4421 lines
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- *600112 - DYNEIN, CYTOPLASMIC 1, HEAVY CHAIN 1; DYNC1H1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600112</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600112">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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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<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 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=ENSG00000197102;t=ENST00000360184" 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=1778" 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=600112" 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 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=ENSG00000197102;t=ENST00000360184" 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_001376" 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_001376" 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=600112" 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=02524&isoform_id=02524_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/DYNC1H1" 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/397774,1314643,1549349,7025519,33350932,40352901,50345286,57015308,119602165,119602166,119602167,119602168,119602169,119602170,166788526,194389534,211826822,929653974,2175795909,2175795911,2175795913,2175795915" 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/Q14204" 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=1778" 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=ENSG00000197102;t=ENST00000360184" 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=DYNC1H1" 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=DYNC1H1" 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+1778" 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/DYNC1H1" 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:1778" 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/1778" 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=chr14&hgg_gene=ENST00000360184.10&hgg_start=101964573&hgg_end=102056443&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:2961" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2961" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/dync1h1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600112[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=600112[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://www.deciphergenomics.org/gene/DYNC1H1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000197102" 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=DYNC1H1" 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=DYNC1H1" 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=DYNC1H1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DYNC1H1&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/PA27432" 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:2961" 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/FBgn0261797.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:103147" 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/DYNC1H1#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:103147" 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/1778/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://omia.org/OMIA000061/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1778" 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=WBGene00000962;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-7050" 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:1778" 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=DYNC1H1&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> 782829002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600112
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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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DYNEIN, CYTOPLASMIC 1, HEAVY CHAIN 1; DYNC1H1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
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DNCH1<br />
|
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DYNEIN, CYTOPLASMIC-LIKE; DNCL; DNECL<br />
|
|
DYNEIN HEAVY POLYPEPTIDE, CYTOPLASMIC; DHC1; DHC1A<br />
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DNCHC1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DYNC1H1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DYNC1H1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
|
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/14/559?start=-3&limit=10&highlight=559">14q32.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:101964573-102056443&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'})">14:101,964,573-102,056,443</a> </span>
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614228,614563,158600" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/14/559?start=-3&limit=10&highlight=559">
|
|
14q32.31
|
|
</a>
|
|
</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Charcot-Marie-Tooth disease, axonal, type 2O
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614228"> 614228 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="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>
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<p>The DYNC1H1 gene encodes a large (over 530 kD) crucial subunit of the cytoplasmic dynein complex (summary by <a href="#18" class="mim-tip-reference" title="Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. <strong>Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.</strong> Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23603762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23603762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23603762[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.2613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23603762">Poirier et al., 2013</a>). Dyneins are a group of microtubule-activated ATPases that serve to convert chemical energy into mechanical energy. They have been divided into 2 large subgroups, namely, the axonemal and cytoplasmic dyneins. Cytoplasmic dynein has been implicated in a variety of other forms of intracellular motility, including retrograde axonal transport, protein sorting between apical and basolateral surfaces, and redistribution of organelles like endosomes and lysosomes. Molecules of conventional cytoplasmic dynein contain 2 heavy chain polypeptides and a number of intermediate and light chains. They sediment at approximately 20S (<a href="#23" class="mim-tip-reference" title="Vaisberg, E. A., Koonce, M. P., McIntosh, J. R. <strong>Cytoplasmic dynein plays a role in mammalian mitotic spindle formation.</strong> J. Cell Biol. 123: 849-858, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8227145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8227145</a>] [<a href="https://doi.org/10.1083/jcb.123.4.849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8227145">Vaisberg et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8227145+23603762" 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="#13" class="mim-tip-reference" title="Mikami, A., Paschal, B. M., Mazumdar, M., Vallee, R. B. <strong>Molecular cloning of retrograde transport motor cytoplasmic dynein (MAP 1C).</strong> Neuron 10: 787-796, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684232</a>] [<a href="https://doi.org/10.1016/0896-6273(93)90195-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684232">Mikami et al. (1993)</a> isolated cDNAs encoding the heavy chain of MAP1C, a rat cytoplasmic dynein. The predicted 4,644-amino acid protein contains 4 ATP-binding consensus sequences. Southern blot analysis suggested that there is a single cytoplasmic dynein gene in rat. <a href="#6" class="mim-tip-reference" title="Gibbons, B. H., Asai, D. J., Tang, W.-J. Y., Hays, T. S., Gibbons, I. R. <strong>Phylogeny and expression of axonemal and cytoplasmic dynein genes in sea urchins.</strong> Molec. Biol. Cell 5: 57-70, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8186465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8186465</a>] [<a href="https://doi.org/10.1091/mbc.5.1.57" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8186465">Gibbons et al. (1994)</a> identified DYH1a, a sea urchin cytoplasmic dynein with homology to MAP1C. <a href="#3" class="mim-tip-reference" title="Criswell, P. S., Ostrowski, L. E., Asai, D. J. <strong>A novel cytoplasmic dynein heavy chain: expression of DHC1b in mammalian ciliated epithelial cells.</strong> J. Cell Sci. 109: 1891-1898, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8832411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8832411</a>] [<a href="https://doi.org/10.1242/jcs.109.7.1891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8832411">Criswell et al. (1996)</a> reported that MAP1C, or DHC1a, expression was unchanged during ciliogenesis in primary rat tracheal epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8186465+7684232+8832411" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By screening an adenocarcinoma cell line library with p22, <a href="#22" class="mim-tip-reference" title="Vaisberg, E. A., Grissom, P. M., McIntosh, J. R. <strong>Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles.</strong> J. Cell Biol. 133: 831-842, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666668</a>] [<a href="https://doi.org/10.1083/jcb.133.4.831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8666668">Vaisberg et al. (1996)</a> isolated a DHC1 cDNA. The predicted partial protein sequence shares 99% and 34% identity with rat DHC1a and human DNHC2 (<a href="/entry/603297">603297</a>), respectively. Antibodies against DHC1 recognized a high molecular mass protein on Western blots of extracts from several mammalian cell lines. Northern blot analysis revealed that DHC1 is expressed as an approximately 15-kb mRNA in several mammalian cells lines and human tissues, including those that make neither cilia nor flagella. By immunofluorescence, <a href="#22" class="mim-tip-reference" title="Vaisberg, E. A., Grissom, P. M., McIntosh, J. R. <strong>Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles.</strong> J. Cell Biol. 133: 831-842, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666668</a>] [<a href="https://doi.org/10.1083/jcb.133.4.831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8666668">Vaisberg et al. (1996)</a> found that DHC1 localizes in a punctate pattern in the cytoplasm that is generally brighter in the perinuclear area and dimmer near the cell periphery. DHC1 redistributes during mitosis to the kinetochores and mitotic spindle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8666668" 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="#23" class="mim-tip-reference" title="Vaisberg, E. A., Koonce, M. P., McIntosh, J. R. <strong>Cytoplasmic dynein plays a role in mammalian mitotic spindle formation.</strong> J. Cell Biol. 123: 849-858, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8227145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8227145</a>] [<a href="https://doi.org/10.1083/jcb.123.4.849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8227145">Vaisberg et al. (1993)</a> cloned a partial cDNA (p22) encoding the putative ATP-hydrolytic site of the human conventional cytoplasmic dynein heavy chain (DHC). Antibodies against the resulting polypeptide inhibited dynein motor activity in vitro. Injection of these antibodies into mitotic mammalian cells blocked the formation of spindles in prophase or during recovery from nocodazole treatment at later stages of mitosis. The cells became arrested with unseparated centrosomes and formed monopolar spindles. However, there was no detectable effect on chromosome attachment to a bipolar spindle or on chromosome movements during anaphase. <a href="#23" class="mim-tip-reference" title="Vaisberg, E. A., Koonce, M. P., McIntosh, J. R. <strong>Cytoplasmic dynein plays a role in mammalian mitotic spindle formation.</strong> J. Cell Biol. 123: 849-858, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8227145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8227145</a>] [<a href="https://doi.org/10.1083/jcb.123.4.849" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8227145">Vaisberg et al. (1993)</a> suggested that cytoplasmic dynein plays a unique and important role in the initial events of bipolar spindle formation, while any later roles in mitosis may be redundant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8227145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Sasaki, S., Shionoya, A., Ishida, M., Gambello, M. J., Yingling, J., Wynshaw-Boris, A., Hirotsune, S. <strong>A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system.</strong> Neuron 28: 681-696, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163259</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)00146-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163259">Sasaki et al. (2000)</a> demonstrated that Lis1 (PAFAH1B1; <a href="/entry/601545">601545</a>) directly interacts with Dync1h1 and Ndel1 (<a href="/entry/607538">607538</a>) in the developing mouse brain. Lis1 and Ndel1 colocalized predominantly at the centrosome in early neuroblasts, but redistributed to axons in association with retrograde dynein motor proteins. Ndel1 and Lis1 regulated the distribution of Dync1h1 along microtubules, establishing a direct functional link between LIS1, NDEL1, and microtubule motors during neuronal migration and axonal retrograde transport in the mammalian brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Kural, C., Kim, H., Syed, S., Goshima, G., Gelfand, V. I., Selvin, P. R. <strong>Kinesin and dynein move a peroxisome in vivo: a tug-of-war or coordinated movement?