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Entry
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- *126455 - SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3; SLC6A3
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*126455</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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</li>
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<li role="presentation">
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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>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<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="#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>
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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/126455">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=ENSG00000142319;t=ENST00000270349" 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=6531" 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=126455" 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=ENSG00000142319;t=ENST00000270349" 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_001044" 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_001044" 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=126455" 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=00543&isoform_id=00543_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/SLC6A3" 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/181656,256313,258935,266667,401765,553260,1752666,2447032,2654488,4507041,4588756,7108463,11275971,47777657,83684650,119628563,119628564,119628565,124376240,124376650,139522363,309697710,315001133,315001222,315002023,317421717,317424609,317424698,328267447,328268163,328357861,329637955,329742947,329743036,330754726,330766739,346433401" 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/Q01959" 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=6531" 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=ENSG00000142319;t=ENST00000270349" 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=SLC6A3" 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=SLC6A3" 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+6531" 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/SLC6A3" 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:6531" 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/6531" 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=ENST00000270349.12&hgg_start=1392794&hgg_end=1445440&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11049" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:11049" 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/slc6a3" 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=126455[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=126455[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/ENSG00000142319" 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=SLC6A3" 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=SLC6A3" 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=SLC6A3" 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="http://www.LOVD.nl/SLC6A3" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SLC6A3&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/PA311" 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:11049" 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/FBgn0034136.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:94862" 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/SLC6A3#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:94862" 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/6531/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=6531" 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=WBGene00000934;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-010316-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:126455" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6531" 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=SLC6A3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
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126455
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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 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3; SLC6A3
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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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DOPAMINE TRANSPORTER; DAT<br />
|
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DAT1
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SLC6A3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SLC6A3</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/5/24?start=-3&limit=10&highlight=24">5p15.33</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:1392794-1445440&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'})">5:1,392,794-1,445,440</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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|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=188890,613135" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
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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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<p>The dopamine transporter (DAT), which is encoded by the SLC6A3 gene, mediates the active reuptake of dopamine from the synapse and is a principal regulator of dopaminergic neurotransmission. The SLC6A3 gene has been implicated in human disorders such as parkinsonism, Tourette syndrome, and substance abuse (<a href="#30" class="mim-tip-reference" title="Vandenbergh, D. J., Persico, A. M., Uhl, G. R. <strong>A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.</strong> Molec. Brain Res. 15: 161-166, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1359373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1359373</a>] [<a href="https://doi.org/10.1016/0169-328x(92)90165-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1359373">Vandenbergh et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1359373" 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="#30" class="mim-tip-reference" title="Vandenbergh, D. J., Persico, A. M., Uhl, G. R. <strong>A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.</strong> Molec. Brain Res. 15: 161-166, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1359373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1359373</a>] [<a href="https://doi.org/10.1016/0169-328x(92)90165-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1359373">Vandenbergh et al. (1992)</a> cloned cDNAs encoding the entire coding sequence and 3-prime untranslated sequence of the human DAT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1359373" 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="#19" class="mim-tip-reference" title="Kurian, M. A., Zhen, J., Cheng, S.-Y., Li, Y., Mordekar, S. R., Jardine, P., Morgan, N. V., Meyer, E., Tee, L., Pasha, S., Wassmer, E., Heales, S. J. R., Gissen, P., Reith, M. E. A., Maher, E. R. <strong>Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.</strong> J. Clin. Invest. 119: 1595-1603, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19478460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19478460</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19478460[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/10.1172/JCI39060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19478460">Kurian et al. (2009)</a> noted that SLC6A3 contains 12 transmembrane domains with helically unwound regions in the first and sixth domains. Extracellular and intracellular loops include helical portions E2, E3, E4A, E4B, I1, and I5. Mature, glycosylated DAT has a molecular mass of 85 kD, whereas immature nonglycosylated DAT has a molecular mass of 55 kD and does not transport dopamine as efficiently as the mature protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19478460" 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="#24" class="mim-tip-reference" title="Navaroli, D. M., Stevens, Z. H., Uzelac, Z., Gabriel, L., King, M. J., Lifshitz, L. M., Sitte, H. H., Melikian, H. E. <strong>The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking.</strong> J. Neurosci. 31: 13758-13770, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21957239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21957239</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21957239[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/10.1523/JNEUROSCI.2649-11.2011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21957239">Navaroli et al. (2011)</a> reported that DAT has an endocytic signal near the C terminus that modulates both basal and protein kinase C (PKC; see <a href="/entry/176960">176960</a>)-enhanced DAT internalization. Immunohistochemical analysis revealed that rat Dat localized to plasma membrane foci that corresponded to both lipid rafts and non-raft microdomains in PC12 pheochromocytoma cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21957239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By yeast 2-hybrid analysis of a human substantia nigra cDNA library, <a href="#24" class="mim-tip-reference" title="Navaroli, D. M., Stevens, Z. H., Uzelac, Z., Gabriel, L., King, M. J., Lifshitz, L. M., Sitte, H. H., Melikian, H. E. <strong>The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking.</strong> J. Neurosci. 31: 13758-13770, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21957239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21957239</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21957239[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/10.1523/JNEUROSCI.2649-11.2011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21957239">Navaroli et al. (2011)</a> found that the small GTPase RIN (RIT2; <a href="/entry/609592">609592</a>) interacted with the isolated C-terminal endocytic signal of human DAT. Coimmunoprecipitation and protein pull-down assays with PC12 cells that were transfected with human DAT revealed direct interaction between DAT and Rin. Rin did not interact with other members of the SLC6 transporter family. DAT colocalized with Rin at plasma membrane foci, predominantly at lipid rafts, in transfected PC12 cells. Phorbol ester-induced PKC activation enhanced DAT-Rin interaction, followed by their dissociation and DAT internalization into endocytic vesicles. These effects did not occur with a DAT mutant lacking the C-terminal endocytic signal or with a Rin mutant lacking GTPase activity. Knockdown of Rin via short hairpin RNA completely inhibited PKC-induced DAT internalization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21957239" 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>The SLC6A3 gene contains 15 exons spanning approximately 60 kb (<a href="#30" class="mim-tip-reference" title="Vandenbergh, D. J., Persico, A. M., Uhl, G. R. <strong>A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.</strong> Molec. Brain Res. 15: 161-166, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1359373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1359373</a>] [<a href="https://doi.org/10.1016/0169-328x(92)90165-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1359373">Vandenbergh et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1359373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By in situ hybridization and by PCR amplification of rodent/human somatic cell hybrid DNAs, <a href="#29" class="mim-tip-reference" title="Vandenbergh, D. J., Persico, A. M., Hawkins, A. L., Griffin, C. A., Li, X., Jabs, E. W., Uhl, G. R. <strong>Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR.</strong> Genomics 14: 1104-1106, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1478653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1478653</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80138-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1478653">Vandenbergh et al. (1992)</a> and <a href="#10" class="mim-tip-reference" title="Giros, B., El Mestikawy, S., Godinot, N., Zheng, K., Han, H., Yang-Feng, T., Caron, M. G. <strong>Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter.</strong> Molec. Pharm. 42: 383-390, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1406597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1406597</a>]" pmid="1406597">Giros et al. (1992)</a> mapped the SLC6A3 gene to chromosome 5p15.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1406597+1478653" 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="#23" class="mim-tip-reference" title="Lossie, A. C., Vandenbergh, D. J., Uhl, G. R., Camper, S. A. <strong>Localization of the dopamine transporter gene, Dat1, on mouse chromosome 13.</strong> Mammalian Genome 5: 117-118, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8180472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8180472</a>] [<a href="https://doi.org/10.1007/BF00292340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8180472">Lossie et al. (1994)</a> mapped the mouse Dat1 homolog to chromosome 15 by linkage analysis of an interspecific backcross. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8180472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Gelernter, J., Vandenbergh, D., Kruger, S. D., Pauls, D. L., Kurlan, R., Pakstis, A. J., Kidd, K. K., Uhl, G. <strong>The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette syndrome.</strong> Genomics 30: 459-463, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825631</a>] [<a href="https://doi.org/10.1006/geno.1995.1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825631">Gelernter et al. (1995)</a> demonstrated close linkage between the SLC6A3 gene and several markers previously mapped to distal chromosome 5p. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8825631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#32" class="mim-tip-reference" title="Zhou, Z., Zhen, J., Karpowich, N. K., Goetz, R. M., Law, C. J., Reith, M. E. A., Wang, D.-N. <strong>LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.