2843 lines
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- *603531 - ADAPTOR-RELATED PROTEIN COMPLEX 1, SIGMA-1 SUBUNIT; AP1S1
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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">*603531</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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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#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/603531">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000106367;t=ENST00000337619" 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=1174" 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=603531" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<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=ENSG00000106367;t=ENST00000337619" 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_001283" 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_001283" 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=603531" 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=04635&isoform_id=04635_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/AP1S1" 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/3641678,4557471,5630084,13097711,30582397,48428719,119570583,119570584,119570585,189053279" 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/P61966" 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=1174" 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=ENSG00000106367;t=ENST00000337619" 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=AP1S1" 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=AP1S1" 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+1174" 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/AP1S1" 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:1174" 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/1174" 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=chr7&hgg_gene=ENST00000337619.11&hgg_start=101154476&hgg_end=101161276&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:559" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603531[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=603531[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000106367" 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=AP1S1" 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=AP1S1" 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=AP1S1" 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=AP1S1&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/PA24850" 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:559" 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/FBgn0039132.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:1098244" 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/AP1S1#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:1098244" 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/1174/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1174" 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=WBGene00000159;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-040426-1119" 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:1174" 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=AP1S1&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> 722035007<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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603531
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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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ADAPTOR-RELATED PROTEIN COMPLEX 1, SIGMA-1 SUBUNIT; AP1S1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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CLATHRIN-ASSOCIATED/ASSEMBLY/ADAPTOR PROTEIN, SMALL 1; CLAPS1<br />
|
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CLATHRIN ADAPTOR PROTEIN 19; AP19<br />
|
|
CLATHRIN ADAPTOR COMPLEX AP1, SIGMA-1A SUBUNIT
|
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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=AP1S1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AP1S1</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/7/528?start=-3&limit=10&highlight=528">7q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:101154476-101161276&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'})">7:101,154,476-101,161,276</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/7/528?start=-3&limit=10&highlight=528">
|
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7q22.1
|
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</a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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MEDNIK syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
|
<a href="/entry/609313"> 609313 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603531" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603531" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
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<p>The AP1S1 gene encodes the small subunit of the AP-1 complex, which is involved in protein trafficking by clathrin-coated vesicles. Clathrin and its associated heterotetrameric protein complexes (APs) are the main protein components of the coat surrounding the cytoplasmic face of coated vesicles. Two main types of APs, AP-1 and AP-2, are found in clathrin-coated structures located at the Golgi complex and the plasma membrane of mammalian cells, respectively. AP-1 is composed of 2 large chains, beta-prime-adaptin (<a href="/entry/600157">600157</a>) and gamma-adaptin (<a href="/entry/603533">603533</a>); a medium (mu) chain, AP47 (<a href="/entry/603535">603535</a>); and a small (sigma) chain, AP19 (summary by <a href="#3" class="mim-tip-reference" title="Kirchhausen, T., Davis, A. C., Frucht, S., O'Brine Greco, B., Payne, G. S., Tubb, B. <strong>AP17 and AP19, the mammalian small chains of the clathrin-associated protein complexes show homology to Yap17p, their putative homolog in yeast.</strong> J. Biol. Chem. 266: 11153-11157, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2040623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2040623</a>]" pmid="2040623">Kirchhausen et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2040623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Kirchhausen, T., Davis, A. C., Frucht, S., O'Brine Greco, B., Payne, G. S., Tubb, B. <strong>AP17 and AP19, the mammalian small chains of the clathrin-associated protein complexes show homology to Yap17p, their putative homolog in yeast.</strong> J. Biol. Chem. 266: 11153-11157, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2040623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2040623</a>]" pmid="2040623">Kirchhausen et al. (1991)</a> isolated cDNAs encoding mouse AP19 and rat AP17 (<a href="/entry/602242">602242</a>), the small subunit of AP-2. The predicted rat AP17 shares 45% protein sequence identity with mouse AP19. <a href="#8" class="mim-tip-reference" title="Takatsu, H., Sakurai, M., Shin, H.-W., Murakami, K., Nakayama, K. <strong>Identification and characterization of novel clathrin adaptor-related proteins.