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Entry
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- *606686 - EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 1; EIF2B1
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- OMIM
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<p>
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<span class="h4">*606686</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</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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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</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/606686">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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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<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 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=ENSG00000111361;t=ENST00000424014" 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=1967" 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=606686" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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<div 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=ENSG00000111361;t=ENST00000424014" 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_001414" 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_001414" 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=606686" 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=09458&isoform_id=09458_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/EIF2B1" 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/1200232,2494303,4503503,48145779,74355528,74355777,74355779,119618830,119618831,194378362" 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/Q14232" 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=1967" 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=ENSG00000111361;t=ENST00000424014" 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=EIF2B1" 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=EIF2B1" 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+1967" 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/EIF2B1" 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:1967" 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/1967" 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=chr12&hgg_gene=ENST00000424014.7&hgg_start=123620406&hgg_end=123633686&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3257" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3257" 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/eif2b1" 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=606686[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=606686[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/ENSG00000111361" 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=EIF2B1" 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=EIF2B1" 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=EIF2B1" 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=EIF2B1&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/PA27688" 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:3257" 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/FBgn0039726.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:2384802" 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/EIF2B1#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:2384802" 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/1967/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=1967" 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=WBGene00014221;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-040625-25" 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:1967" 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=EIF2B1&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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606686
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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 1; EIF2B1
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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, ALPHA<br />
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EIF2B-ALPHA
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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=EIF2B1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EIF2B1</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/12/932?start=-3&limit=10&highlight=932">12q24.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:123620406-123633686&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'})">12:123,620,406-123,633,686</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/12/932?start=-3&limit=10&highlight=932">
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12q24.31
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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">
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Leukoencephalopathy with vanishing white matter 1, 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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<a href="/entry/603896"> 603896 </a>
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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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<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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<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">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/606686" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/606686" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
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</div>
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|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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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<h4>
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<span class="mim-font">
