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- *606687 - EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 4; EIF2B4
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- OMIM
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<p>
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<span class="h4">*606687</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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</li>
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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>
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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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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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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/606687">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></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 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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<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=ENSG00000115211;t=ENST00000347454" 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=8890" 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=606687" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000115211;t=ENST00000347454" 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_001034116,NM_001318965,NM_001318966,NM_001318967,NM_001318968,NM_001318969,NM_015636,NM_172195" 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_001034116" 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=606687" 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=09459&isoform_id=09459_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/EIF2B4" 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/4884138,6010112,6010114,6012057,6012058,6563202,10441948,12804849,28381357,33337571,60688271,62088644,62822294,78000156,78000158,119620992,119620993,119620994,119620995,119620996,119620997,187607323,194374189,391358250,974987436,974987441,974987445,974987447,974987451" 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/Q9UI10" 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=8890" 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=ENSG00000115211;t=ENST00000347454" 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=EIF2B4" 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=EIF2B4" 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+8890" 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/EIF2B4" 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:8890" 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/8890" 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=chr2&hgg_gene=ENST00000347454.9&hgg_start=27364352&hgg_end=27370338&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/genes/HGNC:3260" 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/eif2b4" 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=606687[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=606687[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/ENSG00000115211" 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=EIF2B4" 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=EIF2B4" 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=EIF2B4" 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=EIF2B4&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/PA27691" 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:3260" 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/FBgn0034858.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:95300" 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/EIF2B4#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:95300" 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/8890/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=8890" 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=WBGene00008670;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-030131-955" 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:8890" 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=EIF2B4&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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606687
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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 4; EIF2B4
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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, DELTA<br />
|
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EIF2B-DELTA
|
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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">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EIF2B4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EIF2B4</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/2/133?start=-3&limit=10&highlight=133">2p23.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:27364352-27370338&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'})">2:27,364,352-27,370,338</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>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 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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<div>
|
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<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>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/2/133?start=-3&limit=10&highlight=133">
|
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2p23.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Leukoencephalopathy with vanishing white matter 4, 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">
|
|
|
|
<a href="/entry/620314"> 620314 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
<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">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</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>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606687" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606687" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</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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</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="text" class="mim-anchor"></a>
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<p>EIF2B is a GTP exchange factor that is essential for protein synthesis. Its substrate is EIF2 (see <a href="/entry/603907">603907</a>). EIF2B consists of alpha (EIF2B1; <a href="/entry/606686">606686</a>), beta (EIF2B2; <a href="/entry/606454">606454</a>), gamma (EIF2B3; <a href="/entry/606273">606273</a>), delta (EIF2B4), and epsilon (EIF2B5; <a href="/entry/603945">603945</a>) subunits.</p>