</strong> J. Biol. Chem. 273: 24693-24700, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9733768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9733768</a>] [<a href="https://doi.org/10.1074/jbc.273.38.24693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9733768">Takatsu et al. (1998)</a> identified a human cDNA encoding AP19, which they designated sigma-1A. They reported that the predicted mouse and human AP19 proteins are identical. Northern blot analysis revealed that the approximately 1.4-kb AP19 mRNA was expressed ubiquitously in human tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9733768+2040623" 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="#1" class="mim-tip-reference" title="Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S. <strong>Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network.</strong> Science 297: 1700-1703, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215646</a>] [<a href="https://doi.org/10.1126/science.1075327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215646">Doray et al. (2002)</a> demonstrated that the Golgi-localized, gamma-ear-containing adenosine diphosphate ribosylation factor-binding proteins (GGA1, <a href="/entry/606004">606004</a> and GGA3, <a href="/entry/606006">606006</a>) and the AP-1 complex colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 (see CSNK2A1, <a href="/entry/115440">115440</a>) that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. <a href="#1" class="mim-tip-reference" title="Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S. <strong>Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network.</strong> Science 297: 1700-1703, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215646</a>] [<a href="https://doi.org/10.1126/science.1075327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215646">Doray et al. (2002)</a> demonstrated that this autoinhibition could induce the directed transfer of mannose 6-phosphate receptors (see <a href="/entry/154540">154540</a>) from the GGAs to AP-1. Mannose 6-phosphate receptors that were defective in binding to GGAs were poorly incorporated into adaptor protein complex containing clathrin coated vesicles. Thus, <a href="#1" class="mim-tip-reference" title="Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S. <strong>Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network.</strong> Science 297: 1700-1703, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215646</a>] [<a href="https://doi.org/10.1126/science.1075327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12215646">Doray et al. (2002)</a> concluded that GGAs and the AP-1 complex interact to package mannose 6-phosphate receptors into AP-1-containing coated vesicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12215646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), <a href="#4" class="mim-tip-reference" title="Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F. <strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong> Nature 432: 1036-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616564</a>] [<a href="https://doi.org/10.1038/nature03159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616564">Kittler et al. (2004)</a> identified 37 genes required for cell division, one of which was AP1S1. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616564" 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 analysis of a somatic cell hybrid panel, <a href="#7" class="mim-tip-reference" title="Peyrard, M., Parveneh, S., Lagercrantz, S., Ekman, M., Fransson, I., Sahlen, S., Dumanski, J. P. <strong>Cloning, expression pattern, and chromosomal assignment to 16q23 of the human gamma-adaptin gene (ADTG).</strong> Genomics 50: 275-280, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653655</a>] [<a href="https://doi.org/10.1006/geno.1998.5289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653655">Peyrard et al. (1998)</a> mapped the AP19 gene to human chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 4 families from Quebec with MEDNIK syndrome (MEDNIK; <a href="/entry/609313">609313</a>), <a href="#6" class="mim-tip-reference" title="Montpetit, A., Cote, S., Brustein, E., Drouin, C. A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T. J., Drapeau, P., Cossette, P. <strong>Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.</strong> PLoS Genet. 4: e1000296, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19057675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19057675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19057675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19057675">Montpetit et al. (2008)</a> identified a homozygous splice site mutation in the AP1S1 gene (<a href="#0001">603531.0001</a>). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation was predicted to result in a truncated protein with loss of function, but a small amount of an AP1S1 protein with an in-frame deletion was also produced, which may have contributed some residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in skin and neurologic defects (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19057675" 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 an 8-year-old girl, born of consanguineous Sephardic Jewish parents, with MEDNIK, <a href="#5" class="mim-tip-reference" title="Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. <strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong> Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>] [<a href="https://doi.org/10.1093/brain/awt012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23423674">Martinelli et al. (2013)</a> identified homozygosity for a 1-bp insertion of a G within a string of Gs (nucleotides 356-365) in exon 4 of the AP1S1 gene (<a href="#0002">603531.0002</a>). In a 10-year-old girl, born to consanguineous Turkish parents, with MEDNIK, <a href="#2" class="mim-tip-reference" title="Incecik, F., Bisgin, A., Yilmaz, M. <strong>MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.</strong> Metab. Brain Dis. 33: 2065-2068, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244301</a>] [<a href="https://doi.org/10.1007/s11011-018-0313-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30244301">Incecik et al. (2018)</a> identified the mutation as a duplication at nucleotide 364 (c.364dupG). <a href="#5" class="mim-tip-reference" title="Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. <strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong> Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>] [<a href="https://doi.org/10.1093/brain/awt012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23423674">Martinelli et al. (2013)</a> found the mutation by whole-exome sequencing and <a href="#2" class="mim-tip-reference" title="Incecik, F., Bisgin, A., Yilmaz, M. <strong>MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.