</strong> Science 308: 1469-1472, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15817813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15817813</a>] [<a href="https://doi.org/10.1126/science.1108408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15817813">Kural et al. (2005)</a> used fluorescence imaging with 1-nanometer accuracy (FIONA) to analyze organelle movement by conventional kinesin (<a href="/entry/602809">602809</a>) and cytoplasmic dynein in a cell. They located a green fluorescent protein (GFP)-tagged peroxisome in cultured Drosophila S2 cells to within 1.5 nanometers in 1.1 milliseconds, a 400-fold improvement in temporal resolution, sufficient to determine the average step size to be approximately 8 nanometers for both dynein and kinesin. Furthermore, <a href="#12" class="mim-tip-reference" title="Kural, C., Kim, H., Syed, S., Goshima, G., Gelfand, V. I., Selvin, P. R. <strong>Kinesin and dynein move a peroxisome in vivo: a tug-of-war or coordinated movement?</strong> Science 308: 1469-1472, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15817813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15817813</a>] [<a href="https://doi.org/10.1126/science.1108408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15817813">Kural et al. (2005)</a> found that dynein and kinesin do not work against each other in vivo during peroxisome transport. Rather, multiple kinesins or multiple dyneins work together, producing up to 10 times the in vitro speed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15817813" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the effects of tau (<a href="/entry/157140">157140</a>) on dynein and kinesin motility, <a href="#4" class="mim-tip-reference" title="Dixit, R., Ross, J. L., Goldman, Y. E., Holzbaur, E. L. F. <strong>Differential regulation of dynein and kinesin motor proteins by tau.</strong> Science 319: 1086-1089, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18202255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18202255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18202255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1152993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18202255">Dixit et al. (2008)</a> conducted single-molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction, whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at about a tenth of the tau concentration that inhibited dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggested that microtubule-associated proteins (MAPs) can spatially regulate the balance of microtubule-dependent axonal transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18202255" 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="#14" class="mim-tip-reference" title="Narayan, D., Desai, T., Banks, A., Patanjali, S. R., Ravikumar, T. S., Ward, D. C. <strong>Localization of the human cytoplasmic dynein heavy chain (DNECL) to 14qter by fluorescence in situ hybridization.</strong> Genomics 22: 660-661, 1994. Note: Erratum: Genomics 24: 618 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8001984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8001984</a>] [<a href="https://doi.org/10.1006/geno.1994.1447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8001984">Narayan et al. (1994)</a> localized the heavy chain gene of human cytoplasmic dynein to the terminal region of 14q. Indirect confirmation of this result was provided by the fact that the mouse cytoplasmic dynein heavy chain had been localized to murine chromosome 12, which shows extensive homology of synteny with human 14 (<a href="#13" class="mim-tip-reference" title="Mikami, A., Paschal, B. M., Mazumdar, M., Vallee, R. B. <strong>Molecular cloning of retrograde transport motor cytoplasmic dynein (MAP 1C).</strong> Neuron 10: 787-796, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7684232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7684232</a>] [<a href="https://doi.org/10.1016/0896-6273(93)90195-w" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7684232">Mikami et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8001984+7684232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By genomic sequence analysis, <a href="#17" class="mim-tip-reference" title="Pazour, G. J., Agrin, N., Walker, B. L., Witman, G. B. <strong>Identification of predicted human outer dynein arm genes: candidates for primary ciliary dyskinesia genes. (Letter)</strong> J. Med. Genet. 43: 62-73, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15937072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15937072</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15937072[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/10.1136/jmg.2005.033001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15937072">Pazour et al. (2006)</a> mapped the DNCH1 gene to chromosome 14q32. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15937072" 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="#2" class="mim-tip-reference" title="Carter, A. P., Garbarino, J. E., Wilson-Kubalek, E. M., Shipley, W. E., Cho, C., Milligan, R. A., Vale, R. D., Gibbons, I. R. <strong>Structure and functional role of dynein's microtubule-binding domain.</strong> Science 322: 1691-1695, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19074350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19074350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19074350[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1164424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19074350">Carter et al. (2008)</a> reported the crystal structure of the mouse cytoplasmic dynein microtubule binding domain (MTBD) and a portion of the coiled coil, which supports a mechanism by which the ATPase domain and the MTBD may communicate through a shift in the heptad registry of the coiled coil. Surprisingly, functional data suggested that the MTBD and not the ATPase domain is the main determinant of the direction of dynein motility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19074350" 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="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 to dynactin (<a href="/entry/601143">601143</a>). 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="#21" 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="#21" 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><strong><em>Charcot-Marie-Tooth Disease, Axonal, Type 2O</em></strong></p><p>
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In affected members of a large 4-generation family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; <a href="/entry/614228">614228</a>), <a href="#25" class="mim-tip-reference" title="Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. <strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong> Am. J. Hum. Genet. 89: 308-312, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820100">Weedon et al. (2011)</a> identified a heterozygous mutation in the DYNC1H1 gene (H306R; <a href="#0001">600112.0001</a>). The mutation was identified by exome sequencing. Affected individuals had onset in childhood of delayed motor milestones and abnormal gait and falls associated with distal lower limb weakness and wasting and distal sensory impairment. <a href="#25" class="mim-tip-reference" title="Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. <strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong> Am. J. Hum. Genet. 89: 308-312, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820100">Weedon et al. (2011)</a> noted that mouse models had implicated mutations in this gene in neuropathic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820100" 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>Complex Cortical Dysplasia with Other Brain Malformations 13</em></strong></p><p>
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By family-based exome sequencing of 10 case-parent trios with global developmental delay, <a href="#24" class="mim-tip-reference" title="Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., van Bon, B. W. M., Hoischen, A., de Vries, B. B. A., Brunner, H. G., Veltman, J. A. <strong>A de novo paradigm for mental retardation.</strong> Nature Genet. 42: 1109-1112, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21076407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21076407</a>] [<a href="https://doi.org/10.1038/ng.712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21076407">Vissers et al. (2010)</a> identified a de novo heterozygous mutation in the DYNC1H1 gene (H3822P; <a href="#0002">600112.0002</a>) in 1 patient. He had hypotonia and mild dysmorphic facial features. Follow-up of the patient at age 6 years by <a href="#26" class="mim-tip-reference" title="Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. <strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong> J. Med. Genet. 49: 179-183, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22368300">Willemsen et al. (2012)</a> noted that he had hypotonia, hyporeflexia, and broad-based waddling gait with toe-walking. Reevaluation of brain MRI showed complex cortical dysplasia with other brain malformations (CDCBM13; <a href="/entry/614563">614563</a>). <a href="#26" class="mim-tip-reference" title="Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. <strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong> J. Med. Genet. 49: 179-183, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22368300">Willemsen et al. (2012)</a> identified a second de novo heterozygous mutation in the DYNC1H1 gene (E1518K; <a href="#0003">600112.0003</a>) in a 51-year-old woman with severe developmental delay since infancy and an inability to walk or speak. She had mild dysmorphic features, seizures, and spastic tetraplegia. Cerebral CT scan at the age 46 years showed enlarged ventricles and clear signs of cortical malformation with wide opercular regions and an abnormal flat cortex with only a few simple and shallow sulci; MRI scan was not possible. <a href="#26" class="mim-tip-reference" title="Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. <strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong> J. Med. Genet. 49: 179-183, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22368300">Willemsen et al. (2012)</a> noted that DYNC1H1 interacts with LIS1 (<a href="/entry/601545">601545</a>), haploinsufficiency of which results in the severe neuronal migration disorder lissencephaly-1 (<a href="/entry/607432">607432</a>), and that Dync1h1 mutant mice show neuronal migration defects (<a href="#15" class="mim-tip-reference" title="Ori-McKenney, K. M., Vallee, R. B. <strong>Neuronal migration defects in the Loa dynein mutant mouse.</strong> Neural Dev. 6: 26, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21612657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21612657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21612657[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/1749-8104-6-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21612657">Ori-McKenney and Vallee, 2011</a>), providing evidence of the pathogenicity of the mutations. <a href="#26" class="mim-tip-reference" title="Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. <strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong> J. Med. Genet. 49: 179-183, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22368300">Willemsen et al. (2012)</a> also noted that their 2 patients showed variable signs consistent with peripheral neuropathy and that some of the patients with CMT2O (<a href="#25" class="mim-tip-reference" title="Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. <strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong> Am. J. Hum. Genet. 89: 308-312, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820100">Weedon et al., 2011</a>) showed learning difficulties, indicating that DYNC1H1 mutations may result in a broad neurologic phenotypic spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22368300+21612657+21820100+21076407" 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="#18" class="mim-tip-reference" title="Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. <strong>Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.</strong> Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23603762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23603762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23603762[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.2613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23603762">Poirier et al. (2013)</a> identified 8 different de novo heterozygous mutations in the DYNC1H1 gene (see, e.g., <a href="#0007">600112.0007</a>-<a href="#0009">600112.0009</a>) in 8 unrelated patients ascertained for evaluation due to malformations of cortical development (CDCBM13). The patients had global developmental delay, and most had early-onset seizures. Mutations in the first several patients were found by whole-exome sequencing, whereas subsequent patients were identified by direct sequencing of this gene in a larger cohort of affected individuals. In vitro functional expression studies of 2 of the variants showed that the mutant proteins had decreased microtubule binding affinity compared to wildtype. In addition, there was 1 family in which a mother and her 2 children carried a missense variant (K3241T): 1 of the children had mild intellectual disability, but the mother and the other child had normal cognition. All 3 were normocephalic, showed posterior pachygyria, and had focal seizures. No functional studies were performed on the K3241T variant, which occurred at a nonconserved residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23603762" 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="#11" class="mim-tip-reference" title="Jamuar, S. S., Lam, A. N., Kircher, M., D'Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., and 20 others. <strong>Somatic mutations in cerebral cortical malformations.</strong> New Eng. J. Med. 371: 733-743, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25140959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25140959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25140959[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/10.1056/NEJMoa1314432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25140959">Jamuar et al. (2014)</a> used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. They found potentially causal mutations in the candidate gene DYNC1H1 in 2 individuals with pachygyria; in a parallel study they found de novo mutations in DYNC1H1 in 2 other individuals with pachygyria. The 4 individuals had strikingly similar MRI findings, with posterior-predominant pachygyria, thickened cortex in the perisylvian region, and mildly dysmorphic corpus callosum (CDCBM13). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25140959" 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>Spinal Musucular Atrophy, Lower Extremity-Predominant 1, Autosomal Dominant</em></strong></p><p>
