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<title>
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Entry
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- *600111 - SOLUTE CARRIER FAMILY 1 (GLIAL HIGH AFFINITY GLUTAMATE TRANSPORTER), MEMBER 3; SLC1A3
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- OMIM
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<a href="#" id="mimShowTips" class="mim-tip-hint" title="Click to reveal all tips on the page. You can also hover over individual elements to reveal the tip."><span class="mim-navbar-menu-font"><span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span></span></a>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<li class="dropdown-header">
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<a href="/history"> Search History </a>
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</form>
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<div class="row">
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600111</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600111">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000079215;t=ENST00000265113" 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=6507" 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=600111" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000079215;t=ENST00000265113" 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_001166695,NM_001166696,NM_001289939,NM_001289940,NM_004172,XM_005248342,XM_047417539,XM_047417540" 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_004172" 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=600111" 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=02523&isoform_id=02523_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/SLC1A3" 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/487339,825504,825663,1169458,22713616,32450689,63053861,119576349,119576350,169790839,189065391,194375862,194379072,194381260,262359914,262359916,374252093,374252095,530378898,584277111,584277117,2217356844,2217356846,2462603771,2462603773,2462603775" 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/P43003" 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=6507" 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=ENSG00000079215;t=ENST00000265113" 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=SLC1A3" 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=SLC1A3" 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+6507" 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/SLC1A3" 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:6507" 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/6507" 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=chr5&hgg_gene=ENST00000265113.9&hgg_start=36606606&hgg_end=36688334&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:10941" 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/slc1a3" 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=600111[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=600111[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/ENSG00000079215" 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=SLC1A3" 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=SLC1A3" 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=SLC1A3" 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=SLC1A3&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/PA35828" 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:10941" 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/FBgn0026439.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:99917" 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/SLC1A3#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:99917" 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/6507/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=6507" 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=WBGene00001622;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2159" 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:6507" 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=SLC1A3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 718753002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600111
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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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SOLUTE CARRIER FAMILY 1 (GLIAL HIGH AFFINITY GLUTAMATE TRANSPORTER), MEMBER 3; SLC1A3
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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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EXCITATORY AMINO ACID TRANSPORTER 1; EAAT1<br />
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GLIAL HIGH AFFINITY GLUTAMATE TRANSPORTER<br />
|
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GLUTAMATE/ASPARTATE TRANSPORTER, HIGH AFFINITY, SODIUM-DEPENDENT; GLAST1<br />
|
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GLAST
|
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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=SLC1A3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SLC1A3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/5/114?start=-3&limit=10&highlight=114">5p13.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:36606606-36688334&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'})">5:36,606,606-36,688,334</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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Episodic ataxia, type 6
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PheneGene Graphics <span class="caret"></span>
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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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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>Glutamate and aspartate are excitatory neurotransmitters that have been implicated in a number of pathologic states of the nervous system. Accumulation of extracellular excitatory amino acids can be cytotoxic and may also lower the seizure threshold in epilepsy. EAAT1 (SLC1A3) is a member of a family of high-affinity sodium-dependent transporter molecules that regulate neurotransmitter concentrations at the excitatory glutamatergic synapses of the mammalian central nervous system (<a href="#8" class="mim-tip-reference" title="Kirschner, M. A., Arriza, J. L., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Magenis, E., Amara, S. G. <strong>The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5.</strong> Genomics 22: 631-633, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001975</a>] [<a href="https://doi.org/10.1006/geno.1994.1437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001975">Kirschner et al., 1994</a>). SLC1A3 also functions as a glutamate-activated anion channel (summary by <a href="#15" class="mim-tip-reference" title="Winter, N., Kovermann, P., Fahlke, C. <strong>A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents.</strong> Brain 135: 3416-3425, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23107647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23107647</a>] [<a href="https://doi.org/10.1093/brain/aws255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23107647">Winter et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8001975+23107647" 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="#11" class="mim-tip-reference" title="Shashidharan, P., Huntley, G. W., Meyer, T., Morrison, J. H., Plaitakis, A. <strong>Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain.</strong> Brain Res. 662: 245-250, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7859077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7859077</a>] [<a href="https://doi.org/10.1016/0006-8993(94)90819-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7859077">Shashidharan et al. (1994)</a> isolated a novel cDNA from a human brain cDNA library. The cDNA encoded a deduced protein that was 95% homologous to a previously reported rabbit glutamate/aspartate transporter. Northern blot analysis demonstrated expression of the corresponding mRNA in human brain, liver, muscle, ovary, testis, and in retinoblastoma cell lines. The highest expression was found in the substantia nigra, red nucleus, and hippocampus, and in cerebral cortical layers. <a href="#11" class="mim-tip-reference" title="Shashidharan, P., Huntley, G. W., Meyer, T., Morrison, J. H., Plaitakis, A. <strong>Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain.</strong> Brain Res. 662: 245-250, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7859077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7859077</a>] [<a href="https://doi.org/10.1016/0006-8993(94)90819-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7859077">Shashidharan et al. (1994)</a> referred to this as human glutamate transporter III and showed that it is structurally distinct from the previously described brain-specific glutamate transporters SLC1A1 (<a href="/entry/133550">133550</a>) and SLC1A2 (<a href="/entry/600300">600300</a>). The novel cDNA likely corresponded to the SLC1A3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7859077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Stoffel, W., Sasse, J., Duker, M., Muller, R., Hofmann, K., Fink, T., Lichter, P. <strong>Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12.</strong> FEBS Lett. 386: 189-193, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8647279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8647279</a>] [<a href="https://doi.org/10.1016/0014-5793(96)00424-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8647279">Stoffel et al. (1996)</a> isolated the human sodium-dependent L-glutamate/L-aspartate transporter gene, which they referred to as GLAST1, and found that it encodes a putative 542-amino acid protein. They stated that the gene is unrelated to any previously described neurotransmitter transporter gene family, but its exon/intron structure corresponds largely to that of the sodium-dependent neutral amino acid transporter ASCT1 (SLC1A4; <a href="/entry/600229">600229</a>). GLAST1, ASCT1, and the glutamate transporters GLT1 (SLC1A2) and EAAC1 (SLC1A1) have similar amino acid sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8647279" 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="#12" class="mim-tip-reference" title="Stoffel, W., Sasse, J., Duker, M., Muller, R., Hofmann, K., Fink, T., Lichter, P. <strong>Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12.</strong> FEBS Lett. 386: 189-193, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8647279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8647279</a>] [<a href="https://doi.org/10.1016/0014-5793(96)00424-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8647279">Stoffel et al. (1996)</a> determined that the human GLAST1 gene contains 10 exons spanning at least 85 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8647279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Hagiwara, T., Tanaka, K., Takai, S., Maeno-Hikichi, Y., Mukainaka, Y., Wada, K. <strong>Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3.</strong> Genomics 33: 508-515, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661010</a>] [<a href="https://doi.org/10.1006/geno.1996.0226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661010">Hagiwara et al. (1996)</a> showed that the mouse Slcla3 gene contains 10 exons spanning more than 56 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661010" 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><strong><em>Crystal Structure</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Canul-Tec, J. C., Assal, R., Cirri, E., Legrand, P., Brier, S., Chamot-Rooke, J., Reyes, N. <strong>Structure and allosteric inhibition of excitatory amino acid transporter 1.</strong> Nature 544: 446-451, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28424515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28424515</a>] [<a href="https://doi.org/10.1038/nature22064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28424515">Canul-Tec et al. (2017)</a> presented the crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter-1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures revealed architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids, and posttranslational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry revealed a mechanism of inhibition in which the transporter is locked in the outward-facing states of the transport cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28424515" 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="#8" class="mim-tip-reference" title="Kirschner, M. A., Arriza, J. L., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Magenis, E., Amara, S. G. <strong>The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5.</strong> Genomics 22: 631-633, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001975</a>] [<a href="https://doi.org/10.1006/geno.1994.1437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001975">Kirschner et al. (1994)</a> mapped the human EAAT1 gene to chromosome 5p13 by fluorescence in situ hybridization (FISH). They used interspecific backcross analysis to map the mouse homolog to chromosome 15 in a region of homology to human 5p13. They commented that the EAAT1 locus may be related to the syndrome of microcephaly and mental retardation observed by <a href="#7" class="mim-tip-reference" title="Keppen, L. D., Gollin, S. M., Edwards, D., Sawyer, J., Wilson, W., Overhauser, J. <strong>Clinical phenotype and molecular analysis of a three-generation family with an interstitial deletion of the short arm of chromosome 5.</strong> Am. J. Med. Genet. 44: 356-360, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1488985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1488985</a>] [<a href="https://doi.org/10.1002/ajmg.1320440317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1488985">Keppen et al. (1992)</a> in association with interstitial deletion of distal band 5p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1488985+8001975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By FISH, <a href="#13" class="mim-tip-reference" title="Takai, S., Yamada, K., Kawakami, H., Tanaka, K., Nakamura, S. <strong>Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization.</strong> Cytogenet. Cell Genet. 69: 209-210, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698014</a>] [<a href="https://doi.org/10.1159/000133965" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7698014">Takai et al. (1995)</a> also mapped the SLC1A3 gene to chromosome 5p13. <a href="#12" class="mim-tip-reference" title="Stoffel, W., Sasse, J., Duker, M., Muller, R., Hofmann, K., Fink, T., Lichter, P. <strong>Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12.</strong> FEBS Lett. 386: 189-193, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8647279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8647279</a>] [<a href="https://doi.org/10.1016/0014-5793(96)00424-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8647279">Stoffel et al. (1996)</a> mapped the GLAST1 gene to 5p12-p11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7698014+8647279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Hagiwara, T., Tanaka, K., Takai, S., Maeno-Hikichi, Y., Mukainaka, Y., Wada, K. <strong>Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3.</strong> Genomics 33: 508-515, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661010</a>] [<a href="https://doi.org/10.1006/geno.1996.0226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661010">Hagiwara et al. (1996)</a> mapped the mouse Slc1a3 gene to chromosome 15A2 by FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 10-year-old boy with episodic ataxia, seizures, migraine, and alternating hemiplegia consistent with episodic ataxia type 6 (EA6; <a href="/entry/612656">612656</a>), <a href="#6" class="mim-tip-reference" title="Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W. <strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong> Neurology 65: 529-534, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116111</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172638.58172.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116111">Jen et al. (2005)</a> identified a heterozygous mutation in the SLC1A3 gene (<a href="#0001">600111.