3326 lines
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Entry
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- *606273 - EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 3; EIF2B3
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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">*606273</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li 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/606273">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000070785;t=ENST00000360403" 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=8891" 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=606273" 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 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=ENSG00000070785;t=ENST00000360403" 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_001166588,NM_001261418,NM_020365,XM_047433499,XM_047433500,XM_047433501" 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_020365" 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=606273" 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=09379&isoform_id=09379_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/EIF2B3" 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/9651997,9966779,10433787,10436247,17511746,18203317,21739873,48146687,119627416,119627417,119627418,119627419,119627420,119627421,189054452,262205273,387527981,2217272078,2217272080,2217272082,2462515101,2462515103,2462515105" 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/Q9NR50" 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=8891" 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=ENSG00000070785;t=ENST00000360403" 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=EIF2B3" 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=EIF2B3" 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+8891" 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/EIF2B3" 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:8891" 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/8891" 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=chr1&hgg_gene=ENST00000360403.7&hgg_start=44850522&hgg_end=44986595&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3259" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3259" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/eif2b3" 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=606273[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=606273[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/ENSG00000070785" 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=EIF2B3" 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=EIF2B3" 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=EIF2B3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EIF2B3&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/PA27690" 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:3259" 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/FBgn0034029.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:1313286" 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/EIF2B3#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:1313286" 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/8891/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=8891" 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=WBGene00004090;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-040426-1039" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:8891" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=EIF2B3&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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</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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606273
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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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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 3; EIF2B3
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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">
|
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, GAMMA<br />
|
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EIF2B-GAMMA
|
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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=EIF2B3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EIF2B3</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>
|
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Cytogenetic location: <a href="/geneMap/1/549?start=-3&limit=10&highlight=549">1p34.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:44850522-44986595&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'})">1:44,850,522-44,986,595</a> </span>
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</em>
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</strong>
|
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<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>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</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>
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|
Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
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</tr>
|
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</thead>
|
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<tbody>
|
|
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|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/549?start=-3&limit=10&highlight=549">
|
|
1p34.1
|
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</a>
|
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</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure
|