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In affected members of a large family with autosomal dominant lower extremity-predominant spinal muscular atrophy-1 (SMALED1; <a href="/entry/158600">158600</a>) originally reported by <a href="#9" class="mim-tip-reference" title="Harms, M. B., Allred, P., Gardner, R., Jr., Fernandes Filho, J. A., Florence, J., Pestronk, A., Al-Lozi, M., Baloh, R. H. <strong>Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32.</strong> Neurology 75: 539-546, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20697106[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.0b013e3181ec800c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20697106">Harms et al. (2010)</a>, <a href="#10" class="mim-tip-reference" title="Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., Baloh, R. H. <strong>Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.</strong> Neurology 78: 1714-1720, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22459677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22459677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22459677[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.0b013e3182556c05" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22459677">Harms et al. (2012)</a> identified a heterozygous mutation in the DYNC1H1 gene (I584L; <a href="#0004">600112.0004</a>). Patient skin fibroblasts showed normal binding to microtubules in the absence of ATP, but markedly decreased binding to microtubules in the presence of ATP. The mutant dynein also appeared to disrupt the stability of the dynein complex. Two additional families with a similar disorder were found to carry heterozygous DYNC1H1 mutations (<a href="#0005">600112.0005</a> and <a href="#0006">600112.0006</a>). The findings were similar to those observed in Loa homozygous mice (<a href="#7" class="mim-tip-reference" title="Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S., Morgan, P. J., Oozageer, R., and 27 others. <strong>Mutations in dynein link motor neuron degeneration to defects in retrograde transport.</strong> Science 300: 808-812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730604</a>] [<a href="https://doi.org/10.1126/science.1083129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730604">Hafezparast et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12730604+22459677+20697106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Japanese sibs with autosomal dominant lower extremity spinal muscular atrophy and no sensory symptoms, <a href="#20" class="mim-tip-reference" title="Tsurusaki, Y., Saitoh, S., Tomizawa, K., Sudo, A., Asahina, N., Shiraishi, H., Ito, J., Tanaka, H., Doi, H., Saitsu, H., Miyake, N., Matsumoto, N. <strong>A DYNC1H1 mutation causes a dominant spinal muscular atrophy with lower extremity predominance.</strong> Neurogenetics 13: 327-332, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22847149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22847149</a>] [<a href="https://doi.org/10.1007/s10048-012-0337-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22847149">Tsurusaki et al. (2012)</a> identified a heterozygous missense mutation in the DYNC1H1 gene (H306R; <a href="#0001">600112.0001</a>). The mutation, which was found by exome sequencing, was inherited from their mother, who had mild symptoms. The same mutation had previously been found by <a href="#25" class="mim-tip-reference" title="Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. <strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong> Am. J. Hum. Genet. 89: 308-312, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820100">Weedon et al. (2011)</a> in a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; <a href="/entry/614228">614228</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22847149+21820100" 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 findings in mutant mice, <a href="#5" class="mim-tip-reference" title="Eschbach, J., Sinniger, J., Bouitbir, J., Fergani, A., Schlagowski, A.-I., Zoll, J., Geny, B., Rene, F., Larmet, Y., Marion, V., Baloh, R. H., Harms, M. B., Shy, M. E., Messadeq, N., Weydt, P., Loeffler, J.-P., Ludolph, A. C., Dupuis, L. <strong>Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.</strong> Neurobiol. Dis. 58: 220-230, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23742762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23742762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23742762[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.nbd.2013.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23742762">Eschbach et al. (2013)</a> studied the mitochondria in fibroblasts derived from SMALED1 patients with the K671E (<a href="#0005">600112.0005</a>) and I584L mutations. Both cell lines showed intensely fragmented mitochondria, with smaller mitochondria in K671E cells and increased areas of individual mitochondria in I584L cells. Both cell lines also showed decreased levels of mitofusin-1 (MFN1; <a href="/entry/608506">608506</a>). <a href="#5" class="mim-tip-reference" title="Eschbach, J., Sinniger, J., Bouitbir, J., Fergani, A., Schlagowski, A.-I., Zoll, J., Geny, B., Rene, F., Larmet, Y., Marion, V., Baloh, R. H., Harms, M. B., Shy, M. E., Messadeq, N., Weydt, P., Loeffler, J.-P., Ludolph, A. C., Dupuis, L. <strong>Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.</strong> Neurobiol. Dis. 58: 220-230, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23742762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23742762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23742762[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.nbd.2013.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23742762">Eschbach et al. (2013)</a> suggested that dysfunction of mitochondrial transport may contribute to disease pathogenesis in patients with DYNC1H1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23742762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Harada, A., Takei, Y., Kanai, Y., Tanaka, Y., Nonaka, S., Hirokawa, N. <strong>Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein.</strong> J. Cell Biol. 141: 51-59, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9531547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9531547</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9531547[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.141.1.51" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9531547">Harada et al. (1998)</a> generated Dnchc1 knockout mice by targeted disruption. No embryos were identified at 8.5 days postcoitum. Cultured blastocysts of Dnchc1-null embryos demonstrated a highly vesiculated Golgi complex that was distributed throughout the cytoplasm. Endosomes and lysosomes were not concentrated near the nucleus but were distributed evenly throughout the cytoplasm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9531547" 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>'Legs at odd angles' (Loa) and 'Cramping 1' (cra1) are mouse phenotypes that arose from ENU (N-ethyl-N-nitrosourea) mutagenesis. They are transmitted as autosomal dominant traits and give rise to age-related progressive loss of muscle tone and locomotor ability in heterozygous mice without a major reduction in life span. Homozygous mice show a more severe phenotype with an inability to feed and move, and die within 24 hours of birth. <a href="#7" class="mim-tip-reference" title="Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S., Morgan, P. J., Oozageer, R., and 27 others. <strong>Mutations in dynein link motor neuron degeneration to defects in retrograde transport.</strong> Science 300: 808-812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730604</a>] [<a href="https://doi.org/10.1126/science.1083129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730604">Hafezparast et al. (2003)</a> showed that Loa is caused by a T-to-A transversion in the Dnchc1 gene that changes the phenylalanine at codon 580 to a tyrosine. The Cra1 phenotype results from an A-to-G transition leading to a tyrosine-to-cysteine substitution at codon 1055 of the Dnchc1 gene. Intercrossing heterozygous Cra1/+ with Loa/+ heterozygous mice yielded compound heterozygotes that died shortly after birth, demonstrating that the phenotypes are allelic. Homozygous and compound heterozygous mice developed Lewy-like inclusion bodies, and homozygous mice displayed significant loss of spinal anterior horn cells in utero. The Loa and Cra1 mutations do not cause overt deficits across the range of known DNCHC1 functions but result in a specific defect in fast retrograde transport that appears to manifest only in alpha motor neurons. <a href="#7" class="mim-tip-reference" title="Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S., Morgan, P. J., Oozageer, R., and 27 others. <strong>Mutations in dynein link motor neuron degeneration to defects in retrograde transport.</strong> Science 300: 808-812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730604</a>] [<a href="https://doi.org/10.1126/science.1083129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730604">Hafezparast et al. (2003)</a> concluded that the Loa and Cra1 mutations exhibit remarkable similarities to specific features of human pathology for amyotrophic lateral sclerosis (ALS; <a href="/entry/105400">105400</a>) and other motor neuron degeneration phenotypes including Lewy body-like inclusions containing SOD1 (<a href="/entry/147450">147450</a>), CDK5 (<a href="/entry/123831">123831</a>), neurofilaments, and ubiquitin (<a href="/entry/191339">191339</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730604" 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="#1" class="mim-tip-reference" title="Braunstein, K. E., Eschbach, J., Rona-Voros, K., Soylu, R., Mikrouli, E., Larmet, Y., Rene, F., Gonzalez De Aguilar, J.-L., Loeffler, J.-P., Muller, H.-P., Bucher, S., Kaulisch, T., and 10 others. <strong>A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.</strong> Hum. Molec. Genet. 19: 4385-4398, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20807776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20807776</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20807776[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20807776">Braunstein et al. (2010)</a> studied the 'cramping' mouse (Cra), which is heterozygous for a tyr1055-to-cys mutation in Dync1h1 that impairs retrograde axonal transport. These mice exhibited motor and behavioral abnormalities including hindlimb clasping, early muscle weakness, incoordination, and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signaling, decreased dopamine D1 receptor (DRD1; <a href="/entry/126449">126449</a>) and D2 receptor (DRD2; <a href="/entry/126450">126450</a>) binding in positron emission tomography SCAN, and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. The authors concluded that dynein is required for the normal morphology and function of striatal neurons, and may play a role in the pathogenesis of neurodegenerative disorders of the basal ganglia such as Perry syndrome (<a href="/entry/168605">168605</a>) and Huntington disease (HD; <a href="/entry/143100">143100</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20807776" 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="Eschbach, J., Sinniger, J., Bouitbir, J., Fergani, A., Schlagowski, A.-I., Zoll, J., Geny, B., Rene, F., Larmet, Y., Marion, V., Baloh, R. H., Harms, M. B., Shy, M. E., Messadeq, N., Weydt, P., Loeffler, J.-P., Ludolph, A. C., Dupuis, L. <strong>Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.</strong> Neurobiol. Dis. 58: 220-230, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23742762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23742762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23742762[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.nbd.2013.