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<p>The EIF2B1 gene encodes EIF2B-alpha, the smallest subunit of the eukaryotic translation initiation factor eIF2B, which is a heterodecameric complex comprising 5 subunits: alpha (EIF2B1), beta (EIF2B2; <a href="/entry/606454">606454</a>), gamma (EIF2B3; <a href="/entry/606273">606273</a>), delta (EIF2B4; <a href="/entry/606687">606687</a>), and epsilon (EIF2B5; <a href="/entry/603945">603945</a>). EIF2B is a GTP exchange factor that is essential for protein synthesis: its substrate is eIF2 (see <a href="/entry/603907">603907</a>). GTP-bound eIF2 is responsible for loading the initiator methionyl-tRNA onto the ribosome to allow initiation of protein synthesis to take place. EIF2B-alpha, -beta, and -delta form the regulatory subcomplex, whereas EIF2B-gamma and -epsilon form the catalytic subcomplex (summary by <a href="#11" class="mim-tip-reference" title="Wortham, N. C., Proud, C. G. <strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong> BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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/10.1186/s12881-015-0204-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285592">Wortham and Proud, 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#2" class="mim-tip-reference" title="Flowers, K. M., Mellor, H., Kimball, S. R., Jefferson, L. S. <strong>Structure and sequence of the gene encoding the alpha-subunit of rat translation initiation factor-2B.</strong> Biochim. Biophys. Acta 1264: 163-167, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7495858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7495858</a>] [<a href="https://doi.org/10.1016/0167-4781(95)00160-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7495858">Flowers et al. (1995)</a> cloned a rat cDNA encoding Eif2b1. The deduced 305-amino acid rat protein (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AAA91276" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AAA91276</a>) is 92% identical to the human protein (<a href="#1" class="mim-tip-reference" title="Converse, P. J. <strong>Personal Communication.</strong> Baltimore, Md. 2/12/2002."None>Converse, 2002</a>). By Northern blot analysis, <a href="#2" class="mim-tip-reference" title="Flowers, K. M., Mellor, H., Kimball, S. R., Jefferson, L. S. <strong>Structure and sequence of the gene encoding the alpha-subunit of rat translation initiation factor-2B.</strong> Biochim. Biophys. Acta 1264: 163-167, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7495858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7495858</a>] [<a href="https://doi.org/10.1016/0167-4781(95)00160-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7495858">Flowers et al. (1995)</a> detected equivalent expression of rat Eif2b1 in all tissues tested; in contrast, Eif2b5 is predominantly expressed in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7495858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#2" class="mim-tip-reference" title="Flowers, K. M., Mellor, H., Kimball, S. R., Jefferson, L. S. <strong>Structure and sequence of the gene encoding the alpha-subunit of rat translation initiation factor-2B.</strong> Biochim. Biophys. Acta 1264: 163-167, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7495858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7495858</a>] [<a href="https://doi.org/10.1016/0167-4781(95)00160-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7495858">Flowers et al. (1995)</a> determined that the rat Eif2b1 gene has 9 exons and spans 8.5 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7495858" 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="#5" class="mim-tip-reference" title="Kenner, L. R., Anand, A. A., Nguyen, H. C., Myasnikov, A. G., Klose, C. J., McGeever, L. A., Tsai, J. C., Miller-Vedam, L. E., Walter, P., Frost, A. <strong>eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response.</strong> Science 364: 491-495, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31048491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31048491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31048491[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.aaw2922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31048491">Kenner et al. (2019)</a> reported cryoelectron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures revealed that the eIF2B decamer is a static platform upon which 1 or 2 flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2-alpha (<a href="/entry/603907">603907</a>), allowing it to contact eIF2B at a different interface and, the authors surmised, thereby sequestering it into a nonproductive complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31048491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To elucidate how eIF2 phosphorylation status regulates the eIF2B activity, <a href="#4" class="mim-tip-reference" title="Kashiwagi, K., Yokoyama, T., Nishimoto, M., Takahashi, M., Sakamoto, A., Yonemochi, M., Shirouzu, M., Ito, T. <strong>Structural basis for eIF2B inhibition in integrated stress response.</strong> Science 364: 495-499, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31048492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31048492</a>] [<a href="https://doi.org/10.1126/science.aaw4104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31048492">Kashiwagi et al. (2019)</a> determined cryoelectron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. <a href="#4" class="mim-tip-reference" title="Kashiwagi, K., Yokoyama, T., Nishimoto, M., Takahashi, M., Sakamoto, A., Yonemochi, M., Shirouzu, M., Ito, T. <strong>Structural basis for eIF2B inhibition in integrated stress response.</strong> Science 364: 495-499, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31048492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31048492</a>] [<a href="https://doi.org/10.1126/science.aaw4104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31048492">Kashiwagi et al. (2019)</a> concluded that these structures explained how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31048492" 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="#3" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 5/28/2015."None>Gross (2015)</a> mapped the EIF2B1 gene to chromosome 12q24.31 based on an alignment of the EIF2B1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC103763" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC103763</a>) with the genomic sequence (GRCh38).</p>
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<p>Leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>) is an autosomal recessive disorder characterized by a chronic and progressive course with additional episodes of rapid deterioration provoked by fever and minor head trauma. In a patient with VWM1, <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">van der Knaap et al. (2002)</a> found compound heterozygosity for 2 mutations in the EIF2B1 gene (<a href="#0001">606686.0001</a> and <a href="#0002">606686.0002</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 2 sisters with a moderate form of VWM1, <a href="#7" class="mim-tip-reference" title="Ohlenbusch, A., Henneke, M., Brockmann, K., Goerg, M., Hanefeld, F., Kohlschutter, A., Gartner, J. <strong>Identification of ten novel mutations in patients with eIF2B-related disorders.</strong> Hum. Mutat. 25: 411, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776425</a>] [<a href="https://doi.org/10.1002/humu.9325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776425">Ohlenbusch et al. (2005)</a> identified a homozygous missense mutation in the EIF2B1 gene (V183F; <a href="#0003">606686.0003</a>). These patients were reported to have ovarian failure. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776425" 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 patient with leukoencephalopathy with vanishing white matter, <a href="#6" class="mim-tip-reference" title="Maletkovic, J., Schiffmann, R., Gorospe, J. R., Gordon, E. S., Mintz, M., Hoffman, E. P., Alper, G., Lynch, D. R., Singhal, B. S., Harding, C., Amartino, H., Brown, C. M., and 12 others. <strong>Genetic and clinical heterogeneity in eIF2B-related disorder.</strong> J. Child Neurol. 23: 205-215, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18263758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18263758</a>] [<a href="https://doi.org/10.1177/0883073807308705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18263758">Maletkovic et al. (2008)</a> identified compound heterozygous mutations in the EIF2B1 gene (<a href="#0005">606686.0005</a> and <a href="#0006">606686.0006</a>). Functional studies of the variants were not performed. The patient was 1 of 15 VWM patients with mutations in 1 of the EIF2B genes. The authors noted that mutations in the EIF2B1 gene account for only approximately 4% of all reported mutations and are found in approximately 1% of patients reported with EIF2B-related disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18263758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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In in vitro functional expression studies, <a href="#11" class="mim-tip-reference" title="Wortham, N. C., Proud, C. G. <strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong> BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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/10.1186/s12881-015-0204-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285592">Wortham and Proud (2015)</a> found that the V183F (<a href="#0003">606686.0003</a>), gly204del (<a href="#0005">606686.0005</a>), and Y275C (<a href="#0006">606686.0006</a>) EIF2B1 mutations affected formation of the EIF2B complex. Gly204del was unable to interact with any of the other subunits in the complex, whereas V183F and Y275C led to a 50% reduction in binding to the rest of the complex, which was presumed to result in decreased catalytic activity of the overall complex. Further activity studies showed a 30% decrease in EIF2B GEF activity for the V183F mutant. The N208Y mutation (<a href="#0002">606686.0002</a>) resulted in a 40% increase in EIF2B GEF activity compared to wildtype, whereas P278R (<a href="#0004">606686.0004</a>) had no effect on GEF activity. The results indicated that different mutations in the EIF2B1 gene have a wide variety of effects on the EIF2B complex, rendering it difficult to interpret pathogenic effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606686[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</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> rs113994006 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994006;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/rs113994006?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=rs113994006" 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=rs113994006" 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=RCV000004339 OR RCV000255352 OR RCV003492283" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004339, RCV000255352, RCV003492283" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004339...</a>
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<p>In a patient with leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>), <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">van der Knaap et al. (2002)</a> found compound heterozygosity for 2 mutations in the EIF2B1 gene: IVS2+1G-A and a 622A-T transversion in exon 6, causing an asn208-to-tyr (N208Y) missense change in the polypeptide (<a href="#0002">606686.0002</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>.0002 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
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EIF2B1, ASN208TYR
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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> rs113994007 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994007;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/rs113994007?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=rs113994007" 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=rs113994007" 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=RCV000004340 OR RCV001851642" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004340, RCV001851642" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004340...</a>
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<p>For discussion of the asn208-to-tyr (N208Y) mutation in the EIF2B1 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>) by <a href="#10" class="mim-tip-reference" title="van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. <strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong> Ann. Neurol. 51: 264-270, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>] [<a href="https://doi.org/10.1002/ana.10112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11835386">van der Knaap et al. (2002)</a>, see <a href="#0001">606686.0001</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 in vitro functional studies, <a href="#11" class="mim-tip-reference" title="Wortham, N. C., Proud, C. G. <strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong> BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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/10.1186/s12881-015-0204-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285592">Wortham and Proud (2015)</a> found that the N208Y mutation resulted in a 40% increase in EIF2B GEF activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285592" 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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<span class="mim-font">
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<strong>.0003 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
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EIF2B1, VAL183PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225048 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225048;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=rs863225048" 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=rs863225048" 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=RCV000201228" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201228" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201228</a>