</strong> Science 317: 1390-1393, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690258</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17690258[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1147614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17690258">Zhou et al. (2007)</a> determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT (<a href="/entry/182138">182138</a>), NET (<a href="/entry/163970">163970</a>), and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17690258" 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="#30" class="mim-tip-reference" title="Vandenbergh, D. J., Persico, A. M., Uhl, G. R. <strong>A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.</strong> Molec. Brain Res. 15: 161-166, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1359373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1359373</a>] [<a href="https://doi.org/10.1016/0169-328x(92)90165-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1359373">Vandenbergh et al. (1992)</a> identified a 40-bp variable-number tandem repeat (VNTR) polymorphism in the 3-prime untranslated region of the DAT1 gene with repeat copy numbers ranging from 3 to 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1359373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Byerley, W., Hoff, M., Holik, J., Caron, M. G., Giros, B. <strong>VNTR polymorphism for the human dopamine transporter gene (DAT1).</strong> Hum. Molec. Genet. 2: 335, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098980</a>] [<a href="https://doi.org/10.1093/hmg/2.3.335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8098980">Byerley et al. (1993)</a> demonstrated a VNTR polymorphism related to the DAT1 gene. <a href="#5" class="mim-tip-reference" title="Doucette-Stamm, L., Blakely, D. J., Tian, J., Mockus, S., Mao, J. <strong>Population genetic study of the human dopamine transporter gene (DAT1).</strong> Genet. Epidemiol. 12: 303-308, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7557351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7557351</a>] [<a href="https://doi.org/10.1002/gepi.1370120307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7557351">Doucette-Stamm et al. (1995)</a> established allele frequencies for the 40-bp VNTR polymorphism. Differences were found between black Americans and Caucasians or Hispanics, but there were no differences between Caucasians and Hispanics. A previously unreported allele was detected in all 3 populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8098980+7557351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Attention-Deficit Hyperactivity Disorder</em></strong></p><p>
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Attention-deficit hyperactivity disorder (ADHD; <a href="/entry/143465">143465</a>) is presumably heritable in some cases. Some ADHD patients respond to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion. <a href="#4" class="mim-tip-reference" title="Cook, E. H., Jr., Stein, M. A., Krasowski, M. D., Cox, N. J., Olkon, D. M., Kieffer, J. E., Leventhal, B. L. <strong>Association of attention-deficit disorder and the dopamine transporter gene.</strong> Am. J. Hum. Genet. 56: 993-998, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7717410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7717410</a>]" pmid="7717410">Cook et al. (1995)</a> used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the DAT1 locus and 49 cases of ADHD. Eight cases of undifferentiated attention-deficit disorder (UADD) were also studied. All cases were studied in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHD/UADD and the 480-bp DAT1 allele. When cases of UADD were dropped from the analysis, similar results were found. <a href="#4" class="mim-tip-reference" title="Cook, E. H., Jr., Stein, M. A., Krasowski, M. D., Cox, N. J., Olkon, D. M., Kieffer, J. E., Leventhal, B. L. <strong>Association of attention-deficit disorder and the dopamine transporter gene.</strong> Am. J. Hum. Genet. 56: 993-998, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7717410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7717410</a>]" pmid="7717410">Cook et al. (1995)</a> suggested that molecular analysis of DAT1 may identify mutations that increase susceptibility to this disorder and that biochemical analysis of such mutations may lead to development of more effective therapeutic interventions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7717410" 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="Gill, M., Daly, G., Heron, S., Hawi, Z., Fitgerald, M. <strong>Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism.</strong> Molec. Psychiat. 2: 311-313, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246671</a>] [<a href="https://doi.org/10.1038/sj.mp.4000290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9246671">Gill et al. (1997)</a> found a significant association between ADHD and the 480-bp DAT1 VNTR allele. <a href="#9" class="mim-tip-reference" title="Gill, M., Daly, G., Heron, S., Hawi, Z., Fitgerald, M. <strong>Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism.</strong> Molec. Psychiat. 2: 311-313, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246671</a>] [<a href="https://doi.org/10.1038/sj.mp.4000290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9246671">Gill et al. (1997)</a> reported concordance rates for ADHD in monozygotic and dizygotic twins of 81% and 29%, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9246671" 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="#31" class="mim-tip-reference" title="Waldman, I. D., Rowe, D. C., Abramowitz, A., Kozel, S. T., Mohr, J. H., Sherman, S. L., Cleveland, H. H., Sanders, M. L., Gard, J. M. C., Stever, C. <strong>Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity.</strong> Am. J. Hum. Genet. 63: 1767-1776, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837830</a>] [<a href="https://doi.org/10.1086/302132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9837830">Waldman et al. (1998)</a> used 4 analytic strategies to examine the association and linkage of the DAT1 gene with ADHD. The study group comprised 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and sibs. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp DAT1 allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Sibs discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibs with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relationship was especially strong with the combined but not the inattentive subtype. The findings were believed to represent one of the first replicated relations of a candidate gene and a psychiatric disorder in children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9837830" 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="#17" class="mim-tip-reference" title="Kahn, R. S., Khoury, J., Nichols, W. C., Lanphear, B. P. <strong>Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors.</strong> J. Pediat. 143: 104-110, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915833</a>] [<a href="https://doi.org/10.1016/S0022-3476(03)00208-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915833">Kahn et al. (2003)</a> found a significant association between homozygosity for the 480-bp DAT allele and hyperactivity-impulsivity and oppositional behaviors only in the presence of maternal prenatal smoking. They emphasized the importance of incorporating environmental cofactors in genetic studies of ADHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Langley, K., Turic, D., Peirce, T. R., Mills, S., Van Den Bree, M. B., Owen, M. J., O'Donovan, M. C., Thapar, A. <strong>No support for association between the dopamine transporter (DAT1) gene and ADHD.</strong> Am. J. Med. Genet. 139B: 7-10, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16082688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16082688</a>] [<a href="https://doi.org/10.1002/ajmg.b.30206" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16082688">Langley et al. (2005)</a> tested the DAT1 3-prime VNTR and 3 putative DAT1 promoter SNPs for association with ADHD in 263 parent-proband trios using family-based association methods. No evidence of association with any of the promoter region SNPs or the VNTR was seen. Haplotype analysis was also nonsignificant, and no association was found between the VNTR and response to stimulant medications. By case-control analysis of the VNTR in 263 cases and 287 controls, the 10-repeat allele showed no significant association compared to all other alleles combined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16082688" 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="#6" class="mim-tip-reference" title="Feng, Y., Wigg, K. G., Makkar, R., Ickowicz, A., Pathare, T., Tannock, R., Roberts, W., Malone, M., Kennedy, J. L., Schachar, R., Barr, C. L. <strong>Sequence variation in the 3-prime-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD).</strong> Am. J. Med. Genet. 139B: 1-6, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16082693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16082693</a>] [<a href="https://doi.org/10.1002/ajmg.b.30190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16082693">Feng et al. (2005)</a> investigated whether the DAT1 3-prime UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. Variants included an MspI polymorphism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs27072;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs27072</a>), a DraI T-C transition reported to influence DAT1 expression levels, and a BstUI polymorphism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3863145;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3863145</a>), in addition to the VNTR. They found an association between the G allele of the MspI SNP and ADHD (P = 0.009) but not with alleles of the VNTR polymorphism or the BstUI polymorphism, and they did not observe the DraI SNP. <a href="#6" class="mim-tip-reference" title="Feng, Y., Wigg, K. G., Makkar, R., Ickowicz, A., Pathare, T., Tannock, R., Roberts, W., Malone, M., Kennedy, J. L., Schachar, R., Barr, C. L. <strong>Sequence variation in the 3-prime-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD).</strong> Am. J. Med. Genet. 139B: 1-6, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16082693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16082693</a>] [<a href="https://doi.org/10.1002/ajmg.b.30190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16082693">Feng et al. (2005)</a> screened the VNTR region by direct sequencing to determine if there were additional variants within the repeats that could account for association with ADHD and found no variation in the VNTR region for either the 10- or 9-repeat alleles in the probands screened. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16082693" 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 both a Taiwanese ADHD sample and an English ADHD sample, <a href="#1" class="mim-tip-reference" title="Brookes, K.-J., Mill, J., Guindalini, C., Curran, S., Xu, X., Knight, J., Chen, C.-K., Huang, Y.-S., Sethna, V., Taylor, E., Chen, W., Breen, G., Asherson, P. <strong>A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.</strong> Arch. Gen. Psychiat. 63: 74-81, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16389200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16389200</a>] [<a href="https://doi.org/10.1001/archpsyc.63.1.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16389200">Brookes et al. (2006)</a> identified association with the DAT1 3-prime UTR VNTR and a novel DAT1 intron 8 repeat polymorphism. A risk haplotype composed of the 2 repeat polymorphisms was also associated with ADHD in both populations, and the authors found that the risk haplotype showed significant interactions with maternal use of alcohol during pregnancy in the English sample. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16389200" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Hebebrand, J., Dempfle, A., Saar, K., Thiele, H., Herpertz-Dahlmann, B., Linder, M., Kiefl, H., Remschmidt, H., Hemminger, U., Warnke, A., Knolker, U., Heiser, P., Friedel, S., Hinney, A., Schafer, H., Nurnberg, P., Konrad, K. <strong>A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs.</strong> Molec. Psychiat. 11: 196-205, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16222334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16222334</a>] [<a href="https://doi.org/10.1038/sj.mp.4001761" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16222334">Hebebrand et al. (2006)</a> found no evidence of association between ADHD and the DAT1 VNTR in 102 German families with 2 or more offspring who fulfilled diagnostic criteria for ADHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16222334" 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="Cheuk, D. K. L., Li, S. Y. H., Wong, V. <strong>No association between VNTR polymorphisms of dopamine transporter gene and attention deficit hyperactivity disorder in Chinese children.</strong> Am. J. Med. Genet. 141B: 123-125, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16402340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16402340</a>] [<a href="https://doi.org/10.1002/ajmg.b.30280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16402340">Cheuk et al. (2006)</a> studied the association between the DAT1 VNTR and ADHD in Chinese children (64 ADHD cases, including 52 boys and 12 girls, their families, and 64 sex-matched normal controls) in Hong Kong. Patients were diagnosed with combined, hyperactive-impulsive, or inattentive subtypes of ADHD. The 10-repeat allele (92.6%) and the 10/10 (85.2%) repeat genotype were most prevalent. Both family-based and case-control analyses showed no association between the DAT1 polymorphisms and ADHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16402340" 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>Animal studies suggest that the development of substance dependence (e.g., alcoholism) is associated with dopaminergic activity in striatum and the limbic system (<a href="#28" class="mim-tip-reference" title="Tiihonen, J., Kuikka, J., Bergstrom, K., Hakola, P., Karhu, J., Ryynanen, O.