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23742762">Eschbach et al. (2013)</a> found that cultured embryonic fibroblasts from Cra1 mice had profoundly disrupted mitochondrial networks, including fragmented mitochondria and mitochondrial aggregates, associated with decreased mitofusin-1 (MFN1; <a href="/entry/608506">608506</a>). Skeletal muscle from these mice showed progressive mitochondrial dysfunction with decreased respiration and altered energy metabolism. In addition, mutant mice developed late-onset glucose intolerance consistent with mitochondrial dysfunction. Dync1h1 mutant fibroblasts showed impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. These findings indicated that dynein function is required for the maintenance of mitochondrial morphology and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23742762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Ori-McKenney, K. M., Vallee, R. B. <strong>Neuronal migration defects in the Loa dynein mutant mouse.</strong> Neural Dev. 6: 26, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21612657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21612657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21612657[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/1749-8104-6-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21612657">Ori-McKenney and Vallee (2011)</a> demonstrated that Loa homozygous mice had defects in neocortical lamination and neuronal migration resulting from a reduction in the rate of radial migration of bipolar neurons. Examination of brains from mutant mice showed blurred laminar boundaries, indicating cortical disorganization. The hippocampal dentate gyrus was smaller than wildtype. There was also a decrease in axonal extension within the brain, indicating that dynein processivity is necessary for axon elongation. The findings were similar, but less severe, than those reported in Lis1 (<a href="/entry/601545">601545</a>) compound heterozygous mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21612657" 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>9 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600112[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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2O</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">rs387906738 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906738;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=rs387906738" 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=rs387906738" 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=RCV000022929 OR RCV000055662 OR RCV000192255 OR RCV001091151" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022929, RCV000055662, RCV000192255, RCV001091151" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022929...</a>
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<p><strong><em>Charcot-Marie-Tooth Disease, Axonal, Type 2O</em></strong></p><p>
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In affected members of a large 4-generation family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; <a href="/entry/614228">614228</a>), <a href="#25" class="mim-tip-reference" title="Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. <strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong> Am. J. Hum. Genet. 89: 308-312, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820100">Weedon et al. (2011)</a> identified a heterozygous 917A-G transition in the DYNC1H1 gene, resulting in a his306-to-arg (H306R) substitution at a highly conserved residue in the homodimerization domain. Affected individuals had onset in childhood of delayed motor milestones and abnormal gait and falls associated with distal lower limb weakness and wasting and distal sensory impairment. <a href="#25" class="mim-tip-reference" title="Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. <strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong> Am. J. Hum. Genet. 89: 308-312, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21820100">Weedon et al. (2011)</a> noted that mouse models had implicated mutations in this gene in neuropathic disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21820100" 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>Spinal Muscular Atrophy, Lower Extremity-Predominant 1, Autosomal Dominant</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Tsurusaki, Y., Saitoh, S., Tomizawa, K., Sudo, A., Asahina, N., Shiraishi, H., Ito, J., Tanaka, H., Doi, H., Saitsu, H., Miyake, N., Matsumoto, N. <strong>A DYNC1H1 mutation causes a dominant spinal muscular atrophy with lower extremity predominance.</strong> Neurogenetics 13: 327-332, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22847149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22847149</a>] [<a href="https://doi.org/10.1007/s10048-012-0337-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22847149">Tsurusaki et al. (2012)</a> identified a heterozygous H306R mutation in the DYNC1H1 gene in 2 Japanese sibs with autosomal dominant lower extremity-predominant spinal muscular atrophy-1 (SMALED1; <a href="/entry/158600">158600</a>) without sensory impairment. The mother, who had mild symptoms, also carried the mutation. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP or 1000 Genomes databases, in 33 in-house exomes, or in 177 Japanese control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22847149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</strong>
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DYNC1H1, HIS3822PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906739 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906739;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=rs387906739" 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=rs387906739" 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=RCV000022930 OR RCV003447090" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022930, RCV003447090" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022930...</a>
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<p>In a 4-year-old boy with complex cortical dysplasia with other brain malformations-13 (CDCBM13; <a href="/entry/614563">614563</a>), <a href="#24" class="mim-tip-reference" title="Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., van Bon, B. W. M., Hoischen, A., de Vries, B. B. A., Brunner, H. G., Veltman, J. A. <strong>A de novo paradigm for mental retardation.</strong> Nature Genet. 42: 1109-1112, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21076407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21076407</a>] [<a href="https://doi.org/10.1038/ng.712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21076407">Vissers et al. (2010)</a> identified a de novo heterozygous c.11465A-C transversion (c.11465A-C, NM_001376) in the DYNC1H1 gene, resulting in a his3822-to-pro (H3822P) substitution at a highly conserved residue in the stem domain of the protein. The mutation was found by family-based exome sequencing, and was not found in 1,664 control chromosomes. The patient showed hypotonia at age 6 months, followed by delayed psychomotor development. Mild dysmorphic features included prominent forehead, plagiocephaly, hypotonic face with downslanting palpebral fissures, and short, broad hands and feet. Brain MRI was reported as normal. Follow-up of the patient at age 6 years by <a href="#26" class="mim-tip-reference" title="Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. <strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong> J. Med. Genet. 49: 179-183, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22368300">Willemsen et al. (2012)</a> noted that he had hypotonia, hyporeflexia, and broad-based waddling gait with toe-walking. Reevaluation of brain MRI showed signs of bilateral cortical malformation with deficient gyration of the frontal lobes and an area suggestive of focal cortical dysplasia, consistent with a neuronal migration defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22368300+21076407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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">rs387906740 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906740;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=rs387906740" 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=rs387906740" 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=RCV000022931 OR RCV003447091" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022931, RCV003447091" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022931...</a>
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<p>In a 51-year-old woman with complex cortical dysplasia with other brain malformations-13 (CDCBM13; <a href="/entry/614563">614563</a>), <a href="#26" class="mim-tip-reference" title="Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. <strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong> J. Med. Genet. 49: 179-183, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22368300">Willemsen et al. (2012)</a> identified a de novo heterozygous c.4552G-A transition (c.4552G-A, NM_001376.4) in the DYNC1H1 gene, resulting in a glu1518-to-lys (E1518K) substitution at a highly conserved residue in the motor domain of the protein. The mutation was not found in 445 control exomes. She had severe developmental delay with an inability to walk or speak and generalized seizures since age 3 years. Craniofacial features included brachycephaly, prominent forehead, hypertelorism, deep-set eyes, wide mouth with everted lower lip, and downturned corners of the mouth. Other features included short stature, microcephaly, clubfeet, small hands and feet with short toes, kyphoscoliosis, spastic tetraplegia, and swallowing difficulties. Cerebral CT scan at the age 46 years showed enlarged ventricles and clear signs of cortical malformation with wide opercular regions and an abnormal flat cortex with only a few simple and shallow sulci; MRI scan was not possible. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22368300" 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 SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT</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">rs387906741 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906741;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=rs387906741" 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=rs387906741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large family with autosomal dominant lower extremity-predominant spinal muscular atrophy (SMALED1; <a href="/entry/158600">158600</a>) originally reported by <a href="#9" class="mim-tip-reference" title="Harms, M. B., Allred, P., Gardner, R., Jr., Fernandes Filho, J. A., Florence, J., Pestronk, A., Al-Lozi, M., Baloh, R. H. <strong>Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32.</strong> Neurology 75: 539-546, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20697106[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.0b013e3181ec800c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20697106">Harms et al. (2010)</a>, <a href="#10" class="mim-tip-reference" title="Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., Baloh, R. H. <strong>Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.</strong> Neurology 78: 1714-1720, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22459677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22459677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22459677[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.0b013e3182556c05" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22459677">Harms et al. (2012)</a> identified a heterozygous 1750A-C transversion in exon 8 of the DYNC1H1 gene, resulting in an ile584-to-leu (I584L) substitution at a highly conserved residue in the tail domain of the dynein heavy chain, a highly conserved region critical for organizing multiple dynein subunits into a complex. The mutation was not found in 500 controls or the 1000 Genomes Project. Affected individuals had early-childhood onset of proximal leg weakness with muscle atrophy and nonlength-dependent motor neuron disease without sensory involvement. Patient skin fibroblasts showed normal binding to microtubules in the absence of ATP, but markedly decreased binding to microtubules in the presence of ATP. The mutant dynein also appeared to disrupt the stability of the dynein complex. The findings were similar to those observed in Loa homozygous mice (<a href="#7" class="mim-tip-reference" title="Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S., Morgan, P. J., Oozageer, R., and 27 others. <strong>Mutations in dynein link motor neuron degeneration to defects in retrograde transport.</strong> Science 300: 808-812, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730604</a>] [<a href="https://doi.org/10.1126/science.1083129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730604">Hafezparast et al., 2003</a>; <a href="#16" class="mim-tip-reference" title="Ori-McKenney, K. M., Xu, J., Gross, S. P., Vallee, R. B. <strong>A cytoplasmic dynein tail mutation impairs motor processivity.</strong> Nature Cell Biol. 12: 1228-1234, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21102439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21102439</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21102439[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/ncb2127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21102439">Ori-McKenney et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12730604+21102439+22459677+20697106" 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 SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT</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">rs387906742 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906742;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=rs387906742" 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=rs387906742" 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=RCV000022933 OR RCV003447093" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022933, RCV003447093" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022933...</a>
