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Entry
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- *300172 - CALCIUM/CALMODULIN-DEPENDENT SERINE PROTEIN KINASE; CASK
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- OMIM
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<p>
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<span class="h4">*300172</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/300172">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>
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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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000147044;t=ENST00000378163" 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=8573" 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=300172" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000147044;t=ENST00000378163" 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_001126054,NM_001126055,NM_001367721,NM_001410745,NM_003688,XM_006724566,XM_011543993,XM_011543994,XM_011543995,XM_011543996,XM_011543997,XM_047442601" 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_001367721" 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=300172" 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=02164&isoform_id=02164_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/CASK" 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/2641549,2661106,8101952,8101954,13359271,51847840,62087298,109658702,119579794,119579795,119579796,119579797,145559462,186700627,186700629,186972120,219518817,219519993,578838134,754496389,768035908,768035970,768035974,768035977,768035983,1535530868,2194521890,2217395990,2286439284,2462631438,2462631441,2462631443,2462631445,2462631448,2462631450,2462631452" 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/O14936" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=8573" 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=ENSG00000147044;t=ENST00000378163" 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=CASK" 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=CASK" 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+8573" 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/CASK" 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:8573" 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/8573" 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=chrX&hgg_gene=ENST00000378163.7&hgg_start=41514934&hgg_end=41923554&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1497" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1497" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/cask" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300172[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=300172[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/CASK/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/ENSG00000147044" 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=CASK" 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=CASK" 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=CASK" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/CASK" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CASK&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/PA26081" 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:1497" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0013759.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1309489" 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/CASK#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:1309489" 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/8573/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=8573" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002991;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-020802-4" 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://reactome.org/content/query?q=CASK&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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300172
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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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CALCIUM/CALMODULIN-DEPENDENT SERINE PROTEIN KINASE; CASK
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
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VERTEBRATE LIN2 HOMOLOG; LIN2<br />
|
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CAMGUK, DROSOPHILA, HOMOLOG OF; CMG
|
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</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CASK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CASK</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>
|
|
Cytogenetic location: <a href="/geneMap/X/180?start=-3&limit=10&highlight=180">Xp11.4</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:41514934-41923554&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'})">X:41,514,934-41,923,554</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300422,300749,300422" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/180?start=-3&limit=10&highlight=180">
|
|
Xp11.4
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
FG syndrome 4
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300422"> 300422 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked recessive">XLR</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/300749"> 300749 </a>
|
|
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="X-linked">XL</abbr>
|
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|
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</span>
|
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</td>
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<p>The CASK gene encodes a calcium/calmodulin-dependent serine protein kinase that is a member of the membrane-associated guanylate kinase (MAGUK) protein family. MAGUKs are scaffolding proteins associated with intercellular junctions (summary by <a href="#1" class="mim-tip-reference" title="Atasoy, D., Schoch, S., Ho, A., Nadasy, K. A., Liu, X., Zhang, W., Mukherjee, K., Nosyreva, E. D., Fernandez-Chacon, R., Missler, M., Kavalali, E. T., Sudhof, T. C. <strong>Deletion of CASK in mice is lethal and impairs synaptic function.</strong> Proc. Nat. Acad. Sci. 104: 2525-2530, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17287346[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611003104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17287346">Atasoy et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Cohen, A. R., Woods, D. F., Marfatia, S. M., Walther, Z., Chishti, A. H., Anderson, J. M. <strong>Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.