3084 lines
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Entry
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- *607244 - ADAPTOR-RELATED PROTEIN COMPLEX 4, EPSILON-1 SUBUNIT; AP4E1
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- OMIM
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<p>
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<span class="h4">*607244</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/607244">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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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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<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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<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=ENSG00000081014;t=ENST00000261842" 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=23431" 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=607244" 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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<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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<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=ENSG00000081014;t=ENST00000261842" 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_001252127,NM_007347,XM_005254264,XM_006720447,XM_047432324,XM_047432325,XM_047432326,XM_047432327" 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_007347" 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=607244" 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=06258&isoform_id=06258_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/AP4E1" 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/5689377,6960319,37675283,51476865,116496867,119597817,120660384,145559441,194386392,355477272,444738663,530405602,578826761,2217300629,2217300633,2217300635,2217300637,2462543475,2462543477,2462543479,2462543481,2462543483,2462543485" 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/Q9UPM8" 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 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=23431" 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=ENSG00000081014;t=ENST00000261842" 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=AP4E1" 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=AP4E1" 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+23431" 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/AP4E1" 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:23431" 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/23431" 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=chr15&hgg_gene=ENST00000261842.10&hgg_start=50907492&hgg_end=51005895&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 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:573" 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=607244[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=607244[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/AP4E1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000081014" 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=AP4E1" 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=AP4E1" 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=AP4E1" 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=AP4E1&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/PA24865" 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:573" 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://www.mousephenotype.org/data/genes/MGI:1336993" 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/AP4E1#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:1336993" 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/23431/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=23431" 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://zfin.org/ZDB-GENE-061221-3" 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:23431" 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=AP4E1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607244
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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 4, EPSILON-1 SUBUNIT; AP4E1
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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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<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=AP4E1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">AP4E1</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/15/210?start=-3&limit=10&highlight=210">15q21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:50907492-51005895&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'})">15:50,907,492-51,005,895</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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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=613744,184450" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
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View Clinical Synopses
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</a>
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</span>
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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="2">
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<span class="mim-font">
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<a href="/geneMap/15/210?start=-3&limit=10&highlight=210">
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15q21.2
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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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Spastic paraplegia 51, 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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<a href="/entry/613744"> 613744 </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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<tr>
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<td>
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<span class="mim-font">
|