</strong> Metab. Brain Dis. 33: 2065-2068, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244301</a>] [<a href="https://doi.org/10.1007/s11011-018-0313-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30244301">Incecik et al. (2018)</a> found it by targeted gene sequencing. The mutation segregated with the disorder in both families. <a href="#5" class="mim-tip-reference" title="Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. <strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong> Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>] [<a href="https://doi.org/10.1093/brain/awt012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23423674">Martinelli et al. (2013)</a> found that fibroblasts in their patient showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23423674+30244301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Montpetit, A., Cote, S., Brustein, E., Drouin, C. A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T. J., Drapeau, P., Cossette, P. <strong>Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.</strong> PLoS Genet. 4: e1000296, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19057675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19057675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19057675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19057675">Montpetit et al. (2008)</a> found that knockdown of the Ap1s1 gene in zebrafish caused smaller larvae with reduced pigmentation compared to wildtype. The larvae had prominent changes in the skin organization with disorganized fins. Immunolabeling showed abnormal localization of laminin (see, e.g., <a href="/entry/150320">150320</a>) and cadherin (see, e.g., <a href="/entry/192090">192090</a>) in the skin, which was predicted to lead to a loss of epidermal layer integrity. Knockdown of Ap1s1 in zebrafish also caused severe motor impairment and impaired spinal cord development with decreased numbers of interneurons. These defects could be rescued by injection of human wildtype AP1S1. Knockdown of Ap1s1 was lethal at later embryonic stages. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19057675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimAllelicVariantsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>2 Selected Examples</a>):</strong>
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<a href="/allelicVariants/603531" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603531[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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<a id="0001" class="mim-anchor"></a>
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<strong>.0001 MEDNIK SYNDROME</strong>
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AP1S1, IVS2AS, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs751430853 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs751430853;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs751430853?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs751430853" 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=rs751430853" 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=RCV000033081 OR RCV003574705 OR RCV004758617" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033081, RCV003574705, RCV004758617" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033081...</a>
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<p>In affected members of 4 families from Quebec with impaired intellectual development, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK; <a href="/entry/609313">609313</a>), <a href="#6" class="mim-tip-reference" title="Montpetit, A., Cote, S., Brustein, E., Drouin, C. A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T. J., Drapeau, P., Cossette, P. <strong>Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.</strong> PLoS Genet. 4: e1000296, 2008. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19057675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19057675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19057675[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000296" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19057675">Montpetit et al. (2008)</a> identified a homozygous A-to-G transition in intron 2 of the AP1S1 gene, resulting in the skipping of exon 3 and premature termination, consistent with a loss of function. RT-PCR analysis of patient fibroblasts showed no full-length AP1S1 mRNA species, but there was an mRNA isoform predicted to result in a protein with an in-frame deletion generated by use of a cryptic splice acceptor site. Patients had less than 10% of the expected amount of mRNA, but the in-frame deletion protein may have contributed some residual activity. The mutation was found by linkage analysis followed by candidate gene sequencing. All unaffected parents were heterozygous for the mutation, which was not found in 180 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19057675" 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 fibroblasts from a French Canadian patient (patient 4) with the homozygous IVS2-2A-G transition in the AP1S1 gene, <a href="#5" class="mim-tip-reference" title="Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. <strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong> Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>] [<a href="https://doi.org/10.1093/brain/awt012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23423674">Martinelli et al. (2013)</a> showed mislocalization of the ATP7A (<a href="/entry/300011">300011</a>) protein to the cell periphery both at baseline and after increased copper supplementation, whereas in control cells the ATP7A protein was localized to the trans-Golgi network at baseline. Overexpression of wildtype AP1S1 in patient fibroblasts restored the correct localization of ATP7A to the trans-Golgi network. <a href="#5" class="mim-tip-reference" title="Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. <strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong> Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>] [<a href="https://doi.org/10.1093/brain/awt012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23423674">Martinelli et al. (2013)</a> also showed decreased expression of the copper-containing enzymes superoxide dismutase (<a href="/entry/147450">147450</a>), COX II, and COX IV, and a severe reduction of COX activity in patient fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23423674" 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 id="0002" class="mim-anchor"></a>
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<strong>.0002 MEDNIK SYNDROME</strong>
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AP1S1, 1-BP DUP, 364G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs767358930 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs767358930;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs767358930?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs767358930" 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=rs767358930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000598932 OR RCV001215772" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000598932, RCV001215772" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000598932...</a>
