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Entry
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- *601143 - DYNACTIN 1; DCTN1
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601143</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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 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 role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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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/601143">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000204843;t=ENST00000628224" 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=1639" 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=601143" 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=ENSG00000204843;t=ENST00000628224" 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_001135040,NM_001135041,NM_001190836,NM_001190837,NM_001378991,NM_001378992,NM_004082,NM_023019,NR_033935" 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_004082" 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=601143" 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=07206&isoform_id=07206_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/DCTN1" 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/1419567,1945400,4099849,4139121,5915904,5915905,13259508,13259510,17375490,30582355,34364922,47938109,50949611,50949613,62088830,119620090,119620091,119620092,119620093,194386386,205277392,205277396,299890871,299890875,444738363,1821619526,1821619560" 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/Q14203" 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=1639" 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=ENSG00000204843;t=ENST00000628224" 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=DCTN1" 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=DCTN1" 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+1639" 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/DCTN1" 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:1639" 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/1639" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr2&hgg_gene=ENST00000628224.3&hgg_start=74361155&hgg_end=74391866&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2711" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601143[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=601143[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/ENSG00000204843" 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=DCTN1" 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=DCTN1" 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=DCTN1" 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.molgen.ua.ac.be/CMTMutations/" 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=DCTN1&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/PA27180" 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:2711" 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/FBgn0001108.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:107745" 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/DCTN1#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:107745" 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/1639/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=1639" 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=WBGene00001017;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-050419-28" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:1639" 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=DCTN1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 699184009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
601143
|
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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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DYNACTIN 1; DCTN1
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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>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
p150(GLUED), DROSOPHILA, HOMOLOG OF
|
|
</span>
|
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</h4>
|
|
</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=DCTN1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DCTN1</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">
|
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<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/2/377?start=-3&limit=10&highlight=377">2p13.1</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:74361155-74391866&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">2:74,361,155-74,391,866</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<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>
|
|
<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=105400,607641,168605" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/377?start=-3&limit=10&highlight=377">
|
|
2p13.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Amyotrophic lateral sclerosis, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/105400"> 105400 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Neuronopathy, distal hereditary motor, autosomal dominant 14
|
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|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607641"> 607641 </a>
|
|
|
|
</span>
|
|
</td>
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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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<p>The DCTN1 gene encodes p150(Glued), the largest polypeptide of the dynactin complex, which binds directly to microtubules and to cytoplasmic dynein (DYNC1H1; <a href="/entry/600112">600112</a>), a microtubule-based biologic motor protein (<a href="#6" class="mim-tip-reference" title="Holzbaur, E. L. F., Tokito, M. K. <strong>Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.</strong> Genomics 31: 398-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838327</a>] [<a href="https://doi.org/10.1006/geno.1996.0068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838327">Holzbaur and Tokito, 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838327" 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="Holzbaur, E. L. F., Tokito, M. K. <strong>Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.</strong> Genomics 31: 398-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838327</a>] [<a href="https://doi.org/10.1006/geno.1996.0068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838327">Holzbaur and Tokito (1996)</a> noted that dyneins were initially discovered as enzymes that couple ATP hydrolysis to provide a force for cellular motility in eukaryotic cilia and flagella. A distinct cytoplasmic form of dynein was subsequently characterized and thought to be responsible for the intracellular retrograde motility of vesicles and organelles along microtubules (<a href="#7" class="mim-tip-reference" title="Holzbaur, E. L. F., Vallee, R. B. <strong>Dyneins: molecular structure and cellular function.</strong> Ann. Rev. Cell Biol. 10: 339-372, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7888180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7888180</a>] [<a href="https://doi.org/10.1146/annurev.cb.10.110194.002011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7888180">Holzbaur and Vallee, 1994</a>). A large macromolecular complex, dynactin, is required for the cytoplasmic dynein-driven movement of organelles along microtubules. Dynactin is composed of 10 distinct polypeptides of 150, 135, 62, 50 (DCTN2; <a href="/entry/607376">607376</a>), 45, 42, 37, 32, 27, and 24 kD, with a combined mass of 10 million daltons. The binding of dynactin to dynein is critical for neuronal function, as antibodies that specifically disrupt this binding block vesicle motility along microtubules in extruded squid axoplasm. <a href="#6" class="mim-tip-reference" title="Holzbaur, E. L. F., Tokito, M. K. <strong>Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.</strong> Genomics 31: 398-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838327</a>] [<a href="https://doi.org/10.1006/geno.1996.0068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838327">Holzbaur and Tokito (1996)</a> stated that the dynein-dynactin interaction is probably a key component of the mechanism of axonal transport of vesicles and organelles. Further evidence for a critical role for dynactin in vivo comes from the analysis of mutations in the homologous gene in Drosophila. Mutant alleles of the 'glued' gene induced disruption of the neurons of the optic lobe and compound eye in heterozygotes; null mutations are lethal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8838327+7888180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Holzbaur, E. L. F., Tokito, M. K. <strong>Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.</strong> Genomics 31: 398-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838327</a>] [<a href="https://doi.org/10.1006/geno.1996.0068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838327">Holzbaur and Tokito (1996)</a> isolated and characterized cDNA clones encoding human p150(Glued), as well as alternatively spliced isoforms. Using these to isolate genomic clones, they found by genomic Southern blots that there is a single gene in the human, as had previously been observed in rat and chick. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838327" 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="Jang, W., Weber, J. S., Tokito, M. K., Holzbaur, E. L. F., Meisler, M. H. <strong>Mouse p150(Glued) (dynactin 1) cDNA sequence and evaluation as a candidate for the neuromuscular disease mutation mnd2.</strong> Biochem. Biophys. Res. Commun. 231: 344-347, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9070275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9070275</a>] [<a href="https://doi.org/10.1006/bbrc.1997.6095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9070275">Jang et al. (1997)</a> cloned and characterized mouse Dctn1. The mouse protein shares 95% amino acid identity with the human protein. The authors found no abnormalities of the gene in mnd2 mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9070275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Eaton, B. A., Fetter, R. D., Davis, G. W. <strong>Dynactin is necessary for synapse stabilization.</strong> Neuron 34: 729-741, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062020</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00721-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062020">Eaton et al. (2002)</a> disrupted the dynactin complex in Drosophila, using 3 separate perturbations: dsRNA interference with arp1 (homolog of ACTR1A; <a href="/entry/605143">605143</a>), mutation in p150/Glued, and a dominant-negative Glued transgene. In all 3 cases, the disruption resulted in an increase in the frequency and extent of synaptic retraction events at the neuromuscular junction. <a href="#3" class="mim-tip-reference" title="Eaton, B. A., Fetter, R. D., Davis, G. W. <strong>Dynactin is necessary for synapse stabilization.