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<p>By screening human genomic and cDNA libraries, followed by probing mouse cDNA libraries, <a href="#8" class="mim-tip-reference" title="Henderson, R. A., Krissansen, G. W., Yong, R. Y. Y., Leung, E., Watson, J. D., Dholakia, J. N. <strong>The delta-subunit of murine guanine nucleotide exchange factor eIF-2B: characterization of cDNAs predicts isoforms differing at the amino-terminal end.</strong> J. Biol. Chem. 269: 30517-30523, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7982969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7982969</a>]" pmid="7982969">Henderson et al. (1994)</a> cloned cDNAs encoding 2 isoforms of mouse Eif2b4, one containing 544 amino acids and the other containing 524 amino acids. The isoforms differ at their N termini. <a href="#8" class="mim-tip-reference" title="Henderson, R. A., Krissansen, G. W., Yong, R. Y. Y., Leung, E., Watson, J. D., Dholakia, J. N. <strong>The delta-subunit of murine guanine nucleotide exchange factor eIF-2B: characterization of cDNAs predicts isoforms differing at the amino-terminal end.</strong> J. Biol. Chem. 269: 30517-30523, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7982969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7982969</a>]" pmid="7982969">Henderson et al. (1994)</a> stated that the shorter isoform is present in rabbit and human cells. Northern blot analysis revealed wide expression of a 1.9-kb Eif2b4 transcript in mouse. Western blot analysis showed expression of an approximately 60-kD protein, close to the predicted size. <a href="#10" class="mim-tip-reference" title="Price, N. T., Mellor, H., Craddock, B. L., Flowers, K. M., Kimball, S. R., Wilmer, T., Jefferson, L. S., Proud, C. G. <strong>eIF2B, the guanine nucleotide-exchange factor for eukaryotic initiation factor 2: sequence conservation between the alpha, beta and delta subunits of eIF2B from mammals and yeast.</strong> Biochem. J. 318: 637-643, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929216</a>] [<a href="https://doi.org/10.1042/bj3180637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929216">Price et al. (1996)</a> cloned a cDNA encoding rat Eif2b4. The 525-amino acid rat protein is 96% identical to the 524-amino acid mouse isoform. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7982969+8929216" 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="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, EIF2B3, EIF2B4, and EIF2B5 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="#4" 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><p>The integrated stress response (ISR) modulates mRNA translation to regulate the mammalian unfolded protein response (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action, <a href="#11" class="mim-tip-reference" title="Sekine, Y., Zyryanova, A., Crespillo-Casado, A., Fischer, P. M., Harding, H. P., Ron, D. <strong>Mutations in a translation initiation factor identify the target of a memory-enhancing compound.</strong> Science 348: 1027-1030, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25858979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25858979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25858979[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.aaa6986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25858979">Sekine et al. (2015)</a> screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the amino-terminal portion of the delta subunit of GEF EIF2B (EIF2B4). When reintroduced by CRISPR-Cas9 gene editing of wildtype cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on EIF2B GEF activity toward its substrate, the translation initiation factor EIF2 (see EIF2A, <a href="/entry/609234">609234</a>), in vitro. <a href="#11" class="mim-tip-reference" title="Sekine, Y., Zyryanova, A., Crespillo-Casado, A., Fischer, P. M., Harding, H. P., Ron, D. <strong>Mutations in a translation initiation factor identify the target of a memory-enhancing compound.</strong> Science 348: 1027-1030, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25858979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25858979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25858979[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.aaa6986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25858979">Sekine et al. (2015)</a> concluded that ISRIB targets an interaction between EIF2 and EIF2B that lies at the core of the ISR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25858979" 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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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="#12" 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.[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="#12" 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.[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><p><a href="#15" class="mim-tip-reference" title="Zyryanova, A. F., Weis, F., Faille, A., Alard, A. A., Crespillo-Casado, A., Sekine, Y., Harding, H. P., Allen, F., Parts, L., Fromont, C., Fischer, P. M., Warren, A. J., Ron, D. <strong>Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.</strong> Science 359: 1533-1536, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599245</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599245[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.aar5129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29599245">Zyryanova et al. (2018)</a> described a 4.1-angstrom resolution cryoelectron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the beta and delta regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchic cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. <a href="#15" class="mim-tip-reference" title="Zyryanova, A. F., Weis, F., Faille, A., Alard, A. A., Crespillo-Casado, A., Sekine, Y., Harding, H. P., Allen, F., Parts, L., Fromont, C., Fischer, P. M., Warren, A. J., Ron, D. <strong>Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.</strong> Science 359: 1533-1536, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599245</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599245[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.aar5129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29599245">Zyryanova et al. (2018)</a> concluded that their findings pointed to a site in eIF2B that can be exploited by ISRIB to regulate translation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29599245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 5/28/2015."None>Gross (2015)</a> mapped the EIF2B4 gene to chromosome 2p23.3 based on an alignment of the EIF2B4 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC091502" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC091502</a>) with the genomic sequence (GRCh38).</p>
