3896 lines
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Entry
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- *603722 - ELONGATOR COMPLEX PROTEIN 1; ELP1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603722</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603722">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000070061;t=ENST00000374647" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=8518" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603722" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000070061;t=ENST00000374647" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001318360,NM_001330749,NM_003640,XM_047423991" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_003640" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603722" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04763&isoform_id=04763_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/ELP1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/3757822,4884192,12002688,21619844,38569394,51476493,119579431,119579432,119579433,119579434,119579435,158260947,193784730,193785306,193785657,193785839,193786065,194388234,215274166,929654748,971460848,1061899769,2217381925,2462626957" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O95163" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=8518" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000070061;t=ENST00000374647" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ELP1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=ELP1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+8518" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/ELP1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:8518" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/8518" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr9&hgg_gene=ENST00000374647.10&hgg_start=108867517&hgg_end=108934124&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/elp1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603722[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603722[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000070061" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ELP1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ELP1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ELP1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/shared/genes/IKBKAP" title="LOVD 3.0 shared installation (IKBKAP)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">LOVD 3.0 shared installati…</a></div><div style="margin-left: 0.5em;"><a href="http://www.dmd.nl/nmdb2/home.php?select_db=IKBKAP" title="Leiden Muscular Dystrophy pages (IKBKAP)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Leiden Muscular Dystrophy …</a></div><div style="margin-left: 0.5em;"><a href="http://www.molgen.ua.ac.be/CMTMutations/" title="Inherited Peripheral Neuropathies Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Inherited Peripheral Neuro…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ELP1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA29775" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:5959" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0037926.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1914544" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ELP1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1914544" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/8518/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=8518" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00022463;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-071116-7" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:603722" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=ELP1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1156923005, 29159009, 443333004<br />
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<strong>ICD10CM:</strong> G90.1<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603722
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ELONGATOR COMPLEX PROTEIN 1; ELP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE COMPLEX-ASSOCIATED PROTEIN; IKBKAP<br />
|
|
IKK COMPLEX-ASSOCIATED PROTEIN; IKAP<br />
|
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ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 1; ELP1<br />
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ELP1, YEAST, HOMOLOG OF
|
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</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ELP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ELP1</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/9/397?start=-3&limit=10&highlight=397">9q31.3</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:108867517-108934124&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'})">9:108,867,517-108,934,124</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=155255,223900" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
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</thead>
|
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<tbody>
|
|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>ELP1 is a component of Elongator, a highly conserved transcription elongation factor complex that has histone acetyltransferase activity, primarily directed toward histone H3. A substantial fraction of Elongator is cytoplasmic, however, suggesting that the complex performs additional functions. ELP1 was initially described as IKBKAP (IKAP), a scaffold protein of the IKK complex involved in NF-kappa-B (see <a href="/entry/164011">164011</a>) activation, but a role for IKAP in this pathway was later disproved (summary by <a href="#5" class="mim-tip-reference" title="Close, P., Hawkes, N., Cornez, I., Creppe, C., Lambert, C. A., Rogister, B., Siebenlist, U., Merville, M.-P., Slaugenhaupt, S. A., Bours, V., Svejstrup, J. Q., Chariot, A. <strong>Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia.</strong> Molec. Cell 22: 521-531, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713582</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.04.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713582">Close et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713582" 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="#6" class="mim-tip-reference" title="Cohen, L., Henzel, W. J., Baeuerle, P. A. <strong>IKAP is a scaffold protein of the I-kappa-B kinase complex.</strong> Nature 395: 292-296, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9751059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9751059</a>] [<a href="https://doi.org/10.1038/26254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9751059">Cohen et al. (1998)</a> isolated large, IL1-inducible IKK complexes containing NF-kappa-B-inducing kinase (NIK; <a href="/entry/604655">604655</a>), IKK-alpha (<a href="/entry/600664">600664</a>), IKK-beta (<a href="/entry/603258">603258</a>), I-kappa-B-alpha (<a href="/entry/164008">164008</a>), NF-kappa-B/RelA (<a href="/entry/164014">164014</a>), and a 150-kD protein that they called IKAP for 'IKK complex-associated protein.' The IKAP open reading frame of 3,996 nucleotides is flanked by 303 bp and 501 bp of 5-prime and 3-prime untranslated sequence, respectively. A 4.8-kb mRNA was detected in most human tissues. IKAP shows 22% overall identity with the yeast protein IKI3, which may be involved in the yeast response to toxins. There appeared to be 5 WD-like repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9751059" 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="#7" class="mim-tip-reference" title="Coli, R., Anderson, S. L., Volpi, S. A., Rubin, B. Y. <strong>Genomic organization and chromosomal localization of the mouse IKBKAP gene.</strong> Gene 279: 81-89, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11722848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11722848</a>] [<a href="https://doi.org/10.1016/s0378-1119(01)00737-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11722848">Coli et al. (2001)</a> cloned Ikbkap cDNA from mouse spleen. The mouse cDNA shares 77% nucleotide identity with human IKBKAP. The deduced mouse protein contains 1,333 amino acids, and the human protein contains 1,332. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11722848" 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="#6" class="mim-tip-reference" title="Cohen, L., Henzel, W. J., Baeuerle, P. A. <strong>IKAP is a scaffold protein of the I-kappa-B kinase complex.</strong> Nature 395: 292-296, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9751059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9751059</a>] [<a href="https://doi.org/10.1038/26254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9751059">Cohen et al. (1998)</a> found that IKAP could bind NIK and IKKs through separate domains and assemble them into an active kinase complex. Thus, IKAP is a scaffold protein and a regulator for 3 different kinases involved in proinflammatory signaling. IKAP sequence encompassing only the fifth WD-like motif was sufficient for binding of NIK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9751059" 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="Krappmann, D., Hatada, E. N., Tegethoff, S., Li, J., Klippel, A., Giese, K., Baeuerle, P. A., Scheidereit, C. <strong>The I-kappa-B kinase (IKK) complex is tripartite and contains IKK-gamma but not IKAP as a regular component.</strong> J. Biol. Chem. 275: 29779-29787, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10893415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10893415</a>] [<a href="https://doi.org/10.1074/jbc.M003902200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10893415">Krappmann et al. (2000)</a> found IKBKAP associated with a high molecular mass complex containing additional proteins of 100, 70, 45, and 39 kD in HeLa cells. However, they found no association of IKBKAP with the IKK complex. Overexpression of IKBKAP repressed expression of reporter plasmids driven by thymidine kinase (<a href="/entry/188300">188300</a>) and beta-actin (<a href="/entry/102630">102630</a>) promoters, in addition to the NF-kappa-B promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10893415" 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 examining the elongator complex purified from HeLa cells, <a href="#12" class="mim-tip-reference" title="Hawkes, N. A., Otero, G., Winkler, G. S., Marshall, N., Dahmus, M. E., Krappmann, D., Scheidereit, C., Thomas, C. L., Schiavo, G., Erdjument-Bromage, H., Tempst, P., Svejstrup, J. Q. <strong>Purification and characterization of the human elongator complex.