</strong> Neuron 34: 729-741, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062020</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00721-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062020">Eaton et al. (2002)</a> concluded that dynactin functions locally within the presynaptic arbor to promote synapse stability at the neuromuscular junction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12062020" 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="Kim, J. C., Badano, J. L., Sibold, S., Esmail, M. A., Hill, J., Hoskins, B. E., Leitch, C. C., Venner, K., Ansley, S. J., Ross, A. J., Leroux, M. R., Katsanis, N., Beales, P. L. <strong>The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.</strong> Nature Genet. 36: 462-470, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15107855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15107855</a>] [<a href="https://doi.org/10.1038/ng1352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15107855">Kim et al. (2004)</a> showed that BBS4 (<a href="/entry/600374">600374</a>) protein localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit pericentriolar material-1 protein (PCM1; <a href="/entry/600299">600299</a>) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division, and apoptotic cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15107855" 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="#5" class="mim-tip-reference" title="Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lebmann, V., Humbert, S., Saudou, F. <strong>Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.</strong> Cell 118: 127-138, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15242649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15242649</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15242649">Gauthier et al. (2004)</a> showed that huntingtin (<a href="/entry/613004">613004</a>) specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>) along microtubules. They determined that huntingtin-mediated transport involves huntingtin-associated protein-1 (HAP1; <a href="/entry/600947">600947</a>) and the p150(Glued) subunit of dynactin, an essential component of molecular motors. BDNF transport was attenuated both in the disease context and by reducing the levels of wildtype huntingtin. The alteration of the huntingtin/HAP1/p150(Glued) complex correlated with reduced association of motor proteins with microtubules. The polyglutamine-huntingtin-induced transport deficit resulted in the loss of neurotrophic support and neuronal toxicity. <a href="#5" class="mim-tip-reference" title="Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lebmann, V., Humbert, S., Saudou, F. <strong>Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.</strong> Cell 118: 127-138, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15242649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15242649</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15242649">Gauthier et al. (2004)</a> concluded that a key role of huntingtin is to promote BDNF transport and suggested that loss of this function might contribute to pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15242649" 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 yeast 2-hybrid and immunoprecipitation analyses, <a href="#19" class="mim-tip-reference" title="Shimojo, M. <strong>Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150-Glued.</strong> J. Biol. Chem. 283: 34880-34886, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18922795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18922795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18922795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M804183200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18922795">Shimojo (2008)</a> showed that human RILP (PRICKLE1; <a href="/entry/608500">608500</a>) and huntingtin interacted directly with dynactin-1 to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in non-neuronal cells. In neuronal cells, the complex also contained HAP1, which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18922795" 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 in vivo skin-specific lentiviral RNA interference, <a href="#22" class="mim-tip-reference" title="Williams, S. E., Beronja, S., Pasolli, H. A., Fuchs, E. <strong>Asymmetric cell divisions promote Notch-dependent epidermal differentiation.</strong> Nature 470: 353-358, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21331036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21331036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21331036[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21331036">Williams et al. (2011)</a> investigated spindle orientation regulation and provided direct evidence that LGN (<a href="/entry/609245">609245</a>), NuMA (<a href="/entry/164009">164009</a>), and dynactin are involved. In compromising asymmetric cell divisions, <a href="#22" class="mim-tip-reference" title="Williams, S. E., Beronja, S., Pasolli, H. A., Fuchs, E. <strong>Asymmetric cell divisions promote Notch-dependent epidermal differentiation.</strong> Nature 470: 353-358, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21331036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21331036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21331036[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21331036">Williams et al. (2011)</a> uncovered profound defects in stratification, differentiation, and barrier formation, and implicated Notch (<a href="/entry/190198">190198</a>) signaling as an important effector. <a href="#22" class="mim-tip-reference" title="Williams, S. E., Beronja, S., Pasolli, H. A., Fuchs, E. <strong>Asymmetric cell divisions promote Notch-dependent epidermal differentiation.</strong> Nature 470: 353-358, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21331036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21331036</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21331036[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21331036">Williams et al. (2011)</a> concluded that asymmetric cell division components act by reorientating mitotic spindles to achieve perpendicular divisions, which in turn promote stratification and differentiation. Furthermore, the resemblance between their knockdown phenotypes and Rbpj (<a href="/entry/147183">147183</a>) loss-of-function mutants provided important clues that suprabasal Notch signaling is impaired when asymmetric cell divisions do not occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21331036" 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 mouse and human constructs, <a href="#23" class="mim-tip-reference" title="Zhapparova, O. N., Fokin, A. I., Vorobyeva, N. E., Bryantseva, S. A., Nadezhdina, E. S. <strong>Ste20-like protein kinase SLK (LOSK) regulates microtubule organization by targeting dynactin to the centrosome.</strong> Molec. Biol. Cell 24: 3205-3214, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23985322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23985322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23985322[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/10.1091/mbc.E13-03-0137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23985322">Zhapparova et al. (2013)</a> found that SLK (<a href="/entry/616563">616563</a>) phosphorylated a serine in the basic microtubule-binding domain of the minor p150(GLUED)1A isoform of DCTN1 and regulated dynactin centrosomal localization. This phosphorylation did not affect dynactin microtubule-organizing properties. Phosphorylation of p150(GLUED)1A was also involved in Golgi reorientation in polarized cells. The authors noted that the predominant isoform of DCTN1, p150(GLUED)1B, lacks 20 amino acids in the basic microtubule-binding region, including the serine phosphorylated by SLK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23985322" 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="mim-changed mim-change"><p><a href="#2" class="mim-tip-reference" title="Collin, G. B., Nishina, P. M., Marshall, J. D., Naggert, J. K. <strong>Human DCTN1: genomic structure and evaluation as a candidate for Alstrom syndrome.</strong> Genomics 53: 359-364, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9799602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9799602</a>] [<a href="https://doi.org/10.1006/geno.1998.5542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9799602">Collin et al. (1998)</a> found that the DCTN1 gene spans approximately 19.4 kb of genomic DNA and contains at least 32 exons ranging in size from 15 to 499 bp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9799602" 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></div>
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<p><a href="#18" class="mim-tip-reference" title="Pushkin, A., Abuladze, N., Newman, D., Tatishchev, S., Kurtz, I. <strong>Genomic organization of the DCTN1-SLC4A5 locus encoding both NBC4 and p150(Glued).</strong> Cytogenet. Cell Genet. 95: 163-168, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12063394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12063394</a>] [<a href="https://doi.org/10.1159/000059340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12063394">Pushkin et al. (2001)</a> showed by Southern blot and BAC analyses that the DCTN1 and SLC4A5 (<a href="/entry/606757">606757</a>) proteins are encoded by a single locus. The DCTN1-SLC4A5 locus spans approximately 230 kb and contains 66 exons. Approximately 200 kb encode SLC4A5. DCTN1 is encoded by exons 1 through alternative exon 32. The same locus therefore uniquely encodes both a membrane protein (SLC4A5) and a cytoplasmic protein (DCTN1) with distinct functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12063394" 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="#20" class="mim-tip-reference" title="Urnavicius, L., Lau, C. K., Elshenawy, M. M., Morales-Rios, E., Motz, C., Yildiz, A., Carter, A. P. <strong>Cryo-EM shows how dynactin recruits two dyneins for faster movement.</strong> Nature 554: 202-206, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29420470[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature25462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420470">Urnavicius et al. (2018)</a> used electron microscopy and single-molecule studies to show that adaptors can recruit a second dynein (<a href="/entry/600112">600112</a>) to dynactin. Whereas BICD2 (<a href="/entry/609797">609797</a>) is biased towards recruiting a single dynein, the adaptors BICDR1 (<a href="/entry/617002">617002</a>) and HOOK3 (<a href="/entry/607825">607825</a>) predominantly recruit 2 dyneins. <a href="#20" class="mim-tip-reference" title="Urnavicius, L., Lau, C. K., Elshenawy, M. M., Morales-Rios, E., Motz, C., Yildiz, A., Carter, A. P. <strong>Cryo-EM shows how dynactin recruits two dyneins for faster movement.