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<p>Leukoencephalopathy with vanishing white matter (VWM4; <a href="/entry/620314">620314</a>) is an autosomal recessive disorder characterized by a chronic progressive course with additional episodes of rapid deterioration provoked by fever and minor head trauma. <a href="#13" 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 translation initiation factor eIF2B can cause this disorder, including mutations in the EIF2B4 gene. <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="#2" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a> identified mutations in the EIF2B2, EIF2B4, and EIF2B5 genes in patients with VWM4 with ovarian failure, which they referred to as ovarioleukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" 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 3 patients with antenatal-onset encephalopathy, <a href="#14" class="mim-tip-reference" title="van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. <strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong> Am. J. Hum. Genet. 73: 1199-1207, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/379524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566705">van der Knaap et al. (2003)</a> performed mutational analysis of the EIF2B1-EIF2B5 genes and detected different novel homozygous missense mutations in EIF2B4: R483W (<a href="#0007">606687.0007</a>) in sib patients 4 and 5, and A391D (<a href="#0008">606687.0008</a>) in patient 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566705" 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 12-month old Turkish boy with intractable seizures and VWM disease, <a href="#7" class="mim-tip-reference" title="Gungor, O., Ozkaya, A. K., Hirfanoglu, T., Dilber, C., Aydin, K. <strong>A rare mutation in EIF2B4 gene in an epileptic child with vanishing white matter disease: a case report.</strong> Genet. Counsel. 26: 41-46, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26043506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26043506</a>]" pmid="26043506">Gungor et al. (2015)</a> detected a homozygous missense mutation (R374C; <a href="#0002">606687.0002</a>) in exon 11 in the EIF2B4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26043506" 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 Sanger sequencing of all 5 EIF2B subunit genes, <a href="#9" class="mim-tip-reference" title="Kanbayashi, T., Saito, F., Matsukawa, T., Oba, H., Hokkoku, K., Hatanaka, Y., Tsuji, S., Sonoo, M. <strong>Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4.</strong> Clin. Genet. 88: 401-403, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25600065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25600065</a>] [<a href="https://doi.org/10.1111/cge.12554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25600065">Kanbayashi et al. (2015)</a> found compound heterozygosity for novel missense mutations in the EIF2B4 gene (M206T, <a href="#0009">606687.0009</a> and I318V, <a href="#0010">606687.0010</a>) in a 59-year-old Japanese woman with adult-onset VWM disease. Amino acid ile318 is highly conserved through zebrafish, and met206 is highly conserved among mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25600065" 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> rs113994033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994033;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/rs113994033?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=rs113994033" 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=rs113994033" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (vwm239) with leukoencephalopathy with vanishing white matter (VWM4; <a href="/entry/620314">620314</a>), <a href="#13" 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 EIF2B4 gene: an arg357 to gln (R357Q) mutation and an arg374 to cys (R374C; <a href="#0002">606687.0002</a>) mutation, both in exon 11. <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> rs113994035 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994035;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/rs113994035?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=rs113994035" 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=rs113994035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the arg374-to-cys (R374C) mutation in the EIF2B4 gene that was found in compound heterozygous state in patient vwm239 with leukoencephalopathy with vanishing white matter (VWM4; <a href="/entry/620314">620314</a>) by <a href="#13" 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">606687.0001</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><p>In a 12-month old Turkish boy with intractable seizures and vanishing white matter disease, <a href="#7" class="mim-tip-reference" title="Gungor, O., Ozkaya, A. K., Hirfanoglu, T., Dilber, C., Aydin, K. <strong>A rare mutation in EIF2B4 gene in an epileptic child with vanishing white matter disease: a case report.</strong> Genet. Counsel. 26: 41-46, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26043506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26043506</a>]" pmid="26043506">Gungor et al. (2015)</a> detected a homozygous c.1091G-A substitution in exon 11 in the EIF2B4 gene resulting in a R374C substitution. The mutation was identified by next-generation sequencing and confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26043506" 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">rs113994037 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994037;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=rs113994037" 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=rs113994037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient (vwm244) with leukoencephalopathy with vanishing white matter (VWM4; <a href="/entry/620314">620314</a>), <a href="#13" 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 EIF2B4 gene: a splice site mutation, IVS11+1G-A, which resulted in the insertion of 11 amino acids following glu397; and an ala228-to-val (A228V) mutation in exon 7 (<a href="#0004">606687.0004</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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<strong>.0004 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113994027 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994027;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/rs113994027?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=rs113994027" 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=rs113994027" 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=RCV003221396" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003221396" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003221396</a>