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16116111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 affected members of a family with EA6, <a href="#2" class="mim-tip-reference" title="de Vries, B., Mamsa, H., Stam, A. H., Wan, J., Bakker, S. L. M., Vanmolkot, K. R. J., Haan, J., Terwindt, G. M., Boon, E. M. J., Howard, B. D., Frants, R. R., Baloh, R. W., Ferrari, M. D., Jen, J. C., van den Maagdenberg, A. M. J. M. <strong>Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.</strong> Arch. Neurol. 66: 97-101, 2009. Note: Erratum: Arch. Neurol. 66: 497 only, 2009; Erratum: Arch. Neurol. 66: 772 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19139306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19139306</a>] [<a href="https://doi.org/10.1001/archneurol.2008.535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19139306">de Vries et al. (2009)</a> identified a heterozygous mutation in the SLC1A3 gene (<a href="#0002">600111.0002</a>). There was 1 unaffected carrier of the mutation, indicating reduced penetrance. Functional expression studies showed that the mutation resulted in an 18% decrease in glutamate uptake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19139306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In the retina, the glutamate transporter GLAST is expressed in Muller cells, whereas the glutamate transporter GLT1 is found only in cones and various types of bipolar cells. To investigate the functional role of this differential distribution of glutamate transporters, <a href="#4" class="mim-tip-reference" title="Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K., Tanaka, K. <strong>Functions of the two glutamate transporters GLAST and GLT-1 in the retina.</strong> Proc. Nat. Acad. Sci. 95: 4663-4666, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9539795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9539795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9539795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.8.4663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9539795">Harada et al. (1998)</a> analyzed Glast and Glt1 mutant mice. In Glast-deficient mice, the electroretinogram b-wave and oscillatory potentials were reduced and retinal damage after ischemia was exacerbated, whereas Glt1-deficient mice showed almost normal electroretinograms and mildly increased retinal damage after ischemia. These results demonstrated that Glast is required for normal signal transmission between photoreceptors and bipolar cells and that both Glast and Glt1 play a neuroprotective role during ischemia in the retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9539795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Watase, K., Hashimoto, K., Kano, M., Yamada, K., Watanabe, M., Inoue, Y., Okuyama, S., Sakagawa, T., Ogawa, S., Kawashima, N., Hori, S., Takimoto, M., Wada, K., Tanaka, K. <strong>Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice.</strong> Europ. J. Neurosci. 10: 976-988, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753165</a>] [<a href="https://doi.org/10.1046/j.1460-9568.1998.00108.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9753165">Watase et al. (1998)</a> found that mouse Glast was most abundantly expressed in the Bergmann glia in the cerebellum. Glast-deficient mice developed normally and could manage simple coordinated tasks, such as staying on a stationary or a slowly rotating rod, but failed more challenging tests, such as staying on a quickly rotating rod. Electrophysiologic studies showed that Purkinje cells in the mutant mice remained multiply innervated by climbing fibers, even at the adult stage. After cold-induced injury, the mutant mice had significantly more cerebellar edema compared to wildtype mice, indicating that Glast is essential for preventing neuronal injury after traumatic cerebellar injury. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Matsugami, T. R., Tanemura, K., Mieda, M., Nakatomi, R., Yamada, K., Kondo, T., Ogawa, M., Obata, K., Watanabe, M., Hashikawa, T., Tanaka, K. <strong>Indispensability of the glutamate transporters GLAST and GLT1 to brain development.</strong> Proc. Nat. Acad. Sci. 103: 12161-12166, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880397</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880397[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0509144103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880397">Matsugami et al. (2006)</a> found that the brains of mice lacking Glast or Glt1 developed normally but that Glast/Glt1 double-knockout mice died around embryonic days 17 to 18 and exhibited cortical, hippocampal, and olfactory bulb disorganization. Several essential aspects of neuronal development, such as stem cell proliferation, radial migration, neuronal differentiation, and survival of subplate neurons, were impaired. <a href="#9" class="mim-tip-reference" title="Matsugami, T. R., Tanemura, K., Mieda, M., Nakatomi, R., Yamada, K., Kondo, T., Ogawa, M., Obata, K., Watanabe, M., Hashikawa, T., Tanaka, K. <strong>Indispensability of the glutamate transporters GLAST and GLT1 to brain development.</strong> Proc. Nat. Acad. Sci. 103: 12161-12166, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880397</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880397[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0509144103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880397">Matsugami et al. (2006)</a> concluded that the regulation of extracellular glutamate concentration and the maintenance of glutamate-mediated synaptic transmission is necessary for normal brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16880397" 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">rs137852619 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852619;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=rs137852619" 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=rs137852619" 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 10-year-old boy with episodic ataxia, seizures, migraine, and alternating hemiplegia (EA6; <a href="/entry/612656">612656</a>), <a href="#6" class="mim-tip-reference" title="Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W. <strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong> Neurology 65: 529-534, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116111</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172638.58172.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116111">Jen et al. (2005)</a> identified a heterozygous 1047C-G transversion in the SLC1A3 gene, resulting in a pro290-to-arg substitution in a highly conserved residue within the fifth transmembrane domain. The mutation was not identified in either unaffected parent or in 232 control chromosomes. From birth, the child had experienced 4 discrete episodes of ataxia and slurred speech, seemingly triggered by a febrile illness. At age 6 years, he developed a severe right-sided headache followed by hemiparesis and decreased consciousness lasting 5 days. MRI showed cerebellar atrophy, and neurologic examination showed mild interictal truncal ataxia. Functional expression studies showed decreased expression of the mutant protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant transporter multimerized with the wildtype transporter to exert a dominant-negative effect. <a href="#6" class="mim-tip-reference" title="Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W. <strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong> Neurology 65: 529-534, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116111</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172638.58172.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116111">Jen et al. (2005)</a> postulated a role for abnormal glutamate transmission in the neurologic features seen in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16116111" 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 electrophysiologic studies, <a href="#15" class="mim-tip-reference" title="Winter, N., Kovermann, P., Fahlke, C. <strong>A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents.</strong> Brain 135: 3416-3425, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23107647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23107647</a>] [<a href="https://doi.org/10.1093/brain/aws255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23107647">Winter et al. (2012)</a> found that the P290R mutation increased SLC1A3 anion currents compared to wildtype in both the presence and the absence of glutamate. These changes were observed in addition to the reduction of glutamate transport. <a href="#15" class="mim-tip-reference" title="Winter, N., Kovermann, P., Fahlke, C. <strong>A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents.</strong> Brain 135: 3416-3425, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23107647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23107647</a>] [<a href="https://doi.org/10.1093/brain/aws255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23107647">Winter et al. (2012)</a> suggested that the relatively severe phenotype of the patient reported by <a href="#6" class="mim-tip-reference" title="Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W. <strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong> Neurology 65: 529-534, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116111</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172638.58172.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116111">Jen et al. (2005)</a> resulted from a gain-of-function effect of the P290R mutation on the anion channel function of SLC1A3, perhaps by altering the anion current in glial cells and GABAergic synaptic transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16116111+23107647" 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>Because the P290R substitution reduces expression of human SLC1A3 in Xenopus oocytes, <a href="#5" class="mim-tip-reference" title="Hotzy, J., Schneider, N., Kovermann, P., Fahlke, C. <strong>Muting a conserved proline residue within the trimerization domain modifies Na+ binding to excitatory amino acid transporters and associated conformational changes.</strong> J. Biol. Chem. 288: 36492-36501, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24214974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24214974</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24214974[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M113.489385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24214974">Hotzy et al. (2013)</a> studied the homologous mutation (P259R) in SLC1A1 (<a href="/entry/133550">133550</a>), which is robustly expressed in Xenopus oocytes. They found that, compared with wildtype, the substitution decelerated a conformational change that accompanies binding of sodium to the glutamate-free form of the transporter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24214974" 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 EPISODIC ATAXIA, TYPE 6</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">rs137852620 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852620;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=rs137852620" 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=rs137852620" 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=RCV000010049" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010049" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010049</a>
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<p>In 3 affected members of a Dutch family with episodic ataxia-6 (EA6; <a href="/entry/612656">612656</a>), <a href="#2" class="mim-tip-reference" title="de Vries, B., Mamsa, H., Stam, A. H., Wan, J., Bakker, S. L. M., Vanmolkot, K. R. J., Haan, J., Terwindt, G. M., Boon, E. M. J., Howard, B. D., Frants, R. R., Baloh, R. W., Ferrari, M. D., Jen, J. C., van den Maagdenberg, A. M. J. M. <strong>Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.</strong> Arch. Neurol. 66: 97-101, 2009. Note: Erratum: Arch. Neurol. 66: 497 only, 2009; Erratum: Arch. Neurol. 66: 772 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19139306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19139306</a>] [<a href="https://doi.org/10.1001/archneurol.2008.535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19139306">de Vries et al. (2009)</a> identified a heterozygous 556T-A transversion in the SLC1A3 gene, resulting in a cys186-to-ser (C186S) substitution in a highly conserved residue in transmembrane segment 4b. In vitro functional expression studies in COS-7 cells showed that the mutant EAAT1 resulted in an 18% decrease in glutamate uptake compared to the wildtype channel. <a href="#2" class="mim-tip-reference" title="de Vries, B., Mamsa, H., Stam, A. H., Wan, J., Bakker, S. L. M., Vanmolkot, K. R. J., Haan, J., Terwindt, G. M., Boon, E. M. J., Howard, B. D., Frants, R. R., Baloh, R. W., Ferrari, M. D., Jen, J. C., van den Maagdenberg, A. M. J. M. <strong>Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.</strong> Arch. Neurol. 66: 97-101, 2009. Note: Erratum: Arch. Neurol. 66: 497 only, 2009; Erratum: Arch. Neurol. 66: 772 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19139306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19139306</a>] [<a href="https://doi.org/10.1001/archneurol.2008.535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19139306">De Vries et al. (2009)</a> noted that the phenotype was less severe than that reported by <a href="#6" class="mim-tip-reference" title="Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W. <strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong> Neurology 65: 529-534, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116111</a>] [<a href="https://doi.org/10.1212/01.wnl.0000172638.58172.5a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116111">Jen et al. (2005)</a>, as the P290R mutation (<a href="#0001">600111.0001</a>) resulted in markedly decreased glutamate uptake. The C186S mutation was not identified in 200 Dutch controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19139306+16116111" 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>.0003 EPISODIC ATAXIA, TYPE 6</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> rs138085358 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138085358;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/rs138085358?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=rs138085358" 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=rs138085358" 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=RCV000234998 OR RCV000500491 OR RCV000727383" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000234998, RCV000500491, RCV000727383" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000234998...</a>
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<p>In 2 first cousins of European descent with a variant of episodic ataxia-6 (EA6; <a href="/entry/612656">612656</a>), <a href="#10" class="mim-tip-reference" title="Pyle, A., Smertenko, T., Bargiela, D., Griffin, H., Duff, J., Appleton, M., Douroudis, K., Pfeffer, G., Santibanez-Koref, M., Eglon, G., Yu-Wai-Man, P., Ramesh, V., Horvath, R., Chinnery, P. F. <strong>Exome sequencing in undiagnosed inherited and sporadic ataxias.</strong> Brain 138: 276-283, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25497598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25497598</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25497598[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awu348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25497598">Pyle et al. (2015)</a> identified a heterozygous c.1361G-A transition in the SLC1A3 gene, resulting in an arg454-to-gln (R454Q) substitution. The mutation, which was found by exome sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases, as well as 286 in-house controls. The mutation segregated with the disorder in the family. Functional studies of the variant were not performed. The patients had onset of gait ataxia and dysarthria in their thirties; the disorder was not described as episodic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25497598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Canul-Tec, J. C., Assal, R., Cirri, E., Legrand, P., Brier, S., Chamot-Rooke, J., Reyes, N.