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<p>In 2 sisters (patients 3252 and 3253) with leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>), <a href="#7" class="mim-tip-reference" title="Ohlenbusch, A., Henneke, M., Brockmann, K., Goerg, M., Hanefeld, F., Kohlschutter, A., Gartner, J. <strong>Identification of ten novel mutations in patients with eIF2B-related disorders.</strong> Hum. Mutat. 25: 411, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776425</a>] [<a href="https://doi.org/10.1002/humu.9325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15776425">Ohlenbusch et al. (2005)</a> identified a homozygous c.547G-T transversion (c.547G-T, NM_001414.1) in the EIF2B1 gene, resulting in a val183-to-phe (V183F) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 100 controls. The girls presented at ages 10 and 17 years, respectively, with a history of mental retardation and cognitive and behavioral signs. They had a stable disease course, with brain and ovarian involvement; they were moderately disabled. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776425" 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 in vitro functional expression studies, <a href="#11" class="mim-tip-reference" title="Wortham, N. C., Proud, C. G. <strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong> BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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/10.1186/s12881-015-0204-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285592">Wortham and Proud (2015)</a> found that the V183F mutation affected formation of the EIF2B complex and led to a 50% reduction in binding to the rest of the complex, which was presumed to result in decreased catalytic activity of the overall complex. Further activity studies showed a 30% decrease in EIF2B GEF activity for the V183F mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285592" 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 1</strong>
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EIF2B1, PRO278ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs863225049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225049;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=rs863225049" 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=rs863225049" 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=RCV000201220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201220</a>
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<p>In a review of leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>), <a href="#8" class="mim-tip-reference" title="Pronk, J. C., van Kollenburg, B., Scheper, G. C., van der Knaap, M. S. <strong>Vanishing white matter disease: a review with focus on its genetics.</strong> Ment. Retard. Dev. Disabil. Res. Rev. 12: 123-128, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16807905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16807905</a>] [<a href="https://doi.org/10.1002/mrdd.20104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16807905">Pronk et al. (2006)</a> reported a patient with a c.833C-G transversion in the EIF2B1 gene, resulting in a pro278-to-arg (P278R) substitution. Clinical details and functional studies of the variant were not provided. (In the article by <a href="#8" class="mim-tip-reference" title="Pronk, J. C., van Kollenburg, B., Scheper, G. C., van der Knaap, M. S. <strong>Vanishing white matter disease: a review with focus on its genetics.</strong> Ment. Retard. Dev. Disabil. Res. Rev. 12: 123-128, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16807905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16807905</a>] [<a href="https://doi.org/10.1002/mrdd.20104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16807905">Pronk et al. (2006)</a>, this mutation is incorrectly given as P287R.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16807905" 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 in vitro functional expression studies, <a href="#11" class="mim-tip-reference" title="Wortham, N. C., Proud, C. G. <strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong> BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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/10.1186/s12881-015-0204-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285592">Wortham and Proud (2015)</a> found that the P278R mutation had no effect on GEF activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285592" 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 1</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">rs863225051 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225051;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=rs863225051" 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=rs863225051" 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 with leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>), <a href="#6" class="mim-tip-reference" title="Maletkovic, J., Schiffmann, R., Gorospe, J. R., Gordon, E. S., Mintz, M., Hoffman, E. P., Alper, G., Lynch, D. R., Singhal, B. S., Harding, C., Amartino, H., Brown, C. M., and 12 others. <strong>Genetic and clinical heterogeneity in eIF2B-related disorder.</strong> J. Child Neurol. 23: 205-215, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18263758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18263758</a>] [<a href="https://doi.org/10.1177/0883073807308705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18263758">Maletkovic et al. (2008)</a> identified compound heterozygous mutations in the EIF2B1 gene: an in-frame 3-bp deletion (c.610_612), resulting in the deletion of residue gly204, and a c.824A-G transition, resulting in a tyr275-to-cys (Y275C; <a href="#0006">606686.0006</a>) substitution at a conserved residue. The mutations were not found in 48 control chromosomes. Clinical details of the patient and functional studies of the variants were not provided. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18263758" 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 in vitro functional expression studies, <a href="#11" class="mim-tip-reference" title="Wortham, N. C., Proud, C. G. <strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong> BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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/10.1186/s12881-015-0204-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26285592">Wortham and Proud (2015)</a> found that the gly204del mutation affected formation of the EIF2B complex; the mutant protein was unable to interact with any of the other subunits in the complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26285592" 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> rs758746181 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs758746181;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/rs758746181?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=rs758746181" 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=rs758746181" 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=RCV000201219 OR RCV002282035 OR RCV003556247 OR RCV005008139" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201219, RCV002282035, RCV003556247, RCV005008139" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201219...</a>