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<p>In an 8-year-old girl (patient 1), born to consanguineous Sephardic Jewish parents, with impaired intellectual development, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK; <a href="/entry/609313">609313</a>), <a href="#5" class="mim-tip-reference" title="Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C. <strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong> Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>] [<a href="https://doi.org/10.1093/brain/awt012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23423674">Martinelli et al. (2013)</a> identified a homozygous 1-bp insertion (c.356_365insG) in a stretch of 8 consecutive Gs between nucleotides 356 and 365 in exon 4 of the AP1S1 gene, predicting a frameshift and stop codon after 17 amino acids (Asp322GlyfsTer17). The mutation, which was identified by targeted gene sequencing, was present in heterozygous state in the parents and an unaffected sib. Patient fibroblasts showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression. The carrier parents and sister showed a 40-fold reduction in APS1 mRNA expression. Patient fibroblasts showed decreased expression of the copper-containing enzymes superoxide dismutase (<a href="/entry/147450">147450</a>), COX II, and COX IV, and a severe reduction of COX activity. There was also mislocalization of the ATP7A protein (<a href="/entry/300011">300011</a>) to the cell periphery both at baseline and after increased copper supplementation n patient fibroblasts, whereas in control cells the ATP7A protein was localized to the trans-Golgi network at baseline. Overexpression of wildtype AP1S1 in patient fibroblasts restored the correct localization of ATP7A, and incorporation rate and copper retention rate were both reduced in patient fibroblasts compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23423674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 10-year-old girl with MEDNIK, born to consanguineous Turkish parents, <a href="#2" class="mim-tip-reference" title="Incecik, F., Bisgin, A., Yilmaz, M. <strong>MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.</strong> Metab. Brain Dis. 33: 2065-2068, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244301</a>] [<a href="https://doi.org/10.1007/s11011-018-0313-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30244301">Incecik et al. (2018)</a> identified homozygosity for this 1-bp duplication of a G at nucleotide 364 (c.364dupG, NM_001283.4) in the AP1S1 gene, predicting a frameshift and a premature termination codon 18 residues downstream (Glu122GlyfsTer18). The mutation was identified by targeted gene sequencing. The parents were heterozygous for the mutation. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244301" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Doray2002" class="mim-anchor"></a>
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Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S.
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<strong>Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network.</strong>
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Science 297: 1700-1703, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12215646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12215646</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12215646" 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.1075327" target="_blank">Full Text</a>]
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Incecik, F., Bisgin, A., Yilmaz, M.
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<strong>MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.</strong>
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Metab. Brain Dis. 33: 2065-2068, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30244301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30244301</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30244301" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s11011-018-0313-4" target="_blank">Full Text</a>]
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Kirchhausen, T., Davis, A. C., Frucht, S., O'Brine Greco, B., Payne, G. S., Tubb, B.
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<strong>AP17 and AP19, the mammalian small chains of the clathrin-associated protein complexes show homology to Yap17p, their putative homolog in yeast.</strong>
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J. Biol. Chem. 266: 11153-11157, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2040623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2040623</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2040623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F.
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<strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong>
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Nature 432: 1036-1040, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616564</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature03159" target="_blank">Full Text</a>]
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Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C.
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<strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong>
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Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23423674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23423674</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23423674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awt012" target="_blank">Full Text</a>]
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Montpetit2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Montpetit, A., Cote, S., Brustein, E., Drouin, C. A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T. J., Drapeau, P., Cossette, P.
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<strong>Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.</strong>
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PLoS Genet. 4: e1000296, 2008. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19057675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19057675</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19057675[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=19057675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1371/journal.pgen.1000296" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="Peyrard1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Peyrard, M., Parveneh, S., Lagercrantz, S., Ekman, M., Fransson, I., Sahlen, S., Dumanski, J. P.
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<strong>Cloning, expression pattern, and chromosomal assignment to 16q23 of the human gamma-adaptin gene (ADTG).</strong>
|
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Genomics 50: 275-280, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653655</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5289" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Takatsu1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Takatsu, H., Sakurai, M., Shin, H.-W., Murakami, K., Nakayama, K.