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<strong>Structure and allosteric inhibition of excitatory amino acid transporter 1.</strong>
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Nature 544: 446-451, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28424515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28424515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28424515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature22064" target="_blank">Full Text</a>]
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de Vries, B., Mamsa, H., Stam, A. H., Wan, J., Bakker, S. L. M., Vanmolkot, K. R. J., Haan, J., Terwindt, G. M., Boon, E. M. J., Howard, B. D., Frants, R. R., Baloh, R. W., Ferrari, M. D., Jen, J. C., van den Maagdenberg, A. M. J. M.
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<strong>Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.</strong>
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Arch. Neurol. 66: 97-101, 2009. Note: Erratum: Arch. Neurol. 66: 497 only, 2009; Erratum: Arch. Neurol. 66: 772 only, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19139306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19139306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19139306" 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/10.1001/archneurol.2008.535" target="_blank">Full Text</a>]
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Hagiwara, T., Tanaka, K., Takai, S., Maeno-Hikichi, Y., Mukainaka, Y., Wada, K.
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<strong>Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3.</strong>
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Genomics 33: 508-515, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661010</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661010" 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/10.1006/geno.1996.0226" target="_blank">Full Text</a>]
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Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K., Tanaka, K.
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<strong>Functions of the two glutamate transporters GLAST and GLT-1 in the retina.</strong>
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Proc. Nat. Acad. Sci. 95: 4663-4666, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9539795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9539795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9539795[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=9539795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.95.8.4663" target="_blank">Full Text</a>]
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Hotzy, J., Schneider, N., Kovermann, P., Fahlke, C.
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<strong>Muting a conserved proline residue within the trimerization domain modifies Na+ binding to excitatory amino acid transporters and associated conformational changes.</strong>
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J. Biol. Chem. 288: 36492-36501, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24214974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24214974</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24214974[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=24214974" 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/10.1074/jbc.M113.489385" target="_blank">Full Text</a>]
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Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W.
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<strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong>
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Neurology 65: 529-534, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116111</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16116111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000172638.58172.5a" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Keppen1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Keppen, L. D., Gollin, S. M., Edwards, D., Sawyer, J., Wilson, W., Overhauser, J.
|
|
<strong>Clinical phenotype and molecular analysis of a three-generation family with an interstitial deletion of the short arm of chromosome 5.</strong>
|
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Am. J. Med. Genet. 44: 356-360, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1488985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1488985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1488985" 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/ajmg.1320440317" 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="Kirschner1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Kirschner, M. A., Arriza, J. L., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Magenis, E., Amara, S. G.
|
|
<strong>The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5.</strong>
|
|
Genomics 22: 631-633, 1994.
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001975/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001975</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8001975" 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/10.1006/geno.1994.1437" 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="9" class="mim-anchor"></a>
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<a id="Matsugami2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Matsugami, T. R., Tanemura, K., Mieda, M., Nakatomi, R., Yamada, K., Kondo, T., Ogawa, M., Obata, K., Watanabe, M., Hashikawa, T., Tanaka, K.
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<strong>Indispensability of the glutamate transporters GLAST and GLT1 to brain development.</strong>
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Proc. Nat. Acad. Sci. 103: 12161-12166, 2006.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880397</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880397[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=16880397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0509144103" 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="10" class="mim-anchor"></a>
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<a id="Pyle2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pyle, A., Smertenko, T., Bargiela, D., Griffin, H., Duff, J., Appleton, M., Douroudis, K., Pfeffer, G., Santibanez-Koref, M., Eglon, G., Yu-Wai-Man, P., Ramesh, V., Horvath, R., Chinnery, P. F.
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|
<strong>Exome sequencing in undiagnosed inherited and sporadic ataxias.</strong>
|
|
Brain 138: 276-283, 2015.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25497598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25497598</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25497598[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=25497598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awu348" 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="11" class="mim-anchor"></a>
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<a id="Shashidharan1994" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Shashidharan, P., Huntley, G. W., Meyer, T., Morrison, J. H., Plaitakis, A.
|
|
<strong>Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain.</strong>
|
|
Brain Res. 662: 245-250, 1994.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7859077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7859077</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7859077" 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/10.1016/0006-8993(94)90819-2" 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="12" class="mim-anchor"></a>
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<a id="Stoffel1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stoffel, W., Sasse, J., Duker, M., Muller, R., Hofmann, K., Fink, T., Lichter, P.