-P., Fohr, J. <strong>Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics.</strong> Nature Med. 1: 654-657, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7585146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7585146</a>] [<a href="https://doi.org/10.1038/nm0795-654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7585146">Tiihonen et al., 1995</a>). Several genetic studies had indicated that allele A1 at the DRD2 (<a href="/entry/126450">126450</a>) locus is associated with both density of dopamine receptor-2 and alcoholism. <a href="#28" class="mim-tip-reference" title="Tiihonen, J., Kuikka, J., Bergstrom, K., Hakola, P., Karhu, J., Ryynanen, O.-P., Fohr, J. <strong>Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics.</strong> Nature Med. 1: 654-657, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7585146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7585146</a>] [<a href="https://doi.org/10.1038/nm0795-654" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7585146">Tiihonen et al. (1995)</a> studied striatal dopamine reuptake sites in 19 healthy controls, 19 habitually impulsive violent alcoholics, and 10 nonviolent alcoholics with single photon emission computed tomography (SPECT) using iodine-123-labeled beta-CIT as a tracer. Blind quantitative analysis revealed that the striatal dopamine transporter density was markedly lower in nonviolent alcoholics than in healthy controls (P less than 0.001), while violent alcoholics had slightly higher dopamine transporter densities than controls (P less than 0.10). <a href="#12" class="mim-tip-reference" title="Goldman, D. <strong>Dopamine transporter, alcoholism and other diseases.</strong> Nature Med. 1: 624-625, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7585136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7585136</a>] [<a href="https://doi.org/10.1038/nm0795-624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7585136">Goldman (1995)</a> suggested that the next step would be to look for inherited variants of the DAT1 gene that may influence vulnerability to alcoholism and other psychiatric diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7585136+7585146" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Tourette Syndrome</em></strong></p><p>
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In a large Canadian Mennonite pedigree segregating for Tourette syndrome (<a href="/entry/137580">137580</a>) (<a href="#20" class="mim-tip-reference" title="Kurlan, R., Behr, J., Medved, L., Shoulson, I., Pauls, D., Kidd, J. R., Kidd, K. K. <strong>Familial Tourette's syndrome: report of a large pedigree and potential for linkage analysis.</strong> Neurology 36: 772-776, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3458031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3458031</a>] [<a href="https://doi.org/10.1212/wnl.36.6.772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3458031">Kurlan et al., 1986</a>), <a href="#8" class="mim-tip-reference" title="Gelernter, J., Vandenbergh, D., Kruger, S. D., Pauls, D. L., Kurlan, R., Pakstis, A. J., Kidd, K. K., Uhl, G. <strong>The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette syndrome.</strong> Genomics 30: 459-463, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8825631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8825631</a>] [<a href="https://doi.org/10.1006/geno.1995.1265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8825631">Gelernter et al. (1995)</a> excluded linkage to SLC6A3. They cautiously pointed out, however, that these results did not exclude a role for the dopamine transporter in influencing risk for Tourette syndrome in combination with other loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8825631+3458031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Cigarette Smoking</em></strong></p><p>
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Dopaminergic genes are likely candidates for heritable influences on cigarette smoking (<a href="/entry/188890">188890</a>). <a href="#22" class="mim-tip-reference" title="Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., Boyd, N. R., Shields, P. G. <strong>Evidence suggesting the role of specific genetic factors in cigarette smoking.</strong> Health Psychol. 18: 14-20, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925041</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925041">Lerman et al. (1999)</a> and <a href="#26" class="mim-tip-reference" title="Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H. <strong>A genetic association for cigarette smoking behavior.</strong> Health Psychol. 18: 7-13, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925040">Sabol et al. (1999)</a> reported associations between allele 9 of a DAT1 polymorphism, SLC6A3*9 (<a href="#0001">126455.0001</a>), and smoking status. While <a href="#22" class="mim-tip-reference" title="Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., Boyd, N. R., Shields, P. G. <strong>Evidence suggesting the role of specific genetic factors in cigarette smoking.</strong> Health Psychol. 18: 14-20, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925041</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925041">Lerman et al. (1999)</a> reported association of the SLC6A3*9 allele with lack of smoking, late initiation of smoking, and length of quitting attempts, <a href="#26" class="mim-tip-reference" title="Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H. <strong>A genetic association for cigarette smoking behavior.</strong> Health Psychol. 18: 7-13, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925040">Sabol et al. (1999)</a> reported that the significant association between SLC6A3*9 and smoking status was due to an effect on cessation rather than initiation. The SLC6A3*9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9925041+9925040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Bipolar Disorder</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Greenwood, T. A., Alexander, M., Keck, P. E., McElroy, S., Sadovnick, A. D., Remick, R. A., Kelsoe, J. R. <strong>Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.</strong> Am. J. Med. Genet. 105: 145-151, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11304827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11304827</a>] [<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1161>3.0.co;2-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11304827">Greenwood et al. (2001)</a> reported evidence for an association between DAT1 and bipolar disorder (MAFD1; <a href="/entry/125480">125480</a>) in a sample of 50 parent-proband trios. Using the transmission disequilibrium test (TDT), they showed an association between a haplotype composed of 5 SNPs in the 3-prime region of the DAT1 gene, exon 9 through exon 15, and bipolar disorder (allele-wise TDT empirical P = 0.001; genotype-wise TDT empirical P = 0.0004). <a href="#14" class="mim-tip-reference" title="Greenwood, T. A., Schork, N. J., Eskin, E., Kelsoe, J. R. <strong>Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples.</strong> Molec. Psychiat. 11: 125-133, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16261167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16261167</a>] [<a href="https://doi.org/10.1038/sj.mp.4001764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16261167">Greenwood et al. (2006)</a> analyzed a total of 22 SNPs in the 50 previously studied parent-proband trios and an independent set of 70 parent-proband trios. Using TDT analysis, an intron 8 SNP and an intron 13 SNP were found to be moderately associated with bipolar disorder, each in 1 of the 2 independent samples. Analysis of haplotypes of all 22 SNPs in sliding windows of 5 adjacent SNPs revealed an association to the region near intron 7 and 8 in both samples (empirical P values of 0.002 and 0.001, respectively, for the same window). The haplotype block structure observed by <a href="#13" class="mim-tip-reference" title="Greenwood, T. A., Alexander, M., Keck, P. E., McElroy, S., Sadovnick, A. D., Remick, R. A., Kelsoe, J. R. <strong>Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.</strong> Am. J. Med. Genet. 105: 145-151, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11304827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11304827</a>] [<a href="https://doi.org/10.1002/1096-8628(2001)9999:9999<::aid-ajmg1161>3.0.co;2-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11304827">Greenwood et al. (2001)</a> was confirmed in this new sample with the greater resolution allowing for discrimination of a third haplotype block in the middle of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16261167+11304827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Infantile Parkinsonism-Dystonia 1</em></strong></p><p>
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By linkage analysis followed by candidate gene sequencing of a consanguineous Pakistani family with infantile parkinsonism-dystonia (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#19" class="mim-tip-reference" title="Kurian, M. A., Zhen, J., Cheng, S.-Y., Li, Y., Mordekar, S. R., Jardine, P., Morgan, N. V., Meyer, E., Tee, L., Pasha, S., Wassmer, E., Heales, S. J. R., Gissen, P., Reith, M. E. A., Maher, E. R. <strong>Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.</strong> J. Clin. Invest. 119: 1595-1603, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19478460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19478460</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19478460[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/10.1172/JCI39060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19478460">Kurian et al. (2009)</a> identified a homozygous mutation (L368Q; <a href="#0002">126455.0002</a>) in the SLC6A3 gene. A similarly affected individual from a second family had a different homozygous mutation (P395L; <a href="#0003">126455.0003</a>). In vitro functional expression studies showed that both mutant proteins had no dopamine uptake activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19478460" 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 8 unrelated patients with dopamine transporter deficiency syndrome, <a href="#18" class="mim-tip-reference" title="Kurian, M. A., Li, Y., Zhen, J., Meyer, E., Hai, N., Christen, H.-J., Hoffmann, G. F., Jardine, P., von Moers, A., Mordekar, S. R., O'Callaghan, F., Wassmer, E., and 10 others. <strong>Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study.</strong> Lancet Neurol. 10: 54-62, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21112253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21112253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21112253[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S1474-4422(10)70269-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21112253">Kurian et al. (2011)</a> identified homozygous or compound heterozygous mutations in the SLC6A3 gene (see, e.g., <a href="#0005">126455.0005</a>-<a href="#0007">126455.0007</a>). None of the patients shared a mutation, suggesting the absence of mutational hotspots. In vitro functional expression studies in HEK293 cells showed that the mutations caused a loss of transporter function and decreased expression of the normal protein. All patients presented in early infancy with a complex motor disorder involving both hypo- and hyperkinetic movements. There was no effective treatment, and several patients died in the teenage years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21112253" 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 homozygosity mapping followed by exome sequencing of a Mennonite family in which 2 sisters had infantile parkinsonism-dystonia, <a href="#25" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others. <strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong> PLoS One 7: e28936, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22279524[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0028936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22279524">Puffenberger et al. (2012)</a> identified a homozygous splice site mutation in the SLC6A3 gene (<a href="#0004">126455.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22279524" 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="Giros, B., Jaber, M., Jones, S. R., Wightman, R. M., Caron, M. G. <strong>Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine receptor.</strong> Nature 379: 606-612, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8628395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8628395</a>] [<a href="https://doi.org/10.1038/379606a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8628395">Giros et al. (1996)</a> found that the disruption of the mouse Dat1 gene results in spontaneous hyperlocomotion despite major adaptive changes such as decreases in neurotransmitter and receptor levels. In homozygous-null mice, dopamine persisted at least 100 times longer in the extracellular space, providing a biochemical explanation of the hyperdopaminergic phenotype and demonstrating the critical role of DAT1 in regulating neurotransmission. The authors noted that the dopamine transporter is an obligatory target of cocaine and amphetamine, as demonstrated by the fact that these psychostimulants had no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter. <a href="#11" class="mim-tip-reference" title="Giros, B., Jaber, M., Jones, S. R., Wightman, R. M., Caron, M. G. <strong>Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine receptor.</strong> Nature 379: 606-612, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8628395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8628395</a>] [<a href="https://doi.org/10.1038/379606a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8628395">Giros et al. (1996)</a> noted that there are similarities between the hyperdopaminergic phenotype of the knockout mice and some of the positive symptoms of patients with schizophrenia. The authors also postulated that specific blockade of DAT1 with high-affinity inhibitors may be beneficial in illnesses such as Parkinson disease (see <a href="/entry/168600">168600</a>), where the effective levels of dopamine are markedly reduced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8628395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Gainetdinov, R. R., Wetsel, W. C., Jones, S. R., Levin, E. D., Jaber, M., Caron, M. G. <strong>Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.