</strong> Nature 554: 202-206, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29420470[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature25462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420470">Urnavicius et al. (2018)</a> found that the shift towards a double dynein complex increases both the force and speed of the microtubule motor. The 3.5-angstrom resolution cryoelectron microscopy reconstruction of a dynein tail-dynactin-BICDR1 complex revealed how dynactin can act as a scaffold to coordinate 2 dyneins side by side. <a href="#20" class="mim-tip-reference" title="Urnavicius, L., Lau, C. K., Elshenawy, M. M., Morales-Rios, E., Motz, C., Yildiz, A., Carter, A. P. <strong>Cryo-EM shows how dynactin recruits two dyneins for faster movement.</strong> Nature 554: 202-206, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29420470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29420470</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29420470[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature25462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29420470">Urnavicius et al. (2018)</a> concluded that their work provided a structural basis for understanding how diverse adaptors recruit different numbers of dyneins and regulate the motile properties of the dynein-dynactin transport machine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29420470" 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 fluorescence in situ hybridization, <a href="#6" class="mim-tip-reference" title="Holzbaur, E. L. F., Tokito, M. K. <strong>Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.</strong> Genomics 31: 398-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838327</a>] [<a href="https://doi.org/10.1006/geno.1996.0068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838327">Holzbaur and Tokito (1996)</a> mapped the DCTN1 gene to 2p13. They noted that the location of the gene corresponds to that of a form of recessive limb-girdle muscular dystrophy (see LGMD2B; <a href="/entry/253601">253601</a>). Also, this region of human chromosome 2 shows syntenic homology with a region of mouse chromosome 6 containing the mnd2 mouse mutation, which exhibits symptoms resembling human motor neuron disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838327" 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="#10" class="mim-tip-reference" title="Korthaus, D., Wedemeyer, N., Lengeling, A., Ronsiek, M., Jockusch, H., Schmitt-John, T. <strong>Integrated radiation hybrid map of human chromosome 2p13: possible involvement of dynactin in neuromuscular diseases.</strong> Genomics 43: 242-244, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244444</a>] [<a href="https://doi.org/10.1006/geno.1997.4789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244444">Korthaus et al. (1997)</a> presented evidence that the DCTN1 gene maps to chromosome 2 between TGFA and D2S1394. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9244444" 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="#21" class="mim-tip-reference" title="Vilarino-Guell, C., Wider, C., Soto-Ortolaza, A. I., Cobb, S. A., Kachergus, J. M., Keeling, B. H., Dachsel, J. C., Hulihan, M. M., Dickson, D. W., Wszolek, Z. K., Uitti, R. J., Graff-Radford, N. R., and 14 others. <strong>Characterization of DCTN1 genetic variability in neurodegeneration.</strong> Neurology 72: 2024-2028, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19506225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19506225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19506225[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/10.1212/WNL.0b013e3181a92c4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19506225">Vilarino-Guell et al. (2009)</a> sequenced the DCTN1 gene in 286 individuals with Parkinson disease (PD; <a href="/entry/168600">168600</a>), frontotemporal lobar degeneration (FTLD; <a href="/entry/600274">600274</a>), or amyotrophic lateral sclerosis (ALS; <a href="/entry/105400">105400</a>). None of the 36 variants identified segregated conclusively within families, suggesting that DCTN1 mutations are rare and do not play a common role in these diseases. Further analysis of 440 patients with PD, 374 with FTLD, and 372 with ALS who lacked a family history also failed to find an association between DCTN1 variants and disease. In fact, the previously reported pathogenic mutation T1249I (<a href="#0002">601143.0002</a>), which was identified in 3 of 435 controls, did not segregate in a large pedigree with Parkinson disease, thus weakening the evidence for the pathogenicity of this variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19506225" 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>Autosomal Dominant Distal Hereditary Motor Neuronopathy 14</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Puls, I., Jonnakuty, C., LaMonte, B. H., Holzbaur, E. L. F., Tokito, M., Mann, E., Floeter, M. K., Bidus, K., Drayna, D., Oh, S. J., Brown, R. H., Jr., Ludlow, C. L., Fischbeck, K. H. <strong>Mutant dynactin in motor neuron disease.</strong> Nature Genet. 33: 455-456, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627231</a>] [<a href="https://doi.org/10.1038/ng1123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627231">Puls et al. (2003)</a> identified a gly59-to-ser mutation (<a href="#0001">601143.0001</a>) in the DCTN1 gene in a family with slowly progressive autosomal dominant distal hereditary motor neuronopathy with vocal paresis (HMND14; <a href="/entry/607641">607641</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627231" 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>Susceptibility to Amyotrophic Lateral Sclerosis</em></strong></p><p>
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Among 250 patients with a putative diagnosis of amyotrophic lateral sclerosis (ALS; <a href="/entry/105400">105400</a>), <a href="#15" class="mim-tip-reference" title="Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.</strong> Neurology 63: 724-726, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326253</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134608.83927.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326253">Munch et al. (2004)</a> identified 3 mutations in the DCTN1 gene (<a href="#0002">601143.0002</a>-<a href="#0004">601143.0004</a>) in 3 families. The authors distinguished the phenotype in their patients from that reported by <a href="#17" class="mim-tip-reference" title="Puls, I., Jonnakuty, C., LaMonte, B. H., Holzbaur, E. L. F., Tokito, M., Mann, E., Floeter, M. K., Bidus, K., Drayna, D., Oh, S. J., Brown, R. H., Jr., Ludlow, C. L., Fischbeck, K. H. <strong>Mutant dynactin in motor neuron disease.</strong> Nature Genet. 33: 455-456, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627231</a>] [<a href="https://doi.org/10.1038/ng1123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627231">Puls et al. (2003)</a> by the presence of upper motor neuron signs, although specific clinical details were lacking. <a href="#15" class="mim-tip-reference" title="Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.</strong> Neurology 63: 724-726, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326253</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134608.83927.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326253">Munch et al. (2004)</a> suggested that mutations in the DCTN1 gene may be a susceptibility factor for ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15326253+12627231" 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>Perry Syndrome</em></strong></p><p>
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In affected members of 8 families with Perry syndrome (<a href="/entry/168605">168605</a>), <a href="#4" class="mim-tip-reference" title="Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others. <strong>DCTN1 mutations in Perry syndrome.</strong> Nature Genet. 41: 163-165, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136952">Farrer et al. (2009)</a> identified 5 different heterozygous mutations in the DCTN1 gene (see, e.g., <a href="#0006">601143.0006</a>-<a href="#0007">601143.0007</a>). In vitro functional expression studies indicated that the mutations resulted in decreased microtubule binding and intracytoplasmic inclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136952" 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 4 affected members of a large 3-generation French family with Perry syndrome, <a href="#1" class="mim-tip-reference" title="Caroppo, P., Le Ber, I., Clot, F., Rivaud-Pechoux, S., Camuzat, A., De Septenville, A., Boutoleau-Bretonniere, C., Mourlon, V., Sauvee, M., Lebouvier, T., Bonnet, A.-M., Levy, R., Vercelletto, M., Brice, A. <strong>DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.</strong> JAMA Neurol. 71: 208-215, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24343258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24343258</a>] [<a href="https://doi.org/10.1001/jamaneurol.2013.5100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24343258">Caroppo et al. (2014)</a> identified a heterozygous missense mutation in the DCTN1 gene (G71E; <a href="#0008">601143.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24343258" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>8 Selected Examples</a>):</strong>