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<p>For discussion of the c.824A-G transition in the EIF2B1 gene, resulting in a tyr275-to-cys (Y275C) substitution that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>) by <a href="#6" class="mim-tip-reference" title="Maletkovic, J., Schiffmann, R., Gorospe, J. R., Gordon, E. S., Mintz, M., Hoffman, E. P., Alper, G., Lynch, D. R., Singhal, B. S., Harding, C., Amartino, H., Brown, C. M., and 12 others. <strong>Genetic and clinical heterogeneity in eIF2B-related disorder.</strong> J. Child Neurol. 23: 205-215, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18263758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18263758</a>] [<a href="https://doi.org/10.1177/0883073807308705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18263758">Maletkovic et al. (2008)</a>, see <a href="#0005">606686.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18263758" 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">rs863225052 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225052;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=rs863225052" 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=rs863225052" 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=RCV000201226" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201226" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201226</a>
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<p>In a 61-year-old Japanese woman, born of consanguineous parents, with leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>), <a href="#9" class="mim-tip-reference" title="Shimada, S., Shimojima, K., Sangu, N., Hoshino, A., Hachiya, Y., Ohto, T., Hashi, Y., Nishida, K., Mitani, M., Kinjo, S., Tsurusaki, Y., Matsumoto, N., Morimoto, M., Yamamoto, T. <strong>Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease.</strong> Brain Dev. 37: 960-966, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25843247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25843247</a>] [<a href="https://doi.org/10.1016/j.braindev.2015.03.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25843247">Shimada et al. (2015)</a> identified a homozygous c.715T-G transversion in exon 8 of the EIF2B1 gene, resulting in a phe239-to-val (F239V) substitution. The mutation was not present in the dbSNP (build 138) database; segregation of the mutation in the family was not confirmed, and functional studies were not performed. The patient presented with neurologic symptoms with gait disturbances at age 29 years. She also had mild cognitive impairment (IQ of 66), motor incoordination, spasticity, and seizures. Brain imaging showed nonspecific white matter abnormalities. The disorder was progressive, and she was bedridden at the time of the report. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25843247" 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">rs863225050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225050;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=rs863225050" 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=rs863225050" 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=RCV000201227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201227</a>
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<p>In a 2-year-old Chinese girl (case 29) with early-childhood onset of leukoencephalopathy with vanishing white matter (VWM1; <a href="/entry/603896">603896</a>), <a href="#12" class="mim-tip-reference" title="Zhang, H., Dai, L., Chen, N., Zang, L., Leng, X., Du, L., Wang, J., Jiang, Y., Zhang, F., Wu, X., Wu, Y. <strong>Fifteen novel EIF2B1-5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up.</strong> PLoS One 10: e0118001, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25761052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25761052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25761052[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/10.1371/journal.pone.0118001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25761052">Zhang et al. (2015)</a> identified a homozygous c.328A-G transition (c.328A-G, NM_001414) in exon 4 of the EIF2B1 gene, resulting in a lys110-to-glu (KL110E) substitution. Functional studies of the variant were not performed. The patient had seizures, episodic aggravation, and progressive significant loss of motor function on follow-up about a year later. The patient was 1 (3%) of a cohort of 34 patients with the disorder who underwent sequencing of EIF2B genes, and was the only patient who carried an EIF2B1 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25761052" 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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Converse, P. J.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 2/12/2002.
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Flowers, K. M., Mellor, H., Kimball, S. R., Jefferson, L. S.
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<strong>Structure and sequence of the gene encoding the alpha-subunit of rat translation initiation factor-2B.</strong>
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Biochim. Biophys. Acta 1264: 163-167, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7495858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7495858</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7495858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0167-4781(95)00160-i" target="_blank">Full Text</a>]
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Kashiwagi, K., Yokoyama, T., Nishimoto, M., Takahashi, M., Sakamoto, A., Yonemochi, M., Shirouzu, M., Ito, T.
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<strong>Structural basis for eIF2B inhibition in integrated stress response.</strong>
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Science 364: 495-499, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31048492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31048492</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31048492" 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.aaw4104" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Kenner2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kenner, L. R., Anand, A. A., Nguyen, H. C., Myasnikov, A. G., Klose, C. J., McGeever, L. A., Tsai, J. C., Miller-Vedam, L. E., Walter, P., Frost, A.
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<strong>eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response.</strong>
|
|
Science 364: 491-495, 2019.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31048491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31048491</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31048491[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=31048491" 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.aaw2922" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Maletkovic2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Maletkovic, J., Schiffmann, R., Gorospe, J. R., Gordon, E. S., Mintz, M., Hoffman, E. P., Alper, G., Lynch, D. R., Singhal, B. S., Harding, C., Amartino, H., Brown, C. M., and 12 others.