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<strong>Identification and characterization of novel clathrin adaptor-related proteins.</strong>
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J. Biol. Chem. 273: 24693-24700, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9733768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9733768</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9733768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.38.24693" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</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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Hilary J. Vernon - updated : 07/10/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/11/2012<br>Ada Hamosh - updated : 3/8/2005<br>Ada Hamosh - updated : 10/23/2002
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</span>
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</div>
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</div>
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<div>
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<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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Rebekah S. Rasooly : 2/15/1999
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/21/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/20/2022<br>carol : 12/18/2022<br>carol : 01/26/2021<br>carol : 07/13/2020<br>carol : 07/10/2020<br>carol : 09/24/2013<br>carol : 9/19/2013<br>tpirozzi : 9/19/2013<br>carol : 8/16/2013<br>carol : 3/15/2013<br>carol : 12/14/2012<br>ckniffin : 12/11/2012<br>alopez : 3/8/2005<br>alopez : 10/23/2002<br>alopez : 10/23/2002<br>carol : 4/11/2001<br>carol : 4/11/2001<br>alopez : 2/15/1999
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</span>
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</div>
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<div class="container visible-print-block">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603531
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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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ADAPTOR-RELATED PROTEIN COMPLEX 1, SIGMA-1 SUBUNIT; AP1S1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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CLATHRIN-ASSOCIATED/ASSEMBLY/ADAPTOR PROTEIN, SMALL 1; CLAPS1<br />
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CLATHRIN ADAPTOR PROTEIN 19; AP19<br />
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CLATHRIN ADAPTOR COMPLEX AP1, SIGMA-1A SUBUNIT
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: AP1S1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 722035007;
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</span>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:101,154,476-101,161,276 </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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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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7q22.1
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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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MEDNIK syndrome
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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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609313
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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 recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<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 AP1S1 gene encodes the small subunit of the AP-1 complex, which is involved in protein trafficking by clathrin-coated vesicles. Clathrin and its associated heterotetrameric protein complexes (APs) are the main protein components of the coat surrounding the cytoplasmic face of coated vesicles. Two main types of APs, AP-1 and AP-2, are found in clathrin-coated structures located at the Golgi complex and the plasma membrane of mammalian cells, respectively. AP-1 is composed of 2 large chains, beta-prime-adaptin (600157) and gamma-adaptin (603533); a medium (mu) chain, AP47 (603535); and a small (sigma) chain, AP19 (summary by Kirchhausen et al., 1991). </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>Kirchhausen et al. (1991) isolated cDNAs encoding mouse AP19 and rat AP17 (602242), the small subunit of AP-2. The predicted rat AP17 shares 45% protein sequence identity with mouse AP19. Takatsu et al. (1998) identified a human cDNA encoding AP19, which they designated sigma-1A. They reported that the predicted mouse and human AP19 proteins are identical. Northern blot analysis revealed that the approximately 1.4-kb AP19 mRNA was expressed ubiquitously in human tissues. </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>Doray et al. (2002) demonstrated that the Golgi-localized, gamma-ear-containing adenosine diphosphate ribosylation factor-binding proteins (GGA1, 606004 and GGA3, 606006) and the AP-1 complex colocalize in clathrin-coated buds of the trans-Golgi networks of mouse L cells and human HeLa cells. Binding studies revealed a direct interaction between the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further, AP-1 contained bound casein kinase-2 (see CSNK2A1, 115440) that phosphorylated GGA1 and GGA3, thereby causing autoinhibition. Doray et al. (2002) demonstrated that this autoinhibition could induce the directed transfer of mannose 6-phosphate receptors (see 154540) from the GGAs to AP-1. Mannose 6-phosphate receptors that were defective in binding to GGAs were poorly incorporated into adaptor protein complex containing clathrin coated vesicles. Thus, Doray et al. (2002) concluded that GGAs and the AP-1 complex interact to package mannose 6-phosphate receptors into AP-1-containing coated vesicles. </p><p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was AP1S1. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>By analysis of a somatic cell hybrid panel, Peyrard et al. (1998) mapped the AP19 gene to human chromosome 7. </p>
|