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<a href="/allelicVariants/601143" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601143[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 14</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">rs121909342 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909342;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=rs121909342" 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=rs121909342" 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 North American family with a slowly progressive, autosomal dominant form of lower motor neuron with vocal cord paresis but without sensory symptoms (HMND14; <a href="/entry/607641">607641</a>), <a href="#17" class="mim-tip-reference" title="Puls, I., Jonnakuty, C., LaMonte, B. H., Holzbaur, E. L. F., Tokito, M., Mann, E., Floeter, M. K., Bidus, K., Drayna, D., Oh, S. J., Brown, R. H., Jr., Ludlow, C. L., Fischbeck, K. H. <strong>Mutant dynactin in motor neuron disease.</strong> Nature Genet. 33: 455-456, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627231</a>] [<a href="https://doi.org/10.1038/ng1123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627231">Puls et al. (2003)</a> found a single-basepair change in the DCTN1 gene (c.957C-T) resulting in an amino acid substitution of serine for glycine at position 59 in affected family members. The G59S substitution occurred in the highly conserved CAP-Gly motif of the p150(Glued) subunit of dynactin, a domain that binds directly to microtubules. The transport protein dynactin is required for dynein-mediated retrograde transport of vesicles and organelles along microtubules. Overexpression of dynamitin (<a href="/entry/607376">607376</a>), the p50 subunit of the dynactin complex, disrupts the complex and produces a late-onset, progressive motor neuron disease in transgenic mice (<a href="#11" class="mim-tip-reference" title="LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascano, J., Tokito, M., Van Winkle, T., Howland, D. S., Holzbaur, E. L. F. <strong>Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.</strong> Neuron 34: 715-727, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12062019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12062019</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00696-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12062019">LaMonte et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12062019+12627231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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Using in vitro studies, <a href="#12" class="mim-tip-reference" title="Levy, J. R., Sumner, C. J., Caviston, J. P., Tokito, M. K., Ranganathan, S., Ligon, L. A., Wallace, K. E., LaMonte, B. H., Harmison, G. G., Puls, I., Fischbeck, K. H., Holzbaur, E. L. F. <strong>A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation.</strong> J. Cell Biol. 172: 733-745, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16505168[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/10.1083/jcb.200511068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505168">Levy et al. (2006)</a> demonstrated that the mutant G59S mutation disrupted the binding of DCTN1 to microtubules and to EB1 (<a href="/entry/603108">603108</a>). Studies of fibroblasts and lymphoblasts derived from patients with the mutation suggested that the mutant protein is expressed and incorporated into the dynactin complex. Under stress conditions, the mutant cells showed impaired recovery of Golgi complex morphology compared to controls, consistent with a subtle defect. The G59S mutation disrupted the folding of the CAP-Gly domain, resulting in aggregation of the mutant protein, which promoted cell death in a motor cell line. Overexpression of the chaperone Hsp70 (<a href="/entry/140550">140550</a>) inhibited aggregate formation and prevented cell death. These data suggested that the G59S mutation causes both a subtle loss of function and a gain of toxic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16505168" 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>Based on crystal structure, gly59 is embedded in a beta-sheet. In budding yeast, <a href="#13" class="mim-tip-reference" title="Moore, J. K., Sept, D., Cooper, J. A. <strong>Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration.</strong> Proc. Nat. Acad. Sci. 106: 5147-5152, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19279216/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19279216</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19279216[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0810828106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19279216">Moore et al. (2009)</a> generated a G59S-analogous mutation that resulted in complete loss of the CAP-Gly domain. Functional expression studies showed that the CAP-Gly domain has a critical role in the initiation and persistence of dynein-dependent movement of the mitotic spindle and nucleus, but was otherwise dispensable for dynein-based movement. The function also appeared to be context-dependent, such as during mitosis, indicating that CAP-Gly activity may only be necessary when dynein needs to overcome high force thresholds to produce movement. The CAP-Gly domain was not the primary link between dynactin and microtubules, although it was involved in the interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19279216" 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> rs72466496 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72466496;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/rs72466496?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=rs72466496" 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=rs72466496" 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=RCV000008910 OR RCV000143802 OR RCV000263003 OR RCV000986779 OR RCV001082630 OR RCV001142310 OR RCV002345235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008910, RCV000143802, RCV000263003, RCV000986779, RCV001082630, RCV001142310, RCV002345235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008910...</a>
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<p>In a woman with a disorder similar to amyotrophic lateral sclerosis (<a href="/entry/105400">105400</a>), <a href="#15" class="mim-tip-reference" title="Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.</strong> Neurology 63: 724-726, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326253</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134608.83927.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326253">Munch et al. (2004)</a> identified a heterozygous 4546C-T transition in exon 13 of the DCTN1 gene, resulting in a thr1249-to-ile (T1249I) substitution. She had disease onset at age 56 years, with gait disturbance and distal lower limb muscle weakness and atrophy. The symptoms were slowly progressive over 4 years. There was no involvement of the upper limbs or bulbar region. There was no family history. The mutation was not identified in 150 control subjects. See also <a href="/entry/607641">607641</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326253" 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="Vilarino-Guell, C., Wider, C., Soto-Ortolaza, A. I., Cobb, S. A., Kachergus, J. M., Keeling, B. H., Dachsel, J. C., Hulihan, M. M., Dickson, D. W., Wszolek, Z. K., Uitti, R. J., Graff-Radford, N. R., and 14 others. <strong>Characterization of DCTN1 genetic variability in neurodegeneration.</strong> Neurology 72: 2024-2028, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19506225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19506225</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19506225[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/10.1212/WNL.0b013e3181a92c4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19506225">Vilarino-Guell et al. (2009)</a> identified the T1249I variant in 3 of 435 controls, 5 of 440 patients with Parkinson disease (<a href="/entry/168600">168600</a>), 1 of 374 with frontotemporal lobar degeneration (<a href="/entry/600274">600274</a>), and 5 of 372 patients with ALS. Lack of segregation of the variant in a large pedigree with Parkinson disease weakened the evidence for the pathogenicity of this variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19506225" 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> rs121909343 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909343;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/rs121909343?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=rs121909343" 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=rs121909343" 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=RCV000008911 OR RCV003447081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008911, RCV003447081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008911...</a>
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<p>In a woman with probable ALS (<a href="/entry/105400">105400</a>), <a href="#15" class="mim-tip-reference" title="Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.</strong> Neurology 63: 724-726, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326253</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134608.83927.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326253">Munch et al. (2004)</a> identified a heterozygous 2512T-C transition in exon 15 of the DCTN1 gene, resulting in a met571-to-thr (M571T) substitution. She had onset of upper limb involvement at age 48 years and developed bulbar symptoms within 8 years. Her sister was similarly affected, although DNA was not available. The mutation was not identified in 150 control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326253" 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 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO</strong>
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DCTN1, ARG785TRP
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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> rs121909344 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909344;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/rs121909344?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=rs121909344" 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=rs121909344" 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=RCV000008912 OR RCV000144867 OR RCV000644476 OR RCV000986781 OR RCV001140673 OR RCV001140674 OR RCV001572734 OR RCV002444424 OR RCV003952351" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008912, RCV000144867, RCV000644476, RCV000986781, RCV001140673, RCV001140674, RCV001572734, RCV002444424, RCV003952351" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008912...</a>
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<p>In 2 brothers with probable ALS (<a href="/entry/105400">105400</a>), <a href="#15" class="mim-tip-reference" title="Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., Prudlo, J., Peraus, G., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS.</strong> Neurology 63: 724-726, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15326253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15326253</a>] [<a href="https://doi.org/10.1212/01.wnl.0000134608.83927.b1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15326253">Munch et al. (2004)</a> identified a heterozygous 3153C-T transition in exon 20 of the DCTN1 gene, resulting in an arg785-to-trp (R785W) substitution. The proband had upper limb onset at age 55 years, whereas his brother had bulbar onset at age 64 years. The asymptomatic mother and sister carried the same mutation, suggesting incomplete penetrance. The mutation was not identified in 150 control subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15326253" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO</strong>
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DCTN1, ARG1101LYS