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|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620313"> 620313 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606273" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606273" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The EIF2B3 gene contains a subunit of eIF2B, a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2 (see <a href="/entry/603907">603907</a>). EIF2B catalyzes the exchange of GDP for GTP (summary by <a href="#2" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" 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>Translation of mRNA usually requires modification of the 5-prime cap, but some viral and cellular mRNAs use a cap-independent mechanism of ribosome binding mediated by an internal ribosomal entry site (IRES). The 5-prime untranslated region of hepatitis C virus (HCV) is highly conserved in all strains and folds into an IRES that binds directly to 40S ribosome subunits. Among the relatively limited number of cellular cofactors binding to the HCV IRES/40S subunit is EIF2 (see <a href="/entry/603907">603907</a>). Using a ribozyme-based selection system to identify cellular factors involved in HCV IRES function, followed by database searches and 5-prime RACE with ribozyme-binding sequences as primers, <a href="#5" class="mim-tip-reference" title="Kruger, M., Beger, C., Li, Q.-X., Welch, P. J., Tritz, R., Leavitt, M., Barber, J. R., Wong-Staal, F. <strong>Identification of eIF2B-gamma and eIF2-gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach.</strong> Proc. Nat. Acad. Sci. 97: 8566-8571, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10900014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10900014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10900014[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.15.8566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10900014">Kruger et al. (2000)</a> isolated a cDNA encoding EIF2B3, which they called EIF2B-gamma. The deduced 452-amino acid protein is 91% identical to rat Eif2b-gamma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10900014" 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 human EST database searching and PCR, followed by screening of a rat cDNA library, <a href="#8" class="mim-tip-reference" title="Price, N. T., Kimball, S. R., Jefferson, L. S., Proud, C. G. <strong>Cloning of cDNA for the gamma-subunit of mammalian translation initiation factor 2B, the guanine nucleotide-exchange factor for eukaryotic initiation factor 2.</strong> Biochem. J. 318: 631-636, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8809057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8809057</a>] [<a href="https://doi.org/10.1042/bj3180631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8809057">Price et al. (1996)</a> obtained a partial cDNA encoding human EIF2B3 and a full-length rat clone encoding Eif2b3. Northern blot analysis revealed wide expression of an approximately 1.8-kb Eif2b3 transcript in rat tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8809057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies (<a href="/entry/603896">603896</a>) with homozygous or compound heterozygous mutations in EIF2B2 (<a href="/entry/606454">606454</a>), EIF2B3, EIF2B4 (<a href="/entry/606687">606687</a>), and EIF2B5 (<a href="/entry/603945">603945</a>) compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. <a href="#2" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" 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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Integrated stress response inhibitor (ISRIB) is a drug-like eIF2B activator that reverses the effects of eIF2 phosphorylation. In rodents, it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, <a href="#9" class="mim-tip-reference" title="Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P. <strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong> Science 359: eaaq0939, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599213[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/10.1126/science.aaq0939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29599213">Tsai et al. (2018)</a> solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryoelectron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of 2 identical tetrameric subcomplexes involving EIF2B-beta (EIF2B2), -gamma (EIF2B3), -delta (EIF2B4), and -epsilon (EIF2B5), and ISRIB promoted this step by cross-bridging a central symmetry interface. <a href="#9" class="mim-tip-reference" title="Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P. <strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong> Science 359: eaaq0939, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599213[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/10.1126/science.aaq0939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29599213">Tsai et al. (2018)</a> concluded that thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29599213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 5/28/2015."None>Gross (2015)</a> mapped the EIF2B3 gene to chromosome 1p34.1 based on an alignment of the EIF2B3 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC018728" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC018728</a>) with the genomic sequence (GRCh38).</p>
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<p>Leukoencephalopathy with vanishing white matter (VWM3; <a href="/entry/620313">620313</a>) is an autosomal recessive disorder characterized by a chronic and progressive course with additional episodes of rapid deterioration provoked by fever and minor head trauma. <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">Van der Knaap et al. (2002)</a> demonstrated that mutations in each of the 5 subunits of the translation initiation factor eIF2B can cause the disorder. Two mutations were found in the EIF2B3 gene in compound heterozygous state (<a href="#0001">606273.0001</a>, <a href="#0002">606273.0002</a>); 1 was found in homozygosity (<a href="#0003">606273.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" 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 5 of 11 unrelated Chinese patients with leukoencephalopathy with vanishing white matter, <a href="#11" class="mim-tip-reference" title="Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. <strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong> J. Hum. Genet. 54: 74-77, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>] [<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158808">Wu et al. (2009)</a> identified mutations in the EIF2B3 gene, including 4 patients with the same mutation (I346T; <a href="#0004">606273.0004</a>), of whom 2 were homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 66-year old woman with adult-onset vanishing white matter disease, <a href="#3" class="mim-tip-reference" title="Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N. <strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong> Neurology 79: 2077-2078, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23115207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23115207</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182749edc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23115207">Ghezzi et al. (2012)</a> identified a homozygous missense mutation (A87V; <a href="#0003">606273.0003</a>) in EIF2B3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23115207" 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>Variant Function</em></strong></p><p>