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<strong>Genetic and clinical heterogeneity in eIF2B-related disorder.</strong>
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J. Child Neurol. 23: 205-215, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18263758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18263758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18263758" 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/10.1177/0883073807308705" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Ohlenbusch2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ohlenbusch, A., Henneke, M., Brockmann, K., Goerg, M., Hanefeld, F., Kohlschutter, A., Gartner, J.
|
|
<strong>Identification of ten novel mutations in patients with eIF2B-related disorders.</strong>
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|
Hum. Mutat. 25: 411, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15776425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15776425</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15776425" 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/humu.9325" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Pronk2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pronk, J. C., van Kollenburg, B., Scheper, G. C., van der Knaap, M. S.
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<strong>Vanishing white matter disease: a review with focus on its genetics.</strong>
|
|
Ment. Retard. Dev. Disabil. Res. Rev. 12: 123-128, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16807905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16807905</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16807905" 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/mrdd.20104" 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="9" class="mim-anchor"></a>
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<a id="Shimada2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shimada, S., Shimojima, K., Sangu, N., Hoshino, A., Hachiya, Y., Ohto, T., Hashi, Y., Nishida, K., Mitani, M., Kinjo, S., Tsurusaki, Y., Matsumoto, N., Morimoto, M., Yamamoto, T.
|
|
<strong>Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease.</strong>
|
|
Brain Dev. 37: 960-966, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25843247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25843247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25843247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.braindev.2015.03.003" target="_blank">Full Text</a>]
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="van der Knaap2002" class="mim-anchor"></a>
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<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.
|
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<strong>Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.</strong>
|
|
Ann. Neurol. 51: 264-270, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11835386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11835386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11835386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10112" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Wortham2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wortham, N. C., Proud, C. G.
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<strong>Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease.</strong>
|
|
BMC Med. Genet. 16: 64, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26285592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26285592</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26285592[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=26285592" 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/10.1186/s12881-015-0204-z" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Zhang2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, H., Dai, L., Chen, N., Zang, L., Leng, X., Du, L., Wang, J., Jiang, Y., Zhang, F., Wu, X., Wu, Y.
|
|
<strong>Fifteen novel EIF2B1-5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up.</strong>
|
|
PLoS One 10: e0118001, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25761052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25761052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25761052[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=25761052" 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/10.1371/journal.pone.0118001" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 06/06/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/19/2015<br>Matthew B. Gross - updated : 5/28/2015<br>Victor A. McKusick - updated : 11/11/2002
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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>
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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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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/04/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 04/17/2023<br>alopez : 06/06/2019<br>alopez : 06/06/2019<br>carol : 12/30/2015<br>carol : 10/19/2015<br>ckniffin : 10/19/2015<br>mcolton : 8/18/2015<br>mgross : 5/28/2015<br>cwells : 11/20/2003<br>alopez : 11/12/2002<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>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 606686
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 1; EIF2B1
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, ALPHA<br />
|
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EIF2B-ALPHA
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: EIF2B1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 12q24.31
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 12:123,620,406-123,633,686 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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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>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
12q24.31
|
|
</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Leukoencephalopathy with vanishing white matter 1, with or without ovarian failure
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