</strong> Science 283: 397-401, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9888856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9888856</a>] [<a href="https://doi.org/10.1126/science.283.5400.397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9888856">Gainetdinov et al. (1999)</a> continued the studies of <a href="#10" class="mim-tip-reference" title="Giros, B., El Mestikawy, S., Godinot, N., Zheng, K., Han, H., Yang-Feng, T., Caron, M. G. <strong>Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter.</strong> Molec. Pharm. 42: 383-390, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1406597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1406597</a>]" pmid="1406597">Giros et al. (1992)</a>, which demonstrated mice lacking the gene encoding the plasma membrane dopamine transporter have elevated dopaminergic tone and are hyperactive. They found that this activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission, and emphasized the importance of a relative balance of the serotonin and dopamine systems for normal motor activity. The parallels between the DAT knockout mice and individuals with ADHD suggested that common mechanisms may underlie some of their behaviors and responses to psychostimulants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9888856+1406597" 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="#27" class="mim-tip-reference" title="Sotnikova, T. D., Caron, M. G., Gainetdinov, R. R. <strong>DDD mice, a novel acute mouse model of Parkinson's disease.</strong> Neurology 67 (suppl. 2): S12-S17, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030735</a>] [<a href="https://doi.org/10.1212/wnl.67.7_suppl_2.s12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030735">Sotnikova et al. (2006)</a> developed a novel acute mouse model of severe dopamine deficiency using Dat-null mice and pharmacologic inhibition of tyrosine hydroxylase. Dopamine-deficient Dat-null mice (DDD) demonstrated severe akinesia, rigidity, tremor, and ptosis, similar to behaviors observed in patients with Parkinson disease. Interestingly, DDD mice were able to swim in water, indicating that certain movements and conditions can occur independently of dopamine. Dopamine agonists such as L-DOPA temporarily restored locomotion in DDD mice, and amphetamine derivatives showed effectiveness in reducing motor abnormalities in DDD mice. <a href="#27" class="mim-tip-reference" title="Sotnikova, T. D., Caron, M. G., Gainetdinov, R. R. <strong>DDD mice, a novel acute mouse model of Parkinson's disease.</strong> Neurology 67 (suppl. 2): S12-S17, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030735</a>] [<a href="https://doi.org/10.1212/wnl.67.7_suppl_2.s12" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17030735">Sotnikova et al. (2006)</a> noted that the DDD mouse model provides a unique opportunity to screen potential therapeutic agents for the treatment of Parkinson disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using an in silico search, followed by PCR, <a href="#16" class="mim-tip-reference" title="Hejjas, K., Vas, J., Kubinyi, E., Sasvari-Szekely, M., Miklosi, A., Ronai, Z. <strong>Novel repeat polymorphisms of the dopaminergic neurotransmitter genes among dogs and wolves.</strong> Mammalian Genome 18: 871-879, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18049838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18049838</a>] [<a href="https://doi.org/10.1007/s00335-007-9070-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18049838">Hejjas et al. (2007)</a> identified VNTR polymorphisms in genes of the dopaminergic system in 4 dog breeds and European gray wolves. Polymorphisms of the DRD4 (<a href="/entry/126452">126452</a>), DBH (<a href="/entry/609312">609312</a>), and DAT genes were associated with attention deficit, but not activity-impulsivity, in Belgian Tervuerens, a breed that had almost all genetic variants identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18049838" 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">rs28363170 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28363170;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=rs28363170" 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=rs28363170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#22" class="mim-tip-reference" title="Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., Boyd, N. R., Shields, P. G. <strong>Evidence suggesting the role of specific genetic factors in cigarette smoking.</strong> Health Psychol. 18: 14-20, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925041</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925041">Lerman et al. (1999)</a> reported associations between allele 9 of the SLC6A3 gene (SLC6A3*9), a polymorphism containing 9 repeats of the 40-basepair 3-prime VNTR, and lack of smoking, late initiation of smoking, and length of quitting attempts (see <a href="/entry/188890">188890</a>). The association with smoking risk was modified by the DRD2 (<a href="/entry/126450">126450</a>) genotype, resulting in a 50% reduction in smoking risk for individuals carrying both SLC6A3*9 and DRD2-A2. <a href="#26" class="mim-tip-reference" title="Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H. <strong>A genetic association for cigarette smoking behavior.</strong> Health Psychol. 18: 7-13, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925040">Sabol et al. (1999)</a> extended this study by examining both smoking behavior and personality traits of 1,107 individuals in a diverse population of nonsmokers, current smokers, and former smokers. A significant association between SLC6A3*9 and smoking status was confirmed and was due to an effect on cessation rather than initiation. The SLC6A3*9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. <a href="#26" class="mim-tip-reference" title="Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H. <strong>A genetic association for cigarette smoking behavior.</strong> Health Psychol. 18: 7-13, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925040">Sabol et al. (1999)</a> hypothesized that individuals carrying the SLC6A3*9 polymorphism have altered dopamine transmission, which reduces their need for novelty and reward by external stimuli, including cigarettes. <a href="#26" class="mim-tip-reference" title="Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H. <strong>A genetic association for cigarette smoking behavior.</strong> Health Psychol. 18: 7-13, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925040">Sabol et al. (1999)</a> found that individuals carrying the SLC6A3*9 allele were 1.5-fold more likely to have quit smoking than were individuals lacking this polymorphism. The results supported the finding of <a href="#22" class="mim-tip-reference" title="Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., Boyd, N. R., Shields, P. G. <strong>Evidence suggesting the role of specific genetic factors in cigarette smoking.</strong> Health Psychol. 18: 14-20, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925041</a>] [<a href="https://doi.org/10.1037//0278-6133.18.1.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9925041">Lerman et al. (1999)</a> of an association between SLC6A3 and length of previous cessation attempts in current smokers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9925041+9925040" 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">rs267607068 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607068;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=rs267607068" 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=rs267607068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 affected members of a consanguineous Pakistani family with infantile parkinsonism-dystonia (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#19" class="mim-tip-reference" title="Kurian, M. A., Zhen, J., Cheng, S.-Y., Li, Y., Mordekar, S. R., Jardine, P., Morgan, N. V., Meyer, E., Tee, L., Pasha, S., Wassmer, E., Heales, S. J. R., Gissen, P., Reith, M. E. A., Maher, E. R. <strong>Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.</strong> J. Clin. Invest. 119: 1595-1603, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19478460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19478460</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19478460[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/10.1172/JCI39060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19478460">Kurian et al. (2009)</a> identified a homozygous 1103T-A transversion in exon 8 of the SLC6A3 gene, resulting in a leu368-to-gln (L368Q) substitution in a highly conserved residue in transmembrane domain-7 toward the exterior of the protein surface. In vitro functional expression assays in HEK293 cells showed that L368Q-mutant DAT had no dopamine reuptake activity. Binding affinity for a cocaine analog was near normal, but the potency of dopamine in inhibiting cocaine analog binding was greatly reduced in the L368Q mutant, indicating reduced dopamine binding affinity. The mutant protein also resulted in a profound reduction in mature glycosylated DAT, which likely impaired transport function. The mutation was not identified in 544 alleles from Asian individuals or in 438 alleles from individuals of mixed European descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19478460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267607069 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607069;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/rs267607069?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=rs267607069" 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=rs267607069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient of European descent, born of consanguineous parents, with infantile parkinsonism-dystonia (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#19" class="mim-tip-reference" title="Kurian, M. A., Zhen, J., Cheng, S.-Y., Li, Y., Mordekar, S. R., Jardine, P., Morgan, N. V., Meyer, E., Tee, L., Pasha, S., Wassmer, E., Heales, S. J. R., Gissen, P., Reith, M. E. A., Maher, E. R. <strong>Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.</strong> J. Clin. Invest. 119: 1595-1603, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19478460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19478460</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19478460[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/10.1172/JCI39060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19478460">Kurian et al. (2009)</a> identified a homozygous 1184C-T transition in exon 9 of the SLC6A3 gene, resulting in a pro395-to-leu (P395L) substitution in a highly conserved residue of the E4B loop close to transmembrane domain-8. In vitro functional expression assays in HEK293 cells showed that the P395L-mutant protein had no dopamine reuptake activity. Binding affinity for a cocaine analog was near normal, and the potency of dopamine in inhibiting cocaine analog binding was near normal in the P395L mutant, suggesting no impact on dopamine binding affinity. The mutant protein did result in a profound reduction in mature glycosylated DAT, which likely impaired transport function. The mutation was not identified in 544 alleles from Asian individuals or in 438 alleles from individuals of mixed European descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19478460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs431905504 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs431905504;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/rs431905504?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=rs431905504" 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=rs431905504" 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=RCV000022531 OR RCV000493130 OR RCV003593863" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022531, RCV000493130, RCV003593863" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022531...</a>
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<p>In 2 Mennonite sisters with infantile parkinsonism-dystonia (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#25" class="mim-tip-reference" title="Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others. <strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong> PLoS One 7: e28936, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22279524[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0028936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22279524">Puffenberger et al. (2012)</a> identified a homozygous G-to-T transversion in intron 9 of the SLC6A3 gene. The mutation was found by homozygosity mapping followed by exome sequencing of the candidate region. No carriers of this mutation were found among 201 Mennonite control samples. The proband developed irritability and feeding difficulties soon after birth, followed by generalized rigidity and dystonia during early infancy. She had impaired motor development and severe rigid parkinsonism by late childhood. She could not speak or use her hands to communicate, and it was difficult to assess cognitive function or thought content. Brain structure was normal. Cerebrospinal fluid showed increased homovanillic acid (HVA). A similarly affected sister had died. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22279524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000083262 OR RCV002228329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000083262, RCV002228329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000083262...</a>