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Using molecular modeling, <a href="#6" class="mim-tip-reference" title="Lee, Y. R., Kim, S. H., Ben-Mahmoud, A., Kim, O. H., Choi, T. I., Lee, K. H., Ku, B., Eum, J., Kee, Y., Lee, S., Cha, J., Won, D., Lee, S. T., Choi, J. R., Lee, J. S., Kim, H. D., Kim, H. G., Bonkowsky, J. L., Kang, H. C., Kim, C. H. <strong>Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.</strong> Hum. Molec. Genet. 30: 331-342, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33517449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33517449</a>] [<a href="https://doi.org/10.1093/hmg/ddab033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33517449">Lee et al. (2021)</a> found that 6 mutations in EIF2B3 in patients with VWM all caused misfolding and steric hindrance in the EIF2B3 protein, consistent with the altered unfolded protein response (UPR) pathway found in eif2b3 -/- zebrafish (see ANIMAL MODEL). Furthermore, none of 19 missense mutations in EIF2B3 associated with VWM in humans could rescue the morphologic phenotype of eif2b3 -/- zebrafish, validating the pathogenicity of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33517449" 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>In a 30-year-old Japanese woman, born of consanguineous parents, with adult-onset VWM, <a href="#7" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> identified a homozygous missense mutation in the EIF2B3 gene (L27Q; <a href="#0005">606273.0005</a>). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B3 was significantly decreased (40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" 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>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), <a href="#1" class="mim-tip-reference" title="Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. <strong>High-throughput discovery of novel developmental phenotypes.</strong> Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27626380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27626380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27626380[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/nature19356" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27626380">Dickinson et al. (2016)</a> found that knockout of the mouse homolog of human EIF2B3 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27626380" 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 RT-PCR and situ hybridization analyses, <a href="#6" class="mim-tip-reference" title="Lee, Y. R., Kim, S. H., Ben-Mahmoud, A., Kim, O. H., Choi, T. I., Lee, K. H., Ku, B., Eum, J., Kee, Y., Lee, S., Cha, J., Won, D., Lee, S. T., Choi, J. R., Lee, J. S., Kim, H. D., Kim, H. G., Bonkowsky, J. L., Kang, H. C., Kim, C. H. <strong>Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.</strong> Hum. Molec. Genet. 30: 331-342, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33517449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33517449</a>] [<a href="https://doi.org/10.1093/hmg/ddab033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33517449">Lee et al. (2021)</a> showed that eif2b3 was primarily expressed both maternally and zygotically in proliferating cells during early development of zebrafish. <a href="#6" class="mim-tip-reference" title="Lee, Y. R., Kim, S. H., Ben-Mahmoud, A., Kim, O. H., Choi, T. I., Lee, K. H., Ku, B., Eum, J., Kee, Y., Lee, S., Cha, J., Won, D., Lee, S. T., Choi, J. R., Lee, J. S., Kim, H. D., Kim, H. G., Bonkowsky, J. L., Kang, H. C., Kim, C. H. <strong>Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.</strong> Hum. Molec. Genet. 30: 331-342, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33517449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33517449</a>] [<a href="https://doi.org/10.1093/hmg/ddab033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33517449">Lee et al. (2021)</a> found that eif2b3 -/- and wildtype zebrafish had similar gross morphology until 3 days postfertilization (dpf). At 5 dpf, mutant fish had small eyes and heart edema, resulting in lethality by 8 dpf. Development of early nervous system was normal in mutant fish, as indicated by tail coiling movements, but myelin development and glial cell differentiation were defective. Moreover, expression of genes in the UPR pathway was increased in eif2b3 -/- fish, and mutant fish exhibited endoplasmic reticulum stress and ectopic angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33517449" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606273[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p>In a patient (vwm91) with leukoencephalopathy with vanishing white matter (VWM3; <a href="/entry/620313">620313</a>), <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">van der Knaap et al. (2002)</a> found compound heterozygosity for 2 mutations in the EIF2B3 gene: arg225 to gln (R225Q) and c.1295_1296delTG (<a href="#0002">606273.0002</a>). The R225Q substitution was caused by a G-to-A transition in exon 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" 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>For discussion of the 2-bp deletion in the EIF2B3 gene (c.1295_1296delTG) that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM3; <a href="/entry/620313">620313</a>) by <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">van der Knaap et al. (2002)</a>, see <a href="#0001">606273.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" 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> rs113994022 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994022;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/rs113994022?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=rs113994022" 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=rs113994022" 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=RCV000004689 OR RCV001377725 OR RCV003221406 OR RCV003914806" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004689, RCV001377725, RCV003221406, RCV003914806" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004689...</a>