|
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<strong>Human high affinity, Na(+)-dependent L-glutamate/L-aspartate transporter GLAST-1 (EAAT-1): gene structure and localization to chromosome 5p11-p12.</strong>
|
|
FEBS Lett. 386: 189-193, 1996.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8647279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8647279</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8647279" 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/10.1016/0014-5793(96)00424-3" 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="13" class="mim-anchor"></a>
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<a id="Takai1995" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
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Takai, S., Yamada, K., Kawakami, H., Tanaka, K., Nakamura, S.
|
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<strong>Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization.</strong>
|
|
Cytogenet. Cell Genet. 69: 209-210, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698014</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7698014" 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/10.1159/000133965" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Watase1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Watase, K., Hashimoto, K., Kano, M., Yamada, K., Watanabe, M., Inoue, Y., Okuyama, S., Sakagawa, T., Ogawa, S., Kawashima, N., Hori, S., Takimoto, M., Wada, K., Tanaka, K.
|
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<strong>Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice.</strong>
|
|
Europ. J. Neurosci. 10: 976-988, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753165</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753165" 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/10.1046/j.1460-9568.1998.00108.x" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Winter2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winter, N., Kovermann, P., Fahlke, C.
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<strong>A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents.</strong>
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Brain 135: 3416-3425, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23107647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23107647</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23107647" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/aws255" 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 : 04/02/2018
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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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Patricia A. Hartz - updated : 9/23/2014<br>Cassandra L. Kniffin - updated : 1/7/2014<br>Cassandra L. Kniffin - updated : 3/12/2009<br>Patricia A. Hartz - updated : 9/15/2006<br>Cassandra L. Kniffin - reorganized : 11/29/2005<br>Cassandra L. Kniffin - updated : 11/16/2005<br>Victor A. McKusick - updated : 5/21/1998<br>Alan F. Scott - updated : 5/22/1996
|
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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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Victor A. McKusick : 9/13/1994
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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 : 04/02/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 07/13/2016<br>alopez : 7/12/2016<br>ckniffin : 6/29/2016<br>mgross : 9/26/2014<br>mcolton : 9/23/2014<br>carol : 1/8/2014<br>ckniffin : 1/7/2014<br>carol : 12/19/2013<br>carol : 10/1/2013<br>terry : 10/10/2012<br>wwang : 3/24/2009<br>ckniffin : 3/12/2009<br>wwang : 9/22/2006<br>terry : 9/15/2006<br>carol : 12/22/2005<br>ckniffin : 12/20/2005<br>carol : 11/29/2005<br>ckniffin : 11/16/2005<br>tkritzer : 2/10/2005<br>terry : 1/26/2005<br>carol : 3/8/2002<br>terry : 3/8/2002<br>terry : 6/16/1998<br>terry : 6/16/1998<br>terry : 5/21/1998<br>mark : 6/12/1997<br>terry : 6/10/1997<br>mark : 9/25/1996<br>terry : 9/11/1996<br>terry : 5/22/1996<br>mark : 2/22/1996<br>mark : 6/27/1995<br>carol : 1/3/1995<br>carol : 9/13/1994
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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">
|
|
<strong>*</strong> 600111
|
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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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|
|
SOLUTE CARRIER FAMILY 1 (GLIAL HIGH AFFINITY GLUTAMATE TRANSPORTER), MEMBER 3; SLC1A3
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
EXCITATORY AMINO ACID TRANSPORTER 1; EAAT1<br />
|
|
GLIAL HIGH AFFINITY GLUTAMATE TRANSPORTER<br />
|
|
GLUTAMATE/ASPARTATE TRANSPORTER, HIGH AFFINITY, SODIUM-DEPENDENT; GLAST1<br />
|
|
GLAST
|
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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: SLC1A3</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 718753002;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: 5p13.2
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 5:36,606,606-36,688,334 </span>
|
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</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
5p13.2
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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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Episodic ataxia, type 6
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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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612656
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</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>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Glutamate and aspartate are excitatory neurotransmitters that have been implicated in a number of pathologic states of the nervous system. Accumulation of extracellular excitatory amino acids can be cytotoxic and may also lower the seizure threshold in epilepsy. EAAT1 (SLC1A3) is a member of a family of high-affinity sodium-dependent transporter molecules that regulate neurotransmitter concentrations at the excitatory glutamatergic synapses of the mammalian central nervous system (Kirschner et al., 1994). SLC1A3 also functions as a glutamate-activated anion channel (summary by Winter et al., 2012). </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>Shashidharan et al. (1994) isolated a novel cDNA from a human brain cDNA library. The cDNA encoded a deduced protein that was 95% homologous to a previously reported rabbit glutamate/aspartate transporter. Northern blot analysis demonstrated expression of the corresponding mRNA in human brain, liver, muscle, ovary, testis, and in retinoblastoma cell lines. The highest expression was found in the substantia nigra, red nucleus, and hippocampus, and in cerebral cortical layers. Shashidharan et al. (1994) referred to this as human glutamate transporter III and showed that it is structurally distinct from the previously described brain-specific glutamate transporters SLC1A1 (133550) and SLC1A2 (600300). The novel cDNA likely corresponded to the SLC1A3 gene. </p><p>Stoffel et al. (1996) isolated the human sodium-dependent L-glutamate/L-aspartate transporter gene, which they referred to as GLAST1, and found that it encodes a putative 542-amino acid protein. They stated that the gene is unrelated to any previously described neurotransmitter transporter gene family, but its exon/intron structure corresponds largely to that of the sodium-dependent neutral amino acid transporter ASCT1 (SLC1A4; 600229). GLAST1, ASCT1, and the glutamate transporters GLT1 (SLC1A2) and EAAC1 (SLC1A1) have similar amino acid sequences. </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>Stoffel et al. (1996) determined that the human GLAST1 gene contains 10 exons spanning at least 85 kb. </p><p>Hagiwara et al. (1996) showed that the mouse Slcla3 gene contains 10 exons spanning more than 56 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>Crystal Structure</em></strong></p><p>