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<p>For discussion of the ala228-to-val (A228V) mutation in the EIF2B4 gene that was found in compound heterozygous state in patient vwm244 with leukoencephalopathy with vanishing white matter (VWM4; <a href="/entry/620314">620314</a>) by <a href="#13" 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="#0003">606687.0003</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>
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<strong>.0005 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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EIF2B4, CYS465ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs113994038 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994038;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=rs113994038" 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=rs113994038" 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=RCV003221397" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003221397" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003221397</a>
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<p>In 2 sisters (941-1 and 941-2) with vanishing white matter leukodystrophy and ovarian failure (VWM4; <a href="/entry/620314">620314</a>), <a href="#2" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a> found compound heterozygosity for a c.1393C-T transition in the EIF2B4 gene, resulting in a cys465-to-arg (C465R) mutation, and a c.1465C-T transition resulting in a tyr489-to-his mutation (Y489H; <a href="#0006">606687.0006</a>). They were examined at 23 and 24 years of age, respectively. Both had had difficulties in school. In both there was spasticity of gait and gait instability having begun at ages 10 and 15 years, respectively; 1 required the use of a walker at age 16 years. Optic atrophy was present in both. Cognitive function was mildly to moderately reduced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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EIF2B4, TYR489HIS
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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> rs113994040 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994040;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/rs113994040?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=rs113994040" 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=rs113994040" 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=RCV003221398 OR RCV004585985" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003221398, RCV004585985" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003221398...</a>
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<p>For discussion of the tyr489-to-his (Y489H) mutation in the EIF2B4 gene that was found in compound heterozygous state in 2 sisters with vanishing white matter leukodystrophy and ovarian failure (VWM4; <a href="/entry/620314">620314</a>) by <a href="#2" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a>, see <a href="#0005">606687.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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</span>
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</h4>
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</div>
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EIF2B4, ARG483TRP
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003448660" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003448660" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003448660</a>
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<p>In sibs (patients 4 and 5) with antenatal-onset leukoencephalopathy (VWM4; <a href="/entry/620314">620314</a>), <a href="#14" class="mim-tip-reference" title="van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. <strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong> Am. J. Hum. Genet. 73: 1199-1207, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/379524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566705">van der Knaap et al. (2003)</a> detected a novel homozygous c.1447C-T transition in the EIF2B4 gene resulting in an arg483-to-trp (R483W) substitution. The brother and sister had fetal growth retardation, oligohydramnios, and microcephaly noted at birth. Their clinical course deteriorated with feeding difficulties, vomiting, apathy, axial hypotonia, hypertonia and hyperreflexia of the extremities, seizures, and ultimately apneic events. The patients died at 3.5 and 4 months of age, respectively. Arginine-483 is conserved in mammals only but the mutation to tryptophan is likely to result in a substantial alteration in the 3-dimensional structure of the protein, since tryptophan is a more bulky amino acid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566705" 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="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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EIF2B4, ALA391ASP
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003448661" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003448661" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003448661</a>
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<span class="mim-text-font">
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<p>In an infant girl (patient 6) with antenatal-onset leukoencephalopathy (VWM4; <a href="/entry/620314">620314</a>), <a href="#14" class="mim-tip-reference" title="van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. <strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong> Am. J. Hum. Genet. 73: 1199-1207, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/379524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566705">van der Knaap et al. (2003)</a> detected a novel homozygous c.1172C-A transversion in the EIF2B4 gene resulting in an ala391-to-asp (A391D) substitution. She had a history of growth retardation and oligohydramnios noted at 31 weeks' gestation. She was born at 38 weeks' gestation with microcephaly, bilateral cataracts, and mild contractures. Her clinical course was significant for impaired swallowing, failure to thrive, myoclonic convulsions, and absence of psychomotor development. Aspiration pneumonia led to death at 10 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566705" 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="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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EIF2B4, MET206THR