603896
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>The EIF2B1 gene encodes EIF2B-alpha, the smallest subunit of the eukaryotic translation initiation factor eIF2B, which is a heterodecameric complex comprising 5 subunits: alpha (EIF2B1), beta (EIF2B2; 606454), gamma (EIF2B3; 606273), delta (EIF2B4; 606687), and epsilon (EIF2B5; 603945). EIF2B is a GTP exchange factor that is essential for protein synthesis: its substrate is eIF2 (see 603907). GTP-bound eIF2 is responsible for loading the initiator methionyl-tRNA onto the ribosome to allow initiation of protein synthesis to take place. EIF2B-alpha, -beta, and -delta form the regulatory subcomplex, whereas EIF2B-gamma and -epsilon form the catalytic subcomplex (summary by Wortham and Proud, 2015). </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>Flowers et al. (1995) cloned a rat cDNA encoding Eif2b1. The deduced 305-amino acid rat protein (GenBank AAA91276) is 92% identical to the human protein (Converse, 2002). By Northern blot analysis, Flowers et al. (1995) detected equivalent expression of rat Eif2b1 in all tissues tested; in contrast, Eif2b5 is predominantly expressed in testis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Flowers et al. (1995) determined that the rat Eif2b1 gene has 9 exons and spans 8.5 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Kenner et al. (2019) reported cryoelectron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures revealed that the eIF2B decamer is a static platform upon which 1 or 2 flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2-alpha (603907), allowing it to contact eIF2B at a different interface and, the authors surmised, thereby sequestering it into a nonproductive complex. </p><p>To elucidate how eIF2 phosphorylation status regulates the eIF2B activity, Kashiwagi et al. (2019) determined cryoelectron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. Kashiwagi et al. (2019) concluded that these structures explained how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B. </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 EIF2B1 gene to chromosome 12q24.31 based on an alignment of the EIF2B1 sequence (GenBank BC103763) 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 (VWM1; 603896) is an autosomal recessive disorder characterized by a chronic and progressive course with additional episodes of rapid deterioration provoked by fever and minor head trauma. In a patient with VWM1, van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B1 gene (606686.0001 and 606686.0002). </p><p>In 2 sisters with a moderate form of VWM1, Ohlenbusch et al. (2005) identified a homozygous missense mutation in the EIF2B1 gene (V183F; 606686.0003). These patients were reported to have ovarian failure. Functional studies of the variant were not performed. </p><p>In a patient with leukoencephalopathy with vanishing white matter, Maletkovic et al. (2008) identified compound heterozygous mutations in the EIF2B1 gene (606686.0005 and 606686.0006). Functional studies of the variants were not performed. The patient was 1 of 15 VWM patients with mutations in 1 of the EIF2B genes. The authors noted that mutations in the EIF2B1 gene account for only approximately 4% of all reported mutations and are found in approximately 1% of patients reported with EIF2B-related disorders. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
In in vitro functional expression studies, Wortham and Proud (2015) found that the V183F (606686.0003), gly204del (606686.0005), and Y275C (606686.0006) EIF2B1 mutations affected formation of the EIF2B complex. Gly204del was unable to interact with any of the other subunits in the complex, whereas V183F and Y275C led to a 50% reduction in binding to the rest of the complex, which was presumed to result in decreased catalytic activity of the overall complex. Further activity studies showed a 30% decrease in EIF2B GEF activity for the V183F mutant. The N208Y mutation (606686.0002) resulted in a 40% increase in EIF2B GEF activity compared to wildtype, whereas P278R (606686.0004) had no effect on GEF activity. The results indicated that different mutations in the EIF2B1 gene have a wide variety of effects on the EIF2B complex, rendering it difficult to interpret pathogenic effects. </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>8 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">
|
|
<strong>.0001 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</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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EIF2B1, IVS2DS, G-A, +1
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<br />
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SNP: rs113994006,
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gnomAD: rs113994006,
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ClinVar: RCV000004339, RCV000255352, RCV003492283
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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 with leukoencephalopathy with vanishing white matter (VWM1; 603896), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B1 gene: IVS2+1G-A and a 622A-T transversion in exon 6, causing an asn208-to-tyr (N208Y) missense change in the polypeptide (606686.0002). </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>.0002 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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EIF2B1, ASN208TYR
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<br />
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SNP: rs113994007,
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gnomAD: rs113994007,
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|
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|
|
ClinVar: RCV000004340, RCV001851642
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the asn208-to-tyr (N208Y) mutation in the EIF2B1 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896) by van der Knaap et al. (2002), see 606686.0001. </p><p>In in vitro functional studies, Wortham and Proud (2015) found that the N208Y mutation resulted in a 40% increase in EIF2B GEF activity. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B1, VAL183PHE