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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> rs121909345 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909345;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/rs121909345?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=rs121909345" 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=rs121909345" 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=RCV000008913 OR RCV001202903 OR RCV002453250 OR RCV003447082 OR RCV004700205" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008913, RCV001202903, RCV002453250, RCV003447082, RCV004700205" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008913...</a>
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<p>In a patient with amyotrophic lateral sclerosis (<a href="/entry/105400">105400</a>), <a href="#14" class="mim-tip-reference" title="Munch, C., Rosenbohm, A., Sperfeld, A.-D., Uttner, I., Reske, S., Krause, B. J., Sedlmeier, R., Meyer, T., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD.</strong> Ann. Neurol. 58: 777-780, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240349</a>] [<a href="https://doi.org/10.1002/ana.20631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240349">Munch et al. (2005)</a> identified a heterozygous 4102G-A transition in the DCTN1 gene, resulting in an arg1101-to-lys (R1101K) substitution. The patient's brother, who also carried the R1101K mutation, had frontotemporal dementia without motor involvement. Family history revealed that 2 additional family members reportedly had motor neuron disease and frontotemporal dementia, respectively, but their DNA was not available for testing. The mutation was not identified in 500 control individuals. Despite the molecular findings, <a href="#14" class="mim-tip-reference" title="Munch, C., Rosenbohm, A., Sperfeld, A.-D., Uttner, I., Reske, S., Krause, B. J., Sedlmeier, R., Meyer, T., Hanemann, C. O., Stumm, G., Ludolph, A. C. <strong>Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD.</strong> Ann. Neurol. 58: 777-780, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16240349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16240349</a>] [<a href="https://doi.org/10.1002/ana.20631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16240349">Munch et al. (2005)</a> suggested that the R1101K variant may not be the primary gene defect in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16240349" 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>.0006 PERRY SYNDROME</strong>
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DCTN1, GLY71ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs72466485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72466485;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=rs72466485" 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=rs72466485" 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=RCV000008914 OR RCV004766988" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008914, RCV004766988" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008914...</a>
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<p>In affected members of 2 unrelated families with Perry syndrome (<a href="/entry/168605">168605</a>), <a href="#4" class="mim-tip-reference" title="Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others. <strong>DCTN1 mutations in Perry syndrome.</strong> Nature Genet. 41: 163-165, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136952">Farrer et al. (2009)</a> identified a heterozygous 211G-A transition in exon 2 of the DCTN1 gene, resulting in a gly71-to-arg (G71R) substitution at a highly conserved residue within the GKNDG binding motif of the CAP-Gly domain. The families were of Canadian and Turkish ancestry, respectively, and haplotype analysis excluded a founder effect. In vitro functional expression studies showed that the mutation decreased microtubule binding and resulted in intracytoplasmic inclusions. <a href="#4" class="mim-tip-reference" title="Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others. <strong>DCTN1 mutations in Perry syndrome.</strong> Nature Genet. 41: 163-165, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136952">Farrer et al. (2009)</a> also identified a different mutation in the same codon (G71E; <a href="#0008">601143.0008</a>) in patients with this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136952" 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="#16" class="mim-tip-reference" title="Newsway, V., Fish, M., Rohrer, J. D., Majounie, E., Williams, N., Hack, M., Warren, J. D., Morris, H. R. <strong>Perry syndrome due to the DCTN1 G71R mutation: a distinctive levodopa responsive disorder with behavioral syndrome, vertical gaze palsy, and respiratory failure.</strong> Mov. Disord. 25: 767-770, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20437543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20437543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20437543[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/10.1002/mds.22950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20437543">Newsway et al. (2010)</a> identified a heterozygous G71R mutation in the DCTN1 gene in a man who developed symptoms in his mid-forties. In addition to parkinsonism, psychiatric disturbances, and weight loss, he showed signs of frontotemporal dementia as well as slowing of vertical downgaze and midbrain atrophy, reminiscent of progressive supranuclear palsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20437543" 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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DCTN1, GLN74PRO
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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> rs72466487 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs72466487;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/rs72466487?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=rs72466487" 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=rs72466487" 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=RCV000008915 OR RCV001531490" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008915, RCV001531490" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008915...</a>
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<p>In affected members of a Japanese family with Perry syndrome (<a href="/entry/168605">168605</a>), <a href="#4" class="mim-tip-reference" title="Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others. <strong>DCTN1 mutations in Perry syndrome.</strong> Nature Genet. 41: 163-165, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136952">Farrer et al. (2009)</a> identified a heterozygous 221A-C transversion in exon 2 of the DCTN1 gene, resulting in a gln74-to-pro (Q74P) substitution at a highly conserved residue adjacent to the GKNDG binding motif of the CAP-Gly domain. In vitro functional expression studies showed that the mutation decreased microtubule binding and resulted in intracytoplasmic inclusions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136952" 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>.0008 PERRY SYNDROME</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">rs67586389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs67586389;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=rs67586389" 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=rs67586389" 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=RCV000020576 OR RCV001531491 OR RCV003764613" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020576, RCV001531491, RCV003764613" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020576...</a>
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<p>In 4 affected members of a 3-generation French family with various manifestations of a neurodegenerative disorder consistent with Perry syndrome (<a href="/entry/168605">168605</a>), <a href="#1" class="mim-tip-reference" title="Caroppo, P., Le Ber, I., Clot, F., Rivaud-Pechoux, S., Camuzat, A., De Septenville, A., Boutoleau-Bretonniere, C., Mourlon, V., Sauvee, M., Lebouvier, T., Bonnet, A.-M., Levy, R., Vercelletto, M., Brice, A. <strong>DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.</strong> JAMA Neurol. 71: 208-215, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24343258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24343258</a>] [<a href="https://doi.org/10.1001/jamaneurol.2013.5100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24343258">Caroppo et al. (2014)</a> identified a heterozygous c.212G-A transition in exon 2 of the DCTN1 gene, resulting in a gly71-to-glu (G71E) substitution at a highly conserved residue in the GKNDG domain. The mutation segregated with the disorder in the family and was not present in the Exome Variant Server database. In addition to the cardinal features of Perry syndrome, some patients showed frontotemporal dementia and features reminiscent of progressive supranuclear palsy. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24343258" 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>This mutation had previously been reported by <a href="#4" class="mim-tip-reference" title="Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others. <strong>DCTN1 mutations in Perry syndrome.</strong> Nature Genet. 41: 163-165, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136952">Farrer et al. (2009)</a> in affected members of an unrelated French family with Perry syndrome. <a href="#4" class="mim-tip-reference" title="Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others. <strong>DCTN1 mutations in Perry syndrome.</strong> Nature Genet. 41: 163-165, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136952">Farrer et al. (2009)</a> also identified a different mutation in the same codon (G71R; <a href="#0006">601143.0006</a>) in patients with this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136952" 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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Caroppo, P., Le Ber, I., Clot, F., Rivaud-Pechoux, S., Camuzat, A., De Septenville, A., Boutoleau-Bretonniere, C., Mourlon, V., Sauvee, M., Lebouvier, T., Bonnet, A.-M., Levy, R., Vercelletto, M., Brice, A.
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<strong>DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24343258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24343258</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24343258" 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/jamaneurol.2013.5100" target="_blank">Full Text</a>]
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Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others.
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<strong>DCTN1 mutations in Perry syndrome.</strong>
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Nature Genet. 41: 163-165, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136952/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136952</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136952[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=19136952" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lebmann, V., Humbert, S., Saudou, F.