</strong> J. Biol. Chem. 277: 3047-3052, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11714725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11714725</a>] [<a href="https://doi.org/10.1074/jbc.M110445200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11714725">Hawkes et al. (2002)</a> found that the complex existed in 2 forms, the holo-elongator, which had histone acetyltransferase activity directed against histones H3 (see <a href="/entry/602810">602810</a>) and H4 (see <a href="/entry/602822">602822</a>), and a 3-subunit core form, which did not have histone acetyltransferase activity despite containing the catalytic subunit ELP3 (<a href="/entry/612722">612722</a>). ELP2 (<a href="/entry/616054">616054</a>) and IKAP were also detected in the core elongator complex. ELP4 (<a href="/entry/606985">606985</a>), ELP5 (<a href="/entry/615019">615019</a>), and ELP6 (<a href="/entry/615020">615020</a>) were detected in the active holo-elongator complex. <a href="#12" class="mim-tip-reference" title="Hawkes, N. A., Otero, G., Winkler, G. S., Marshall, N., Dahmus, M. E., Krappmann, D., Scheidereit, C., Thomas, C. L., Schiavo, G., Erdjument-Bromage, H., Tempst, P., Svejstrup, J. Q. <strong>Purification and characterization of the human elongator complex.</strong> J. Biol. Chem. 277: 3047-3052, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11714725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11714725</a>] [<a href="https://doi.org/10.1074/jbc.M110445200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11714725">Hawkes et al. (2002)</a> proposed that the elongator complex serves a role in RNA polymerase II (see <a href="/entry/180660">180660</a>)-associated chromatin remodeling during transcriptional elongation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11714725" 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="Rahl, P. B., Chen, C. Z., Collins, R. N. <strong>Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation.</strong> Molec. Cell 17: 841-853, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780940</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.02.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780940">Rahl et al. (2005)</a> found that the yeast homolog of IKBKAP, Elp1, physically interacted with the yeast Rab guanine nucleotide exchange factor Sec2. The Sec2 interaction domain of Elp1 was necessary for both Elp1 function and for the polarized localization of Sec2. <a href="#20" class="mim-tip-reference" title="Rahl, P. B., Chen, C. Z., Collins, R. N. <strong>Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation.</strong> Molec. Cell 17: 841-853, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780940</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.02.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15780940">Rahl et al. (2005)</a> proposed that familial dysautonomia (FD; <a href="/entry/223900">223900</a>), which results from mutation in IKBKAP, may be a defect in polarized exocytosis in neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15780940" 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 RNA interference and DNA microarray analysis, <a href="#5" class="mim-tip-reference" title="Close, P., Hawkes, N., Cornez, I., Creppe, C., Lambert, C. A., Rogister, B., Siebenlist, U., Merville, M.-P., Slaugenhaupt, S. A., Bours, V., Svejstrup, J. Q., Chariot, A. <strong>Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia.</strong> Molec. Cell 22: 521-531, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713582</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.04.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713582">Close et al. (2006)</a> found that IKAP depletion in human cells affected expression of a number of genes, with correlated effects on histone H3 acetylation and transcriptional elongation. Several affected genes were implicated in cell motility, and cells with decreased IKAP levels displayed motility defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713582" 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="Creppe, C., Malinouskaya, L., Volvert, M.-L., Gillard, M., Close, P., Malaise, O., Laguesse, S., Cornez, I., Rahmouni, S., Ormenese, S., Belachew, S., Malgrange, B., Chapelle, J.-P., Siebenlist, U., Moonen, G., Chariot, A., Nguyen, L. <strong>Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin.</strong> Cell 136: 551-564, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19185337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19185337</a>] [<a href="https://doi.org/10.1016/j.cell.2008.11.043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19185337">Creppe et al. (2009)</a> found that Elp1 was highly expressed throughout the rostrocaudal axis of the mouse telencephalon during development. Silencing of Elp1 impaired radial migration, resulting in accumulation of cells in the ventricular and subventricular zones and a reduced percentage of projection neurons in the cortical plate compared with controls. The migration defect was temporary, and Elp1-depleted neurons eventually reached their terminal destination. Elp1 silencing affected the morphology, but not the survival, of projection neurons in the cortical plate, with impaired growth of dendrites and axons, but not the soma perimeter. Depletion of ELP1 in a human colorectal carcinoma cell line resulted in abnormally rounded cell shapes and major delays in cell spreading. Endogenous ELP1 interacted with ELP3 in all human cell lines examined. ELP1 and ELP3 associated with microtubules, and depletion of either ELP1 or ELP3 resulted in reduced acetylation of alpha-tubulin (see TUBA1A; <a href="/entry/602529">602529</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19185337" 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 RNA interference, <a href="#4" class="mim-tip-reference" title="Close, P., Gillard, M., Ladang, A., Jiang, Z., Papuga, J., Hawkes, N., Nguyen, L., Chapelle, J.-P., Bouillenne, F., Svejstrup, J., Fillet, M., Chariot, A. <strong>DERP6 (ELP5) and C3ORF75 (ELP6) regulate tumorigenicity and migration of melanoma cells as subunits of elongator.</strong> J. Biol. Chem. 287: 32535-32545, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22854966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22854966</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22854966[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M112.402727" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22854966">Close et al. (2012)</a> found that depletion of any of the elongator complex components Elp1, Elp3, Elp5 (<a href="/entry/615019">615019</a>), or Elp6 (<a href="/entry/615020">615020</a>) in B16-F10 mouse melanoma cells reduced cell motility in a wound-healing assay and reduced the capacity of cells to form colonies in soft agar. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22854966" 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="#7" class="mim-tip-reference" title="Coli, R., Anderson, S. L., Volpi, S. A., Rubin, B. Y. <strong>Genomic organization and chromosomal localization of the mouse IKBKAP gene.</strong> Gene 279: 81-89, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11722848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11722848</a>] [<a href="https://doi.org/10.1016/s0378-1119(01)00737-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11722848">Coli et al. (2001)</a> determined that the mouse Ikbkap gene, like the human IKBKAP gene, contains 37 exons. The mouse Ikbkap gene spans about 51 kb, and the consensus donor splice site of intron 20, which is altered in a major mutation (<a href="#0001">603722.0001</a>) leading to familial dysautonomia (FD; <a href="/entry/223900">223900</a>), is conserved in the mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11722848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By sequence analysis, <a href="#22" class="mim-tip-reference" title="Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F. <strong>Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.</strong> Am. J. Hum. Genet. 68: 598-605, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179008">Slaugenhaupt et al. (2001)</a> mapped the IKBKAP gene to chromosome 9q31. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179008" 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 backcross analysis, <a href="#7" class="mim-tip-reference" title="Coli, R., Anderson, S. L., Volpi, S. A., Rubin, B. Y. <strong>Genomic organization and chromosomal localization of the mouse IKBKAP gene.</strong> Gene 279: 81-89, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11722848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11722848</a>] [<a href="https://doi.org/10.1016/s0378-1119(01)00737-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11722848">Coli et al. (2001)</a> mapped the mouse Ikbkap gene to a central region of chromosome 4 that shows homology of synteny to human chromosome 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11722848" 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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Familial dysautonomia (FD; <a href="/entry/223900">223900</a>), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. <a href="#2" class="mim-tip-reference" title="Blumenfeld, A., Slaugenhaupt, S. A., Axelrod, F. B., Lucente, D. E., Maayan, C., Liebert, C. B., Ozelius, L. J., Trofatter, J. A., Haines, J. L., Breakefield, X. O., Gusella, J. F. <strong>Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis.</strong> Nature Genet. 4: 160-164, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102296</a>] [<a href="https://doi.org/10.1038/ng0693-160" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8102296">Blumenfeld et al. (1993)</a> mapped the familial dysautonomia locus to 9q31; by haplotype analysis, <a href="#3" class="mim-tip-reference" title="Blumenfeld, A., Slaugenhaupt, S. A., Liebert, C. B., Temper, V., Maayan, C., Gill, S., Lucente, D. E., Idelson, M., MacCormack, K., Monahan, M. A., Mull, J., Leyne, M., Mendillo, M., Schiripo, T., Mishori, E., Breakefield, X., Axelrod, F. B., Gusella, J. F. <strong>Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.</strong> Am. J. Hum. Genet. 64: 1110-1118, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090896</a>] [<a href="https://doi.org/10.1086/302339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090896">Blumenfeld et al. (1999)</a> narrowed the location to a 471-kb interval. They had shown that the ethnic bias is due to a founder effect, with more than 99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of the familial dysautonomia, <a href="#22" class="mim-tip-reference" title="Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F. <strong>Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.</strong> Am. J. Hum. Genet. 68: 598-605, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179008">Slaugenhaupt et al. (2001)</a> sequenced the candidate region and cloned and characterized the 5 genes located therein. IKBKAP was one of these genes and was found to harbor 2 mutations that can cause FD. The major haplotype mutation was located at the donor splice site of intron 20 (IVS20DS+6T-C; <a href="#0001">603722.0001</a>). This mutation results in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wildtype message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wildtype, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in 4 patients is an arg696-to-pro missense mutation (<a href="#0002">603722.0002</a>) in exon 19, which is predicted to disrupt a potential phosphorylation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10090896+8102296+11179008" 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>Simultaneously and independently, <a href="#1" class="mim-tip-reference" title="Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y. <strong>Familial dysautonomia is caused by mutations of the IKAP gene.</strong> Am. J. Hum. Genet. 68: 753-758, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179021[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179021">Anderson et al. (2001)</a> found the splice site mutation as the predominant one in familial dysautonomia, and identified, in individuals bearing a minor FD haplotype, the missense mutation in exon 19 that disrupts a consensus serine/threonine kinase phosphorylation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179021" 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="Cuajungco, M. P., Leyne, M., Mull, J., Gill, S. P., Lu, W., Zagzag, D., Axelrod, F. B., Maayan, C., Gusella, J. F., Slaugenhaupt, S. A. <strong>Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia.</strong> Am. J. Hum. Genet. 72: 749-758, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12577200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12577200</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12577200[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/368263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12577200">Cuajungco et al. (2003)</a> characterized the consequences of the major splice site mutation in IKBKAP responsible for FD (<a href="#0001">603722.0001</a>) by examining the ratio of wildtype to mutant IKBKAP transcript in Epstein-Barr virus-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with the disorder. They consistently found that wildtype IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem dysautonomia tissues. Furthermore, a corresponding decrease in the level of wildtype protein was seen in FD cell lines and tissues. The wildtype-to-mutant ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative PCR, the authors found that relative wildtype-to-mutant IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggested that the relative inefficiency of wildtype IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12577200" 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>Medulloblastoma</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Waszak, S. M., Robinson, G. W., Gudenas, B. L., Smith, K. S., Forget, A., Kojic, M., Garcia-Lopez, J., Hadley, J., Hamilton, K. V., Indersie, E., Buchhalter, I., Kerssemakers, J., and 51 others. <strong>Germline Elongator mutations in sonic hedgehog medulloblastoma.</strong> Nature 580: 396-401, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32296180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32296180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32296180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2164-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32296180">Waszak et al. (2020)</a> analyzed all protein-coding genes and identified and replicated rare germline loss-of-function variants across the ELP1 gene in 14% of pediatric patients with medulloblastoma in subgroup sonic hedgehog (MB-SHH; <a href="/entry/155255">155255</a>). Parent-offspring and pedigree analysis identified germline mutations in 2 families with a history of pediatric medulloblastoma; see <a href="#0004">603722.0004</a> and <a href="#0005">603722.0005</a>. ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among pediatric patients with MB-SHH. ELP1-associated medulloblastomas were restricted to the SHH-alpha subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1 (<a href="/entry/601309">601309</a>). Tumors from patients with ELP1-associated MB-SHH were characterized by a destabilized elongator complex, loss of elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to elongator deficiency in model systems. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32296180" 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="#16" class="mim-tip-reference" title="Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. <strong>Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.</strong> Nature 461: 402-406, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19693009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19693009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19693009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19693009">Lee et al. (2009)</a> reported the derivation of patient-specific FD induced pluripotent stem cells (iPSCs) and the directed differentiation into cells of all 3 germ layers including peripheral neurons. Gene expression analysis in purified FD iPSC-derived lineages demonstrated tissue-specific missplicing of IKBKAP in vitro. Patient-specific neural crest precursors expressed particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis was further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behavior. Furthermore, <a href="#16" class="mim-tip-reference" title="Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. <strong>Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.</strong> Nature 461: 402-406, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19693009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19693009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19693009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19693009">Lee et al. (2009)</a> used FD iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. <a href="#16" class="mim-tip-reference" title="Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., Ganat, Y. M., Menon, J., Shimizu, F., Viale, A., Tabar, V., Sadelain, M., Studer, L. <strong>Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.</strong> Nature 461: 402-406, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19693009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19693009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19693009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19693009">Lee et al. (2009)</a> concluded that their study illustrated the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19693009" 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="#13" class="mim-tip-reference" title="Hims, M. M., Shetty, R. S., Pickel, J., Mull, J., Leyne, M., Liu, L., Gusella, J. F., Slaugenhaupt, S. A. <strong>A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect.</strong> Genomics 90: 389-396, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17644305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17644305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17644305[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.05.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17644305">Hims et al. (2007)</a> created transgenic mice expressing human IKBKAP with the FD-associated IVS20DS+6T-C splice mutation (<a href="#0001">603722.0001</a>). The mutant IKBKAP transgene was misspliced in transgenic mice in a tissue-specific manner that replicated the pattern seen in FD patient tissues. In both FD and transgenic mouse tissues, missplicing predominated in neuronal tissues compared with nonneuronal tissues, and the most accurate splicing was seen in heart and kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17644305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I. <strong>Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.</strong> Hum. Molec. Genet. 