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<p>In a 59-year old Japanese woman with adult-onset vanishing white matter disease (VWM4; <a href="/entry/620314">620314</a>), <a href="#9" class="mim-tip-reference" title="Kanbayashi, T., Saito, F., Matsukawa, T., Oba, H., Hokkoku, K., Hatanaka, Y., Tsuji, S., Sonoo, M. <strong>Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4.</strong> Clin. Genet. 88: 401-403, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25600065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25600065</a>] [<a href="https://doi.org/10.1111/cge.12554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25600065">Kanbayashi et al. (2015)</a> detected compound heterozygosity for mutations in the EIF2B4 gene: a c.617T-C transition in exon 7 resulting in a met206-to-thr (M206T) substitution, and a c.952A-G transition in exon 10 resulting in an ile318-to-val (I318V; <a href="#0008">606687.0008</a>) substitution. The mutation was identified by Sanger sequencing of all 5 EIF2B subunit genes. She presented with gait unsteadiness and forgetfulness at age 56 years. She had no history of episodic neurologic deterioration evoked by stresses. Her childhood development was described as normal and she had no history of ovarian failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25600065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs769371305 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs769371305;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/rs769371305?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=rs769371305" 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=rs769371305" 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=RCV002028917 OR RCV003448918" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002028917, RCV003448918" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002028917...</a>
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<p>For discussion of the ile318-to-val (I318V) mutation in the EIF2B4 gene that was found in compound heterozygous state in a 59-year old Japanese woman with adult-onset vanishing white matter leukodystrophy (VWM4; <a href="/entry/620314">620314</a>) by <a href="#9" class="mim-tip-reference" title="Kanbayashi, T., Saito, F., Matsukawa, T., Oba, H., Hokkoku, K., Hatanaka, Y., Tsuji, S., Sonoo, M. <strong>Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4.</strong> Clin. Genet. 88: 401-403, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25600065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25600065</a>] [<a href="https://doi.org/10.1111/cge.12554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25600065">Kanbayashi et al. (2015)</a>, see <a href="#0009">606687.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25600065" 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="#Fogli2004" 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.">Fogli et al. (2004)</a>; <a href="#Goyal2023" class="mim-tip-reference" title="Goyal, S., Mudabbir, M., Taallapalli, A. V. R., Nashi, S., Kulkarni, G. B. <strong>Vanishing white matter leukodystrophy due to novel EIF2B4 mutation in an adult female.</strong> J Neurosci Rural Pract 14: 191-193, 2023.">Goyal et al. (2023)</a>
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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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[<a href="https://doi.org/10.1038/nature19356" target="_blank">Full Text</a>]
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Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/375404" target="_blank">Full Text</a>]
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Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard-Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., Chaunu, M.-P., Rodriguez, D., Boespflug-Tanguy, O.
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<strong>The effect of genotype on the natural history of eIF2B-related leukodystrophies.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136673</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136673" 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/10.1212/01.wnl.0000123259.67815.db" target="_blank">Full Text</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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Goyal, S., Mudabbir, M., Taallapalli, A. V. R., Nashi, S., Kulkarni, G. B.
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<strong>Vanishing white matter leukodystrophy due to novel EIF2B4 mutation in an adult female.</strong>
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J Neurosci Rural Pract 14: 191-193, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36891084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36891084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36891084[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=36891084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Baltimore, Md. 5/28/2015.
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Gungor, O., Ozkaya, A. K., Hirfanoglu, T., Dilber, C., Aydin, K.
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Kanbayashi, T., Saito, F., Matsukawa, T., Oba, H., Hokkoku, K., Hatanaka, Y., Tsuji, S., Sonoo, M.
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<strong>Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4.</strong>
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Clin. Genet. 88: 401-403, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25600065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25600065</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25600065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Sekine, Y., Zyryanova, A., Crespillo-Casado, A., Fischer, P. M., Harding, H. P., Ron, D.
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<strong>Mutations in a translation initiation factor identify the target of a memory-enhancing compound.</strong>
|
|
Science 348: 1027-1030, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25858979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25858979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25858979[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=25858979" 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.aaa6986" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Tsai2018" class="mim-anchor"></a>
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<div class="">
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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>
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Science 359: eaaq0939, 2018.