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<p>In affected members of a 3-generation family with autosomal dominant lower extremity-predominant spinal muscular atrophy (SMALED1; <a href="/entry/158600">158600</a>), <a href="#10" class="mim-tip-reference" title="Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., Baloh, R. H. <strong>Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.</strong> Neurology 78: 1714-1720, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22459677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22459677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22459677[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.0b013e3182556c05" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22459677">Harms et al. (2012)</a> identified a heterozygous 2011A-G transition in exon 8 of the DYNC1H1 gene, resulting in a lys671-to-glu (K671E) substitution at a highly conserved residue in the tail domain of the dynein heavy chain. The mutation was not found in 500 controls or the 1000 Genomes Project. The 3 affected individuals showed waddling gait from early childhood, with awkward running due to lower limb weakness; upper limbs were not affected. Muscle atrophy and weakness confined to the lower limbs showed little progression throughout life. There was a notable strength discrepancy between knee extension and flexion, with the quadriceps showing significant weakness. Deep tendon reflexes were reduced at the knees, but normal elsewhere. Nerve conduction studies showed small motor responses and normal sensory responses; EMG showed chronic denervation. One patient had heel cord contractures and inturning feet, whereas another had fasciculations of the calves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22459677" 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 SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT</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">rs387906743 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906743;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=rs387906743" 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=rs387906743" 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=RCV000022934 OR RCV003447094" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022934, RCV003447094" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022934...</a>
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<p>In a 3.5-year-old girl with autosomal dominant lower extremity-predominant spinal muscular atrophy (SMALED1; <a href="/entry/158600">158600</a>), <a href="#10" class="mim-tip-reference" title="Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., Baloh, R. H. <strong>Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.</strong> Neurology 78: 1714-1720, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22459677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22459677</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22459677[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.0b013e3182556c05" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22459677">Harms et al. (2012)</a> identified a heterozygous 3170A-G transition in exon 11 of the DYNC1H1 gene, resulting in a tyr970-to-cys (Y970C) substitution at a highly conserved residue. The mutation was not found in 500 controls or the 1000 Genomes Project. The patient showed delayed motor development, calcaneovalgus foot deformities, lower extremity weakness, and mild cognitive delay. At age 3.5 years, she could not run and had an unsteady gait. There was no sensory loss. EMG was consistent with nonlength-dependent motor neuron disease. A sister, who was not studied, reportedly had similar motor delay diagnosed as cerebral palsy, abnormal gait, and polymicrogyria on brain imaging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22459677" 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>.0007 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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">rs397509410 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509410;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=rs397509410" 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=rs397509410" 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=RCV000049270 OR RCV003447108" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049270, RCV003447108" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049270...</a>
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<p>In a 12-year-old patient (P122) with complex cortical dysplasia with other brain malformations-13 (CDCBM13; <a href="/entry/614563">614563</a>), <a href="#18" class="mim-tip-reference" title="Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. <strong>Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.</strong> Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23603762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23603762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23603762[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.2613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23603762">Poirier et al. (2013)</a> identified a de novo heterozygous c.10008G-T transversion in the DYNC1H1 gene, resulting in a lys3336-to-asn (K3336N) substitution at a conserved residue in the microtubule-binding domain. In vitro functional expression studies showed that the mutant protein had decreased microtubule binding affinity compared to wildtype. The mutation was found by whole-exome sequencing and was not present in several large control databases. The patient had microcephaly (-4 SD), early-onset epilepsy, foot deformities consistent with an axonal neuropathy, and was bedridden with spastic tetraplegia. Brain MRI showed posterior pachygyria, frontal polymicrogyria, nodular heterotopia, dysmorphic basal ganglia, and hypoplasia of the corpus callosum, brainstem, and cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23603762" 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">rs397509411 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509411;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=rs397509411" 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=rs397509411" 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=RCV000049271 OR RCV001091160 OR RCV003447109" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049271, RCV001091160, RCV003447109" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049271...</a>
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<p>In a 10-year-old patient (P217) with complex cortical dysplasia with other brain malformations-13 (CDCBM13; <a href="/entry/614563">614563</a>), <a href="#18" class="mim-tip-reference" title="Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. <strong>Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.</strong> Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23603762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23603762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23603762[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.2613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23603762">Poirier et al. (2013)</a> identified a de novo heterozygous c.10151G-A transition (c.10151G-A, NM_001376) in the DYNC1H1 gene, resulting in an arg3384-to-gln (R3384Q) substitution at a conserved residue in the microtubule-binding domain. In vitro functional expression studies showed that the mutant protein had decreased microtubule binding affinity compared to wildtype. The patient had microcephaly (-4 SD), early-onset epilepsy, foot deformities consistent with an axonal neuropathy, and was bedridden with spastic tetraplegia. Brain MRI showed posterior pachygyria, frontal polymicrogyria, dysmorphic basal ganglia and corpus callosum, and hypoplasia of the brainstem and cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23603762" 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>.0009 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</strong>
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DYNC1H1, ARG3344GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509412 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509412;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=rs397509412" 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=rs397509412" 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=RCV000049272 OR RCV001255327 OR RCV001262933 OR RCV001291070" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049272, RCV001255327, RCV001262933, RCV001291070" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049272...</a>
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<p>In 2 unrelated children (P535 and 574C) with complex cortical dysplasia with other brain malformations-13 (CDCBM13; <a href="/entry/614563">614563</a>), <a href="#18" class="mim-tip-reference" title="Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. <strong>Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.</strong> Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23603762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23603762</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23603762[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.2613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23603762">Poirier et al. (2013)</a> identified a de novo heterozygous c.10031G-A transition (c.10031G-A, NM_001376) in the DYNC1H1 gene, resulting in an arg3344-to-gln (R3344Q) substitution at a conserved residue in the microtubule-binding domain. One patient was a 5-year-old with severe intellectual disability and autistic features, early-onset epileptic encephalopathy, and MRI findings of posterior agyria, nodular heterotopia, and dysmorphic basal ganglia and corpus callosum. The other patient was a 3-year-old with moderate intellectual disability, focal seizures, and MRI findings of posterior pachygyria and small cerebellar vermis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23603762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<strong>A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.</strong>
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Carter, A. P., Garbarino, J. E., Wilson-Kubalek, E. M., Shipley, W. E., Cho, C., Milligan, R. A., Vale, R. D., Gibbons, I. R.
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[<a href="https://doi.org/10.1126/science.1164424" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1242/jcs.109.7.1891" target="_blank">Full Text</a>]
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Dixit, R., Ross, J. L., Goldman, Y. E., Holzbaur, E. L. F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18202255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18202255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18202255[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=18202255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1152993" target="_blank">Full Text</a>]
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Eschbach, J., Sinniger, J., Bouitbir, J., Fergani, A., Schlagowski, A.-I., Zoll, J., Geny, B., Rene, F., Larmet, Y., Marion, V., Baloh, R. H., Harms, M. B., Shy, M. E., Messadeq, N., Weydt, P., Loeffler, J.-P., Ludolph, A. C., Dupuis, L.
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[<a href="https://doi.org/10.1016/j.nbd.2013.05.015" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1091/mbc.5.1.57" target="_blank">Full Text</a>]
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Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A. S., Hummerich, H., Nicholson, S., Morgan, P. J., Oozageer, R., and 27 others.
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[<a href="https://doi.org/10.1126/science.1083129" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1083/jcb.141.1.51" target="_blank">Full Text</a>]
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Harms, M. B., Allred, P., Gardner, R., Jr., Fernandes Filho, J. A., Florence, J., Pestronk, A., Al-Lozi, M., Baloh, R. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20697106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20697106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20697106[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=20697106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181ec800c" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21820100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21820100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21820100[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=21820100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.07.002" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Willemsen2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T.