25: 1116-1128, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26769677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26769677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26769677[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddv634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26769677">Morini et al. (2016)</a> generated a transgenic mouse model of FD with the exon 20 splice site mutation (TgFD9;Ikbkap(delta20/flox)). Mutant mice recapitulated many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26769677" 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 transgenic male mice carrying the human exon 20 splice site mutation, <a href="#19" class="mim-tip-reference" title="Morini, E., Gao, D., Montgomery, C. M., Salani, M., Mazzasette, C., Krussig, T. A., Swain, B., Dietrich, P., Narasimhan, J., Gabbeta, V., Dakka, A., Hedrick, J., Zhao, X., Weetall, M., Naryshkin, N. A., Wojtkiewicz, G. G., Ko, C.-P., Talkowski, M. E., Dragatsis, I., Slaugenhaupt, S. A. <strong>ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia.</strong> Am. J. Hum. Genet. 104: 638-650, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30905397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30905397</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30905397[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30905397">Morini et al. (2019)</a> found that treatment right after birth with oral kinetin, a small molecule splicing modulator, resulted in improved sensorimotor coordination, prevention of spinal deformities, and significantly increased survival of proprioceptive neurons in the peripheral nervous system. These clinical benefits were associated with the increased expression of normal IKBKAP transcripts, as well as increased protein expression. Treatment of human fibroblasts carrying the splice site mutation resulted in increased IKBKAP gene expression without significant changes in overall genomic splicing, suggesting that kinetin shows selective splicing modulation activity. The study provided a proof of concept that targeting the underlying genetic mechanism in FD can result in clinical benefits. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30905397" 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="#21" class="mim-tip-reference" title="Romano, G., Riccardi, F., Bussani, E., Vodret, S., Licastro, D., Ragone, I., Ronzitti, G., Morini, E., Slaugenhaupt, S. A., Pagani, F. <strong>Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.</strong> Am. J. Hum. Genet. 109: 1534-1548, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35905737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35905737</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35905737[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2022.07.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35905737">Romano et al. (2022)</a> treated transgenic mice that were heterozygous for the human exon 20 splice site mutation with an AAV9 vector carrying a modified U1 snRNA targeting the exon 20 skipping. The mutant mice were treated with intraventricular and intraperitoneal injections of the modified U1 snRNA at postnatal days 0 and 2, respectively. Treatment resulted in increased wildtype Elp1 gene and protein expression and increased survival of the mutant mice. The treated mice exhibited improved motor and proprioceptive function and improved cardiac and renal function. Gene expression studies in dorsal root ganglia from the treated mice demonstrated very few off-target effects. <a href="#21" class="mim-tip-reference" title="Romano, G., Riccardi, F., Bussani, E., Vodret, S., Licastro, D., Ragone, I., Ronzitti, G., Morini, E., Slaugenhaupt, S. A., Pagani, F. <strong>Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.</strong> Am. J. Hum. Genet. 109: 1534-1548, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35905737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35905737</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35905737[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2022.07.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35905737">Romano et al. (2022)</a> concluded that the phenotypic improvements in the AAV-treated mutant mice, in conjunction with evidence for few off-target effects, provided promising evidence for the application of this therapy in patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35905737" 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="#22" class="mim-tip-reference" title="Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F. <strong>Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.</strong> Am. J. Hum. Genet. 68: 598-605, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179008">Slaugenhaupt et al. (2001)</a> found that more than 99.5% of disease alleles causing familial dysautonomia (<a href="/entry/223900">223900</a>) in Ashkenazi Jewish individuals carried a donor splice site mutation (IVS20+6T-C) which leads to deletion of exon 20 from mRNA. Haplotype analyses were consistent with a common founder. <a href="#1" class="mim-tip-reference" title="Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y. <strong>Familial dysautonomia is caused by mutations of the IKAP gene.</strong> Am. J. Hum. Genet. 68: 753-758, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179021[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179021">Anderson et al. (2001)</a> identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11179008+11179021" 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>To determine why the mutation in position 6 of intron 20 causes aberrant splicing only in certain cases, <a href="#14" class="mim-tip-reference" title="Ibrahim, E. C., Hims, M. M., Shomron, N., Burge, C. B., Slaugenhaupt, S. A., Reed, R. <strong>Weak definition of IKBKAP exon 20 leads to aberrant splicing in familial dysautonomia.</strong> Hum. Mutat. 28: 41-53, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16964593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16964593</a>] [<a href="https://doi.org/10.1002/humu.20401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16964593">Ibrahim et al. (2007)</a> used an in silico approach to identify potential sequences involved in exon 20 skipping. Computational analyses of the exon 20 5-prime splice site itself predicted that this 9-nucleotide splicing signal, even when it contains the T-C mutation, is not sufficiently weak to explain the familial dysautonomia phenotype. However, the computational analysis predicted that both the upstream 3-prime splice site and exon 20 contain weak splicing signals, indicating that the familial dysautonomia 5-prime splice site, together with the surrounding splicing signals, are not adequate for defining exon 20. These in silico predictions were corroborated by IKBKAP minigenes in a rapid and simple in vitro coupled RNA polymerase II (see <a href="/entry/180660">180660</a>) transcription/splicing assay. The weak splicing signals that flank the T-C mutation were validated as the underlying cause of familial dysautonomia in vivo using transient transfection assays. Together, the study demonstrated the general utility of combining in silico data with an in vitro RNA polymerase II transcription/splicing system for rapidly identifying critical sequences that underlie the numerous splicing disorders caused by otherwise silent mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16964593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137853022 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853022;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs137853022?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137853022" 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=rs137853022" 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=RCV000006459 OR RCV000789660 OR RCV001380395 OR RCV002482833" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006459, RCV000789660, RCV001380395, RCV002482833" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006459...</a>
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<p>In 4 Ashkenazi Jewish patients with familial dysautonomia (<a href="/entry/223900">223900</a>), <a href="#22" class="mim-tip-reference" title="Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F. <strong>Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.</strong> Am. J. Hum. Genet. 68: 598-605, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179008">Slaugenhaupt et al. (2001)</a> identified an arg696-to-pro (R696P) mutation in exon 19 of the IKBKAP gene. <a href="#1" class="mim-tip-reference" title="Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y. <strong>Familial dysautonomia is caused by mutations of the IKAP gene.</strong> Am. J. Hum. Genet. 68: 753-758, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179021[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/318808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179021">Anderson et al. (2001)</a> identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11179008+11179021" 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="#10" class="mim-tip-reference" title="Dong, J., Edelmann, L., Bajwa, A. M., Kornreich, R., Desnick, R. J. <strong>Familial dysautonomia: detection of the IKBKAP IVS20+6T-C and R696P mutations and frequencies among Ashkenazi Jews.</strong> Am. J. Med. Genet. 110: 253-257, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12116234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12116234</a>] [<a href="https://doi.org/10.1002/ajmg.10450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12116234">Dong et al. (2002)</a> developed a single PCR and allele-specific oligonucleotide (ASO) hybridization assay for detection of both the IVS20+6T-C splice site mutation (<a href="#0001">603722.0001</a>) and the R696P mutation found in Ashkenazi Jews. Screening of 2,518 anonymous Ashkenazi Jewish individuals from the New York metropolitan area revealed a carrier frequency for the splice mutation of 1 in 32 (3.2%; 95% CI 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P deletion, indicating that the mutation is rare in this population (less than 1 in 2,500). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12116234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28939712 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939712;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=rs28939712" 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=rs28939712" 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=RCV000006460 OR RCV000789661" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006460, RCV000789661" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006460...</a>