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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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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="van der Knaap2002" class="mim-anchor"></a>
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<div class="">
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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>
|
|
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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</div>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="van der Knaap2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C.
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<strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong>
|
|
Am. J. Hum. Genet. 73: 1199-1207, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[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=14566705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/379524" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Zyryanova2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zyryanova, A. F., Weis, F., Faille, A., Alard, A. A., Crespillo-Casado, A., Sekine, Y., Harding, H. P., Allen, F., Parts, L., Fromont, C., Fischer, P. M., Warren, A. J., Ron, D.
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<strong>Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.</strong>
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Science 359: 1533-1536, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599245</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599245[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=29599245" 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.aar5129" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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 : 12/12/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 07/24/2018<br>Ada Hamosh - updated : 07/23/2018<br>Ada Hamosh - updated : 02/16/2017<br>Ada Hamosh - updated : 6/30/2015<br>Matthew B. Gross - updated : 5/28/2015<br>Marla J. F. O'Neill - updated : 2/11/2005<br>Victor A. McKusick - updated : 5/23/2003<br>Joanna S. Amberger - updated : 2/28/2003<br>Victor A. McKusick - updated : 11/11/2002
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse : 2/12/2002
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</span>
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</div>
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<a id="editHistory" 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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 12/12/2023
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 04/17/2023<br>alopez : 07/24/2018<br>alopez : 07/23/2018<br>carol : 02/05/2018<br>alopez : 02/16/2017<br>mcolton : 07/23/2015<br>alopez : 6/30/2015<br>mgross : 5/28/2015<br>wwang : 2/11/2005<br>wwang : 2/11/2005<br>cwells : 11/20/2003<br>mgross : 5/29/2003<br>terry : 5/23/2003<br>joanna : 2/28/2003<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>terry : 11/11/2002<br>mgross : 2/12/2002
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606687
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 4; EIF2B4
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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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<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, DELTA<br />
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EIF2B-DELTA
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EIF2B4</em></strong>
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</span>
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</p>
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</div>
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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: 2p23.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:27,364,352-27,370,338 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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2p23.3
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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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Leukoencephalopathy with vanishing white matter 4, 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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620314
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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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>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>EIF2B is a GTP exchange factor that is essential for protein synthesis. Its substrate is EIF2 (see 603907). EIF2B consists of alpha (EIF2B1; 606686), beta (EIF2B2; 606454), gamma (EIF2B3; 606273), delta (EIF2B4), and epsilon (EIF2B5; 603945) subunits.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By screening human genomic and cDNA libraries, followed by probing mouse cDNA libraries, Henderson et al. (1994) cloned cDNAs encoding 2 isoforms of mouse Eif2b4, one containing 544 amino acids and the other containing 524 amino acids. The isoforms differ at their N termini. Henderson et al. (1994) stated that the shorter isoform is present in rabbit and human cells. Northern blot analysis revealed wide expression of a 1.9-kb Eif2b4 transcript in mouse. Western blot analysis showed expression of an approximately 60-kD protein, close to the predicted size. Price et al. (1996) cloned a cDNA encoding rat Eif2b4. The 525-amino acid rat protein is 96% identical to the 524-amino acid mouse isoform. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>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, EIF2B3, EIF2B4, and EIF2B5 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><p>The integrated stress response (ISR) modulates mRNA translation to regulate the mammalian unfolded protein response (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action, Sekine et al. (2015) screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the amino-terminal portion of the delta subunit of GEF EIF2B (EIF2B4). When reintroduced by CRISPR-Cas9 gene editing of wildtype cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on EIF2B GEF activity toward its substrate, the translation initiation factor EIF2 (see EIF2A, 609234), in vitro. Sekine et al. (2015) concluded that ISRIB targets an interaction between EIF2 and EIF2B that lies at the core of the ISR. </p>