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Stuttering, familial persistent, 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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<a href="/entry/184450"> 184450 </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 dominant">AD</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>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/607244" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607244" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</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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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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<p>The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1; <a href="/entry/607245">607245</a>) and epsilon-4 (AP4E1), a medium chain, mu-4 (AP4M1; <a href="/entry/602296">602296</a>), and a small chain, sigma-4 (AP4S1; <a href="/entry/607243">607243</a>).</p>
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<p>By genomic sequence analysis, <a href="#3" class="mim-tip-reference" title="Dell'Angelica, E. C., Mullins, C., Bonifacino, J. S. <strong>AP-4, a novel protein complex related to clathrin adaptors.</strong> J. Biol. Chem. 274: 7278-7285, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10066790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10066790</a>] [<a href="https://doi.org/10.1074/jbc.274.11.7278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10066790">Dell'Angelica et al. (1999)</a> identified AP4E1 within an EST and found that the deduced protein shares 25 to 30% identity with the trunk region of the AP subunits alpha (see AP2A1; <a href="/entry/601026">601026</a>), gamma (see AP1G1; <a href="/entry/603533">603533</a>), and delta (AP3D1). Northern blot analysis revealed a transcript of 7 kb. By gel filtration and Western blot analysis of human fibroblast cytosol, <a href="#3" class="mim-tip-reference" title="Dell'Angelica, E. C., Mullins, C., Bonifacino, J. S. <strong>AP-4, a novel protein complex related to clathrin adaptors.</strong> J. Biol. Chem. 274: 7278-7285, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10066790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10066790</a>] [<a href="https://doi.org/10.1074/jbc.274.11.7278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10066790">Dell'Angelica et al. (1999)</a> found that AP4E1 shows an apparent molecular mass of about 140 kD and is part of a 280-kD complex containing AP4B1, AP4S1, and AP4M1. By immunoprecipitation and reprecipitation of HeLa cell lysates, they confirmed interaction between AP4B1 and AP4E1. Immunolocalization of the AP4B1 subunit in HeLa cells revealed that the AP4 complex associates with the trans-Golgi network or an adjacent structure. The association was sensitive to brefeldin-A treatment, indicating that the membrane localization of AP4 is dependent upon the small GTP-binding protein ARF1 (<a href="/entry/103180">103180</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10066790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Hirst, J., Bright, N. A., Rous, B., Robinson, M. S. <strong>Characterization of a fourth adaptor-related protein complex.</strong> Molec. Biol. Cell 10: 2787-2802, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10436028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10436028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10436028[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.10.8.2787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10436028">Hirst et al. (1999)</a> identified AP4E1 within an EST from human testis and cloned the full-length cDNA by screening a human heart cDNA library. The deduced protein has a calculated molecular mass of about 127 kD. Within the first 600 amino acids, AP4E1 has homology with the AP subunits gamma, alpha, and delta, including conserved stretches that include a KRIGYL motif and a WIIGEY motif. AP4E1 contains a conserved 600-amino acid N-terminal domain, a hinge domain, and a C-terminal 'ear' domain. Northern blot analysis revealed ubiquitous but weak expression of a 7.5-kb transcript. By coimmunoprecipitation of pig brain cytosol, <a href="#4" class="mim-tip-reference" title="Hirst, J., Bright, N. A., Rous, B., Robinson, M. S. <strong>Characterization of a fourth adaptor-related protein complex.</strong> Molec. Biol. Cell 10: 2787-2802, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10436028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10436028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10436028[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1091/mbc.10.8.2787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10436028">Hirst et al. (1999)</a> confirmed an interaction between AP4E1 and AP4B1. Using yeast 2-hybrid analysis, they found a strong and specific interaction between AP4E1 and AP4S1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10436028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. <strong>Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.</strong> Am. J. Hum. Genet. 88: 788-795, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620353[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620353">Abou Jamra et al. (2011)</a> found ubiquitous AP4S1 expression in all fetal and adult brain structures examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21620353" 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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In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic paraplegia-51 (SPG51; <a href="/entry/613744">613744</a>), <a href="#6" class="mim-tip-reference" title="Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. <strong>Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.</strong> J. Med. Genet. 48: 141-144, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20972249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20972249</a>] [<a href="https://doi.org/10.1136/jmg.2010.082263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20972249">Moreno-De-Luca et al. (2011)</a> identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171) that included the 5-prime end of the AP4E1 gene and the 5-prime end of the SPPL2A gene (<a href="/entry/608238">608238</a>). Noting that mutation in the AP4M1 gene (<a href="/entry/602296">602296</a>), which forms a complex with AP4E1, causes a similar phenotype (SPG50; <a href="/entry/612936">612936</a>), <a href="#6" class="mim-tip-reference" title="Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. <strong>Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.