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[<a href="https://doi.org/10.1146/annurev.cb.10.110194.002011" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bbrc.1997.6095" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1352" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4789" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(02)00696-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.200511068" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0810828106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20631" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000134608.83927.b1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/mds.22950" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1123" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23985322/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23985322</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23985322[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=23985322" 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/10.1091/mbc.E13-03-0137" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 09/23/2019
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Ada Hamosh - updated : 04/16/2018<br>Patricia A. Hartz - updated : 09/21/2015<br>Cassandra L. Kniffin - updated : 8/7/2014<br>Ada Hamosh - updated : 6/29/2011<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Cassandra L. Kniffin - updated : 10/14/2009<br>Cassandra L. Kniffin - updated : 2/10/2009<br>Cassandra L. Kniffin - updated : 3/6/2006<br>Cassandra L. Kniffin - updated : 3/4/2005<br>Stylianos E. Antonarakis - updated : 8/3/2004<br>Victor A. McKusick - updated : 4/27/2004<br>Victor A. McKusick - updated : 3/19/2003<br>Dawn Watkins-Chow - updated : 11/27/2002<br>Paul J. Converse - updated : 6/24/2002<br>Carol A. Bocchini - updated : 2/24/1999<br>Victor A. McKusick - updated : 9/4/1997
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<a id="creationDate" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/20/1996
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 02/19/2025
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alopez : 10/16/2023<br>mgross : 09/23/2019<br>alopez : 04/16/2018<br>mgross : 09/21/2015<br>carol : 8/8/2014<br>mcolton : 8/7/2014<br>ckniffin : 8/7/2014<br>carol : 9/21/2012<br>alopez : 7/5/2011<br>alopez : 7/5/2011<br>terry : 6/29/2011<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 10/23/2009<br>ckniffin : 10/14/2009<br>carol : 9/15/2009<br>wwang : 2/24/2009<br>ckniffin : 2/10/2009<br>ckniffin : 3/16/2007<br>wwang : 3/10/2006<br>ckniffin : 3/6/2006<br>ckniffin : 4/4/2005<br>wwang : 3/17/2005<br>wwang : 3/16/2005<br>wwang : 3/11/2005<br>ckniffin : 3/4/2005<br>mgross : 8/3/2004<br>alopez : 5/3/2004<br>alopez : 4/27/2004<br>alopez : 4/2/2003<br>alopez : 3/20/2003<br>terry : 3/19/2003<br>carol : 12/6/2002<br>tkritzer : 11/27/2002<br>tkritzer : 11/27/2002<br>mgross : 11/22/2002<br>mgross : 6/24/2002<br>mgross : 6/24/2002<br>alopez : 5/11/2001<br>terry : 2/25/1999<br>carol : 2/24/1999<br>terry : 9/10/1997<br>terry : 9/4/1997<br>mark : 3/21/1996
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<span class="mim-font">
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<strong>*</strong> 601143
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<h3>
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DYNACTIN 1; DCTN1
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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p150(GLUED), DROSOPHILA, HOMOLOG OF
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DCTN1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 699184009;
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<strong>
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<em>
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Cytogenetic location: 2p13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:74,361,155-74,391,866 </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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<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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<span class="mim-font">
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2p13.1
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<span class="mim-font">
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{Amyotrophic lateral sclerosis, susceptibility to}
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<span class="mim-font">
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105400
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Autosomal dominant; Autosomal recessive
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<span class="mim-font">
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3
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Neuronopathy, distal hereditary motor, autosomal dominant 14
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<span class="mim-font">
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607641
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<span class="mim-font">
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Autosomal dominant
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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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Perry syndrome
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<span class="mim-font">
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168605
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</h4>
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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 DCTN1 gene encodes p150(Glued), the largest polypeptide of the dynactin complex, which binds directly to microtubules and to cytoplasmic dynein (DYNC1H1; 600112), a microtubule-based biologic motor protein (Holzbaur and Tokito, 1996). </p><p>Holzbaur and Tokito (1996) noted that dyneins were initially discovered as enzymes that couple ATP hydrolysis to provide a force for cellular motility in eukaryotic cilia and flagella. A distinct cytoplasmic form of dynein was subsequently characterized and thought to be responsible for the intracellular retrograde motility of vesicles and organelles along microtubules (Holzbaur and Vallee, 1994). A large macromolecular complex, dynactin, is required for the cytoplasmic dynein-driven movement of organelles along microtubules. Dynactin is composed of 10 distinct polypeptides of 150, 135, 62, 50 (DCTN2; 607376), 45, 42, 37, 32, 27, and 24 kD, with a combined mass of 10 million daltons. The binding of dynactin to dynein is critical for neuronal function, as antibodies that specifically disrupt this binding block vesicle motility along microtubules in extruded squid axoplasm. Holzbaur and Tokito (1996) stated that the dynein-dynactin interaction is probably a key component of the mechanism of axonal transport of vesicles and organelles. Further evidence for a critical role for dynactin in vivo comes from the analysis of mutations in the homologous gene in Drosophila. Mutant alleles of the 'glued' gene induced disruption of the neurons of the optic lobe and compound eye in heterozygotes; null mutations are lethal. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Holzbaur and Tokito (1996) isolated and characterized cDNA clones encoding human p150(Glued), as well as alternatively spliced isoforms. Using these to isolate genomic clones, they found by genomic Southern blots that there is a single gene in the human, as had previously been observed in rat and chick. </p><p>Jang et al. (1997) cloned and characterized mouse Dctn1. The mouse protein shares 95% amino acid identity with the human protein. The authors found no abnormalities of the gene in mnd2 mice. </p>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Eaton et al. (2002) disrupted the dynactin complex in Drosophila, using 3 separate perturbations: dsRNA interference with arp1 (homolog of ACTR1A; 605143), mutation in p150/Glued, and a dominant-negative Glued transgene. In all 3 cases, the disruption resulted in an increase in the frequency and extent of synaptic retraction events at the neuromuscular junction. Eaton et al. (2002) concluded that dynactin functions locally within the presynaptic arbor to promote synapse stability at the neuromuscular junction. </p><p>Kim et al. (2004) showed that BBS4 (600374) protein localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery to recruit pericentriolar material-1 protein (PCM1; 600299) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division, and apoptotic cell death. </p><p>Gauthier et al. (2004) showed that huntingtin (613004) specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF; 113505) along microtubules. They determined that huntingtin-mediated transport involves huntingtin-associated protein-1 (HAP1; 600947) and the p150(Glued) subunit of dynactin, an essential component of molecular motors. BDNF transport was attenuated both in the disease context and by reducing the levels of wildtype huntingtin. The alteration of the huntingtin/HAP1/p150(Glued) complex correlated with reduced association of motor proteins with microtubules. The polyglutamine-huntingtin-induced transport deficit resulted in the loss of neurotrophic support and neuronal toxicity. Gauthier et al. (2004) concluded that a key role of huntingtin is to promote BDNF transport and suggested that loss of this function might contribute to pathogenesis. </p><p>Using yeast 2-hybrid and immunoprecipitation analyses, Shimojo (2008) showed that human RILP (PRICKLE1; 608500) and huntingtin interacted directly with dynactin-1 to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in non-neuronal cells. In neuronal cells, the complex also contained HAP1, which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity. </p><p>Using in vivo skin-specific lentiviral RNA interference, Williams et al. (2011) investigated spindle orientation regulation and provided direct evidence that LGN (609245), NuMA (164009), and dynactin are involved. In compromising asymmetric cell divisions, Williams et al. (2011) uncovered profound defects in stratification, differentiation, and barrier formation, and implicated Notch (190198) signaling as an important effector. Williams et al. (2011) concluded that asymmetric cell division components act by reorientating mitotic spindles to achieve perpendicular divisions, which in turn promote stratification and differentiation. Furthermore, the resemblance between their knockdown phenotypes and Rbpj (147183) loss-of-function mutants provided important clues that suprabasal Notch signaling is impaired when asymmetric cell divisions do not occur. </p><p>Using mouse and human constructs, Zhapparova et al. (2013) found that SLK (616563) phosphorylated a serine in the basic microtubule-binding domain of the minor p150(GLUED)1A isoform of DCTN1 and regulated dynactin centrosomal localization. This phosphorylation did not affect dynactin microtubule-organizing properties. Phosphorylation of p150(GLUED)1A was also involved in Golgi reorientation in polarized cells. The authors noted that the predominant isoform of DCTN1, p150(GLUED)1B, lacks 20 amino acids in the basic microtubule-binding region, including the serine phosphorylated by SLK. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Collin et al. (1998) found that the DCTN1 gene spans approximately 19.4 kb of genomic DNA and contains at least 32 exons ranging in size from 15 to 499 bp. </p><p>Pushkin et al. (2001) showed by Southern blot and BAC analyses that the DCTN1 and SLC4A5 (606757) proteins are encoded by a single locus. The DCTN1-SLC4A5 locus spans approximately 230 kb and contains 66 exons. Approximately 200 kb encode SLC4A5. DCTN1 is encoded by exons 1 through alternative exon 32. The same locus therefore uniquely encodes both a membrane protein (SLC4A5) and a cytoplasmic protein (DCTN1) with distinct functions. </p>
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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>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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Urnavicius et al. (2018) used electron microscopy and single-molecule studies to show that adaptors can recruit a second dynein (600112) to dynactin. Whereas BICD2 (609797) is biased towards recruiting a single dynein, the adaptors BICDR1 (617002) and HOOK3 (607825) predominantly recruit 2 dyneins. Urnavicius et al. (2018) found that the shift towards a double dynein complex increases both the force and speed of the microtubule motor. The 3.5-angstrom resolution cryoelectron microscopy reconstruction of a dynein tail-dynactin-BICDR1 complex revealed how dynactin can act as a scaffold to coordinate 2 dyneins side by side. Urnavicius et al. (2018) concluded that their work provided a structural basis for understanding how diverse adaptors recruit different numbers of dyneins and regulate the motile properties of the dynein-dynactin transport machine. </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>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 fluorescence in situ hybridization, Holzbaur and Tokito (1996) mapped the DCTN1 gene to 2p13. They noted that the location of the gene corresponds to that of a form of recessive limb-girdle muscular dystrophy (see LGMD2B; 253601). Also, this region of human chromosome 2 shows syntenic homology with a region of mouse chromosome 6 containing the mnd2 mouse mutation, which exhibits symptoms resembling human motor neuron disease. </p><p>Korthaus et al. (1997) presented evidence that the DCTN1 gene maps to chromosome 2 between TGFA and D2S1394. </p>
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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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</h4>
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</div>
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<span class="mim-text-font">
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<p>Vilarino-Guell et al. (2009) sequenced the DCTN1 gene in 286 individuals with Parkinson disease (PD; 168600), frontotemporal lobar degeneration (FTLD; 600274), or amyotrophic lateral sclerosis (ALS; 105400). None of the 36 variants identified segregated conclusively within families, suggesting that DCTN1 mutations are rare and do not play a common role in these diseases. Further analysis of 440 patients with PD, 374 with FTLD, and 372 with ALS who lacked a family history also failed to find an association between DCTN1 variants and disease. In fact, the previously reported pathogenic mutation T1249I (601143.0002), which was identified in 3 of 435 controls, did not segregate in a large pedigree with Parkinson disease, thus weakening the evidence for the pathogenicity of this variant. </p><p><strong><em>Autosomal Dominant Distal Hereditary Motor Neuronopathy 14</em></strong></p><p>
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Puls et al. (2003) identified a gly59-to-ser mutation (601143.0001) in the DCTN1 gene in a family with slowly progressive autosomal dominant distal hereditary motor neuronopathy with vocal paresis (HMND14; 607641). </p><p><strong><em>Susceptibility to Amyotrophic Lateral Sclerosis</em></strong></p><p>
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Among 250 patients with a putative diagnosis of amyotrophic lateral sclerosis (ALS; 105400), Munch et al. (2004) identified 3 mutations in the DCTN1 gene (601143.0002-601143.0004) in 3 families. The authors distinguished the phenotype in their patients from that reported by Puls et al. (2003) by the presence of upper motor neuron signs, although specific clinical details were lacking. Munch et al. (2004) suggested that mutations in the DCTN1 gene may be a susceptibility factor for ALS. </p><p><strong><em>Perry Syndrome</em></strong></p><p>
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In affected members of 8 families with Perry syndrome (168605), Farrer et al. (2009) identified 5 different heterozygous mutations in the DCTN1 gene (see, e.g., 601143.0006-601143.0007). In vitro functional expression studies indicated that the mutations resulted in decreased microtubule binding and intracytoplasmic inclusions. </p><p>In 4 affected members of a large 3-generation French family with Perry syndrome, Caroppo et al. (2014) identified a heterozygous missense mutation in the DCTN1 gene (G71E; 601143.0008). </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 14</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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DCTN1, GLY59SER
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<br />
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SNP: rs121909342,
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ClinVar: RCV000008909, RCV000644484, RCV000789086, RCV003447080
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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 North American family with a slowly progressive, autosomal dominant form of lower motor neuron with vocal cord paresis but without sensory symptoms (HMND14; 607641), Puls et al. (2003) found a single-basepair change in the DCTN1 gene (c.957C-T) resulting in an amino acid substitution of serine for glycine at position 59 in affected family members. The G59S substitution occurred in the highly conserved CAP-Gly motif of the p150(Glued) subunit of dynactin, a domain that binds directly to microtubules. The transport protein dynactin is required for dynein-mediated retrograde transport of vesicles and organelles along microtubules. Overexpression of dynamitin (607376), the p50 subunit of the dynactin complex, disrupts the complex and produces a late-onset, progressive motor neuron disease in transgenic mice (LaMonte et al., 2002). </p><p><strong><em>Variant Function</em></strong></p><p>
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Using in vitro studies, Levy et al. (2006) demonstrated that the mutant G59S mutation disrupted the binding of DCTN1 to microtubules and to EB1 (603108). Studies of fibroblasts and lymphoblasts derived from patients with the mutation suggested that the mutant protein is expressed and incorporated into the dynactin complex. Under stress conditions, the mutant cells showed impaired recovery of Golgi complex morphology compared to controls, consistent with a subtle defect. The G59S mutation disrupted the folding of the CAP-Gly domain, resulting in aggregation of the mutant protein, which promoted cell death in a motor cell line. Overexpression of the chaperone Hsp70 (140550) inhibited aggregate formation and prevented cell death. These data suggested that the G59S mutation causes both a subtle loss of function and a gain of toxic function. </p><p>Based on crystal structure, gly59 is embedded in a beta-sheet. In budding yeast, Moore et al. (2009) generated a G59S-analogous mutation that resulted in complete loss of the CAP-Gly domain. Functional expression studies showed that the CAP-Gly domain has a critical role in the initiation and persistence of dynein-dependent movement of the mitotic spindle and nucleus, but was otherwise dispensable for dynein-based movement. The function also appeared to be context-dependent, such as during mitosis, indicating that CAP-Gly activity may only be necessary when dynein needs to overcome high force thresholds to produce movement. The CAP-Gly domain was not the primary link between dynactin and microtubules, although it was involved in the interaction. </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 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO</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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DCTN1, THR1249ILE
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<br />
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SNP: rs72466496,
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gnomAD: rs72466496,
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ClinVar: RCV000008910, RCV000143802, RCV000263003, RCV000986779, RCV001082630, RCV001142310, RCV002345235