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<p>In a patient (vwm47) with leukoencephalopathy with vanishing white matter (VWM3; <a href="/entry/620313">620313</a>), <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">van der Knaap et al. (2002)</a> found homozygosity for an ala87-to-val (A87V) substitution in the EIF2B3 gene, which resulted from a C-to-T transition at nucleotide 362 (c.362C-T) in exon 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N. <strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong> Neurology 79: 2077-2078, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23115207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23115207</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182749edc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23115207">Ghezzi et al. (2012)</a> identified homozygosity for an A87V mutation in a 66-year-old woman with adult-onset VWM disease and a history of premature ovarian failure at 24 years. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances and had experienced a rapid worsening of her clinical condition 10 days prior to evaluation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23115207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3</strong>
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EIF2B3, ILE346THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs119474039 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs119474039;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=rs119474039" 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=rs119474039" 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=RCV000004690 OR RCV003221407 OR RCV005089161" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004690, RCV003221407, RCV005089161" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004690...</a>
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<p>In 4 of 11 unrelated Chinese patients with leukoencephalopathy with vanishing white matter (VWM3; <a href="/entry/620313">620313</a>), <a href="#11" class="mim-tip-reference" title="Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. <strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong> J. Hum. Genet. 54: 74-77, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>] [<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158808">Wu et al. (2009)</a> identified a c.1037T-C transition in exon 9 of the EIF2B3 gene, resulting in an ile346-to-thr (I346T) substitution. The mutation was not observed in 100 control samples. Two patients (8 and 11) were homozygous for the mutation, 1 (7) was compound heterozygous with another pathogenic EIF2B3 mutation, and the second mutation could not be identified in the fourth patient (10). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3, ADULT-ONSET</strong>
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EIF2B3, LEU27GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514647 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514647;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=rs397514647" 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=rs397514647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003221420" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003221420" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003221420</a>
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<span class="mim-text-font">
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<p>In a 30-year-old Japanese woman (patient 3), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM3; <a href="/entry/620313">620313</a>), <a href="#7" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> identified a homozygous c.80T-A transversion in the EIF2B3 gene, resulting in a leu27-to-gln (L27Q) substitution. She developed secondary amenorrhea at age 28 years, left hemianopia at age 29, and weakness in her left leg after a fall. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B was significantly decreased (40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="1" class="mim-anchor"></a>
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<a id="Dickinson2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
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<strong>High-throughput discovery of novel developmental phenotypes.</strong>
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Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27626380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27626380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27626380[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=27626380" 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/nature19356" target="_blank">Full Text</a>]
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<a id="Fogli2004" class="mim-anchor"></a>
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Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O.
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<strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong>
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Europ. J. Hum. Genet. 12: 561-566, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" 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/sj.ejhg.5201189" target="_blank">Full Text</a>]
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<a id="Ghezzi2012" class="mim-anchor"></a>
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Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N.
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<strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong>
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Neurology 79: 2077-2078, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23115207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23115207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23115207" 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/10.1212/WNL.0b013e3182749edc" target="_blank">Full Text</a>]
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<a id="Gross2015" class="mim-anchor"></a>
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Gross, M. B.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 5/28/2015.
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Kruger, M., Beger, C., Li, Q.-X., Welch, P. J., Tritz, R., Leavitt, M., Barber, J. R., Wong-Staal, F.