</strong> J. Med. Genet. 48: 141-144, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20972249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20972249</a>] [<a href="https://doi.org/10.1136/jmg.2010.082263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20972249">Moreno-De-Luca et al. (2011)</a> concluded that disruption of the AP4E1 gene was responsible for the phenotype in their family, although they could not exclude a possible role for disruption of the SPPL2A gene. The authors proposed the designation 'AP4 deficiency syndrome' to refer to disorders caused by disruption of any of the 4 subunits of the AP4 complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20972249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By linkage analysis followed by candidate gene sequencing in a consanguineous Syrian family with mental retardation and spasticity, <a href="#1" class="mim-tip-reference" title="Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. <strong>Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.</strong> Am. J. Hum. Genet. 88: 788-795, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620353[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620353">Abou Jamra et al. (2011)</a> identified a homozygous truncating mutation in the AP4E1 gene (<a href="#0002">607244.0002</a>). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21620353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, <a href="#7" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified homozygosity for a frameshift mutation in the AP4E1 gene (<a href="#0003">607244.0003</a>) in 3 affected members of a consanguineous family segregating SPG51. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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 pair of monozygotic twin sisters, born of consanguineous Moroccan parents, with SPG51, <a href="#5" class="mim-tip-reference" title="Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S. <strong>A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease.</strong> PLoS One 8: e58286, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23472171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23472171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23472171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0058286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23472171">Kong et al. (2013)</a> identified a homozygous nonsense mutation in the AP4E1 gene (R1105X; <a href="#0005">607244.0005</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 1,050 healthy controls or in several control databases. Analysis of patient cells showed normal AP4E1 mRNA levels, but barely detectable protein levels, suggesting an unstable mutant protein. There was also a severe impairment of AP4 complex formation compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23472171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Familial Persistent Stuttering 1</em></strong></p><p>
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In affected members of a large family of Cameroon descent (CAMST01) with autosomal dominant familial persistent stuttering-1 (STUT1; <a href="/entry/184450">184450</a>), originally reported by <a href="#8" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">Raza et al. (2013)</a>, <a href="#9" class="mim-tip-reference" title="Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. <strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong> Am. J. Hum. Genet. 97: 715-725, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26544806">Raza et al. (2015)</a> identified heterozygosity for 2 missense variants in the AP4E1 gene that occurred in cis (V517I and E801K; <a href="#0004">607244.0004</a>). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. The same mutations on the same haplotype were subsequently found in 2 of 96 additional individuals from Cameroon with stuttering. Sequencing of the AP4E1 gene in unrelated affected individuals, including 93 from Cameroon, 132 from Pakistan, and 711 from North America, revealed 23 other rare variants in this gene, including small (1- to 3-bp) deletions, insertions, duplications, frameshifts, and stop codons; no truncating mutations were found in 558 ethnically matched control individuals. Investigation of large population databases, including the 1000 Genomes Project and Exome Sequencing Project, which are not phenotyped for speech fluency, found 3 loss-of-function AP4E1 variants among about 19,000 chromosomes, as well as several rare missense variants; all of these occurred at a significantly lower frequency compared to the variants observed in stuttering individuals. Studies in a yeast 2-hybrid system supported a direct interaction between the AP4 complex and NAGPA (<a href="/entry/607985">607985</a>), variations in which have also been implicated in stuttering (STUT2; <a href="/entry/609261">609261</a>). The findings suggested that defects in intracellular trafficking play a role in persistent stuttering. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26544806+23239121" 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="#2" class="mim-tip-reference" title="De Pace, R., Skirzewski, M., Damme, M., Mattera, R., Mercurio, J., Foster, A. M., Cuitino, L., Jarnik, M., Hoffmann, V., Morris, H. D., Han, T.-U., Mancini, G. M. S., Buonanno, A., Bonifacino, J. S. <strong>Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome.</strong> PLoS Genet. 14: e1007363, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29698489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29698489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29698489[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.1007363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29698489">De Pace et al. (2018)</a> found that Ap4e1-knockout mice exhibited a range of neurologic phenotypes, including hindlimb clasping, decreased motor coordination, and weak grip strength. In addition, the knockout mice had thin corpus callosum and axonal swellings in various regions of brain and spinal cord. Knockout mice showed accumulation of Atg9a (<a href="/entry/612204">612204</a>) at the trans-Golgi network (TGN) in various neuronal types. Similar accumulation of ATG9A was observed in TGN of skin fibroblasts from human patients with AP4M1 mutations. The results indicated that AP4 deficiency impaired delivery of ATG9A from the Golgi complex to the cell periphery. This defect was associated with increased tendency to accumulate mutant huntingtin aggregates in axons of Ap4e1-knockout neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29698489" 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>5 Selected Examples</a>):</strong>