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<p>In a patient with familial dysautonomia (<a href="/entry/223900">223900</a>), previously reported by <a href="#3" class="mim-tip-reference" title="Blumenfeld, A., Slaugenhaupt, S. A., Liebert, C. B., Temper, V., Maayan, C., Gill, S., Lucente, D. E., Idelson, M., MacCormack, K., Monahan, M. A., Mull, J., Leyne, M., Mendillo, M., Schiripo, T., Mishori, E., Breakefield, X., Axelrod, F. B., Gusella, J. F. <strong>Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.</strong> Am. J. Hum. Genet. 64: 1110-1118, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090896</a>] [<a href="https://doi.org/10.1086/302339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090896">Blumenfeld et al. (1999)</a>, <a href="#17" class="mim-tip-reference" title="Leyne, M., Mull, J., Gill, S. P., Cuajungco, M. P., Oddoux, C., Blumenfeld, A., Maayan, C., Guesella, J. F., Axelrod, F. B., Slaugenhaupt, S. A. <strong>Identification of the first non-Jewish mutation in familial dysautonomia.</strong> Am. J. Med. Genet. 118A: 305-308, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12687659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12687659</a>] [<a href="https://doi.org/10.1002/ajmg.a.20052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12687659">Leyne et al. (2003)</a> identified compound heterozygosity for the major FD haplotype (<a href="#0001">603722.0001</a>), which was inherited from the Ashkenazi Jewish father, and a 3051C-T transition in exon 26 of the IKBKAP gene, resulting in a pro914-to-leu (P914L) substitution, from the mother, who was of Irish-German/Sicilian heritage. The patient fulfilled all diagnostic criteria for FD other than pure Ashkenazi Jewish ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10090896+12687659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1564110292 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1564110292;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=rs1564110292" 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=rs1564110292" 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=RCV001730181 OR RCV002246468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001730181, RCV002246468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001730181...</a>
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<p>In a father and daughter with medulloblastoma (<a href="/entry/155255">155255</a>), <a href="#23" class="mim-tip-reference" title="Waszak, S. M., Robinson, G. W., Gudenas, B. L., Smith, K. S., Forget, A., Kojic, M., Garcia-Lopez, J., Hadley, J., Hamilton, K. V., Indersie, E., Buchhalter, I., Kerssemakers, J., and 51 others. <strong>Germline Elongator mutations in sonic hedgehog medulloblastoma.</strong> Nature 580: 396-401, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32296180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32296180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32296180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2164-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32296180">Waszak et al. (2020)</a> identified a heterozygous germline 1-bp duplication (c.138dupT) in the ELP1 gene, resulting in a frameshift. The father was diagnosed at age 17 years and the daughter at age 4 years. There was a paternal family history of death due to brain tumor and the father's sister died of medulloblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32296180" 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 6/7/2020."None>Hamosh (2020)</a> noted that the c.138dupT variant was not present in the gnomAD database.</p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1291760879 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1291760879;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1291760879?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1291760879" 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=rs1291760879" 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=RCV001730182" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001730182" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001730182</a>
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<p>In a 23-year-old man who was diagnosed at age 19 years with medulloblastoma (<a href="/entry/155255">155255</a>), <a href="#23" class="mim-tip-reference" title="Waszak, S. M., Robinson, G. W., Gudenas, B. L., Smith, K. S., Forget, A., Kojic, M., Garcia-Lopez, J., Hadley, J., Hamilton, K. V., Indersie, E., Buchhalter, I., Kerssemakers, J., and 51 others. <strong>Germline Elongator mutations in sonic hedgehog medulloblastoma.</strong> Nature 580: 396-401, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32296180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32296180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32296180[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2164-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32296180">Waszak et al. (2020)</a> identified a heterozygous germline c.312T-C transition in the ELP1 gene. His mother, who was in her fifties, carried the mutation but had not developed medulloblastoma. A distant maternal relative who was diagnosed with medulloblastoma at age 4 years had not been tested for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32296180" 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="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 6/7/2020."None>Hamosh (2020)</a> noted that the c.312T-C variant was not present in the gnomAD database.</p>
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Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., Rubin, B. Y.
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<strong>Familial dysautonomia is caused by mutations of the IKAP gene.</strong>
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Am. J. Hum. Genet. 68: 753-758, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179021[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=11179021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<div class="">
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<p class="mim-text-font">
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Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I.
|
|
<strong>Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.</strong>
|
|
Hum. Molec. Genet. 25: 1116-1128, 2016.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26769677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26769677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26769677[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=26769677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv634" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Morini2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Morini, E., Gao, D., Montgomery, C. M., Salani, M., Mazzasette, C., Krussig, T. A., Swain, B., Dietrich, P., Narasimhan, J., Gabbeta, V., Dakka, A., Hedrick, J., Zhao, X., Weetall, M., Naryshkin, N. A., Wojtkiewicz, G. G., Ko, C.-P., Talkowski, M. E., Dragatsis, I., Slaugenhaupt, S. A.
|
|
<strong>ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia.</strong>
|
|
Am. J. Hum. Genet. 104: 638-650, 2019.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30905397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30905397</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30905397[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=30905397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2019.02.009" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Rahl2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
|
Rahl, P. B., Chen, C. Z., Collins, R. N.
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|
<strong>Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation.</strong>
|
|
Molec. Cell 17: 841-853, 2005.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15780940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15780940</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15780940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2005.02.018" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Romano2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Romano, G., Riccardi, F., Bussani, E., Vodret, S., Licastro, D., Ragone, I., Ronzitti, G., Morini, E., Slaugenhaupt, S. A., Pagani, F.
|
|
<strong>Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.</strong>
|
|
Am. J. Hum. Genet. 109: 1534-1548, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35905737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35905737</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35905737[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=35905737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2022.07.004" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Slaugenhaupt2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Slaugenhaupt, S. A., Blumenfeld, A., Gill, S. P., Leyne, M., Mull, J., Cuajungco, M. P., Liebert, C. B., Chadwick, B., Idelson, M., Reznik, L., Robbins, C. M., Makalowska, I., Brownstein, M. J., Krappmann, D., Scheidereit, C., Maayan, C., Axelrod, F. B., Gusella, J. F.
|
|
<strong>Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.</strong>
|
|
Am. J. Hum. Genet. 68: 598-605, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11179008[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=11179008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/318810" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Waszak2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Waszak, S. M., Robinson, G. W., Gudenas, B. L., Smith, K. S., Forget, A., Kojic, M., Garcia-Lopez, J., Hadley, J., Hamilton, K. V., Indersie, E., Buchhalter, I., Kerssemakers, J., and 51 others.