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<strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong>
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J. Med. Genet. 49: 179-183, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22368300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22368300</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22368300" 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/10.1136/jmedgenet-2011-100542" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<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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Ada Hamosh - updated : 04/16/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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George E. Tiller - updated : 09/12/2017<br>Ada Hamosh - updated : 09/02/2014<br>Cassandra L. Kniffin - updated : 7/1/2014<br>Cassandra L. Kniffin - updated : 9/23/2013<br>Cassandra L. Kniffin - updated : 6/27/2013<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 4/9/2012<br>Cassandra L. Kniffin - updated : 9/15/2011<br>Ada Hamosh - updated : 12/29/2008<br>Ada Hamosh - updated : 4/4/2008<br>Patricia A. Hartz - updated : 4/18/2006<br>Ada Hamosh - updated : 8/2/2005<br>Ada Hamosh - updated : 5/6/2003<br>Rebekah S. Rasooly - updated : 11/18/1998
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 9/13/1994
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/15/2024
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 04/07/2023<br>ckniffin : 04/07/2023<br>alopez : 04/01/2022<br>alopez : 04/01/2022<br>alopez : 04/16/2018<br>carol : 01/05/2018<br>alopez : 09/12/2017<br>alopez : 09/02/2014<br>carol : 7/2/2014<br>mcolton : 7/2/2014<br>ckniffin : 7/1/2014<br>carol : 9/26/2013<br>tpirozzi : 9/26/2013<br>ckniffin : 9/23/2013<br>carol : 8/28/2013<br>carol : 7/10/2013<br>carol : 7/9/2013<br>ckniffin : 6/27/2013<br>carol : 9/19/2012<br>terry : 7/5/2012<br>terry : 5/2/2012<br>carol : 4/27/2012<br>ckniffin : 4/25/2012<br>alopez : 4/10/2012<br>terry : 4/10/2012<br>terry : 4/10/2012<br>ckniffin : 4/9/2012<br>carol : 9/16/2011<br>ckniffin : 9/15/2011<br>alopez : 12/29/2008<br>terry : 12/29/2008<br>alopez : 4/11/2008<br>terry : 4/4/2008<br>mgross : 4/19/2006<br>mgross : 4/18/2006<br>alopez : 8/3/2005<br>terry : 8/2/2005<br>carol : 5/12/2004<br>alopez : 5/8/2003<br>terry : 5/6/2003<br>dkim : 12/18/1998<br>dkim : 12/3/1998<br>psherman : 12/2/1998<br>alopez : 11/18/1998<br>alopez : 8/21/1998<br>mimadm : 9/23/1995<br>carol : 9/13/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600112
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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DYNEIN, CYTOPLASMIC 1, HEAVY CHAIN 1; DYNC1H1
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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DNCH1<br />
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DYNEIN, CYTOPLASMIC-LIKE; DNCL; DNECL<br />
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DYNEIN HEAVY POLYPEPTIDE, CYTOPLASMIC; DHC1; DHC1A<br />
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DNCHC1
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</span>
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</h4>
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</div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DYNC1H1</em></strong>
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</span>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 782829002;
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</span>
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<br />
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 14q32.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:101,964,573-102,056,443 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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14q32.31
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</span>
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</td>
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<td>
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<span class="mim-font">
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Charcot-Marie-Tooth disease, axonal, type 2O
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</span>
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</td>
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<td>
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<span class="mim-font">
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614228
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Cortical dysplasia, complex, with other brain malformations 13
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</span>
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</td>
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<td>
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<span class="mim-font">
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614563
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Spinal muscular atrophy, lower extremity-predominant 1, AD
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</span>
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</td>
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<td>
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<span class="mim-font">
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158600
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The DYNC1H1 gene encodes a large (over 530 kD) crucial subunit of the cytoplasmic dynein complex (summary by Poirier et al., 2013). Dyneins are a group of microtubule-activated ATPases that serve to convert chemical energy into mechanical energy. They have been divided into 2 large subgroups, namely, the axonemal and cytoplasmic dyneins. Cytoplasmic dynein has been implicated in a variety of other forms of intracellular motility, including retrograde axonal transport, protein sorting between apical and basolateral surfaces, and redistribution of organelles like endosomes and lysosomes. Molecules of conventional cytoplasmic dynein contain 2 heavy chain polypeptides and a number of intermediate and light chains. They sediment at approximately 20S (Vaisberg et al., 1993). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Mikami et al. (1993) isolated cDNAs encoding the heavy chain of MAP1C, a rat cytoplasmic dynein. The predicted 4,644-amino acid protein contains 4 ATP-binding consensus sequences. Southern blot analysis suggested that there is a single cytoplasmic dynein gene in rat. Gibbons et al. (1994) identified DYH1a, a sea urchin cytoplasmic dynein with homology to MAP1C. Criswell et al. (1996) reported that MAP1C, or DHC1a, expression was unchanged during ciliogenesis in primary rat tracheal epithelial cells. </p><p>By screening an adenocarcinoma cell line library with p22, Vaisberg et al. (1996) isolated a DHC1 cDNA. The predicted partial protein sequence shares 99% and 34% identity with rat DHC1a and human DNHC2 (603297), respectively. Antibodies against DHC1 recognized a high molecular mass protein on Western blots of extracts from several mammalian cell lines. Northern blot analysis revealed that DHC1 is expressed as an approximately 15-kb mRNA in several mammalian cells lines and human tissues, including those that make neither cilia nor flagella. By immunofluorescence, Vaisberg et al. (1996) found that DHC1 localizes in a punctate pattern in the cytoplasm that is generally brighter in the perinuclear area and dimmer near the cell periphery. DHC1 redistributes during mitosis to the kinetochores and mitotic spindle. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Vaisberg et al. (1993) cloned a partial cDNA (p22) encoding the putative ATP-hydrolytic site of the human conventional cytoplasmic dynein heavy chain (DHC). Antibodies against the resulting polypeptide inhibited dynein motor activity in vitro. Injection of these antibodies into mitotic mammalian cells blocked the formation of spindles in prophase or during recovery from nocodazole treatment at later stages of mitosis. The cells became arrested with unseparated centrosomes and formed monopolar spindles. However, there was no detectable effect on chromosome attachment to a bipolar spindle or on chromosome movements during anaphase. Vaisberg et al. (1993) suggested that cytoplasmic dynein plays a unique and important role in the initial events of bipolar spindle formation, while any later roles in mitosis may be redundant. </p><p>Sasaki et al. (2000) demonstrated that Lis1 (PAFAH1B1; 601545) directly interacts with Dync1h1 and Ndel1 (607538) in the developing mouse brain. Lis1 and Ndel1 colocalized predominantly at the centrosome in early neuroblasts, but redistributed to axons in association with retrograde dynein motor proteins. Ndel1 and Lis1 regulated the distribution of Dync1h1 along microtubules, establishing a direct functional link between LIS1, NDEL1, and microtubule motors during neuronal migration and axonal retrograde transport in the mammalian brain. </p><p>Kural et al. (2005) used fluorescence imaging with 1-nanometer accuracy (FIONA) to analyze organelle movement by conventional kinesin (602809) and cytoplasmic dynein in a cell. They located a green fluorescent protein (GFP)-tagged peroxisome in cultured Drosophila S2 cells to within 1.5 nanometers in 1.1 milliseconds, a 400-fold improvement in temporal resolution, sufficient to determine the average step size to be approximately 8 nanometers for both dynein and kinesin. Furthermore, Kural et al. (2005) found that dynein and kinesin do not work against each other in vivo during peroxisome transport. Rather, multiple kinesins or multiple dyneins work together, producing up to 10 times the in vitro speed. </p><p>To determine the effects of tau (157140) on dynein and kinesin motility, Dixit et al. (2008) conducted single-molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction, whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at about a tenth of the tau concentration that inhibited dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggested that microtubule-associated proteins (MAPs) can spatially regulate the balance of microtubule-dependent axonal transport. </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>
|
|
<span class="mim-font">
|
|
<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">
|
|
<p>By fluorescence in situ hybridization, Narayan et al. (1994) localized the heavy chain gene of human cytoplasmic dynein to the terminal region of 14q. Indirect confirmation of this result was provided by the fact that the mouse cytoplasmic dynein heavy chain had been localized to murine chromosome 12, which shows extensive homology of synteny with human 14 (Mikami et al., 1993). </p><p>By genomic sequence analysis, Pazour et al. (2006) mapped the DNCH1 gene to chromosome 14q32. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Biochemical Features</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Carter et al. (2008) reported the crystal structure of the mouse cytoplasmic dynein microtubule binding domain (MTBD) and a portion of the coiled coil, which supports a mechanism by which the ATPase domain and the MTBD may communicate through a shift in the heptad registry of the coiled coil. Surprisingly, functional data suggested that the MTBD and not the ATPase domain is the main determinant of the direction of dynein motility. </p><p>Urnavicius et al. (2018) used electron microscopy and single-molecule studies to show that adaptors can recruit a second dynein to dynactin (601143). 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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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Charcot-Marie-Tooth Disease, Axonal, Type 2O</em></strong></p><p>
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In affected members of a large 4-generation family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; 614228), Weedon et al. (2011) identified a heterozygous mutation in the DYNC1H1 gene (H306R; 600112.0001). The mutation was identified by exome sequencing. Affected individuals had onset in childhood of delayed motor milestones and abnormal gait and falls associated with distal lower limb weakness and wasting and distal sensory impairment. Weedon et al. (2011) noted that mouse models had implicated mutations in this gene in neuropathic disease. </p><p><strong><em>Complex Cortical Dysplasia with Other Brain Malformations 13</em></strong></p><p>