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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 woman with a disorder similar to amyotrophic lateral sclerosis (105400), Munch et al. (2004) identified a heterozygous 4546C-T transition in exon 13 of the DCTN1 gene, resulting in a thr1249-to-ile (T1249I) substitution. She had disease onset at age 56 years, with gait disturbance and distal lower limb muscle weakness and atrophy. The symptoms were slowly progressive over 4 years. There was no involvement of the upper limbs or bulbar region. There was no family history. The mutation was not identified in 150 control subjects. See also 607641. </p><p>Vilarino-Guell et al. (2009) identified the T1249I variant in 3 of 435 controls, 5 of 440 patients with Parkinson disease (168600), 1 of 374 with frontotemporal lobar degeneration (600274), and 5 of 372 patients with ALS. Lack of segregation of the variant in a large pedigree with Parkinson disease weakened the evidence for the pathogenicity of this variant. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO</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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DCTN1, MET571THR
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<br />
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SNP: rs121909343,
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gnomAD: rs121909343,
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ClinVar: RCV000008911, RCV003447081
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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 woman with probable ALS (105400), Munch et al. (2004) identified a heterozygous 2512T-C transition in exon 15 of the DCTN1 gene, resulting in a met571-to-thr (M571T) substitution. She had onset of upper limb involvement at age 48 years and developed bulbar symptoms within 8 years. Her sister was similarly affected, although DNA was not available. The mutation was not identified in 150 control subjects. </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>.0004 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO</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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DCTN1, ARG785TRP
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<br />
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SNP: rs121909344,
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gnomAD: rs121909344,
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ClinVar: RCV000008912, RCV000144867, RCV000644476, RCV000986781, RCV001140673, RCV001140674, RCV001572734, RCV002444424, RCV003952351
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 brothers with probable ALS (105400), Munch et al. (2004) identified a heterozygous 3153C-T transition in exon 20 of the DCTN1 gene, resulting in an arg785-to-trp (R785W) substitution. The proband had upper limb onset at age 55 years, whereas his brother had bulbar onset at age 64 years. The asymptomatic mother and sister carried the same mutation, suggesting incomplete penetrance. The mutation was not identified in 150 control subjects. </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>.0005 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
DCTN1, ARG1101LYS
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<br />
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|
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SNP: rs121909345,
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|
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gnomAD: rs121909345,
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|
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|
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ClinVar: RCV000008913, RCV001202903, RCV002453250, RCV003447082, RCV004700205
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|
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|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with amyotrophic lateral sclerosis (105400), Munch et al. (2005) identified a heterozygous 4102G-A transition in the DCTN1 gene, resulting in an arg1101-to-lys (R1101K) substitution. The patient's brother, who also carried the R1101K mutation, had frontotemporal dementia without motor involvement. Family history revealed that 2 additional family members reportedly had motor neuron disease and frontotemporal dementia, respectively, but their DNA was not available for testing. The mutation was not identified in 500 control individuals. Despite the molecular findings, Munch et al. (2005) suggested that the R1101K variant may not be the primary gene defect in this family. </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PERRY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DCTN1, GLY71ARG
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs72466485,
|
|
|
|
|
|
|
|
ClinVar: RCV000008914, RCV004766988
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with Perry syndrome (168605), Farrer et al. (2009) identified a heterozygous 211G-A transition in exon 2 of the DCTN1 gene, resulting in a gly71-to-arg (G71R) substitution at a highly conserved residue within the GKNDG binding motif of the CAP-Gly domain. The families were of Canadian and Turkish ancestry, respectively, and haplotype analysis excluded a founder effect. In vitro functional expression studies showed that the mutation decreased microtubule binding and resulted in intracytoplasmic inclusions. Farrer et al. (2009) also identified a different mutation in the same codon (G71E; 601143.0008) in patients with this disorder. </p><p>Newsway et al. (2010) identified a heterozygous G71R mutation in the DCTN1 gene in a man who developed symptoms in his mid-forties. In addition to parkinsonism, psychiatric disturbances, and weight loss, he showed signs of frontotemporal dementia as well as slowing of vertical downgaze and midbrain atrophy, reminiscent of progressive supranuclear palsy. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PERRY SYNDROME</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
DCTN1, GLN74PRO
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<br />
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|
|
SNP: rs72466487,
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|
|
gnomAD: rs72466487,
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|
|
|
|
|
ClinVar: RCV000008915, RCV001531490
|
|
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|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Japanese family with Perry syndrome (168605), Farrer et al. (2009) identified a heterozygous 221A-C transversion in exon 2 of the DCTN1 gene, resulting in a gln74-to-pro (Q74P) substitution at a highly conserved residue adjacent to the GKNDG binding motif of the CAP-Gly domain. In vitro functional expression studies showed that the mutation decreased microtubule binding and resulted in intracytoplasmic inclusions. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PERRY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
DCTN1, GLY71GLU
|
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|
|
<br />
|
|
|
|
SNP: rs67586389,
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|
|
|
|
|
ClinVar: RCV000020576, RCV001531491, RCV003764613
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected members of a 3-generation French family with various manifestations of a neurodegenerative disorder consistent with Perry syndrome (168605), Caroppo et al. (2014) identified a heterozygous c.212G-A transition in exon 2 of the DCTN1 gene, resulting in a gly71-to-glu (G71E) substitution at a highly conserved residue in the GKNDG domain. The mutation segregated with the disorder in the family and was not present in the Exome Variant Server database. In addition to the cardinal features of Perry syndrome, some patients showed frontotemporal dementia and features reminiscent of progressive supranuclear palsy. Functional studies of the variant were not performed. </p><p>This mutation had previously been reported by Farrer et al. (2009) in affected members of an unrelated French family with Perry syndrome. Farrer et al. (2009) also identified a different mutation in the same codon (G71R; 601143.0006) in patients with this disorder. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Caroppo, P., Le Ber, I., Clot, F., Rivaud-Pechoux, S., Camuzat, A., De Septenville, A., Boutoleau-Bretonniere, C., Mourlon, V., Sauvee, M., Lebouvier, T., Bonnet, A.-M., Levy, R., Vercelletto, M., Brice, A.
|
|
<strong>DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.</strong>
|
|
JAMA Neurol. 71: 208-215, 2014.
|
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|
|
[PubMed: 24343258]
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[Full Text: https://doi.org/10.1001/jamaneurol.2013.5100]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Collin, G. B., Nishina, P. M., Marshall, J. D., Naggert, J. K.
|
|
<strong>Human DCTN1: genomic structure and evaluation as a candidate for Alstrom syndrome.</strong>
|
|
Genomics 53: 359-364, 1998.
|
|
|
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|
|
[PubMed: 9799602]
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[Full Text: https://doi.org/10.1006/geno.1998.5542]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Eaton, B. A., Fetter, R. D., Davis, G. W.
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|
<strong>Dynactin is necessary for synapse stabilization.</strong>
|
|
Neuron 34: 729-741, 2002.
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|
[PubMed: 12062020]
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[Full Text: https://doi.org/10.1016/s0896-6273(02)00721-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L., Calne, S., Calne, D. B., Lechevalier, B., Chapon, F., Tsuboi, Y., Yamada, T., and 10 others.
|
|
<strong>DCTN1 mutations in Perry syndrome.</strong>
|
|
Nature Genet. 41: 163-165, 2009.
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[PubMed: 19136952]
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[Full Text: https://doi.org/10.1038/ng.293]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lebmann, V., Humbert, S., Saudou, F.
|
|
<strong>Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.</strong>
|
|
Cell 118: 127-138, 2004.
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[PubMed: 15242649]
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[Full Text: https://doi.org/10.1016/j.cell.2004.06.018]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Holzbaur, E. L. F., Tokito, M. K.
|
|
<strong>Localization of the DCTN1 gene encoding p150(Glued) to human chromosome 2p13 by fluorescence in situ hybridization.</strong>
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