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<strong>Identification of eIF2B-gamma and eIF2-gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach.</strong>
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Proc. Nat. Acad. Sci. 97: 8566-8571, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10900014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10900014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10900014[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=10900014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.97.15.8566" target="_blank">Full Text</a>]
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<a id="Lee2021" class="mim-anchor"></a>
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Lee, Y. R., Kim, S. H., Ben-Mahmoud, A., Kim, O. H., Choi, T. I., Lee, K. H., Ku, B., Eum, J., Kee, Y., Lee, S., Cha, J., Won, D., Lee, S. T., Choi, J. R., Lee, J. S., Kim, H. D., Kim, H. G., Bonkowsky, J. L., Kang, H. C., Kim, C. H.
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<strong>Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.</strong>
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Hum. Molec. Genet. 30: 331-342, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33517449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33517449</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33517449" 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/ddab033" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Matsukawa2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S.
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<strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong>
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Neurogenetics 12: 259-261, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank">Full Text</a>]
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<a id="Price1996" class="mim-anchor"></a>
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Price, N. T., Kimball, S. R., Jefferson, L. S., Proud, C. G.
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<strong>Cloning of cDNA for the gamma-subunit of mammalian translation initiation factor 2B, the guanine nucleotide-exchange factor for eukaryotic initiation factor 2.</strong>
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Biochem. J. 318: 631-636, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8809057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8809057</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8809057" 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/10.1042/bj3180631" target="_blank">Full Text</a>]
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<a id="Tsai2018" class="mim-anchor"></a>
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Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P.
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<strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong>
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Science 359: eaaq0939, 2018. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599213[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=29599213" 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/10.1126/science.aaq0939" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="van der Knaap2002" class="mim-anchor"></a>
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van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C.
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<strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong>
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Ann. Neurol. 51: 264-270, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10112" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Wu2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y.
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<strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong>
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J. Hum. Genet. 54: 74-77, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" 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/jhg.2008.10" target="_blank">Full Text</a>]
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</p>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Kelly A. Przylepa - updated : 12/13/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 02/10/2023<br>Ada Hamosh - updated : 07/23/2018<br>Ada Hamosh - updated : 02/16/2017<br>Matthew B. Gross - updated : 05/28/2015<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Cassandra L. Kniffin - updated : 6/26/2009<br>Marla J. F. O'Neill - updated : 2/11/2005<br>Victor A. McKusick - updated : 11/11/2002<br>Paul J. Converse - updated : 2/15/2002
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<a id="creationDate" class="mim-anchor"></a>
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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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<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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Paul J. Converse : 9/20/2001
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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alopez : 12/13/2023
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<span class="mim-text-font">
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alopez : 12/13/2023<br>alopez : 04/17/2023<br>mgross : 02/10/2023<br>alopez : 11/07/2018<br>alopez : 07/23/2018<br>carol : 02/01/2018<br>alopez : 02/16/2017<br>mgross : 05/28/2015<br>carol : 5/22/2015<br>mcolton : 5/22/2015<br>carol : 3/4/2013<br>ckniffin : 2/13/2013<br>ckniffin : 2/13/2013<br>wwang : 6/26/2009<br>ckniffin : 6/26/2009<br>carol : 9/30/2008<br>ckniffin : 9/29/2008<br>wwang : 2/11/2005<br>mgross : 11/20/2002<br>terry : 11/19/2002<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>mgross : 2/15/2002<br>mgross : 9/20/2001
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<span class="mim-font">
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<strong>*</strong> 606273
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<h3>
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 3; EIF2B3
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</h3>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, GAMMA<br />
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EIF2B-GAMMA
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EIF2B3</em></strong>
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<strong>