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By family-based exome sequencing of 10 case-parent trios with global developmental delay, Vissers et al. (2010) identified a de novo heterozygous mutation in the DYNC1H1 gene (H3822P; 600112.0002) in 1 patient. He had hypotonia and mild dysmorphic facial features. Follow-up of the patient at age 6 years by Willemsen et al. (2012) noted that he had hypotonia, hyporeflexia, and broad-based waddling gait with toe-walking. Reevaluation of brain MRI showed complex cortical dysplasia with other brain malformations (CDCBM13; 614563). Willemsen et al. (2012) identified a second de novo heterozygous mutation in the DYNC1H1 gene (E1518K; 600112.0003) in a 51-year-old woman with severe developmental delay since infancy and an inability to walk or speak. She had mild dysmorphic features, seizures, and spastic tetraplegia. Cerebral CT scan at the age 46 years showed enlarged ventricles and clear signs of cortical malformation with wide opercular regions and an abnormal flat cortex with only a few simple and shallow sulci; MRI scan was not possible. Willemsen et al. (2012) noted that DYNC1H1 interacts with LIS1 (601545), haploinsufficiency of which results in the severe neuronal migration disorder lissencephaly-1 (607432), and that Dync1h1 mutant mice show neuronal migration defects (Ori-McKenney and Vallee, 2011), providing evidence of the pathogenicity of the mutations. Willemsen et al. (2012) also noted that their 2 patients showed variable signs consistent with peripheral neuropathy and that some of the patients with CMT2O (Weedon et al., 2011) showed learning difficulties, indicating that DYNC1H1 mutations may result in a broad neurologic phenotypic spectrum. </p><p>Poirier et al. (2013) identified 8 different de novo heterozygous mutations in the DYNC1H1 gene (see, e.g., 600112.0007-600112.0009) in 8 unrelated patients ascertained for evaluation due to malformations of cortical development (CDCBM13). The patients had global developmental delay, and most had early-onset seizures. Mutations in the first several patients were found by whole-exome sequencing, whereas subsequent patients were identified by direct sequencing of this gene in a larger cohort of affected individuals. In vitro functional expression studies of 2 of the variants showed that the mutant proteins had decreased microtubule binding affinity compared to wildtype. In addition, there was 1 family in which a mother and her 2 children carried a missense variant (K3241T): 1 of the children had mild intellectual disability, but the mother and the other child had normal cognition. All 3 were normocephalic, showed posterior pachygyria, and had focal seizures. No functional studies were performed on the K3241T variant, which occurred at a nonconserved residue. </p><p>Jamuar et al. (2014) used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. They found potentially causal mutations in the candidate gene DYNC1H1 in 2 individuals with pachygyria; in a parallel study they found de novo mutations in DYNC1H1 in 2 other individuals with pachygyria. The 4 individuals had strikingly similar MRI findings, with posterior-predominant pachygyria, thickened cortex in the perisylvian region, and mildly dysmorphic corpus callosum (CDCBM13). </p><p><strong><em>Spinal Musucular Atrophy, Lower Extremity-Predominant 1, Autosomal Dominant</em></strong></p><p>
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|
In affected members of a large family with autosomal dominant lower extremity-predominant spinal muscular atrophy-1 (SMALED1; 158600) originally reported by Harms et al. (2010), Harms et al. (2012) identified a heterozygous mutation in the DYNC1H1 gene (I584L; 600112.0004). Patient skin fibroblasts showed normal binding to microtubules in the absence of ATP, but markedly decreased binding to microtubules in the presence of ATP. The mutant dynein also appeared to disrupt the stability of the dynein complex. Two additional families with a similar disorder were found to carry heterozygous DYNC1H1 mutations (600112.0005 and 600112.0006). The findings were similar to those observed in Loa homozygous mice (Hafezparast et al., 2003). </p><p>In 2 Japanese sibs with autosomal dominant lower extremity spinal muscular atrophy and no sensory symptoms, Tsurusaki et al. (2012) identified a heterozygous missense mutation in the DYNC1H1 gene (H306R; 600112.0001). The mutation, which was found by exome sequencing, was inherited from their mother, who had mild symptoms. The same mutation had previously been found by Weedon et al. (2011) in a family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; 614228). </p><p>Based on findings in mutant mice, Eschbach et al. (2013) studied the mitochondria in fibroblasts derived from SMALED1 patients with the K671E (600112.0005) and I584L mutations. Both cell lines showed intensely fragmented mitochondria, with smaller mitochondria in K671E cells and increased areas of individual mitochondria in I584L cells. Both cell lines also showed decreased levels of mitofusin-1 (MFN1; 608506). Eschbach et al. (2013) suggested that dysfunction of mitochondrial transport may contribute to disease pathogenesis in patients with DYNC1H1 mutations. </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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Harada et al. (1998) generated Dnchc1 knockout mice by targeted disruption. No embryos were identified at 8.5 days postcoitum. Cultured blastocysts of Dnchc1-null embryos demonstrated a highly vesiculated Golgi complex that was distributed throughout the cytoplasm. Endosomes and lysosomes were not concentrated near the nucleus but were distributed evenly throughout the cytoplasm. </p><p>'Legs at odd angles' (Loa) and 'Cramping 1' (cra1) are mouse phenotypes that arose from ENU (N-ethyl-N-nitrosourea) mutagenesis. They are transmitted as autosomal dominant traits and give rise to age-related progressive loss of muscle tone and locomotor ability in heterozygous mice without a major reduction in life span. Homozygous mice show a more severe phenotype with an inability to feed and move, and die within 24 hours of birth. Hafezparast et al. (2003) showed that Loa is caused by a T-to-A transversion in the Dnchc1 gene that changes the phenylalanine at codon 580 to a tyrosine. The Cra1 phenotype results from an A-to-G transition leading to a tyrosine-to-cysteine substitution at codon 1055 of the Dnchc1 gene. Intercrossing heterozygous Cra1/+ with Loa/+ heterozygous mice yielded compound heterozygotes that died shortly after birth, demonstrating that the phenotypes are allelic. Homozygous and compound heterozygous mice developed Lewy-like inclusion bodies, and homozygous mice displayed significant loss of spinal anterior horn cells in utero. The Loa and Cra1 mutations do not cause overt deficits across the range of known DNCHC1 functions but result in a specific defect in fast retrograde transport that appears to manifest only in alpha motor neurons. Hafezparast et al. (2003) concluded that the Loa and Cra1 mutations exhibit remarkable similarities to specific features of human pathology for amyotrophic lateral sclerosis (ALS; 105400) and other motor neuron degeneration phenotypes including Lewy body-like inclusions containing SOD1 (147450), CDK5 (123831), neurofilaments, and ubiquitin (191339). </p><p>Braunstein et al. (2010) studied the 'cramping' mouse (Cra), which is heterozygous for a tyr1055-to-cys mutation in Dync1h1 that impairs retrograde axonal transport. These mice exhibited motor and behavioral abnormalities including hindlimb clasping, early muscle weakness, incoordination, and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signaling, decreased dopamine D1 receptor (DRD1; 126449) and D2 receptor (DRD2; 126450) binding in positron emission tomography SCAN, and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. The authors concluded that dynein is required for the normal morphology and function of striatal neurons, and may play a role in the pathogenesis of neurodegenerative disorders of the basal ganglia such as Perry syndrome (168605) and Huntington disease (HD; 143100). </p><p>Eschbach et al. (2013) found that cultured embryonic fibroblasts from Cra1 mice had profoundly disrupted mitochondrial networks, including fragmented mitochondria and mitochondrial aggregates, associated with decreased mitofusin-1 (MFN1; 608506). Skeletal muscle from these mice showed progressive mitochondrial dysfunction with decreased respiration and altered energy metabolism. In addition, mutant mice developed late-onset glucose intolerance consistent with mitochondrial dysfunction. Dync1h1 mutant fibroblasts showed impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. These findings indicated that dynein function is required for the maintenance of mitochondrial morphology and function. </p><p>Ori-McKenney and Vallee (2011) demonstrated that Loa homozygous mice had defects in neocortical lamination and neuronal migration resulting from a reduction in the rate of radial migration of bipolar neurons. Examination of brains from mutant mice showed blurred laminar boundaries, indicating cortical disorganization. The hippocampal dentate gyrus was smaller than wildtype. There was also a decrease in axonal extension within the brain, indicating that dynein processivity is necessary for axon elongation. The findings were similar, but less severe, than those reported in Lis1 (601545) compound heterozygous mutant mice. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 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 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2O</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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SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT, INCLUDED
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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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DYNC1H1, HIS306ARG
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<br />
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SNP: rs387906738,
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ClinVar: RCV000022929, RCV000055662, RCV000192255, RCV001091151
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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 />
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<p><strong><em>Charcot-Marie-Tooth Disease, Axonal, Type 2O</em></strong></p><p>
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In affected members of a large 4-generation family with autosomal dominant axonal Charcot-Marie-Tooth disease type 2O (CMT2O; 614228), Weedon et al. (2011) identified a heterozygous 917A-G transition in the DYNC1H1 gene, resulting in a his306-to-arg (H306R) substitution at a highly conserved residue in the homodimerization domain. Affected individuals had onset in childhood of delayed motor milestones and abnormal gait and falls associated with distal lower limb weakness and wasting and distal sensory impairment. Weedon et al. (2011) noted that mouse models had implicated mutations in this gene in neuropathic disease. </p><p><strong><em>Spinal Muscular Atrophy, Lower Extremity-Predominant 1, Autosomal Dominant</em></strong></p><p>
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|
Tsurusaki et al. (2012) identified a heterozygous H306R mutation in the DYNC1H1 gene in 2 Japanese sibs with autosomal dominant lower extremity-predominant spinal muscular atrophy-1 (SMALED1; 158600) without sensory impairment. The mother, who had mild symptoms, also carried the mutation. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP or 1000 Genomes databases, in 33 in-house exomes, or in 177 Japanese control individuals. </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 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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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DYNC1H1, HIS3822PRO
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<br />
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SNP: rs387906739,
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ClinVar: RCV000022930, RCV003447090
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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 4-year-old boy with complex cortical dysplasia with other brain malformations-13 (CDCBM13; 614563), Vissers et al. (2010) identified a de novo heterozygous c.11465A-C transversion (c.11465A-C, NM_001376) in the DYNC1H1 gene, resulting in a his3822-to-pro (H3822P) substitution at a highly conserved residue in the stem domain of the protein. The mutation was found by family-based exome sequencing, and was not found in 1,664 control chromosomes. The patient showed hypotonia at age 6 months, followed by delayed psychomotor development. Mild dysmorphic features included prominent forehead, plagiocephaly, hypotonic face with downslanting palpebral fissures, and short, broad hands and feet. Brain MRI was reported as normal. Follow-up of the patient at age 6 years by Willemsen et al. (2012) noted that he had hypotonia, hyporeflexia, and broad-based waddling gait with toe-walking. Reevaluation of brain MRI showed signs of bilateral cortical malformation with deficient gyration of the frontal lobes and an area suggestive of focal cortical dysplasia, consistent with a neuronal migration defect. </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 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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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DYNC1H1, GLU1518LYS
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<br />
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SNP: rs387906740,
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ClinVar: RCV000022931, RCV003447091