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<a href="/allelicVariants/607244" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607244[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</strong>
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AP4E1, 192-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023636" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023636" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023636</a>
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<p>In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic paraplegia-51 (SPG51; <a href="/entry/613744">613744</a>), <a href="#6" class="mim-tip-reference" title="Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. <strong>Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.</strong> J. Med. Genet. 48: 141-144, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20972249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20972249</a>] [<a href="https://doi.org/10.1136/jmg.2010.082263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20972249">Moreno-De-Luca et al. (2011)</a> identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171) that included the 5-prime end of the AP4E1 gene and the 5-prime end of the SPPL2A gene (<a href="/entry/608238">608238</a>). The unaffected mother was heterozygous for the deletion, but no DNA was available from the father, who was inferred to be heterozygous for the deletion. <a href="#6" class="mim-tip-reference" title="Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L. <strong>Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.</strong> J. Med. Genet. 48: 141-144, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20972249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20972249</a>] [<a href="https://doi.org/10.1136/jmg.2010.082263" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20972249">Moreno-De-Luca et al. (2011)</a> concluded that disruption of the AP4E1 gene was responsible for the phenotype, although they could not exclude a possible role for disruption of the SPPL2A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20972249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</strong>
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AP4E1, 4-BP DEL, IVS5DS, 542+1GTAA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2141147450 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2141147450;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2141147450" 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=rs2141147450" 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=RCV001849795 OR RCV002266897" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001849795, RCV002266897" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001849795...</a>
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<p>In 2 affected members of a consanguineous Syrian family with mental retardation and spasticity (SPG51; <a href="/entry/613744">613744</a>), <a href="#1" class="mim-tip-reference" title="Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L. <strong>Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.</strong> Am. J. Hum. Genet. 88: 788-795, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21620353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21620353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21620353[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21620353">Abou Jamra et al. (2011)</a> identified a homozygous 4-bp deletion (542+1delGTAA) in the donor splice site of intron 5 of the AP4E1 gene, resulting in the skipping of exon 5, a frameshift, and premature termination of the protein in exon 6. The mutation was not found in 740 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21620353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</strong>
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AP4E1, VAL454FS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2140861877 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2140861877;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2140861877" 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=rs2140861877" 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=RCV000023638" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023638" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023638</a>
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<p>In family M254, in which 3 of 4 children of first-cousin parents had mental retardation, microcephaly, and spastic paraplegia (SPG51; <a href="/entry/613744">613744</a>), <a href="#7" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a causative homozygous 2-bp insertion at genomic coordinate chr15:49029357 (NCBI36), resulting in a frameshift at codon 454. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 STUTTERING, FAMILIAL PERSISTENT, 1</strong>
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AP4E1, VAL517ILE AND GLU801LYS
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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> rs556450190 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs556450190;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/rs556450190?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=rs556450190" 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=rs556450190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs760021635 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs760021635;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/rs760021635?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=rs760021635" 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=rs760021635" 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=RCV000210065 OR RCV002518399" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210065, RCV002518399" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210065...</a>