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Cytogenetic location: 1p34.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:44,850,522-44,986,595 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<td rowspan="1">
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<span class="mim-font">
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1p34.1
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<td>
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<span class="mim-font">
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Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure
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</span>
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</td>
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<td>
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<span class="mim-font">
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620313
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>The EIF2B3 gene contains a subunit of eIF2B, a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2 (see 603907). EIF2B catalyzes the exchange of GDP for GTP (summary by Fogli et al., 2004). </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>Translation of mRNA usually requires modification of the 5-prime cap, but some viral and cellular mRNAs use a cap-independent mechanism of ribosome binding mediated by an internal ribosomal entry site (IRES). The 5-prime untranslated region of hepatitis C virus (HCV) is highly conserved in all strains and folds into an IRES that binds directly to 40S ribosome subunits. Among the relatively limited number of cellular cofactors binding to the HCV IRES/40S subunit is EIF2 (see 603907). Using a ribozyme-based selection system to identify cellular factors involved in HCV IRES function, followed by database searches and 5-prime RACE with ribozyme-binding sequences as primers, Kruger et al. (2000) isolated a cDNA encoding EIF2B3, which they called EIF2B-gamma. The deduced 452-amino acid protein is 91% identical to rat Eif2b-gamma. </p><p>Using human EST database searching and PCR, followed by screening of a rat cDNA library, Price et al. (1996) obtained a partial cDNA encoding human EIF2B3 and a full-length rat clone encoding Eif2b3. Northern blot analysis revealed wide expression of an approximately 1.8-kb Eif2b3 transcript in rat tissues. </p>
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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>Fogli et al. (2004) measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies (603896) with homozygous or compound heterozygous mutations in EIF2B2 (606454), EIF2B3, EIF2B4 (606687), and EIF2B5 (603945) compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease. </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>Biochemical Features</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><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
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Integrated stress response inhibitor (ISRIB) is a drug-like eIF2B activator that reverses the effects of eIF2 phosphorylation. In rodents, it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, Tsai et al. (2018) solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryoelectron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of 2 identical tetrameric subcomplexes involving EIF2B-beta (EIF2B2), -gamma (EIF2B3), -delta (EIF2B4), and -epsilon (EIF2B5), and ISRIB promoted this step by cross-bridging a central symmetry interface. Tsai et al. (2018) concluded that thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB. </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>Gross (2015) mapped the EIF2B3 gene to chromosome 1p34.1 based on an alignment of the EIF2B3 sequence (GenBank BC018728) with the genomic sequence (GRCh38).</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>Leukoencephalopathy with vanishing white matter (VWM3; 620313) is an autosomal recessive disorder characterized by a chronic and progressive course with additional episodes of rapid deterioration provoked by fever and minor head trauma. Van der Knaap et al. (2002) demonstrated that mutations in each of the 5 subunits of the translation initiation factor eIF2B can cause the disorder. Two mutations were found in the EIF2B3 gene in compound heterozygous state (606273.0001, 606273.0002); 1 was found in homozygosity (606273.0003). </p><p>In 5 of 11 unrelated Chinese patients with leukoencephalopathy with vanishing white matter, Wu et al. (2009) identified mutations in the EIF2B3 gene, including 4 patients with the same mutation (I346T; 606273.0004), of whom 2 were homozygotes. </p><p>In a 66-year old woman with adult-onset vanishing white matter disease, Ghezzi et al. (2012) identified a homozygous missense mutation (A87V; 606273.0003) in EIF2B3. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Using molecular modeling, Lee et al. (2021) found that 6 mutations in EIF2B3 in patients with VWM all caused misfolding and steric hindrance in the EIF2B3 protein, consistent with the altered unfolded protein response (UPR) pathway found in eif2b3 -/- zebrafish (see ANIMAL MODEL). Furthermore, none of 19 missense mutations in EIF2B3 associated with VWM in humans could rescue the morphologic phenotype of eif2b3 -/- zebrafish, validating the pathogenicity of the mutations. </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>Genotype/Phenotype Correlations</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>In a 30-year-old Japanese woman, born of consanguineous parents, with adult-onset VWM, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B3 gene (L27Q; 606273.0005). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B3 was significantly decreased (40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. </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>In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human EIF2B3 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). </p><p>By RT-PCR and situ hybridization analyses, Lee et al. (2021) showed that eif2b3 was primarily expressed both maternally and zygotically in proliferating cells during early development of zebrafish. Lee et al. (2021) found that eif2b3 -/- and wildtype zebrafish had similar gross morphology until 3 days postfertilization (dpf). At 5 dpf, mutant fish had small eyes and heart edema, resulting in lethality by 8 dpf. Development of early nervous system was normal in mutant fish, as indicated by tail coiling movements, but myelin development and glial cell differentiation were defective. Moreover, expression of genes in the UPR pathway was increased in eif2b3 -/- fish, and mutant fish exhibited endoplasmic reticulum stress and ectopic angiogenesis. </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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<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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3</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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EIF2B3, ARG225GLN