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<strong>Germline Elongator mutations in sonic hedgehog medulloblastoma.</strong>
|
|
Nature 580: 396-401, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32296180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32296180</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32296180[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=32296180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-020-2164-5" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/03/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<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">
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/13/2021<br>Cassandra L. Kniffin - updated : 02/10/2020<br>Patricia A. Hartz - updated : 10/14/2014<br>Patricia A. Hartz - updated : 1/11/2013<br>Ada Hamosh - updated : 10/19/2009<br>Patricia A. Hartz - updated : 4/8/2009<br>Patricia A. Hartz - updated : 9/21/2007<br>Victor A. McKusick - updated : 3/12/2007<br>Patricia A. Hartz - updated : 7/18/2006<br>Patricia A. Hartz - updated : 4/19/2005<br>Deborah L. Stone - updated : 11/15/2004<br>Victor A. McKusick - updated : 2/28/2003<br>Victor A. McKusick - updated : 7/2/2002<br>Victor A. McKusick - updated : 3/19/2001
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh : 4/12/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/08/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<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">
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<span class="mim-text-font">
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carol : 10/04/2022<br>carol : 10/03/2022<br>carol : 10/14/2021<br>carol : 10/13/2021<br>alopez : 01/28/2021<br>alopez : 11/20/2020<br>carol : 02/12/2020<br>alopez : 02/11/2020<br>ckniffin : 02/10/2020<br>mgross : 10/14/2014<br>mcolton : 10/14/2014<br>mgross : 1/15/2013<br>terry : 1/11/2013<br>carol : 6/23/2011<br>alopez : 10/26/2009<br>terry : 10/19/2009<br>wwang : 8/14/2009<br>mgross : 4/8/2009<br>mgross : 4/8/2009<br>mgross : 9/26/2007<br>terry : 9/21/2007<br>alopez : 3/21/2007<br>terry : 3/12/2007<br>wwang : 12/5/2006<br>terry : 12/4/2006<br>mgross : 7/19/2006<br>terry : 7/18/2006<br>mgross : 4/20/2005<br>terry : 4/19/2005<br>carol : 12/22/2004<br>tkritzer : 11/15/2004<br>carol : 8/4/2004<br>tkritzer : 3/7/2003<br>tkritzer : 3/6/2003<br>terry : 2/28/2003<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>cwells : 3/30/2001<br>cwells : 3/29/2001<br>terry : 3/19/2001<br>carol : 3/15/2000<br>alopez : 4/12/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603722
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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|
|
ELONGATOR COMPLEX PROTEIN 1; ELP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE COMPLEX-ASSOCIATED PROTEIN; IKBKAP<br />
|
|
IKK COMPLEX-ASSOCIATED PROTEIN; IKAP<br />
|
|
ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 1; ELP1<br />
|
|
ELP1, YEAST, HOMOLOG OF
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ELP1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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|
|
<strong>SNOMEDCT:</strong> 1156923005, 29159009, 443333004;
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<strong>ICD10CM:</strong> G90.1;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 9q31.3
|
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:108,867,517-108,934,124 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
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Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
|
<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
9q31.3
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
{Medulloblastoma}
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
155255
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive; Somatic mutation
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Dysautonomia, familial
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
223900
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>ELP1 is a component of Elongator, a highly conserved transcription elongation factor complex that has histone acetyltransferase activity, primarily directed toward histone H3. A substantial fraction of Elongator is cytoplasmic, however, suggesting that the complex performs additional functions. ELP1 was initially described as IKBKAP (IKAP), a scaffold protein of the IKK complex involved in NF-kappa-B (see 164011) activation, but a role for IKAP in this pathway was later disproved (summary by Close et al., 2006). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Cohen et al. (1998) isolated large, IL1-inducible IKK complexes containing NF-kappa-B-inducing kinase (NIK; 604655), IKK-alpha (600664), IKK-beta (603258), I-kappa-B-alpha (164008), NF-kappa-B/RelA (164014), and a 150-kD protein that they called IKAP for 'IKK complex-associated protein.' The IKAP open reading frame of 3,996 nucleotides is flanked by 303 bp and 501 bp of 5-prime and 3-prime untranslated sequence, respectively. A 4.8-kb mRNA was detected in most human tissues. IKAP shows 22% overall identity with the yeast protein IKI3, which may be involved in the yeast response to toxins. There appeared to be 5 WD-like repeats. </p><p>Coli et al. (2001) cloned Ikbkap cDNA from mouse spleen. The mouse cDNA shares 77% nucleotide identity with human IKBKAP. The deduced mouse protein contains 1,333 amino acids, and the human protein contains 1,332. </p>
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</span>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cohen et al. (1998) found that IKAP could bind NIK and IKKs through separate domains and assemble them into an active kinase complex. Thus, IKAP is a scaffold protein and a regulator for 3 different kinases involved in proinflammatory signaling. IKAP sequence encompassing only the fifth WD-like motif was sufficient for binding of NIK. </p><p>Krappmann et al. (2000) found IKBKAP associated with a high molecular mass complex containing additional proteins of 100, 70, 45, and 39 kD in HeLa cells. However, they found no association of IKBKAP with the IKK complex. Overexpression of IKBKAP repressed expression of reporter plasmids driven by thymidine kinase (188300) and beta-actin (102630) promoters, in addition to the NF-kappa-B promoter. </p><p>By examining the elongator complex purified from HeLa cells, Hawkes et al. (2002) found that the complex existed in 2 forms, the holo-elongator, which had histone acetyltransferase activity directed against histones H3 (see 602810) and H4 (see 602822), and a 3-subunit core form, which did not have histone acetyltransferase activity despite containing the catalytic subunit ELP3 (612722). ELP2 (616054) and IKAP were also detected in the core elongator complex. ELP4 (606985), ELP5 (615019), and ELP6 (615020) were detected in the active holo-elongator complex. Hawkes et al. (2002) proposed that the elongator complex serves a role in RNA polymerase II (see 180660)-associated chromatin remodeling during transcriptional elongation. </p><p>Rahl et al. (2005) found that the yeast homolog of IKBKAP, Elp1, physically interacted with the yeast Rab guanine nucleotide exchange factor Sec2. The Sec2 interaction domain of Elp1 was necessary for both Elp1 function and for the polarized localization of Sec2. Rahl et al. (2005) proposed that familial dysautonomia (FD; 223900), which results from mutation in IKBKAP, may be a defect in polarized exocytosis in neurons. </p><p>Using RNA interference and DNA microarray analysis, Close et al. (2006) found that IKAP depletion in human cells affected expression of a number of genes, with correlated effects on histone H3 acetylation and transcriptional elongation. Several affected genes were implicated in cell motility, and cells with decreased IKAP levels displayed motility defects. </p><p>Creppe et al. (2009) found that Elp1 was highly expressed throughout the rostrocaudal axis of the mouse telencephalon during development. Silencing of Elp1 impaired radial migration, resulting in accumulation of cells in the ventricular and subventricular zones and a reduced percentage of projection neurons in the cortical plate compared with controls. The migration defect was temporary, and Elp1-depleted neurons eventually reached their terminal destination. Elp1 silencing affected the morphology, but not the survival, of projection neurons in the cortical plate, with impaired growth of dendrites and axons, but not the soma perimeter. Depletion of ELP1 in a human colorectal carcinoma cell line resulted in abnormally rounded cell shapes and major delays in cell spreading. Endogenous ELP1 interacted with ELP3 in all human cell lines examined. ELP1 and ELP3 associated with microtubules, and depletion of either ELP1 or ELP3 resulted in reduced acetylation of alpha-tubulin (see TUBA1A; 602529). </p><p>Using RNA interference, Close et al. (2012) found that depletion of any of the elongator complex components Elp1, Elp3, Elp5 (615019), or Elp6 (615020) in B16-F10 mouse melanoma cells reduced cell motility in a wound-healing assay and reduced the capacity of cells to form colonies in soft agar. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Coli et al. (2001) determined that the mouse Ikbkap gene, like the human IKBKAP gene, contains 37 exons. The mouse Ikbkap gene spans about 51 kb, and the consensus donor splice site of intron 20, which is altered in a major mutation (603722.0001) leading to familial dysautonomia (FD; 223900), is conserved in the mouse. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By sequence analysis, Slaugenhaupt et al. (2001) mapped the IKBKAP gene to chromosome 9q31. </p><p>By backcross analysis, Coli et al. (2001) mapped the mouse Ikbkap gene to a central region of chromosome 4 that shows homology of synteny to human chromosome 9. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Familial Dysautonomia</em></strong></p><p>
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Familial dysautonomia (FD; 223900), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Blumenfeld et al. (1993) mapped the familial dysautonomia locus to 9q31; by haplotype analysis, Blumenfeld et al. (1999) narrowed the location to a 471-kb interval. They had shown that the ethnic bias is due to a founder effect, with more than 99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of the familial dysautonomia, Slaugenhaupt et al. (2001) sequenced the candidate region and cloned and characterized the 5 genes located therein. IKBKAP was one of these genes and was found to harbor 2 mutations that can cause FD. The major haplotype mutation was located at the donor splice site of intron 20 (IVS20DS+6T-C; 603722.0001). This mutation results in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wildtype message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wildtype, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in 4 patients is an arg696-to-pro missense mutation (603722.0002) in exon 19, which is predicted to disrupt a potential phosphorylation site. </p><p>Simultaneously and independently, Anderson et al. (2001) found the splice site mutation as the predominant one in familial dysautonomia, and identified, in individuals bearing a minor FD haplotype, the missense mutation in exon 19 that disrupts a consensus serine/threonine kinase phosphorylation site. </p><p>Cuajungco et al. (2003) characterized the consequences of the major splice site mutation in IKBKAP responsible for FD (603722.0001) by examining the ratio of wildtype to mutant IKBKAP transcript in Epstein-Barr virus-transformed lymphoblast lines, primary fibroblasts, freshly collected blood samples, and postmortem tissues from patients with the disorder. They consistently found that wildtype IKBKAP transcripts were present, albeit to varying extents, in all cell lines, blood, and postmortem dysautonomia tissues. Furthermore, a corresponding decrease in the level of wildtype protein was seen in FD cell lines and tissues. The wildtype-to-mutant ratio in cultured lymphoblasts varied with growth phase but not with serum concentration or inclusion of antibiotics. Using both densitometry and real-time quantitative PCR, the authors found that relative wildtype-to-mutant IKBKAP RNA levels were highest in cultured patient lymphoblasts and lowest in postmortem central and peripheral nervous tissues. These observations suggested that the relative inefficiency of wildtype IKBKAP mRNA production from the mutant alleles in the nervous system underlies the selective degeneration of sensory and autonomic neurons in FD. </p><p><strong><em>Medulloblastoma</em></strong></p><p>
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Waszak et al. (2020) analyzed all protein-coding genes and identified and replicated rare germline loss-of-function variants across the ELP1 gene in 14% of pediatric patients with medulloblastoma in subgroup sonic hedgehog (MB-SHH; 155255). Parent-offspring and pedigree analysis identified germline mutations in 2 families with a history of pediatric medulloblastoma; see 603722.0004 and 603722.0005. ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among pediatric patients with MB-SHH. ELP1-associated medulloblastomas were restricted to the SHH-alpha subtype and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1 (601309). Tumors from patients with ELP1-associated MB-SHH were characterized by a destabilized elongator complex, loss of elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to elongator deficiency in model systems. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lee et al. (2009) reported the derivation of patient-specific FD induced pluripotent stem cells (iPSCs) and the directed differentiation into cells of all 3 germ layers including peripheral neurons. Gene expression analysis in purified FD iPSC-derived lineages demonstrated tissue-specific missplicing of IKBKAP in vitro. Patient-specific neural crest precursors expressed particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis was further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behavior. Furthermore, Lee et al. (2009) used FD iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Lee et al. (2009) concluded that their study illustrated the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hims et al. (2007) created transgenic mice expressing human IKBKAP with the FD-associated IVS20DS+6T-C splice mutation (603722.0001). The mutant IKBKAP transgene was misspliced in transgenic mice in a tissue-specific manner that replicated the pattern seen in FD patient tissues. In both FD and transgenic mouse tissues, missplicing predominated in neuronal tissues compared with nonneuronal tissues, and the most accurate splicing was seen in heart and kidney. </p><p>Morini et al. (2016) generated a transgenic mouse model of FD with the exon 20 splice site mutation (TgFD9;Ikbkap(delta20/flox)). Mutant mice recapitulated many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments. </p><p>In transgenic male mice carrying the human exon 20 splice site mutation, Morini et al. (2019) found that treatment right after birth with oral kinetin, a small molecule splicing modulator, resulted in improved sensorimotor coordination, prevention of spinal deformities, and significantly increased survival of proprioceptive neurons in the peripheral nervous system. These clinical benefits were associated with the increased expression of normal IKBKAP transcripts, as well as increased protein expression. Treatment of human fibroblasts carrying the splice site mutation resulted in increased IKBKAP gene expression without significant changes in overall genomic splicing, suggesting that kinetin shows selective splicing modulation activity. The study provided a proof of concept that targeting the underlying genetic mechanism in FD can result in clinical benefits. </p><p>Romano et al. (2022) treated transgenic mice that were heterozygous for the human exon 20 splice site mutation with an AAV9 vector carrying a modified U1 snRNA targeting the exon 20 skipping. The mutant mice were treated with intraventricular and intraperitoneal injections of the modified U1 snRNA at postnatal days 0 and 2, respectively. Treatment resulted in increased wildtype Elp1 gene and protein expression and increased survival of the mutant mice. The treated mice exhibited improved motor and proprioceptive function and improved cardiac and renal function. Gene expression studies in dorsal root ganglia from the treated mice demonstrated very few off-target effects. Romano et al. (2022) concluded that the phenotypic improvements in the AAV-treated mutant mice, in conjunction with evidence for few off-target effects, provided promising evidence for the application of this therapy in patients. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 DYSAUTONOMIA, FAMILIAL</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ELP1, IVS20DS, T-C, +6