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<p>In affected members of a large family of Cameroon descent (CAMST01) with autosomal dominant familial persistent stuttering-1 (STUT1; <a href="/entry/184450">184450</a>), originally reported by <a href="#8" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">Raza et al. (2013)</a>, <a href="#9" class="mim-tip-reference" title="Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. <strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong> Am. J. Hum. Genet. 97: 715-725, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2015.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26544806">Raza et al. (2015)</a> identified heterozygosity for 2 variants in the AP4E1 gene that occurred in cis: a c.1549G-A transition (c.1549G-A, NM_007347.4) in exon 14, resulting in a val517-to-ile (V517I) substitution in the trunk domain, and a c.2401G-A transition (c.2401G-A, NM_00737.4) in exon 18, resulting in a glu801-to-lys (E801K) substitution in the hinge domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues and were not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 558 controls. Sequencing of 96 unrelated affected Cameroonians identified the same 2 variants in 2 individuals; haplotype analysis indicated a founder effect between these individuals and the family. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in slightly decreased assembly of the AP4 complex (about 80% of wildtype). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26544806+23239121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1313275799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1313275799;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/rs1313275799?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=rs1313275799" 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=rs1313275799" 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=RCV001333647 OR RCV001779155 OR RCV001849507" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001333647, RCV001779155, RCV001849507" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001333647...</a>
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<p>In a pair of monozygotic twin sisters, born of consanguineous Moroccan parents, with spastic paraplegia-51 (SPG51; <a href="/entry/613744">613744</a>), <a href="#5" class="mim-tip-reference" title="Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S. <strong>A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease.</strong> PLoS One 8: e58286, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23472171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23472171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23472171[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pone.0058286" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23472171">Kong et al. (2013)</a> identified a homozygous C-to-T transition in the AP4E1 gene, resulting in an arg1105-to-ter (R1105X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 1,050 healthy controls or in several control databases. Analysis of patient cells showed normal AP4E1 mRNA levels, but barely detectable protein levels, suggesting an unstable mutant protein. There was also a severe impairment of AP4 complex formation compared to controls. In addition to SPG51, the patients had IMD86 (<a href="/entry/619549">619549</a>) caused by a homozygous mutation in the SPPL2A gene (<a href="/entry/608238#0001">608238.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23472171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1016/j.ajhg.2011.04.019" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1371/journal.pgen.1007363" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.274.11.7278" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10436028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10436028</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10436028[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=10436028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1091/mbc.10.8.2787" target="_blank">Full Text</a>]
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Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S.
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<strong>A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23472171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23472171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23472171[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=23472171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1371/journal.pone.0058286" target="_blank">Full Text</a>]
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Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L.
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[<a href="https://doi.org/10.1136/jmg.2010.082263" target="_blank">Full Text</a>]
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Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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/nature10423" target="_blank">Full Text</a>]
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Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D.
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Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[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=26544806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bao Lige - updated : 09/18/2018
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Cassandra L. Kniffin - updated : 3/15/2016<br>Ada Hamosh - updated : 1/6/2012<br>Cassandra L. Kniffin - updated : 7/7/2011<br>Cassandra L. Kniffin - updated : 2/23/2011
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ckniffin : 09/29/2021<br>carol : 07/30/2021<br>mgross : 09/18/2018<br>carol : 03/16/2016<br>ckniffin : 3/15/2016<br>alopez : 4/20/2015<br>carol : 9/24/2013<br>carol : 9/19/2013<br>carol : 4/24/2012<br>ckniffin : 4/24/2012<br>carol : 1/6/2012<br>terry : 1/6/2012<br>wwang : 7/7/2011<br>ckniffin : 7/7/2011<br>carol : 3/15/2011<br>wwang : 2/24/2011<br>ckniffin : 2/23/2011<br>carol : 5/28/2003<br>mgross : 9/20/2002<br>mgross : 9/19/2002
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607244
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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 4, EPSILON-1 SUBUNIT; AP4E1
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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-text-font">