|
|
</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">
|
|
<strong>Biochemical Features</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">
|
|
<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
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><p>Zyryanova et al. (2018) described a 4.1-angstrom resolution cryoelectron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the beta and delta regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchic cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Zyryanova et al. (2018) concluded that their findings pointed to a site in eIF2B that can be exploited by ISRIB to regulate translation. </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 EIF2B4 gene to chromosome 2p23.3 based on an alignment of the EIF2B4 sequence (GenBank BC091502) 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 (VWM4; 620314) is an autosomal recessive disorder characterized by a chronic 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 translation initiation factor eIF2B can cause this disorder, including mutations in the EIF2B4 gene. </p><p>Fogli et al. (2003) identified mutations in the EIF2B2, EIF2B4, and EIF2B5 genes in patients with VWM4 with ovarian failure, which they referred to as ovarioleukodystrophy. </p><p>In 3 patients with antenatal-onset encephalopathy, van der Knaap et al. (2003) performed mutational analysis of the EIF2B1-EIF2B5 genes and detected different novel homozygous missense mutations in EIF2B4: R483W (606687.0007) in sib patients 4 and 5, and A391D (606687.0008) in patient 6. </p><p>In a 12-month old Turkish boy with intractable seizures and VWM disease, Gungor et al. (2015) detected a homozygous missense mutation (R374C; 606687.0002) in exon 11 in the EIF2B4 gene. </p><p>By Sanger sequencing of all 5 EIF2B subunit genes, Kanbayashi et al. (2015) found compound heterozygosity for novel missense mutations in the EIF2B4 gene (M206T, 606687.0009 and I318V, 606687.0010) in a 59-year-old Japanese woman with adult-onset VWM disease. Amino acid ile318 is highly conserved through zebrafish, and met206 is highly conserved among mammals. </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 EIF2B4 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning). </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 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 4</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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EIF2B4, ARG357GLN
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<br />
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SNP: rs113994033,
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gnomAD: rs113994033,
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ClinVar: RCV000004333, RCV003221393
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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 (vwm239) with leukoencephalopathy with vanishing white matter (VWM4; 620314), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B4 gene: an arg357 to gln (R357Q) mutation and an arg374 to cys (R374C; 606687.0002) mutation, both in exon 11. </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 4</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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EIF2B4, ARG374CYS
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<br />
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SNP: rs113994035,
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gnomAD: rs113994035,
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ClinVar: RCV001650827, RCV003221394
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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 arg374-to-cys (R374C) mutation in the EIF2B4 gene that was found in compound heterozygous state in patient vwm239 with leukoencephalopathy with vanishing white matter (VWM4; 620314) by van der Knaap et al. (2002), see 606687.0001. </p><p>In a 12-month old Turkish boy with intractable seizures and vanishing white matter disease, Gungor et al. (2015) detected a homozygous c.1091G-A substitution in exon 11 in the EIF2B4 gene resulting in a R374C substitution. The mutation was identified by next-generation sequencing and confirmed by Sanger sequencing. </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>
|
|
<span class="mim-font">
|
|
<strong>.0003 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</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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EIF2B4, IVS11, G-A, +1
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<br />
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SNP: rs113994037,
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ClinVar: RCV003221395
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient (vwm244) with leukoencephalopathy with vanishing white matter (VWM4; 620314), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B4 gene: a splice site mutation, IVS11+1G-A, which resulted in the insertion of 11 amino acids following glu397; and an ala228-to-val (A228V) mutation in exon 7 (606687.0004). </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>
|
|
<span class="mim-font">
|
|
<strong>.0004 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</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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EIF2B4, ALA228VAL
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<br />
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SNP: rs113994027,
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gnomAD: rs113994027,
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ClinVar: RCV003221396
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the ala228-to-val (A228V) mutation in the EIF2B4 gene that was found in compound heterozygous state in patient vwm244 with leukoencephalopathy with vanishing white matter (VWM4; 620314) by van der Knaap et al. (2002), see 606687.0003. </p>