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<p>In a patient, born of consanguineous Turkish parents, with infantile parkinsonism-dystonia (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#18" class="mim-tip-reference" title="Kurian, M. A., Li, Y., Zhen, J., Meyer, E., Hai, N., Christen, H.-J., Hoffmann, G. F., Jardine, P., von Moers, A., Mordekar, S. R., O'Callaghan, F., Wassmer, E., and 10 others. <strong>Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study.</strong> Lancet Neurol. 10: 54-62, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21112253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21112253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21112253[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S1474-4422(10)70269-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21112253">Kurian et al. (2011)</a> identified a homozygous G-to-A transition in intron 7 of the SLC6A3 gene (c.1031+1G-A), predicted to cause aberrant splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21112253" 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">rs431905515 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs431905515;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=rs431905515" 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=rs431905515" 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=RCV000083263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000083263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000083263</a>
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<p>In a patient of mixed European descent, born of consanguineous parents, with PKDYS (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#18" class="mim-tip-reference" title="Kurian, M. A., Li, Y., Zhen, J., Meyer, E., Hai, N., Christen, H.-J., Hoffmann, G. F., Jardine, P., von Moers, A., Mordekar, S. R., O'Callaghan, F., Wassmer, E., and 10 others. <strong>Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study.</strong> Lancet Neurol. 10: 54-62, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21112253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21112253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21112253[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S1474-4422(10)70269-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21112253">Kurian et al. (2011)</a> identified a homozygous c.671T-C transition in exon 5 of the SLC6A3 gene, resulting in a leu224-to-pro (L224P) substitution at a highly conserved residue in mammalian species. In vitro functional expression studies of the mutation in HEK293 cells showed nonspecific uptake for the mutant transporter, and Western blot analysis indicated deficiency of the mature protein. These findings were consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21112253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs431905516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs431905516;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/rs431905516?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=rs431905516" 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=rs431905516" 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=RCV000083264 OR RCV001854451" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000083264, RCV001854451" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000083264...</a>
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<p>In a patient of mixed European descent, born of consanguineous parents, with PKDYS (PKDYS1; <a href="/entry/613135">613135</a>), <a href="#18" class="mim-tip-reference" title="Kurian, M. A., Li, Y., Zhen, J., Meyer, E., Hai, N., Christen, H.-J., Hoffmann, G. F., Jardine, P., von Moers, A., Mordekar, S. R., O'Callaghan, F., Wassmer, E., and 10 others. <strong>Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study.</strong> Lancet Neurol. 10: 54-62, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21112253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21112253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21112253[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S1474-4422(10)70269-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21112253">Kurian et al. (2011)</a> identified a homozygous c.1561C-T transition in exon 12 of the SLC6A3 gene, resulting in an arg521-to-trp (R521W) substitution at a highly conserved residue. In vitro functional expression studies of the mutation in HEK293 cells showed decreased dopamine uptake (27% of wildtype), and Western blot analysis indicated deficiency of the mature protein. These findings were consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21112253" 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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Brookes, K.-J., Mill, J., Guindalini, C., Curran, S., Xu, X., Knight, J., Chen, C.-K., Huang, Y.-S., Sethna, V., Taylor, E., Chen, W., Breen, G., Asherson, P.
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<strong>A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.</strong>
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Arch. Gen. Psychiat. 63: 74-81, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16389200/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16389200</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16389200" 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/archpsyc.63.1.74" target="_blank">Full Text</a>]
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Byerley, W., Hoff, M., Holik, J., Caron, M. G., Giros, B.
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<strong>VNTR polymorphism for the human dopamine transporter gene (DAT1).</strong>
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Hum. Molec. Genet. 2: 335, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8098980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8098980</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8098980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/2.3.335" target="_blank">Full Text</a>]
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Cheuk, D. K. L., Li, S. Y. H., Wong, V.
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<strong>No association between VNTR polymorphisms of dopamine transporter gene and attention deficit hyperactivity disorder in Chinese children.</strong>
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Am. J. Med. Genet. 141B: 123-125, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16402340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16402340</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16402340" 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.b.30280" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3458031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3458031</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3458031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.36.6.772" target="_blank">Full Text</a>]
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Langley, K., Turic, D., Peirce, T. R., Mills, S., Van Den Bree, M. B., Owen, M. J., O'Donovan, M. C., Thapar, A.
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<strong>No support for association between the dopamine transporter (DAT1) gene and ADHD.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16082688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16082688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16082688" 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.b.30206" target="_blank">Full Text</a>]
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Lerman, C., Caporaso, N. E., Audrain, J., Main, D., Bowman, E. D., Lockshin, B., Boyd, N. R., Shields, P. G.
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<strong>Evidence suggesting the role of specific genetic factors in cigarette smoking.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925041</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9925041" 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/10.1037//0278-6133.18.1.14" target="_blank">Full Text</a>]
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<a id="Lossie1994" class="mim-anchor"></a>
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Lossie, A. C., Vandenbergh, D. J., Uhl, G. R., Camper, S. A.
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<strong>Localization of the dopamine transporter gene, Dat1, on mouse chromosome 13.</strong>
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Mammalian Genome 5: 117-118, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8180472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8180472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8180472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00292340" target="_blank">Full Text</a>]
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<a id="Navaroli2011" class="mim-anchor"></a>
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Navaroli, D. M., Stevens, Z. H., Uzelac, Z., Gabriel, L., King, M. J., Lifshitz, L. M., Sitte, H. H., Melikian, H. E.
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<strong>The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking.</strong>
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J. Neurosci. 31: 13758-13770, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21957239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21957239</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21957239[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=21957239" 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/10.1523/JNEUROSCI.2649-11.2011" target="_blank">Full Text</a>]
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<a id="Puffenberger2012" class="mim-anchor"></a>
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Puffenberger, E. G., Jinks, R. N., Sougnez, C., Cibulskis, K., Willert, R. A., Achilly, N. P., Cassidy, R. P., Fiorentini, C. J., Heiken, K. F., Lawrence, J. J., Mahoney, M. H., Miller, C. J., and 13 others.
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<strong>Genetic mapping and exome sequencing identify variants associated with five novel diseases.</strong>
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PLoS One 7: e28936, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279524</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22279524[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=22279524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1371/journal.pone.0028936" target="_blank">Full Text</a>]
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Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R., IV, Benjamin, J., Murphy, D. L., Hamer, D. H.
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<strong>A genetic association for cigarette smoking behavior.</strong>
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Health Psychol. 18: 7-13, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9925040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9925040</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9925040" 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/10.1037//0278-6133.18.1.7" target="_blank">Full Text</a>]
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Sotnikova, T. D., Caron, M. G., Gainetdinov, R. R.
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<strong>DDD mice, a novel acute mouse model of Parkinson's disease.</strong>
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Neurology 67 (suppl. 2): S12-S17, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17030735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17030735</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17030735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.67.7_suppl_2.s12" target="_blank">Full Text</a>]
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<a id="Tiihonen1995" class="mim-anchor"></a>
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Tiihonen, J., Kuikka, J., Bergstrom, K., Hakola, P., Karhu, J., Ryynanen, O.-P., Fohr, J.
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<strong>Altered striatal dopamine re-uptake site densities in habitually violent and non-violent alcoholics.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7585146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7585146</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7585146" 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/nm0795-654" target="_blank">Full Text</a>]
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Vandenbergh, D. J., Persico, A. M., Hawkins, A. L., Griffin, C. A., Li, X., Jabs, E. W., Uhl, G. R.
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<strong>Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR.</strong>
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Genomics 14: 1104-1106, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1478653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1478653</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1478653" 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/s0888-7543(05)80138-7" target="_blank">Full Text</a>]
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Vandenbergh, D. J., Persico, A. M., Uhl, G. R.
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<strong>A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.</strong>
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Molec. Brain Res. 15: 161-166, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1359373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1359373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1359373" 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/10.1016/0169-328x(92)90165-8" target="_blank">Full Text</a>]
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Waldman, I. D., Rowe, D. C., Abramowitz, A., Kozel, S. T., Mohr, J. H., Sherman, S. L., Cleveland, H. H., Sanders, M. L., Gard, J. M. C., Stever, C.
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<strong>Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9837830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302132" target="_blank">Full Text</a>]
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Zhou, Z., Zhen, J., Karpowich, N. K., Goetz, R. M., Law, C. J., Reith, M. E. A., Wang, D.-N.