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Canul-Tec et al. (2017) presented the crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter-1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures revealed architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids, and posttranslational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry revealed a mechanism of inhibition in which the transporter is locked in the outward-facing states of the transport cycle. </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>Kirschner et al. (1994) mapped the human EAAT1 gene to chromosome 5p13 by fluorescence in situ hybridization (FISH). They used interspecific backcross analysis to map the mouse homolog to chromosome 15 in a region of homology to human 5p13. They commented that the EAAT1 locus may be related to the syndrome of microcephaly and mental retardation observed by Keppen et al. (1992) in association with interstitial deletion of distal band 5p13. </p><p>By FISH, Takai et al. (1995) also mapped the SLC1A3 gene to chromosome 5p13. Stoffel et al. (1996) mapped the GLAST1 gene to 5p12-p11. </p><p>Hagiwara et al. (1996) mapped the mouse Slc1a3 gene to chromosome 15A2 by FISH. </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>In a 10-year-old boy with episodic ataxia, seizures, migraine, and alternating hemiplegia consistent with episodic ataxia type 6 (EA6; 612656), Jen et al. (2005) identified a heterozygous mutation in the SLC1A3 gene (600111.0001). </p><p>In 3 affected members of a family with EA6, de Vries et al. (2009) identified a heterozygous mutation in the SLC1A3 gene (600111.0002). There was 1 unaffected carrier of the mutation, indicating reduced penetrance. Functional expression studies showed that the mutation resulted in an 18% decrease in glutamate uptake. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In the retina, the glutamate transporter GLAST is expressed in Muller cells, whereas the glutamate transporter GLT1 is found only in cones and various types of bipolar cells. To investigate the functional role of this differential distribution of glutamate transporters, Harada et al. (1998) analyzed Glast and Glt1 mutant mice. In Glast-deficient mice, the electroretinogram b-wave and oscillatory potentials were reduced and retinal damage after ischemia was exacerbated, whereas Glt1-deficient mice showed almost normal electroretinograms and mildly increased retinal damage after ischemia. These results demonstrated that Glast is required for normal signal transmission between photoreceptors and bipolar cells and that both Glast and Glt1 play a neuroprotective role during ischemia in the retina. </p><p>Watase et al. (1998) found that mouse Glast was most abundantly expressed in the Bergmann glia in the cerebellum. Glast-deficient mice developed normally and could manage simple coordinated tasks, such as staying on a stationary or a slowly rotating rod, but failed more challenging tests, such as staying on a quickly rotating rod. Electrophysiologic studies showed that Purkinje cells in the mutant mice remained multiply innervated by climbing fibers, even at the adult stage. After cold-induced injury, the mutant mice had significantly more cerebellar edema compared to wildtype mice, indicating that Glast is essential for preventing neuronal injury after traumatic cerebellar injury. </p><p>Matsugami et al. (2006) found that the brains of mice lacking Glast or Glt1 developed normally but that Glast/Glt1 double-knockout mice died around embryonic days 17 to 18 and exhibited cortical, hippocampal, and olfactory bulb disorganization. Several essential aspects of neuronal development, such as stem cell proliferation, radial migration, neuronal differentiation, and survival of subplate neurons, were impaired. Matsugami et al. (2006) concluded that the regulation of extracellular glutamate concentration and the maintenance of glutamate-mediated synaptic transmission is necessary for normal brain development. </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>
|
|
<strong>3 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 EPISODIC ATAXIA, TYPE 6</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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SLC1A3, PRO290ARG
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<br />
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SNP: rs137852619,
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ClinVar: RCV000010048
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 10-year-old boy with episodic ataxia, seizures, migraine, and alternating hemiplegia (EA6; 612656), Jen et al. (2005) identified a heterozygous 1047C-G transversion in the SLC1A3 gene, resulting in a pro290-to-arg substitution in a highly conserved residue within the fifth transmembrane domain. The mutation was not identified in either unaffected parent or in 232 control chromosomes. From birth, the child had experienced 4 discrete episodes of ataxia and slurred speech, seemingly triggered by a febrile illness. At age 6 years, he developed a severe right-sided headache followed by hemiparesis and decreased consciousness lasting 5 days. MRI showed cerebellar atrophy, and neurologic examination showed mild interictal truncal ataxia. Functional expression studies showed decreased expression of the mutant protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant transporter multimerized with the wildtype transporter to exert a dominant-negative effect. Jen et al. (2005) postulated a role for abnormal glutamate transmission in the neurologic features seen in this patient. </p><p>In in vitro electrophysiologic studies, Winter et al. (2012) found that the P290R mutation increased SLC1A3 anion currents compared to wildtype in both the presence and the absence of glutamate. These changes were observed in addition to the reduction of glutamate transport. Winter et al. (2012) suggested that the relatively severe phenotype of the patient reported by Jen et al. (2005) resulted from a gain-of-function effect of the P290R mutation on the anion channel function of SLC1A3, perhaps by altering the anion current in glial cells and GABAergic synaptic transmission. </p><p>Because the P290R substitution reduces expression of human SLC1A3 in Xenopus oocytes, Hotzy et al. (2013) studied the homologous mutation (P259R) in SLC1A1 (133550), which is robustly expressed in Xenopus oocytes. They found that, compared with wildtype, the substitution decelerated a conformational change that accompanies binding of sodium to the glutamate-free form of the transporter. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 EPISODIC ATAXIA, TYPE 6</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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SLC1A3, CYS186SER