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<strong><em>HGNC Approved Gene Symbol: AP4E1</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>
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<em>
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Cytogenetic location: 15q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:50,907,492-51,005,895 </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="2">
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<span class="mim-font">
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15q21.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Spastic paraplegia 51, 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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613744
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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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<tr>
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<td>
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<span class="mim-font">
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Stuttering, familial persistent, 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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184450
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1; 607245) and epsilon-4 (AP4E1), a medium chain, mu-4 (AP4M1; 602296), and a small chain, sigma-4 (AP4S1; 607243).</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>By genomic sequence analysis, Dell'Angelica et al. (1999) identified AP4E1 within an EST and found that the deduced protein shares 25 to 30% identity with the trunk region of the AP subunits alpha (see AP2A1; 601026), gamma (see AP1G1; 603533), and delta (AP3D1). Northern blot analysis revealed a transcript of 7 kb. By gel filtration and Western blot analysis of human fibroblast cytosol, Dell'Angelica et al. (1999) found that AP4E1 shows an apparent molecular mass of about 140 kD and is part of a 280-kD complex containing AP4B1, AP4S1, and AP4M1. By immunoprecipitation and reprecipitation of HeLa cell lysates, they confirmed interaction between AP4B1 and AP4E1. Immunolocalization of the AP4B1 subunit in HeLa cells revealed that the AP4 complex associates with the trans-Golgi network or an adjacent structure. The association was sensitive to brefeldin-A treatment, indicating that the membrane localization of AP4 is dependent upon the small GTP-binding protein ARF1 (103180). </p><p>Hirst et al. (1999) identified AP4E1 within an EST from human testis and cloned the full-length cDNA by screening a human heart cDNA library. The deduced protein has a calculated molecular mass of about 127 kD. Within the first 600 amino acids, AP4E1 has homology with the AP subunits gamma, alpha, and delta, including conserved stretches that include a KRIGYL motif and a WIIGEY motif. AP4E1 contains a conserved 600-amino acid N-terminal domain, a hinge domain, and a C-terminal 'ear' domain. Northern blot analysis revealed ubiquitous but weak expression of a 7.5-kb transcript. By coimmunoprecipitation of pig brain cytosol, Hirst et al. (1999) confirmed an interaction between AP4E1 and AP4B1. Using yeast 2-hybrid analysis, they found a strong and specific interaction between AP4E1 and AP4S1. </p><p>Abou Jamra et al. (2011) found ubiquitous AP4S1 expression in all fetal and adult brain structures examined. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Autosomal Recessive Spastic Paraplegia 51</em></strong></p><p>
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In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic paraplegia-51 (SPG51; 613744), Moreno-De-Luca et al. (2011) identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171) that included the 5-prime end of the AP4E1 gene and the 5-prime end of the SPPL2A gene (608238). Noting that mutation in the AP4M1 gene (602296), which forms a complex with AP4E1, causes a similar phenotype (SPG50; 612936), Moreno-De-Luca et al. (2011) concluded that disruption of the AP4E1 gene was responsible for the phenotype in their family, although they could not exclude a possible role for disruption of the SPPL2A gene. The authors proposed the designation 'AP4 deficiency syndrome' to refer to disorders caused by disruption of any of the 4 subunits of the AP4 complex. </p><p>By linkage analysis followed by candidate gene sequencing in a consanguineous Syrian family with mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4E1 gene (607244.0002). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function. </p><p>By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a frameshift mutation in the AP4E1 gene (607244.0003) in 3 affected members of a consanguineous family segregating SPG51. </p><p>In a pair of monozygotic twin sisters, born of consanguineous Moroccan parents, with SPG51, Kong et al. (2013) identified a homozygous nonsense mutation in the AP4E1 gene (R1105X; 607244.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 1,050 healthy controls or in several control databases. Analysis of patient cells showed normal AP4E1 mRNA levels, but barely detectable protein levels, suggesting an unstable mutant protein. There was also a severe impairment of AP4 complex formation compared to controls. </p><p><strong><em>Familial Persistent Stuttering 1</em></strong></p><p>
|
|
In affected members of a large family of Cameroon descent (CAMST01) with autosomal dominant familial persistent stuttering-1 (STUT1; 184450), originally reported by Raza et al. (2013), Raza et al. (2015) identified heterozygosity for 2 missense variants in the AP4E1 gene that occurred in cis (V517I and E801K; 607244.0004). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. The same mutations on the same haplotype were subsequently found in 2 of 96 additional individuals from Cameroon with stuttering. Sequencing of the AP4E1 gene in unrelated affected individuals, including 93 from Cameroon, 132 from Pakistan, and 711 from North America, revealed 23 other rare variants in this gene, including small (1- to 3-bp) deletions, insertions, duplications, frameshifts, and stop codons; no truncating mutations were found in 558 ethnically matched control individuals. Investigation of large population databases, including the 1000 Genomes Project and Exome Sequencing Project, which are not phenotyped for speech fluency, found 3 loss-of-function AP4E1 variants among about 19,000 chromosomes, as well as several rare missense variants; all of these occurred at a significantly lower frequency compared to the variants observed in stuttering individuals. Studies in a yeast 2-hybrid system supported a direct interaction between the AP4 complex and NAGPA (607985), variations in which have also been implicated in stuttering (STUT2; 609261). The findings suggested that defects in intracellular trafficking play a role in persistent stuttering. </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">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