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In affected members of 4 families from Quebec with MEDNIK syndrome (MEDNIK; 609313), Montpetit et al. (2008) identified a homozygous splice site mutation in the AP1S1 gene (603531.0001). The mutation was identified by linkage analysis followed by candidate gene sequencing. The mutation was predicted to result in a truncated protein with loss of function, but a small amount of an AP1S1 protein with an in-frame deletion was also produced, which may have contributed some residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in skin and neurologic defects (see ANIMAL MODEL). </p><p>In an 8-year-old girl, born of consanguineous Sephardic Jewish parents, with MEDNIK, Martinelli et al. (2013) identified homozygosity for a 1-bp insertion of a G within a string of Gs (nucleotides 356-365) in exon 4 of the AP1S1 gene (603531.0002). In a 10-year-old girl, born to consanguineous Turkish parents, with MEDNIK, Incecik et al. (2018) identified the mutation as a duplication at nucleotide 364 (c.364dupG). Martinelli et al. (2013) found the mutation by whole-exome sequencing and Incecik et al. (2018) found it by targeted gene sequencing. The mutation segregated with the disorder in both families. Martinelli et al. (2013) found that fibroblasts in their patient showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Animal Model</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Montpetit et al. (2008) found that knockdown of the Ap1s1 gene in zebrafish caused smaller larvae with reduced pigmentation compared to wildtype. The larvae had prominent changes in the skin organization with disorganized fins. Immunolabeling showed abnormal localization of laminin (see, e.g., 150320) and cadherin (see, e.g., 192090) in the skin, which was predicted to lead to a loss of epidermal layer integrity. Knockdown of Ap1s1 in zebrafish also caused severe motor impairment and impaired spinal cord development with decreased numbers of interneurons. These defects could be rescued by injection of human wildtype AP1S1. Knockdown of Ap1s1 was lethal at later embryonic stages. </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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>2 Selected Examples):</strong>
|
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</span>
|
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</h4>
|
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0001 MEDNIK SYNDROME</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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AP1S1, IVS2AS, A-G, -2
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<br />
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SNP: rs751430853,
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gnomAD: rs751430853,
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ClinVar: RCV000033081, RCV003574705, RCV004758617
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<p>In affected members of 4 families from Quebec with impaired intellectual development, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK; 609313), Montpetit et al. (2008) identified a homozygous A-to-G transition in intron 2 of the AP1S1 gene, resulting in the skipping of exon 3 and premature termination, consistent with a loss of function. RT-PCR analysis of patient fibroblasts showed no full-length AP1S1 mRNA species, but there was an mRNA isoform predicted to result in a protein with an in-frame deletion generated by use of a cryptic splice acceptor site. Patients had less than 10% of the expected amount of mRNA, but the in-frame deletion protein may have contributed some residual activity. The mutation was found by linkage analysis followed by candidate gene sequencing. All unaffected parents were heterozygous for the mutation, which was not found in 180 controls. </p><p>In fibroblasts from a French Canadian patient (patient 4) with the homozygous IVS2-2A-G transition in the AP1S1 gene, Martinelli et al. (2013) showed mislocalization of the ATP7A (300011) protein to the cell periphery both at baseline and after increased copper supplementation, whereas in control cells the ATP7A protein was localized to the trans-Golgi network at baseline. Overexpression of wildtype AP1S1 in patient fibroblasts restored the correct localization of ATP7A to the trans-Golgi network. Martinelli et al. (2013) also showed decreased expression of the copper-containing enzymes superoxide dismutase (147450), COX II, and COX IV, and a severe reduction of COX activity in patient fibroblasts. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 MEDNIK SYNDROME</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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AP1S1, 1-BP DUP, 364G
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SNP: rs767358930,
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gnomAD: rs767358930,
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ClinVar: RCV000598932, RCV001215772
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</span>
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<p>In an 8-year-old girl (patient 1), born to consanguineous Sephardic Jewish parents, with impaired intellectual development, enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK; 609313), Martinelli et al. (2013) identified a homozygous 1-bp insertion (c.356_365insG) in a stretch of 8 consecutive Gs between nucleotides 356 and 365 in exon 4 of the AP1S1 gene, predicting a frameshift and stop codon after 17 amino acids (Asp322GlyfsTer17). The mutation, which was identified by targeted gene sequencing, was present in heterozygous state in the parents and an unaffected sib. Patient fibroblasts showed an 80-fold reduction of AP1S1 mRNA expression and absence of AP1S1 protein expression. The carrier parents and sister showed a 40-fold reduction in APS1 mRNA expression. Patient fibroblasts showed decreased expression of the copper-containing enzymes superoxide dismutase (147450), COX II, and COX IV, and a severe reduction of COX activity. There was also mislocalization of the ATP7A protein (300011) to the cell periphery both at baseline and after increased copper supplementation n patient fibroblasts, whereas in control cells the ATP7A protein was localized to the trans-Golgi network at baseline. Overexpression of wildtype AP1S1 in patient fibroblasts restored the correct localization of ATP7A, and incorporation rate and copper retention rate were both reduced in patient fibroblasts compared to controls. </p><p>In a 10-year-old girl with MEDNIK, born to consanguineous Turkish parents, Incecik et al. (2018) identified homozygosity for this 1-bp duplication of a G at nucleotide 364 (c.364dupG, NM_001283.4) in the AP1S1 gene, predicting a frameshift and a premature termination codon 18 residues downstream (Glu122GlyfsTer18). The mutation was identified by targeted gene sequencing. The parents were heterozygous for the mutation. Functional studies were not performed. </p>
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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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<ol>
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<p class="mim-text-font">
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Doray, B., Ghosh, P., Griffith, J., Geuze, H. J., Kornfeld, S.