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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 51-year-old woman with complex cortical dysplasia with other brain malformations-13 (CDCBM13; 614563), Willemsen et al. (2012) identified a de novo heterozygous c.4552G-A transition (c.4552G-A, NM_001376.4) in the DYNC1H1 gene, resulting in a glu1518-to-lys (E1518K) substitution at a highly conserved residue in the motor domain of the protein. The mutation was not found in 445 control exomes. She had severe developmental delay with an inability to walk or speak and generalized seizures since age 3 years. Craniofacial features included brachycephaly, prominent forehead, hypertelorism, deep-set eyes, wide mouth with everted lower lip, and downturned corners of the mouth. Other features included short stature, microcephaly, clubfeet, small hands and feet with short toes, kyphoscoliosis, spastic tetraplegia, and swallowing difficulties. Cerebral CT scan at the age 46 years showed enlarged ventricles and clear signs of cortical malformation with wide opercular regions and an abnormal flat cortex with only a few simple and shallow sulci; MRI scan was not possible. </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>.0004 SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT</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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DYNC1H1, ILE584LEU
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<br />
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SNP: rs387906741,
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ClinVar: RCV000022932, RCV000789730, RCV003447092
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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 affected members of a large family with autosomal dominant lower extremity-predominant spinal muscular atrophy (SMALED1; 158600) originally reported by Harms et al. (2010), Harms et al. (2012) identified a heterozygous 1750A-C transversion in exon 8 of the DYNC1H1 gene, resulting in an ile584-to-leu (I584L) substitution at a highly conserved residue in the tail domain of the dynein heavy chain, a highly conserved region critical for organizing multiple dynein subunits into a complex. The mutation was not found in 500 controls or the 1000 Genomes Project. Affected individuals had early-childhood onset of proximal leg weakness with muscle atrophy and nonlength-dependent motor neuron disease without sensory involvement. Patient skin fibroblasts showed normal binding to microtubules in the absence of ATP, but markedly decreased binding to microtubules in the presence of ATP. The mutant dynein also appeared to disrupt the stability of the dynein complex. The findings were similar to those observed in Loa homozygous mice (Hafezparast et al., 2003; Ori-McKenney et al., 2010). </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>.0005 SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT</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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DYNC1H1, LYS671GLU
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<br />
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SNP: rs387906742,
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ClinVar: RCV000022933, RCV003447093
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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 affected members of a 3-generation family with autosomal dominant lower extremity-predominant spinal muscular atrophy (SMALED1; 158600), Harms et al. (2012) identified a heterozygous 2011A-G transition in exon 8 of the DYNC1H1 gene, resulting in a lys671-to-glu (K671E) substitution at a highly conserved residue in the tail domain of the dynein heavy chain. The mutation was not found in 500 controls or the 1000 Genomes Project. The 3 affected individuals showed waddling gait from early childhood, with awkward running due to lower limb weakness; upper limbs were not affected. Muscle atrophy and weakness confined to the lower limbs showed little progression throughout life. There was a notable strength discrepancy between knee extension and flexion, with the quadriceps showing significant weakness. Deep tendon reflexes were reduced at the knees, but normal elsewhere. Nerve conduction studies showed small motor responses and normal sensory responses; EMG showed chronic denervation. One patient had heel cord contractures and inturning feet, whereas another had fasciculations of the calves. </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>.0006 SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 1, AUTOSOMAL DOMINANT</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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DYNC1H1, TYR970CYS
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<br />
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SNP: rs387906743,
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ClinVar: RCV000022934, RCV003447094
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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 3.5-year-old girl with autosomal dominant lower extremity-predominant spinal muscular atrophy (SMALED1; 158600), Harms et al. (2012) identified a heterozygous 3170A-G transition in exon 11 of the DYNC1H1 gene, resulting in a tyr970-to-cys (Y970C) substitution at a highly conserved residue. The mutation was not found in 500 controls or the 1000 Genomes Project. The patient showed delayed motor development, calcaneovalgus foot deformities, lower extremity weakness, and mild cognitive delay. At age 3.5 years, she could not run and had an unsteady gait. There was no sensory loss. EMG was consistent with nonlength-dependent motor neuron disease. A sister, who was not studied, reportedly had similar motor delay diagnosed as cerebral palsy, abnormal gait, and polymicrogyria on brain imaging. </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>.0007 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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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DYNC1H1, LYS3336ASN
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<br />
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SNP: rs397509410,
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ClinVar: RCV000049270, RCV003447108
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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 12-year-old patient (P122) with complex cortical dysplasia with other brain malformations-13 (CDCBM13; 614563), Poirier et al. (2013) identified a de novo heterozygous c.10008G-T transversion in the DYNC1H1 gene, resulting in a lys3336-to-asn (K3336N) substitution at a conserved residue in the microtubule-binding domain. In vitro functional expression studies showed that the mutant protein had decreased microtubule binding affinity compared to wildtype. The mutation was found by whole-exome sequencing and was not present in several large control databases. The patient had microcephaly (-4 SD), early-onset epilepsy, foot deformities consistent with an axonal neuropathy, and was bedridden with spastic tetraplegia. Brain MRI showed posterior pachygyria, frontal polymicrogyria, nodular heterotopia, dysmorphic basal ganglia, and hypoplasia of the corpus callosum, brainstem, and cerebellum. </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>.0008 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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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DYNC1H1, ARG3384GLN
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<br />
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SNP: rs397509411,
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ClinVar: RCV000049271, RCV001091160, RCV003447109
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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 10-year-old patient (P217) with complex cortical dysplasia with other brain malformations-13 (CDCBM13; 614563), Poirier et al. (2013) identified a de novo heterozygous c.10151G-A transition (c.10151G-A, NM_001376) in the DYNC1H1 gene, resulting in an arg3384-to-gln (R3384Q) substitution at a conserved residue in the microtubule-binding domain. In vitro functional expression studies showed that the mutant protein had decreased microtubule binding affinity compared to wildtype. The patient had microcephaly (-4 SD), early-onset epilepsy, foot deformities consistent with an axonal neuropathy, and was bedridden with spastic tetraplegia. Brain MRI showed posterior pachygyria, frontal polymicrogyria, dysmorphic basal ganglia and corpus callosum, and hypoplasia of the brainstem and cerebellum. </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>.0009 CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13</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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DYNC1H1, ARG3344GLN
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<br />
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SNP: rs397509412,
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ClinVar: RCV000049272, RCV001255327, RCV001262933, RCV001291070
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated children (P535 and 574C) with complex cortical dysplasia with other brain malformations-13 (CDCBM13; 614563), Poirier et al. (2013) identified a de novo heterozygous c.10031G-A transition (c.10031G-A, NM_001376) in the DYNC1H1 gene, resulting in an arg3344-to-gln (R3344Q) substitution at a conserved residue in the microtubule-binding domain. One patient was a 5-year-old with severe intellectual disability and autistic features, early-onset epileptic encephalopathy, and MRI findings of posterior agyria, nodular heterotopia, and dysmorphic basal ganglia and corpus callosum. The other patient was a 3-year-old with moderate intellectual disability, focal seizures, and MRI findings of posterior pachygyria and small cerebellar vermis. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<strong>A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.</strong>
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Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., Miller, L. J., Jani-Acsadi, A., Pestronk, A., Shy, M. E., Muntoni, F., Vallee, R. B., Baloh, R. H.
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<strong>Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy.</strong>
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Tsurusaki, Y., Saitoh, S., Tomizawa, K., Sudo, A., Asahina, N., Shiraishi, H., Ito, J., Tanaka, H., Doi, H., Saitsu, H., Miyake, N., Matsumoto, N.
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Vaisberg, E. A., Grissom, P. M., McIntosh, J. R.
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<p class="mim-text-font">
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Vaisberg, E. A., Koonce, M. P., McIntosh, J. R.
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<strong>Cytoplasmic dynein plays a role in mammalian mitotic spindle formation.</strong>
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<p class="mim-text-font">
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Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., van Bon, B. W. M., Hoischen, A., de Vries, B. B. A., Brunner, H. G., Veltman, J. A.
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<strong>A de novo paradigm for mental retardation.</strong>
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Nature Genet. 42: 1109-1112, 2010.
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[PubMed: 21076407]
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[Full Text: https://doi.org/10.1038/ng.712]
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Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S.
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<strong>Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease.</strong>
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Am. J. Hum. Genet. 89: 308-312, 2011.
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[PubMed: 21820100]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.07.002]
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Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T.
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<strong>Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects.</strong>
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J. Med. Genet. 49: 179-183, 2012.
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[PubMed: 22368300]
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[Full Text: https://doi.org/10.1136/jmedgenet-2011-100542]
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Ada Hamosh - updated : 04/16/2018<br>George E. Tiller - updated : 09/12/2017<br>Ada Hamosh - updated : 09/02/2014<br>Cassandra L. Kniffin - updated : 7/1/2014<br>Cassandra L. Kniffin - updated : 9/23/2013<br>Cassandra L. Kniffin - updated : 6/27/2013<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 4/9/2012<br>Cassandra L. Kniffin - updated : 9/15/2011<br>Ada Hamosh - updated : 12/29/2008<br>Ada Hamosh - updated : 4/4/2008<br>Patricia A. Hartz - updated : 4/18/2006<br>Ada Hamosh - updated : 8/2/2005<br>Ada Hamosh - updated : 5/6/2003<br>Rebekah S. Rasooly - updated : 11/18/1998
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Victor A. McKusick : 9/13/1994
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