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<br />
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SNP: rs111033171,
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gnomAD: rs111033171,
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ClinVar: RCV000006458, RCV000058928, RCV000789357, RCV003444194, RCV004018577, RCV005041994
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Slaugenhaupt et al. (2001) found that more than 99.5% of disease alleles causing familial dysautonomia (223900) in Ashkenazi Jewish individuals carried a donor splice site mutation (IVS20+6T-C) which leads to deletion of exon 20 from mRNA. Haplotype analyses were consistent with a common founder. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia. </p><p>To determine why the mutation in position 6 of intron 20 causes aberrant splicing only in certain cases, Ibrahim et al. (2007) used an in silico approach to identify potential sequences involved in exon 20 skipping. Computational analyses of the exon 20 5-prime splice site itself predicted that this 9-nucleotide splicing signal, even when it contains the T-C mutation, is not sufficiently weak to explain the familial dysautonomia phenotype. However, the computational analysis predicted that both the upstream 3-prime splice site and exon 20 contain weak splicing signals, indicating that the familial dysautonomia 5-prime splice site, together with the surrounding splicing signals, are not adequate for defining exon 20. These in silico predictions were corroborated by IKBKAP minigenes in a rapid and simple in vitro coupled RNA polymerase II (see 180660) transcription/splicing assay. The weak splicing signals that flank the T-C mutation were validated as the underlying cause of familial dysautonomia in vivo using transient transfection assays. Together, the study demonstrated the general utility of combining in silico data with an in vitro RNA polymerase II transcription/splicing system for rapidly identifying critical sequences that underlie the numerous splicing disorders caused by otherwise silent mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 DYSAUTONOMIA, FAMILIAL</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ELP1, ARG696PRO
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<br />
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SNP: rs137853022,
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gnomAD: rs137853022,
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ClinVar: RCV000006459, RCV000789660, RCV001380395, RCV002482833
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 Ashkenazi Jewish patients with familial dysautonomia (223900), Slaugenhaupt et al. (2001) identified an arg696-to-pro (R696P) mutation in exon 19 of the IKBKAP gene. Anderson et al. (2001) identified the same mutation in Ashkenazi Jewish patients with familial dysautonomia. </p><p>Dong et al. (2002) developed a single PCR and allele-specific oligonucleotide (ASO) hybridization assay for detection of both the IVS20+6T-C splice site mutation (603722.0001) and the R696P mutation found in Ashkenazi Jews. Screening of 2,518 anonymous Ashkenazi Jewish individuals from the New York metropolitan area revealed a carrier frequency for the splice mutation of 1 in 32 (3.2%; 95% CI 2.5-3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P deletion, indicating that the mutation is rare in this population (less than 1 in 2,500). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 DYSAUTONOMIA, FAMILIAL</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ELP1, PRO914LEU
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<br />
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SNP: rs28939712,
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ClinVar: RCV000006460, RCV000789661
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with familial dysautonomia (223900), previously reported by Blumenfeld et al. (1999), Leyne et al. (2003) identified compound heterozygosity for the major FD haplotype (603722.0001), which was inherited from the Ashkenazi Jewish father, and a 3051C-T transition in exon 26 of the IKBKAP gene, resulting in a pro914-to-leu (P914L) substitution, from the mother, who was of Irish-German/Sicilian heritage. The patient fulfilled all diagnostic criteria for FD other than pure Ashkenazi Jewish ancestry. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 MEDULLOBLASTOMA</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ELP1, 1-BP DUP, 138T
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<br />
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SNP: rs1564110292,
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ClinVar: RCV001730181, RCV002246468
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and daughter with medulloblastoma (155255), Waszak et al. (2020) identified a heterozygous germline 1-bp duplication (c.138dupT) in the ELP1 gene, resulting in a frameshift. The father was diagnosed at age 17 years and the daughter at age 4 years. There was a paternal family history of death due to brain tumor and the father's sister died of medulloblastoma. </p><p>Hamosh (2020) noted that the c.138dupT variant was not present in the gnomAD database.</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 MEDULLOBLASTOMA</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ELP1, c.312T-C
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<br />
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SNP: rs1291760879,
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gnomAD: rs1291760879,
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ClinVar: RCV001730182
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 23-year-old man who was diagnosed at age 19 years with medulloblastoma (155255), Waszak et al. (2020) identified a heterozygous germline c.312T-C transition in the ELP1 gene. His mother, who was in her fifties, carried the mutation but had not developed medulloblastoma. A distant maternal relative who was diagnosed with medulloblastoma at age 4 years had not been tested for the mutation. </p><p>Hamosh (2020) noted that the c.312T-C variant was not present in the gnomAD database.</p>
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</span>
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</div>
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<h4>
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<span class="mim-font">
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Hilary J. Vernon - updated : 10/03/2022<br>Ada Hamosh - updated : 10/13/2021<br>Cassandra L. Kniffin - updated : 02/10/2020<br>Patricia A. Hartz - updated : 10/14/2014<br>Patricia A. Hartz - updated : 1/11/2013<br>Ada Hamosh - updated : 10/19/2009<br>Patricia A. Hartz - updated : 4/8/2009<br>Patricia A. Hartz - updated : 9/21/2007<br>Victor A. McKusick - updated : 3/12/2007<br>Patricia A. Hartz - updated : 7/18/2006<br>Patricia A. Hartz - updated : 4/19/2005<br>Deborah L. Stone - updated : 11/15/2004<br>Victor A. McKusick - updated : 2/28/2003<br>Victor A. McKusick - updated : 7/2/2002<br>Victor A. McKusick - updated : 3/19/2001
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Ada Hamosh : 4/12/1999
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alopez : 07/08/2024<br>carol : 10/04/2022<br>carol : 10/03/2022<br>carol : 10/14/2021<br>carol : 10/13/2021<br>alopez : 01/28/2021<br>alopez : 11/20/2020<br>carol : 02/12/2020<br>alopez : 02/11/2020<br>ckniffin : 02/10/2020<br>mgross : 10/14/2014<br>mcolton : 10/14/2014<br>mgross : 1/15/2013<br>terry : 1/11/2013<br>carol : 6/23/2011<br>alopez : 10/26/2009<br>terry : 10/19/2009<br>wwang : 8/14/2009<br>mgross : 4/8/2009<br>mgross : 4/8/2009<br>mgross : 9/26/2007<br>terry : 9/21/2007<br>alopez : 3/21/2007<br>terry : 3/12/2007<br>wwang : 12/5/2006<br>terry : 12/4/2006<br>mgross : 7/19/2006<br>terry : 7/18/2006<br>mgross : 4/20/2005<br>terry : 4/19/2005<br>carol : 12/22/2004<br>tkritzer : 11/15/2004<br>carol : 8/4/2004<br>tkritzer : 3/7/2003<br>tkritzer : 3/6/2003<br>terry : 2/28/2003<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>cwells : 3/30/2001<br>cwells : 3/29/2001<br>terry : 3/19/2001<br>carol : 3/15/2000<br>alopez : 4/12/1999
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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Copyright<sup>®</sup> 1966-2025 Johns Hopkins University.
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Thank you in advance for your generous support, <br />
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