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|
|
|
<br />
|
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|
|
SNP: rs863225048,
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|
|
|
|
|
|
|
ClinVar: RCV000201228
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters (patients 3252 and 3253) with leukoencephalopathy with vanishing white matter (VWM1; 603896), Ohlenbusch et al. (2005) identified a homozygous c.547G-T transversion (c.547G-T, NM_001414.1) in the EIF2B1 gene, resulting in a val183-to-phe (V183F) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 100 controls. The girls presented at ages 10 and 17 years, respectively, with a history of mental retardation and cognitive and behavioral signs. They had a stable disease course, with brain and ovarian involvement; they were moderately disabled. Functional studies of the variant were not performed. </p><p>In in vitro functional expression studies, Wortham and Proud (2015) found that the V183F mutation affected formation of the EIF2B complex and led to a 50% reduction in binding to the rest of the complex, which was presumed to result in decreased catalytic activity of the overall complex. Further activity studies showed a 30% decrease in EIF2B GEF activity for the V183F mutant. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B1, PRO278ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225049,
|
|
|
|
|
|
|
|
ClinVar: RCV000201220
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a review of leukoencephalopathy with vanishing white matter (VWM1; 603896), Pronk et al. (2006) reported a patient with a c.833C-G transversion in the EIF2B1 gene, resulting in a pro278-to-arg (P278R) substitution. Clinical details and functional studies of the variant were not provided. (In the article by Pronk et al. (2006), this mutation is incorrectly given as P287R.) </p><p>In in vitro functional expression studies, Wortham and Proud (2015) found that the P278R mutation had no effect on GEF activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B1, 3-BP DEL, NT610
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225051,
|
|
|
|
|
|
|
|
ClinVar: RCV000201218
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896), Maletkovic et al. (2008) identified compound heterozygous mutations in the EIF2B1 gene: an in-frame 3-bp deletion (c.610_612), resulting in the deletion of residue gly204, and a c.824A-G transition, resulting in a tyr275-to-cys (Y275C; 606686.0006) substitution at a conserved residue. The mutations were not found in 48 control chromosomes. Clinical details of the patient and functional studies of the variants were not provided. </p><p>In in vitro functional expression studies, Wortham and Proud (2015) found that the gly204del mutation affected formation of the EIF2B complex; the mutant protein was unable to interact with any of the other subunits in the complex. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B1, TYR275CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs758746181,
|
|
|
|
|
|
gnomAD: rs758746181,
|
|
|
|
|
|
ClinVar: RCV000201219, RCV002282035, RCV003556247, RCV005008139
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.824A-G transition in the EIF2B1 gene, resulting in a tyr275-to-cys (Y275C) substitution that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896) by Maletkovic et al. (2008), see 606686.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B1, PHE239VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225052,
|
|
|
|
|
|
|
|
ClinVar: RCV000201226
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 61-year-old Japanese woman, born of consanguineous parents, with leukoencephalopathy with vanishing white matter (VWM1; 603896), Shimada et al. (2015) identified a homozygous c.715T-G transversion in exon 8 of the EIF2B1 gene, resulting in a phe239-to-val (F239V) substitution. The mutation was not present in the dbSNP (build 138) database; segregation of the mutation in the family was not confirmed, and functional studies were not performed. The patient presented with neurologic symptoms with gait disturbances at age 29 years. She also had mild cognitive impairment (IQ of 66), motor incoordination, spasticity, and seizures. Brain imaging showed nonspecific white matter abnormalities. The disorder was progressive, and she was bedridden at the time of the report. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EIF2B1, LYS110GLU
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225050,
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|
|
|
|
|
|
|
ClinVar: RCV000201227
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2-year-old Chinese girl (case 29) with early-childhood onset of leukoencephalopathy with vanishing white matter (VWM1; 603896), Zhang et al. (2015) identified a homozygous c.328A-G transition (c.328A-G, NM_001414) in exon 4 of the EIF2B1 gene, resulting in a lys110-to-glu (KL110E) substitution. Functional studies of the variant were not performed. The patient had seizures, episodic aggravation, and progressive significant loss of motor function on follow-up about a year later. The patient was 1 (3%) of a cohort of 34 patients with the disorder who underwent sequencing of EIF2B genes, and was the only patient who carried an EIF2B1 mutation. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
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|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Converse, P. J.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 2/12/2002.
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Flowers, K. M., Mellor, H., Kimball, S. R., Jefferson, L. S.
|
|
<strong>Structure and sequence of the gene encoding the alpha-subunit of rat translation initiation factor-2B.</strong>
|
|
Biochim. Biophys. Acta 1264: 163-167, 1995.
|
|
|
|
|
|
[PubMed: 7495858]
|
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|
|
[Full Text: https://doi.org/10.1016/0167-4781(95)00160-i]
|
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|
|
</p>
|
|
</li>
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