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<strong>Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi network.</strong>
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Science 297: 1700-1703, 2002.
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[PubMed: 12215646]
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[Full Text: https://doi.org/10.1126/science.1075327]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Incecik, F., Bisgin, A., Yilmaz, M.
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<strong>MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features.</strong>
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Metab. Brain Dis. 33: 2065-2068, 2018.
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[PubMed: 30244301]
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[Full Text: https://doi.org/10.1007/s11011-018-0313-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kirchhausen, T., Davis, A. C., Frucht, S., O'Brine Greco, B., Payne, G. S., Tubb, B.
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<strong>AP17 and AP19, the mammalian small chains of the clathrin-associated protein complexes show homology to Yap17p, their putative homolog in yeast.</strong>
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J. Biol. Chem. 266: 11153-11157, 1991.
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[PubMed: 2040623]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F.
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<strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong>
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Nature 432: 1036-1040, 2004.
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[PubMed: 15616564]
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[Full Text: https://doi.org/10.1038/nature03159]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Martinelli, D., Travaglini, L., Drouin, C. A., Ceballos-Picot, I., Rizza, T., Bertini, E., Carrozzo, R., Petrini, S., de Lonlay, P., El Hachem, M., Hubert, L., Montpetit, A., Torre, G., Dionisi-Vici, C.
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<strong>MEDNIK syndrome: a novel defect of copper metabolism treatable by zinc acetate therapy.</strong>
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Brain 136: 872-881, 2013. Note: Erratum: Brain 136: e256, 2013.
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[PubMed: 23423674]
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[Full Text: https://doi.org/10.1093/brain/awt012]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Montpetit, A., Cote, S., Brustein, E., Drouin, C. A., Lapointe, L., Boudreau, M., Meloche, C., Drouin, R., Hudson, T. J., Drapeau, P., Cossette, P.
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<strong>Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.</strong>
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PLoS Genet. 4: e1000296, 2008. Note: Electronic Article.
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[PubMed: 19057675]
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[Full Text: https://doi.org/10.1371/journal.pgen.1000296]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Peyrard, M., Parveneh, S., Lagercrantz, S., Ekman, M., Fransson, I., Sahlen, S., Dumanski, J. P.
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<strong>Cloning, expression pattern, and chromosomal assignment to 16q23 of the human gamma-adaptin gene (ADTG).</strong>
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Genomics 50: 275-280, 1998.
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[PubMed: 9653655]
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[Full Text: https://doi.org/10.1006/geno.1998.5289]
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</p>
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<p class="mim-text-font">
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Takatsu, H., Sakurai, M., Shin, H.-W., Murakami, K., Nakayama, K.
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<strong>Identification and characterization of novel clathrin adaptor-related proteins.</strong>
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J. Biol. Chem. 273: 24693-24700, 1998.
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[PubMed: 9733768]
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[Full Text: https://doi.org/10.1074/jbc.273.38.24693]
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</li>
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</ol>
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<br />
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 07/10/2020<br>Cassandra L. Kniffin - updated : 12/11/2012<br>Ada Hamosh - updated : 3/8/2005<br>Ada Hamosh - updated : 10/23/2002
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Rebekah S. Rasooly : 2/15/1999
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