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</h4>
|
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</div>
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|
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|
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|
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<span class="mim-text-font">
|
|
<p>De Pace et al. (2018) found that Ap4e1-knockout mice exhibited a range of neurologic phenotypes, including hindlimb clasping, decreased motor coordination, and weak grip strength. In addition, the knockout mice had thin corpus callosum and axonal swellings in various regions of brain and spinal cord. Knockout mice showed accumulation of Atg9a (612204) at the trans-Golgi network (TGN) in various neuronal types. Similar accumulation of ATG9A was observed in TGN of skin fibroblasts from human patients with AP4M1 mutations. The results indicated that AP4 deficiency impaired delivery of ATG9A from the Golgi complex to the cell periphery. This defect was associated with increased tendency to accumulate mutant huntingtin aggregates in axons of Ap4e1-knockout neurons. </p>
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</span>
|
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<div>
|
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<br />
|
|
</div>
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|
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</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>5 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</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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|
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AP4E1, 192-KB DEL
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<br />
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ClinVar: RCV000023636
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic paraplegia-51 (SPG51; 613744), Moreno-De-Luca et al. (2011) identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171) that included the 5-prime end of the AP4E1 gene and the 5-prime end of the SPPL2A gene (608238). The unaffected mother was heterozygous for the deletion, but no DNA was available from the father, who was inferred to be heterozygous for the deletion. Moreno-De-Luca et al. (2011) concluded that disruption of the AP4E1 gene was responsible for the phenotype, although they could not exclude a possible role for disruption of the SPPL2A gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0002 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</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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AP4E1, 4-BP DEL, IVS5DS, 542+1GTAA
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<br />
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SNP: rs2141147450,
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ClinVar: RCV001849795, RCV002266897
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 affected members of a consanguineous Syrian family with mental retardation and spasticity (SPG51; 613744), Abou Jamra et al. (2011) identified a homozygous 4-bp deletion (542+1delGTAA) in the donor splice site of intron 5 of the AP4E1 gene, resulting in the skipping of exon 5, a frameshift, and premature termination of the protein in exon 6. The mutation was not found in 740 control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</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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AP4E1, VAL454FS
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<br />
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SNP: rs2140861877,
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ClinVar: RCV000023638
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In family M254, in which 3 of 4 children of first-cousin parents had mental retardation, microcephaly, and spastic paraplegia (SPG51; 613744), Najmabadi et al. (2011) identified a causative homozygous 2-bp insertion at genomic coordinate chr15:49029357 (NCBI36), resulting in a frameshift at codon 454. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 STUTTERING, FAMILIAL PERSISTENT, 1</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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|
|
AP4E1, VAL517ILE AND GLU801LYS
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<br />
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|
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SNP: rs556450190, rs760021635,
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|
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gnomAD: rs556450190, rs760021635,
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|
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ClinVar: RCV000210065, RCV002518399
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|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large family of Cameroon descent (CAMST01) with autosomal dominant familial persistent stuttering-1 (STUT1; 184450), originally reported by Raza et al. (2013), Raza et al. (2015) identified heterozygosity for 2 variants in the AP4E1 gene that occurred in cis: a c.1549G-A transition (c.1549G-A, NM_007347.4) in exon 14, resulting in a val517-to-ile (V517I) substitution in the trunk domain, and a c.2401G-A transition (c.2401G-A, NM_00737.4) in exon 18, resulting in a glu801-to-lys (E801K) substitution in the hinge domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both mutations occurred at highly conserved residues and were not found in the 1000 Genomes Project or Exome Sequencing Project databases or in 558 controls. Sequencing of 96 unrelated affected Cameroonians identified the same 2 variants in 2 individuals; haplotype analysis indicated a founder effect between these individuals and the family. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in slightly decreased assembly of the AP4 complex (about 80% of wildtype). </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 SPASTIC PARAPLEGIA 51, AUTOSOMAL RECESSIVE</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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AP4E1, ARG1105TER