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|
</span>
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|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B4, CYS465ARG
|
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|
|
<br />
|
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|
|
SNP: rs113994038,
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|
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|
|
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|
|
ClinVar: RCV003221397
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters (941-1 and 941-2) with vanishing white matter leukodystrophy and ovarian failure (VWM4; 620314), Fogli et al. (2003) found compound heterozygosity for a c.1393C-T transition in the EIF2B4 gene, resulting in a cys465-to-arg (C465R) mutation, and a c.1465C-T transition resulting in a tyr489-to-his mutation (Y489H; 606687.0006). They were examined at 23 and 24 years of age, respectively. Both had had difficulties in school. In both there was spasticity of gait and gait instability having begun at ages 10 and 15 years, respectively; 1 required the use of a walker at age 16 years. Optic atrophy was present in both. Cognitive function was mildly to moderately reduced. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B4, TYR489HIS
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs113994040,
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|
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|
|
|
gnomAD: rs113994040,
|
|
|
|
|
|
ClinVar: RCV003221398, RCV004585985
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the tyr489-to-his (Y489H) mutation in the EIF2B4 gene that was found in compound heterozygous state in 2 sisters with vanishing white matter leukodystrophy and ovarian failure (VWM4; 620314) by Fogli et al. (2003), see 606687.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B4, ARG483TRP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV003448660
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In sibs (patients 4 and 5) with antenatal-onset leukoencephalopathy (VWM4; 620314), van der Knaap et al. (2003) detected a novel homozygous c.1447C-T transition in the EIF2B4 gene resulting in an arg483-to-trp (R483W) substitution. The brother and sister had fetal growth retardation, oligohydramnios, and microcephaly noted at birth. Their clinical course deteriorated with feeding difficulties, vomiting, apathy, axial hypotonia, hypertonia and hyperreflexia of the extremities, seizures, and ultimately apneic events. The patients died at 3.5 and 4 months of age, respectively. Arginine-483 is conserved in mammals only but the mutation to tryptophan is likely to result in a substantial alteration in the 3-dimensional structure of the protein, since tryptophan is a more bulky amino acid. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
EIF2B4, ALA391ASP
|
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|
|
|
<br />
|
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|
|
|
|
|
|
ClinVar: RCV003448661
|
|
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|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant girl (patient 6) with antenatal-onset leukoencephalopathy (VWM4; 620314), van der Knaap et al. (2003) detected a novel homozygous c.1172C-A transversion in the EIF2B4 gene resulting in an ala391-to-asp (A391D) substitution. She had a history of growth retardation and oligohydramnios noted at 31 weeks' gestation. She was born at 38 weeks' gestation with microcephaly, bilateral cataracts, and mild contractures. Her clinical course was significant for impaired swallowing, failure to thrive, myoclonic convulsions, and absence of psychomotor development. Aspiration pneumonia led to death at 10 months of age. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</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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|
|
EIF2B4, MET206THR
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|
<br />
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|
|
|
ClinVar: RCV003448662
|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 59-year old Japanese woman with adult-onset vanishing white matter disease (VWM4; 620314), Kanbayashi et al. (2015) detected compound heterozygosity for mutations in the EIF2B4 gene: a c.617T-C transition in exon 7 resulting in a met206-to-thr (M206T) substitution, and a c.952A-G transition in exon 10 resulting in an ile318-to-val (I318V; 606687.0008) substitution. The mutation was identified by Sanger sequencing of all 5 EIF2B subunit genes. She presented with gait unsteadiness and forgetfulness at age 56 years. She had no history of episodic neurologic deterioration evoked by stresses. Her childhood development was described as normal and she had no history of ovarian failure. </p>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0010 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 4</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
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|
EIF2B4, ILE318VAL
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<br />
|
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|
|
SNP: rs769371305,
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|
|
gnomAD: rs769371305,
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|
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ClinVar: RCV002028917, RCV003448918
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the ile318-to-val (I318V) mutation in the EIF2B4 gene that was found in compound heterozygous state in a 59-year old Japanese woman with adult-onset vanishing white matter leukodystrophy (VWM4; 620314) by Kanbayashi et al. (2015), see 606687.0009. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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|
</div>
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</div>
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Fogli et al. (2004); Goyal et al. (2023)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
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|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
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