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<br />
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SNP: rs113994024,
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gnomAD: rs113994024,
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ClinVar: RCV002512762, RCV003221404
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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 (vwm91) with leukoencephalopathy with vanishing white matter (VWM3; 620313), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B3 gene: arg225 to gln (R225Q) and c.1295_1296delTG (606273.0002). The R225Q substitution was caused by a G-to-A transition in exon 6. </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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3</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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EIF2B3, 2-BP DEL, 1295TG
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<br />
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SNP: rs113994026,
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ClinVar: RCV003221405
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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>For discussion of the 2-bp deletion in the EIF2B3 gene (c.1295_1296delTG) that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM3; 620313) by van der Knaap et al. (2002), see 606273.0001. </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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3</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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EIF2B3, ALA87VAL
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<br />
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SNP: rs113994022,
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gnomAD: rs113994022,
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ClinVar: RCV000004689, RCV001377725, RCV003221406, RCV003914806
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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 (vwm47) with leukoencephalopathy with vanishing white matter (VWM3; 620313), van der Knaap et al. (2002) found homozygosity for an ala87-to-val (A87V) substitution in the EIF2B3 gene, which resulted from a C-to-T transition at nucleotide 362 (c.362C-T) in exon 2. </p><p>Ghezzi et al. (2012) identified homozygosity for an A87V mutation in a 66-year-old woman with adult-onset VWM disease and a history of premature ovarian failure at 24 years. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances and had experienced a rapid worsening of her clinical condition 10 days prior to evaluation. </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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3</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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EIF2B3, ILE346THR
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<br />
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SNP: rs119474039,
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ClinVar: RCV000004690, RCV003221407, RCV005089161
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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 of 11 unrelated Chinese patients with leukoencephalopathy with vanishing white matter (VWM3; 620313), Wu et al. (2009) identified a c.1037T-C transition in exon 9 of the EIF2B3 gene, resulting in an ile346-to-thr (I346T) substitution. The mutation was not observed in 100 control samples. Two patients (8 and 11) were homozygous for the mutation, 1 (7) was compound heterozygous with another pathogenic EIF2B3 mutation, and the second mutation could not be identified in the fourth patient (10). </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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 3, ADULT-ONSET</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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EIF2B3, LEU27GLN
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<br />
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SNP: rs397514647,
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ClinVar: RCV003221420
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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 30-year-old Japanese woman (patient 3), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM3; 620313), Matsukawa et al. (2011) identified a homozygous c.80T-A transversion in the EIF2B3 gene, resulting in a leu27-to-gln (L27Q) substitution. She developed secondary amenorrhea at age 28 years, left hemianopia at age 29, and weakness in her left leg after a fall. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B was significantly decreased (40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. </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">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others.
|
|
<strong>High-throughput discovery of novel developmental phenotypes.</strong>
|
|
Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017.
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[PubMed: 27626380]
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[Full Text: https://doi.org/10.1038/nature19356]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O.
|
|
<strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong>
|
|
Europ. J. Hum. Genet. 12: 561-566, 2004.
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[PubMed: 15054402]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201189]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N.
|
|
<strong>A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.</strong>
|
|
Neurology 79: 2077-2078, 2012.
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[PubMed: 23115207]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3182749edc]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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|
Gross, M. B.