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<strong>LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.</strong>
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Science 317: 1390-1393, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17690258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17690258</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17690258[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=17690258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1147614" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Patricia A. Hartz - updated : 1/20/2015
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Cassandra L. Kniffin - updated : 1/29/2014<br>Cassandra L. Kniffin - updated : 2/27/2012<br>Cassandra L. Kniffin - updated : 11/23/2009<br>Patricia A. Hartz - updated : 10/24/2008<br>Ada Hamosh - updated : 10/15/2007<br>Cassandra L. Kniffin - updated : 9/10/2007<br>John Logan Black, III - updated : 8/4/2006<br>John Logan Black, III - updated : 6/2/2006<br>John Logan Black, III - updated : 5/17/2006<br>John Logan Black, III - updated : 5/12/2006<br>Natalie E. Krasikov - updated : 3/29/2004<br>Victor A. McKusick - updated : 3/11/1999<br>Victor A. McKusick - updated : 1/14/1999<br>Victor A. McKusick - updated : 12/18/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 8/13/1997
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Victor A. McKusick : 1/8/1993
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carol : 07/09/2018<br>ckniffin : 07/05/2018<br>carol : 06/05/2017<br>carol : 06/02/2017<br>carol : 02/25/2015<br>mgross : 1/26/2015<br>mcolton : 1/20/2015<br>mcolton : 2/21/2014<br>mgross : 2/10/2014<br>ckniffin : 1/29/2014<br>carol : 3/5/2012<br>terry : 3/2/2012<br>ckniffin : 2/27/2012<br>terry : 12/16/2009<br>wwang : 12/11/2009<br>wwang : 12/11/2009<br>ckniffin : 11/23/2009<br>carol : 9/4/2009<br>wwang : 4/16/2009<br>mgross : 10/24/2008<br>mgross : 10/24/2008<br>carol : 7/25/2008<br>alopez : 10/26/2007<br>terry : 10/15/2007<br>wwang : 9/12/2007<br>ckniffin : 9/10/2007<br>carol : 6/15/2007<br>alopez : 10/25/2006<br>carol : 8/29/2006<br>terry : 8/4/2006<br>wwang : 6/6/2006<br>terry : 6/2/2006<br>wwang : 5/22/2006<br>terry : 5/17/2006<br>wwang : 5/16/2006<br>wwang : 5/16/2006<br>terry : 5/12/2006<br>ckniffin : 4/18/2006<br>tkritzer : 3/30/2004<br>terry : 3/29/2004<br>carol : 3/8/2002<br>terry : 3/8/2002<br>terry : 3/16/1999<br>terry : 3/11/1999<br>alopez : 1/15/1999<br>alopez : 1/14/1999<br>joanna : 1/14/1999<br>carol : 12/28/1998<br>terry : 12/18/1998<br>carol : 4/30/1998<br>terry : 4/29/1998<br>terry : 8/13/1997<br>mark : 4/1/1996<br>mark : 2/14/1996<br>mark : 1/21/1996<br>terry : 1/17/1996<br>mark : 12/4/1995<br>terry : 9/13/1995<br>mark : 7/28/1995<br>carol : 2/25/1994<br>carol : 4/27/1993<br>carol : 4/26/1993<br>carol : 2/17/1993
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<h3>
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<span class="mim-font">
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<strong>*</strong> 126455
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</h3>
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<h3>
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<span class="mim-font">
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SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3; SLC6A3
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</span>
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</h3>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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DOPAMINE TRANSPORTER; DAT<br />
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DAT1
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SLC6A3</em></strong>
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</span>
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</p>
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<strong>
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<em>
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Cytogenetic location: 5p15.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:1,392,794-1,445,440 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="2">
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<span class="mim-font">
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5p15.33
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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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{Nicotine dependence, protection against}
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<td>
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<span class="mim-font">
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188890
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<span class="mim-font">
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<span class="mim-font">
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3
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<span class="mim-font">
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Parkinsonism-dystonia, infantile, 1
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<span class="mim-font">
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613135
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The dopamine transporter (DAT), which is encoded by the SLC6A3 gene, mediates the active reuptake of dopamine from the synapse and is a principal regulator of dopaminergic neurotransmission. The SLC6A3 gene has been implicated in human disorders such as parkinsonism, Tourette syndrome, and substance abuse (Vandenbergh et al., 1992). </p>
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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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</h4>
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<span class="mim-text-font">
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<p>Vandenbergh et al. (1992) cloned cDNAs encoding the entire coding sequence and 3-prime untranslated sequence of the human DAT1 gene. </p><p>Kurian et al. (2009) noted that SLC6A3 contains 12 transmembrane domains with helically unwound regions in the first and sixth domains. Extracellular and intracellular loops include helical portions E2, E3, E4A, E4B, I1, and I5. Mature, glycosylated DAT has a molecular mass of 85 kD, whereas immature nonglycosylated DAT has a molecular mass of 55 kD and does not transport dopamine as efficiently as the mature protein. </p><p>Navaroli et al. (2011) reported that DAT has an endocytic signal near the C terminus that modulates both basal and protein kinase C (PKC; see 176960)-enhanced DAT internalization. Immunohistochemical analysis revealed that rat Dat localized to plasma membrane foci that corresponded to both lipid rafts and non-raft microdomains in PC12 pheochromocytoma cells. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>By yeast 2-hybrid analysis of a human substantia nigra cDNA library, Navaroli et al. (2011) found that the small GTPase RIN (RIT2; 609592) interacted with the isolated C-terminal endocytic signal of human DAT. Coimmunoprecipitation and protein pull-down assays with PC12 cells that were transfected with human DAT revealed direct interaction between DAT and Rin. Rin did not interact with other members of the SLC6 transporter family. DAT colocalized with Rin at plasma membrane foci, predominantly at lipid rafts, in transfected PC12 cells. Phorbol ester-induced PKC activation enhanced DAT-Rin interaction, followed by their dissociation and DAT internalization into endocytic vesicles. These effects did not occur with a DAT mutant lacking the C-terminal endocytic signal or with a Rin mutant lacking GTPase activity. Knockdown of Rin via short hairpin RNA completely inhibited PKC-induced DAT internalization. </p>
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</span>
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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>The SLC6A3 gene contains 15 exons spanning approximately 60 kb (Vandenbergh et al., 1992). </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By in situ hybridization and by PCR amplification of rodent/human somatic cell hybrid DNAs, Vandenbergh et al. (1992) and Giros et al. (1992) mapped the SLC6A3 gene to chromosome 5p15.3. </p><p>Lossie et al. (1994) mapped the mouse Dat1 homolog to chromosome 15 by linkage analysis of an interspecific backcross. </p><p>Gelernter et al. (1995) demonstrated close linkage between the SLC6A3 gene and several markers previously mapped to distal chromosome 5p. </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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Zhou et al. (2007) determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT (182138), NET (163970), and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Vandenbergh et al. (1992) identified a 40-bp variable-number tandem repeat (VNTR) polymorphism in the 3-prime untranslated region of the DAT1 gene with repeat copy numbers ranging from 3 to 11. </p><p>Byerley et al. (1993) demonstrated a VNTR polymorphism related to the DAT1 gene. Doucette-Stamm et al. (1995) established allele frequencies for the 40-bp VNTR polymorphism. Differences were found between black Americans and Caucasians or Hispanics, but there were no differences between Caucasians and Hispanics. A previously unreported allele was detected in all 3 populations. </p><p><strong><em>Association with Attention-Deficit Hyperactivity Disorder</em></strong></p><p>
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Attention-deficit hyperactivity disorder (ADHD; 143465) is presumably heritable in some cases. Some ADHD patients respond to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion. Cook et al. (1995) used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the DAT1 locus and 49 cases of ADHD. Eight cases of undifferentiated attention-deficit disorder (UADD) were also studied. All cases were studied in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHD/UADD and the 480-bp DAT1 allele. When cases of UADD were dropped from the analysis, similar results were found. Cook et al. (1995) suggested that molecular analysis of DAT1 may identify mutations that increase susceptibility to this disorder and that biochemical analysis of such mutations may lead to development of more effective therapeutic interventions. </p><p>Gill et al. (1997) found a significant association between ADHD and the 480-bp DAT1 VNTR allele. Gill et al. (1997) reported concordance rates for ADHD in monozygotic and dizygotic twins of 81% and 29%, respectively. </p><p>Waldman et al. (1998) used 4 analytic strategies to examine the association and linkage of the DAT1 gene with ADHD. The study group comprised 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and sibs. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp DAT1 allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Sibs discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibs with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relationship was especially strong with the combined but not the inattentive subtype. The findings were believed to represent one of the first replicated relations of a candidate gene and a psychiatric disorder in children. </p><p>Kahn et al. (2003) found a significant association between homozygosity for the 480-bp DAT allele and hyperactivity-impulsivity and oppositional behaviors only in the presence of maternal prenatal smoking. They emphasized the importance of incorporating environmental cofactors in genetic studies of ADHD. </p><p>Langley et al. (2005) tested the DAT1 3-prime VNTR and 3 putative DAT1 promoter SNPs for association with ADHD in 263 parent-proband trios using family-based association methods. No evidence of association with any of the promoter region SNPs or the VNTR was seen. Haplotype analysis was also nonsignificant, and no association was found between the VNTR and response to stimulant medications. By case-control analysis of the VNTR in 263 cases and 287 controls, the 10-repeat allele showed no significant association compared to all other alleles combined. </p><p>Feng et al. (2005) investigated whether the DAT1 3-prime UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. Variants included an MspI polymorphism (rs27072), a DraI T-C transition reported to influence DAT1 expression levels, and a BstUI polymorphism (rs3863145), in addition to the VNTR. They found an association between the G allele of the MspI SNP and ADHD (P = 0.009) but not with alleles of the VNTR polymorphism or the BstUI polymorphism, and they did not observe the DraI SNP. Feng et al. (2005) screened the VNTR region by direct sequencing to determine if there were additional variants within the repeats that could account for association with ADHD and found no variation in the VNTR region for either the 10- or 9-repeat alleles in the probands screened. </p><p>In both a Taiwanese ADHD sample and an English ADHD sample, Brookes et al. (2006) identified association with the DAT1 3-prime UTR VNTR and a novel DAT1 intron 8 repeat polymorphism. A risk haplotype composed of the 2 repeat polymorphisms was also associated with ADHD in both populations, and the authors found that the risk haplotype showed significant interactions with maternal use of alcohol during pregnancy in the English sample. </p><p>Hebebrand et al. (2006) found no evidence of association between ADHD and the DAT1 VNTR in 102 German families with 2 or more offspring who fulfilled diagnostic criteria for ADHD. </p><p>Cheuk et al. (2006) studied the association between the DAT1 VNTR and ADHD in Chinese children (64 ADHD cases, including 52 boys and 12 girls, their families, and 64 sex-matched normal controls) in Hong Kong. Patients were diagnosed with combined, hyperactive-impulsive, or inattentive subtypes of ADHD. The 10-repeat allele (92.6%) and the 10/10 (85.2%) repeat genotype were most prevalent. Both family-based and case-control analyses showed no association between the DAT1 polymorphisms and ADHD. </p><p>Animal studies suggest that the development of substance dependence (e.g., alcoholism) is associated with dopaminergic activity in striatum and the limbic system (Tiihonen et al., 1995). Several genetic studies had indicated that allele A1 at the DRD2 (126450) locus is associated with both density of dopamine receptor-2 and alcoholism. Tiihonen et al. (1995) studied striatal dopamine reuptake sites in 19 healthy controls, 19 habitually impulsive violent alcoholics, and 10 nonviolent alcoholics with single photon emission computed tomography (SPECT) using iodine-123-labeled beta-CIT as a tracer. Blind quantitative analysis revealed that the striatal dopamine transporter density was markedly lower in nonviolent alcoholics than in healthy controls (P less than 0.001), while violent alcoholics had slightly higher dopamine transporter densities than controls (P less than 0.10). Goldman (1995) suggested that the next step would be to look for inherited variants of the DAT1 gene that may influence vulnerability to alcoholism and other psychiatric diseases. </p><p><strong><em>Association with Tourette Syndrome</em></strong></p><p>
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In a large Canadian Mennonite pedigree segregating for Tourette syndrome (137580) (Kurlan et al., 1986), Gelernter et al. (1995) excluded linkage to SLC6A3. They cautiously pointed out, however, that these results did not exclude a role for the dopamine transporter in influencing risk for Tourette syndrome in combination with other loci. </p><p><strong><em>Association with Cigarette Smoking</em></strong></p><p>
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Dopaminergic genes are likely candidates for heritable influences on cigarette smoking (188890). Lerman et al. (1999) and Sabol et al. (1999) reported associations between allele 9 of a DAT1 polymorphism, SLC6A3*9 (126455.0001), and smoking status. While Lerman et al. (1999) reported association of the SLC6A3*9 allele with lack of smoking, late initiation of smoking, and length of quitting attempts, Sabol et al. (1999) reported that the significant association between SLC6A3*9 and smoking status was due to an effect on cessation rather than initiation. The SLC6A3*9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. </p><p><strong><em>Association with Bipolar Disorder</em></strong></p><p>
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Greenwood et al. (2001) reported evidence for an association between DAT1 and bipolar disorder (MAFD1; 125480) in a sample of 50 parent-proband trios. Using the transmission disequilibrium test (TDT), they showed an association between a haplotype composed of 5 SNPs in the 3-prime region of the DAT1 gene, exon 9 through exon 15, and bipolar disorder (allele-wise TDT empirical P = 0.001; genotype-wise TDT empirical P = 0.0004). Greenwood et al. (2006) analyzed a total of 22 SNPs in the 50 previously studied parent-proband trios and an independent set of 70 parent-proband trios. Using TDT analysis, an intron 8 SNP and an intron 13 SNP were found to be moderately associated with bipolar disorder, each in 1 of the 2 independent samples. Analysis of haplotypes of all 22 SNPs in sliding windows of 5 adjacent SNPs revealed an association to the region near intron 7 and 8 in both samples (empirical P values of 0.002 and 0.001, respectively, for the same window). The haplotype block structure observed by Greenwood et al. (2001) was confirmed in this new sample with the greater resolution allowing for discrimination of a third haplotype block in the middle of the gene. </p><p><strong><em>Infantile Parkinsonism-Dystonia 1</em></strong></p><p>
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By linkage analysis followed by candidate gene sequencing of a consanguineous Pakistani family with infantile parkinsonism-dystonia (PKDYS1; 613135), Kurian et al. (2009) identified a homozygous mutation (L368Q; 126455.0002) in the SLC6A3 gene. A similarly affected individual from a second family had a different homozygous mutation (P395L; 126455.0003). In vitro functional expression studies showed that both mutant proteins had no dopamine uptake activity. </p><p>In 8 unrelated patients with dopamine transporter deficiency syndrome, Kurian et al. (2011) identified homozygous or compound heterozygous mutations in the SLC6A3 gene (see, e.g., 126455.0005-126455.0007). None of the patients shared a mutation, suggesting the absence of mutational hotspots. In vitro functional expression studies in HEK293 cells showed that the mutations caused a loss of transporter function and decreased expression of the normal protein. All patients presented in early infancy with a complex motor disorder involving both hypo- and hyperkinetic movements. There was no effective treatment, and several patients died in the teenage years. </p><p>By homozygosity mapping followed by exome sequencing of a Mennonite family in which 2 sisters had infantile parkinsonism-dystonia, Puffenberger et al. (2012) identified a homozygous splice site mutation in the SLC6A3 gene (126455.0004). </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>Giros et al. (1996) found that the disruption of the mouse Dat1 gene results in spontaneous hyperlocomotion despite major adaptive changes such as decreases in neurotransmitter and receptor levels. In homozygous-null mice, dopamine persisted at least 100 times longer in the extracellular space, providing a biochemical explanation of the hyperdopaminergic phenotype and demonstrating the critical role of DAT1 in regulating neurotransmission. The authors noted that the dopamine transporter is an obligatory target of cocaine and amphetamine, as demonstrated by the fact that these psychostimulants had no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter. Giros et al. (1996) noted that there are similarities between the hyperdopaminergic phenotype of the knockout mice and some of the positive symptoms of patients with schizophrenia. The authors also postulated that specific blockade of DAT1 with high-affinity inhibitors may be beneficial in illnesses such as Parkinson disease (see 168600), where the effective levels of dopamine are markedly reduced. </p><p>Gainetdinov et al. (1999) continued the studies of Giros et al. (1992), which demonstrated mice lacking the gene encoding the plasma membrane dopamine transporter have elevated dopaminergic tone and are hyperactive. They found that this activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission, and emphasized the importance of a relative balance of the serotonin and dopamine systems for normal motor activity. The parallels between the DAT knockout mice and individuals with ADHD suggested that common mechanisms may underlie some of their behaviors and responses to psychostimulants. </p><p>Sotnikova et al. (2006) developed a novel acute mouse model of severe dopamine deficiency using Dat-null mice and pharmacologic inhibition of tyrosine hydroxylase. Dopamine-deficient Dat-null mice (DDD) demonstrated severe akinesia, rigidity, tremor, and ptosis, similar to behaviors observed in patients with Parkinson disease. Interestingly, DDD mice were able to swim in water, indicating that certain movements and conditions can occur independently of dopamine. Dopamine agonists such as L-DOPA temporarily restored locomotion in DDD mice, and amphetamine derivatives showed effectiveness in reducing motor abnormalities in DDD mice. Sotnikova et al. (2006) noted that the DDD mouse model provides a unique opportunity to screen potential therapeutic agents for the treatment of Parkinson disease. </p><p>Using an in silico search, followed by PCR, Hejjas et al. (2007) identified VNTR polymorphisms in genes of the dopaminergic system in 4 dog breeds and European gray wolves. Polymorphisms of the DRD4 (126452), DBH (609312), and DAT genes were associated with attention deficit, but not activity-impulsivity, in Belgian Tervuerens, a breed that had almost all genetic variants identified. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>7 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NICOTINE DEPENDENCE, PROTECTION AGAINST</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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SLC6A3, 9-REPEAT VNTR
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<br />
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SNP: rs28363170,
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ClinVar: RCV000018247
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Lerman et al. (1999) reported associations between allele 9 of the SLC6A3 gene (SLC6A3*9), a polymorphism containing 9 repeats of the 40-basepair 3-prime VNTR, and lack of smoking, late initiation of smoking, and length of quitting attempts (see 188890). The association with smoking risk was modified by the DRD2 (126450) genotype, resulting in a 50% reduction in smoking risk for individuals carrying both SLC6A3*9 and DRD2-A2. Sabol et al. (1999) extended this study by examining both smoking behavior and personality traits of 1,107 individuals in a diverse population of nonsmokers, current smokers, and former smokers. A significant association between SLC6A3*9 and smoking status was confirmed and was due to an effect on cessation rather than initiation. The SLC6A3*9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. Sabol et al. (1999) hypothesized that individuals carrying the SLC6A3*9 polymorphism have altered dopamine transmission, which reduces their need for novelty and reward by external stimuli, including cigarettes. Sabol et al. (1999) found that individuals carrying the SLC6A3*9 allele were 1.5-fold more likely to have quit smoking than were individuals lacking this polymorphism. The results supported the finding of Lerman et al. (1999) of an association between SLC6A3 and length of previous cessation attempts in current smokers. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC6A3, LEU368GLN