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<br />
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SNP: rs1313275799,
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gnomAD: rs1313275799,
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ClinVar: RCV001333647, RCV001779155, RCV001849507
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a pair of monozygotic twin sisters, born of consanguineous Moroccan parents, with spastic paraplegia-51 (SPG51; 613744), Kong et al. (2013) identified a homozygous C-to-T transition in the AP4E1 gene, resulting in an arg1105-to-ter (R1105X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 1,050 healthy controls or in several control databases. Analysis of patient cells showed normal AP4E1 mRNA levels, but barely detectable protein levels, suggesting an unstable mutant protein. There was also a severe impairment of AP4 complex formation compared to controls. In addition to SPG51, the patients had IMD86 (619549) caused by a homozygous mutation in the SPPL2A gene (608238.0001). </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Abou Jamra, R., Philippe, O., Raas-Rothschild, A., Eck, S. H., Graf, E., Buchert, R., Borck, G., Ekici, A., Brockschmidt, F. F., Nothen, M. M., Munnich, A., Strom, T. M., Reis, A., Colleaux, L.
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<strong>Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature.</strong>
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Am. J. Hum. Genet. 88: 788-795, 2011.
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[PubMed: 21620353]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.04.019]
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De Pace, R., Skirzewski, M., Damme, M., Mattera, R., Mercurio, J., Foster, A. M., Cuitino, L., Jarnik, M., Hoffmann, V., Morris, H. D., Han, T.-U., Mancini, G. M. S., Buonanno, A., Bonifacino, J. S.
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<strong>Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome.</strong>
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PLoS Genet. 14: e1007363, 2018. Note: Electronic Article.
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[PubMed: 29698489]
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[Full Text: https://doi.org/10.1371/journal.pgen.1007363]
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Dell'Angelica, E. C., Mullins, C., Bonifacino, J. S.
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<strong>AP-4, a novel protein complex related to clathrin adaptors.</strong>
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Hirst, J., Bright, N. A., Rous, B., Robinson, M. S.
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<strong>Characterization of a fourth adaptor-related protein complex.</strong>
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Molec. Biol. Cell 10: 2787-2802, 1999.
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<p class="mim-text-font">
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Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S.
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<strong>A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease.</strong>
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PLoS One 8: e58286, 2013.
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[PubMed: 23472171]
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[Full Text: https://doi.org/10.1371/journal.pone.0058286]
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Moreno-De-Luca, A., Helmers, S. L., Mao, H., Burns, T. G., Melton, A. M. A., Schmidt, K. R., Fernhoff, P. M., Ledbetter, D. H., Martin, C. L.
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<strong>Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.</strong>
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J. Med. Genet. 48: 141-144, 2011.
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[PubMed: 20972249]
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[Full Text: https://doi.org/10.1136/jmg.2010.082263]
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Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others.
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<strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong>
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Nature 478: 57-63, 2011.
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[PubMed: 21937992]
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[Full Text: https://doi.org/10.1038/nature10423]
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Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D.
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<strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong>
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Hum. Genet. 132: 385-396, 2013.
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[PubMed: 23239121]
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[Full Text: https://doi.org/10.1007/s00439-012-1252-5]
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Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D.
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<strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong>
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Am. J. Hum. Genet. 97: 715-725, 2015.
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[PubMed: 26544806]
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[Full Text: https://doi.org/10.1016/j.ajhg.2015.10.007]
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Bao Lige - updated : 09/18/2018<br>Cassandra L. Kniffin - updated : 3/15/2016<br>Ada Hamosh - updated : 1/6/2012<br>Cassandra L. Kniffin - updated : 7/7/2011<br>Cassandra L. Kniffin - updated : 2/23/2011
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