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<strong>Personal Communication.</strong>
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|
Baltimore, Md. 5/28/2015.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kruger, M., Beger, C., Li, Q.-X., Welch, P. J., Tritz, R., Leavitt, M., Barber, J. R., Wong-Staal, F.
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<strong>Identification of eIF2B-gamma and eIF2-gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach.</strong>
|
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Proc. Nat. Acad. Sci. 97: 8566-8571, 2000.
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[PubMed: 10900014]
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[Full Text: https://doi.org/10.1073/pnas.97.15.8566]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lee, Y. R., Kim, S. H., Ben-Mahmoud, A., Kim, O. H., Choi, T. I., Lee, K. H., Ku, B., Eum, J., Kee, Y., Lee, S., Cha, J., Won, D., Lee, S. T., Choi, J. R., Lee, J. S., Kim, H. D., Kim, H. G., Bonkowsky, J. L., Kang, H. C., Kim, C. H.
|
|
<strong>Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.</strong>
|
|
Hum. Molec. Genet. 30: 331-342, 2021.
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[PubMed: 33517449]
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[Full Text: https://doi.org/10.1093/hmg/ddab033]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S.
|
|
<strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong>
|
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Neurogenetics 12: 259-261, 2011.
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[PubMed: 21484434]
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[Full Text: https://doi.org/10.1007/s10048-011-0284-7]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Price, N. T., Kimball, S. R., Jefferson, L. S., Proud, C. G.
|
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<strong>Cloning of cDNA for the gamma-subunit of mammalian translation initiation factor 2B, the guanine nucleotide-exchange factor for eukaryotic initiation factor 2.</strong>
|
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Biochem. J. 318: 631-636, 1996.
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[PubMed: 8809057]
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[Full Text: https://doi.org/10.1042/bj3180631]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P.
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<strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong>
|
|
Science 359: eaaq0939, 2018. Note: Electronic Article.
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[PubMed: 29599213]
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[Full Text: https://doi.org/10.1126/science.aaq0939]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C.
|
|
<strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong>
|
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Ann. Neurol. 51: 264-270, 2002.
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[PubMed: 11835386]
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[Full Text: https://doi.org/10.1002/ana.10112]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y.
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<strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong>
|
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J. Hum. Genet. 54: 74-77, 2009.
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[PubMed: 19158808]
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[Full Text: https://doi.org/10.1038/jhg.2008.10]
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</p>
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</li>
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</ol>
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<div>
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<br />
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Kelly A. Przylepa - updated : 12/13/2023<br>Bao Lige - updated : 02/10/2023<br>Ada Hamosh - updated : 07/23/2018<br>Ada Hamosh - updated : 02/16/2017<br>Matthew B. Gross - updated : 05/28/2015<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Cassandra L. Kniffin - updated : 6/26/2009<br>Marla J. F. O'Neill - updated : 2/11/2005<br>Victor A. McKusick - updated : 11/11/2002<br>Paul J. Converse - updated : 2/15/2002
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</span>
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</div>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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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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Paul J. Converse : 9/20/2001
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alopez : 12/13/2023<br>alopez : 12/13/2023<br>alopez : 04/17/2023<br>mgross : 02/10/2023<br>alopez : 11/07/2018<br>alopez : 07/23/2018<br>carol : 02/01/2018<br>alopez : 02/16/2017<br>mgross : 05/28/2015<br>carol : 5/22/2015<br>mcolton : 5/22/2015<br>carol : 3/4/2013<br>ckniffin : 2/13/2013<br>ckniffin : 2/13/2013<br>wwang : 6/26/2009<br>ckniffin : 6/26/2009<br>carol : 9/30/2008<br>ckniffin : 9/29/2008<br>wwang : 2/11/2005<br>mgross : 11/20/2002<br>terry : 11/19/2002<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>mgross : 2/15/2002<br>mgross : 9/20/2001
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