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<br />
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SNP: rs267607068,
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ClinVar: RCV000018249
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 affected members of a consanguineous Pakistani family with infantile parkinsonism-dystonia (PKDYS1; 613135), Kurian et al. (2009) identified a homozygous 1103T-A transversion in exon 8 of the SLC6A3 gene, resulting in a leu368-to-gln (L368Q) substitution in a highly conserved residue in transmembrane domain-7 toward the exterior of the protein surface. In vitro functional expression assays in HEK293 cells showed that L368Q-mutant DAT had no dopamine reuptake activity. Binding affinity for a cocaine analog was near normal, but the potency of dopamine in inhibiting cocaine analog binding was greatly reduced in the L368Q mutant, indicating reduced dopamine binding affinity. The mutant protein also resulted in a profound reduction in mature glycosylated DAT, which likely impaired transport function. The mutation was not identified in 544 alleles from Asian individuals or in 438 alleles from individuals of mixed European descent. </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>.0003 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SLC6A3, PRO395LEU
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<br />
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SNP: rs267607069,
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gnomAD: rs267607069,
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ClinVar: RCV000018250
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient of European descent, born of consanguineous parents, with infantile parkinsonism-dystonia (PKDYS1; 613135), Kurian et al. (2009) identified a homozygous 1184C-T transition in exon 9 of the SLC6A3 gene, resulting in a pro395-to-leu (P395L) substitution in a highly conserved residue of the E4B loop close to transmembrane domain-8. In vitro functional expression assays in HEK293 cells showed that the P395L-mutant protein had no dopamine reuptake activity. Binding affinity for a cocaine analog was near normal, and the potency of dopamine in inhibiting cocaine analog binding was near normal in the P395L mutant, suggesting no impact on dopamine binding affinity. The mutant protein did result in a profound reduction in mature glycosylated DAT, which likely impaired transport function. The mutation was not identified in 544 alleles from Asian individuals or in 438 alleles from individuals of mixed European descent. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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SLC6A3, IVS9DS, G-T, +1
|
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<br />
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|
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SNP: rs431905504,
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|
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gnomAD: rs431905504,
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|
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|
|
ClinVar: RCV000022531, RCV000493130, RCV003593863
|
|
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|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In 2 Mennonite sisters with infantile parkinsonism-dystonia (PKDYS1; 613135), Puffenberger et al. (2012) identified a homozygous G-to-T transversion in intron 9 of the SLC6A3 gene. The mutation was found by homozygosity mapping followed by exome sequencing of the candidate region. No carriers of this mutation were found among 201 Mennonite control samples. The proband developed irritability and feeding difficulties soon after birth, followed by generalized rigidity and dystonia during early infancy. She had impaired motor development and severe rigid parkinsonism by late childhood. She could not speak or use her hands to communicate, and it was difficult to assess cognitive function or thought content. Brain structure was normal. Cerebrospinal fluid showed increased homovanillic acid (HVA). A similarly affected sister had died. </p>
|
|
</span>
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</div>
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|
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<div>
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|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC6A3, IVS7DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs431905514,
|
|
|
|
|
|
|
|
ClinVar: RCV000083262, RCV002228329
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient, born of consanguineous Turkish parents, with infantile parkinsonism-dystonia (PKDYS1; 613135), Kurian et al. (2011) identified a homozygous G-to-A transition in intron 7 of the SLC6A3 gene (c.1031+1G-A), predicted to cause aberrant splicing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC6A3, LEU224PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs431905515,
|
|
|
|
|
|
|
|
ClinVar: RCV000083263
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of mixed European descent, born of consanguineous parents, with PKDYS (PKDYS1; 613135), Kurian et al. (2011) identified a homozygous c.671T-C transition in exon 5 of the SLC6A3 gene, resulting in a leu224-to-pro (L224P) substitution at a highly conserved residue in mammalian species. In vitro functional expression studies of the mutation in HEK293 cells showed nonspecific uptake for the mutant transporter, and Western blot analysis indicated deficiency of the mature protein. These findings were consistent with a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PARKINSONISM-DYSTONIA, INFANTILE, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SLC6A3, ARG521TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs431905516,
|
|
|
|
|
|
gnomAD: rs431905516,
|
|
|
|
|
|
ClinVar: RCV000083264, RCV001854451
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of mixed European descent, born of consanguineous parents, with PKDYS (PKDYS1; 613135), Kurian et al. (2011) identified a homozygous c.1561C-T transition in exon 12 of the SLC6A3 gene, resulting in an arg521-to-trp (R521W) substitution at a highly conserved residue. In vitro functional expression studies of the mutation in HEK293 cells showed decreased dopamine uptake (27% of wildtype), and Western blot analysis indicated deficiency of the mature protein. These findings were consistent with a loss of function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brookes, K.-J., Mill, J., Guindalini, C., Curran, S., Xu, X., Knight, J., Chen, C.-K., Huang, Y.-S., Sethna, V., Taylor, E., Chen, W., Breen, G., Asherson, P.
|
|
<strong>A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.</strong>
|
|
Arch. Gen. Psychiat. 63: 74-81, 2006.
|
|
|
|
|
|
[PubMed: 16389200]
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|
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[Full Text: https://doi.org/10.1001/archpsyc.63.1.74]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Byerley, W., Hoff, M., Holik, J., Caron, M. G., Giros, B.
|
|
<strong>VNTR polymorphism for the human dopamine transporter gene (DAT1).</strong>
|
|
Hum. Molec. Genet. 2: 335, 1993.
|
|
|
|
|
|
[PubMed: 8098980]
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|
|
[Full Text: https://doi.org/10.1093/hmg/2.3.335]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Cheuk, D. K. L., Li, S. Y. H., Wong, V.
|
|
<strong>No association between VNTR polymorphisms of dopamine transporter gene and attention deficit hyperactivity disorder in Chinese children.</strong>
|
|
Am. J. Med. Genet. 141B: 123-125, 2006.
|
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|
|
[PubMed: 16402340]
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[Full Text: https://doi.org/10.1002/ajmg.b.30280]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Cook, E. H., Jr., Stein, M. A., Krasowski, M. D., Cox, N. J., Olkon, D. M., Kieffer, J. E., Leventhal, B. L.
|
|
<strong>Association of attention-deficit disorder and the dopamine transporter gene.</strong>
|
|
Am. J. Hum. Genet. 56: 993-998, 1995.
|
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|
|
[PubMed: 7717410]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Doucette-Stamm, L., Blakely, D. J., Tian, J., Mockus, S., Mao, J.
|
|
<strong>Population genetic study of the human dopamine transporter gene (DAT1).</strong>
|
|
Genet. Epidemiol. 12: 303-308, 1995.
|
|
|
|
|
|
[PubMed: 7557351]
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|
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|
|
[Full Text: https://doi.org/10.1002/gepi.1370120307]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Feng, Y., Wigg, K. G., Makkar, R., Ickowicz, A., Pathare, T., Tannock, R., Roberts, W., Malone, M., Kennedy, J. L., Schachar, R., Barr, C. L.
|
|
<strong>Sequence variation in the 3-prime-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD).</strong>
|
|
Am. J. Med. Genet. 139B: 1-6, 2005.
|
|
|
|
|
|
[PubMed: 16082693]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.b.30190]
|
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Gainetdinov, R. R., Wetsel, W. C., Jones, S. R., Levin, E. D., Jaber, M., Caron, M. G.
|
|
<strong>Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.</strong>
|
|
Science 283: 397-401, 1999.
|
|
|
|
|
|
[PubMed: 9888856]
|
|
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|
|
[Full Text: https://doi.org/10.1126/science.283.5400.397]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Gelernter, J., Vandenbergh, D., Kruger, S. D., Pauls, D. L., Kurlan, R., Pakstis, A. J., Kidd, K. K., Uhl, G.
|
|
<strong>The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette syndrome.</strong>
|
|
Genomics 30: 459-463, 1995.
|
|
|
|
|
|
[PubMed: 8825631]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.1995.1265]
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Gill, M., Daly, G., Heron, S., Hawi, Z., Fitgerald, M.
|
|
<strong>Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism.</strong>
|
|
Molec. Psychiat. 2: 311-313, 1997.
|
|
|
|
|
|
[PubMed: 9246671]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.mp.4000290]
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|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Giros, B., El Mestikawy, S., Godinot, N., Zheng, K., Han, H., Yang-Feng, T., Caron, M. G.
|
|
<strong>Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter.</strong>
|
|
Molec. Pharm. 42: 383-390, 1992.
|
|
|
|
|
|
[PubMed: 1406597]
|
|
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</p>
|
|
</li>
|
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|
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<li>
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Patricia A. Hartz - updated : 1/20/2015<br>Cassandra L. Kniffin - updated : 1/29/2014<br>Cassandra L. Kniffin - updated : 2/27/2012<br>Cassandra L. Kniffin - updated : 11/23/2009<br>Patricia A. Hartz - updated : 10/24/2008<br>Ada Hamosh - updated : 10/15/2007<br>Cassandra L. Kniffin - updated : 9/10/2007<br>John Logan Black, III - updated : 8/4/2006<br>John Logan Black, III - updated : 6/2/2006<br>John Logan Black, III - updated : 5/17/2006<br>John Logan Black, III - updated : 5/12/2006<br>Natalie E. Krasikov - updated : 3/29/2004<br>Victor A. McKusick - updated : 3/11/1999<br>Victor A. McKusick - updated : 1/14/1999<br>Victor A. McKusick - updated : 12/18/1998<br>Victor A. McKusick - updated : 4/29/1998<br>Victor A. McKusick - updated : 8/13/1997
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