class="mim-text-font">
Yoo, A. S., Staahl, B. T., Chen, L., Crabtree, G. R.
<strong>MicroRNA-mediated switching of chromatin-remodelling complexes in neural development.</strong>
Nature 460: 642-646, 2009. Note: Erratum: Nature 461: 296 only, 2009.
[PubMed: 19561591]
[Full Text: https://doi.org/10.1038/nature08139]
</p>
</li>
<li>
<p class="mim-text-font">
Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E.
<strong>Loss of huntingtin-mediated BDNF gene transcription in Huntington&#x27;s disease.</strong>
Science 293: 493-498, 2001.
[PubMed: 11408619]
[Full Text: https://doi.org/10.1126/science.1059581]
</p>
</li>
<li>
<p class="mim-text-font">
Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E.
<strong>Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.</strong>
Nature Genet. 35: 76-83, 2003.
[PubMed: 12881722]
[Full Text: https://doi.org/10.1038/ng1219]
</p>
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<li>
<p class="mim-text-font">
Zullo, J. M., Drake, D., Aron, L., O'Hern, P., Dhamne, S. C., Davidsohn, N., Mao, C.-A., Klein, W. H., Rotenberg, A., Bennett, D. A., Church, G. M., Colaiacovo, M. P., Yankner, B. A.
<strong>Regulation of lifespan by neural excitation and REST.</strong>
Nature 574: 359-364, 2019.
[PubMed: 31619788]
[Full Text: https://doi.org/10.1038/s41586-019-1647-8]
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Marla J. F. O&#x27;Neill - updated : 10/31/2024<br>Bao Lige - updated : 01/31/2023<br>Marla J. F. O&#x27;Neill - updated : 04/22/2022<br>Ada Hamosh - updated : 04/09/2020<br>Bao Lige - updated : 01/09/2020<br>Marla J. F. O&#x27;Neill - updated : 11/12/2019<br>Bao Lige - updated : 09/23/2019<br>Cassandra L. Kniffin - updated : 08/14/2017<br>Ada Hamosh - updated : 02/11/2016<br>Ada Hamosh - updated : 4/11/2014<br>George E. Tiller - updated : 8/27/2013<br>Cassandra L. Kniffin - updated : 2/25/2013<br>Patricia A. Hartz - updated : 4/13/2012<br>George E. Tiller - updated : 11/30/2009<br>Ada Hamosh - updated : 8/27/2009<br>Patricia A. Hartz - updated : 8/20/2009<br>Ada Hamosh - updated : 11/5/2008<br>Ada Hamosh - updated : 6/12/2008<br>Ada Hamosh - updated : 5/22/2008<br>Patricia A. Hartz - updated : 9/25/2007<br>Ada Hamosh - updated : 6/15/2007<br>Patricia A. Hartz - updated : 12/12/2005<br>Ada Hamosh - updated : 3/1/2005<br>Victor A. McKusick - updated : 8/15/2003<br>Cassandra L. Kniffin - updated : 6/23/2003<br>Ada Hamosh - updated : 4/3/2003<br>Patricia A. Hartz - updated : 6/13/2002<br>Victor A. McKusick - updated : 9/28/1998
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Alan F. Scott : 6/1/1995
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