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<br />
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SNP: rs137852620,
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ClinVar: RCV000010049
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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 3 affected members of a Dutch family with episodic ataxia-6 (EA6; 612656), de Vries et al. (2009) identified a heterozygous 556T-A transversion in the SLC1A3 gene, resulting in a cys186-to-ser (C186S) substitution in a highly conserved residue in transmembrane segment 4b. In vitro functional expression studies in COS-7 cells showed that the mutant EAAT1 resulted in an 18% decrease in glutamate uptake compared to the wildtype channel. De Vries et al. (2009) noted that the phenotype was less severe than that reported by Jen et al. (2005), as the P290R mutation (600111.0001) resulted in markedly decreased glutamate uptake. The C186S mutation was not identified in 200 Dutch controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 EPISODIC ATAXIA, TYPE 6</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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SLC1A3, ARG454GLN
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<br />
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SNP: rs138085358,
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|
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gnomAD: rs138085358,
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|
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ClinVar: RCV000234998, RCV000500491, RCV000727383
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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 2 first cousins of European descent with a variant of episodic ataxia-6 (EA6; 612656), Pyle et al. (2015) identified a heterozygous c.1361G-A transition in the SLC1A3 gene, resulting in an arg454-to-gln (R454Q) substitution. The mutation, which was found by exome sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases, as well as 286 in-house controls. The mutation segregated with the disorder in the family. Functional studies of the variant were not performed. The patients had onset of gait ataxia and dysarthria in their thirties; the disorder was not described as episodic. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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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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<ol>
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<li>
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<p class="mim-text-font">
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Canul-Tec, J. C., Assal, R., Cirri, E., Legrand, P., Brier, S., Chamot-Rooke, J., Reyes, N.
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<strong>Structure and allosteric inhibition of excitatory amino acid transporter 1.</strong>
|
|
Nature 544: 446-451, 2017.
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[PubMed: 28424515]
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[Full Text: https://doi.org/10.1038/nature22064]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
de Vries, B., Mamsa, H., Stam, A. H., Wan, J., Bakker, S. L. M., Vanmolkot, K. R. J., Haan, J., Terwindt, G. M., Boon, E. M. J., Howard, B. D., Frants, R. R., Baloh, R. W., Ferrari, M. D., Jen, J. C., van den Maagdenberg, A. M. J. M.
|
|
<strong>Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.</strong>
|
|
Arch. Neurol. 66: 97-101, 2009. Note: Erratum: Arch. Neurol. 66: 497 only, 2009; Erratum: Arch. Neurol. 66: 772 only, 2009.
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[PubMed: 19139306]
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[Full Text: https://doi.org/10.1001/archneurol.2008.535]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hagiwara, T., Tanaka, K., Takai, S., Maeno-Hikichi, Y., Mukainaka, Y., Wada, K.
|
|
<strong>Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3.</strong>
|
|
Genomics 33: 508-515, 1996.
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[PubMed: 8661010]
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[Full Text: https://doi.org/10.1006/geno.1996.0226]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K., Tanaka, K.
|
|
<strong>Functions of the two glutamate transporters GLAST and GLT-1 in the retina.</strong>
|
|
Proc. Nat. Acad. Sci. 95: 4663-4666, 1998.
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[PubMed: 9539795]
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[Full Text: https://doi.org/10.1073/pnas.95.8.4663]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hotzy, J., Schneider, N., Kovermann, P., Fahlke, C.
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<strong>Muting a conserved proline residue within the trimerization domain modifies Na+ binding to excitatory amino acid transporters and associated conformational changes.</strong>
|
|
J. Biol. Chem. 288: 36492-36501, 2013.
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[PubMed: 24214974]
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[Full Text: https://doi.org/10.1074/jbc.M113.489385]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W.
|
|
<strong>Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.</strong>
|
|
Neurology 65: 529-534, 2005.
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[PubMed: 16116111]
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[Full Text: https://doi.org/10.1212/01.wnl.0000172638.58172.5a]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Keppen, L. D., Gollin, S. M., Edwards, D., Sawyer, J., Wilson, W., Overhauser, J.
|
|
<strong>Clinical phenotype and molecular analysis of a three-generation family with an interstitial deletion of the short arm of chromosome 5.</strong>
|
|
Am. J. Med. Genet. 44: 356-360, 1992.
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[PubMed: 1488985]
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[Full Text: https://doi.org/10.1002/ajmg.1320440317]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kirschner, M. A., Arriza, J. L., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Magenis, E., Amara, S. G.
|
|
<strong>The mouse and human excitatory amino acid transporter gene (EAAT1) maps to mouse chromosome 15 and a region of syntenic homology on human chromosome 5.</strong>
|
|
Genomics 22: 631-633, 1994.
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[PubMed: 8001975]
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[Full Text: https://doi.org/10.1006/geno.1994.1437]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Matsugami, T. R., Tanemura, K., Mieda, M., Nakatomi, R., Yamada, K., Kondo, T., Ogawa, M., Obata, K., Watanabe, M., Hashikawa, T., Tanaka, K.
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