</strong> J. Cell Biol. 142: 129-138, 1998. Note: Erratum: J. Cell Biol. 142: following 1156, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9660868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.142.1.129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660868">Cohen et al. (1998)</a> used degenerate PCR to clone human CASK cDNAs from several libraries. CASK encodes a 921-amino acid polypeptide with an N-terminal calcium/calmodulin-dependent protein kinase-like domain, PDZ and SH3 domains, a potential protein 4.1-binding motif, and a domain homologous to guanylate kinase. Human CASK is 99% and 52% identical to rat CASK and C. elegans LIN2, respectively. Northern blot analysis demonstrated that CASK is ubiquitously expressed. Immunofluorescence localized the CASK protein to lateral and/or basal plasma membrane domains in epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660868" 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="#4" class="mim-tip-reference" title="Dimitratos, S. D., Stathakis, D. G., Nelson, C. A., Woods, D. F., Bryant, P. J. <strong>The location of human CASK at Xp11.4 identifies this gene as a candidate for X-linked optic atrophy.</strong> Genomics 51: 308-309, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9722958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9722958</a>] [<a href="https://doi.org/10.1006/geno.1998.5404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9722958">Dimitratos et al. (1998)</a> used radiation hybrid panels to map the CASK gene to human chromosome Xp11.4. <a href="#21" class="mim-tip-reference" title="Stevenson, D., Laverty, H. G., Wenwieser, S., Douglas, M., Wilson, J. B. <strong>Mapping and expression analysis of the human CASK gene.</strong> Mammalian Genome 11: 934-937, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11003712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11003712</a>] [<a href="https://doi.org/10.1007/s003350010170" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11003712">Stevenson et al. (2000)</a> confirmed the assignment of the CASK gene to Xp11.4 by inclusion within a YAC contig. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11003712+9722958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Cohen, A. R., Woods, D. F., Marfatia, S. M., Walther, Z., Chishti, A. H., Anderson, J. M. <strong>Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.</strong> J. Cell Biol. 142: 129-138, 1998. Note: Erratum: J. Cell Biol. 142: following 1156, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9660868[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.142.1.129" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660868">Cohen et al. (1998)</a> determined that CASK interacts with both syndecan-2 (SDC2; <a href="/entry/142460">142460</a>) and the actin-binding band 4.1 protein (<a href="/entry/130500">130500</a>). They suggested that CASK may function as a cytoskeletal membrane scaffold that coordinates signal transduction pathways within the cortical cytoskeleton. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Butz, S., Okamoto, M., Sudhof, T. C. <strong>A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.</strong> Cell 94: 773-782, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753324</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81736-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9753324">Butz et al. (1998)</a> identified a complex of 3 proteins in brain that has the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. The 3 proteins are CASK; Mint1 (APBA1; <a href="/entry/602414">602414</a>), a putative vesicular trafficking protein; and Veli1 (<a href="/entry/603380">603380</a>), -2, and -3, vertebrate homologs of C. elegans LIN7. CASK, Mint1, and the Velis form a tight, salt-resistant complex. All of these proteins contain PDZ domains in addition to other modules. <a href="#2" class="mim-tip-reference" title="Butz, S., Okamoto, M., Sudhof, T. C. <strong>A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.</strong> Cell 94: 773-782, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753324</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81736-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9753324">Butz et al. (1998)</a> proposed that the tripartite complex acts as a nucleation site for the assembly of proteins involved in synaptic vesicle exocytosis and synaptic junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoprecipitation experiments, <a href="#22" class="mim-tip-reference" title="Tabuchi, K., Biederer, T., Butz, S., Sudhof, T. C. <strong>CASK participates in alternative tripartite complexes in which Mint1 competes for binding with caskin1, a novel CASK-binding protein.</strong> J. Neurosci. 22: 4264-4273, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12040031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12040031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12040031[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1523/JNEUROSCI.22-11-04264.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12040031">Tabuchi et al. (2002)</a> determined that Caskin1 (<a href="/entry/612184">612184</a>), like Mint1, is stably bound to CASK in the brain. Affinity chromatography experiments determined that Caskin1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin-1 (<a href="/entry/600565">600565</a>), suggesting that CASK and Caskin1 coat the cytoplasmic tails of neurexins and other cell surface proteins. Detailed mapping studies revealed that Caskin1 and Mint1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. GST-pull-down experiments indicated that CASK forms a tripartite complex with Caskin1 and Velis similar to the CASK-Mint1-Veli complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12040031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify binding partners for the guanylate kinase domain of CASK, <a href="#9" class="mim-tip-reference" title="Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M. <strong>Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.</strong> Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749215</a>] [<a href="https://doi.org/10.1038/35005118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749215">Hsueh et al. (2000)</a> carried out a yeast 2-hybrid screen of brain complementary DNA libraries, from which TBR1 (<a href="/entry/604616">604616</a>) was isolated. By deletion analysis, the C-terminal region of TBR1 (residues 342 to 681) was found to be necessary and sufficient for association with the guanylate kinase domain of CASK. When coexpressed in COS-7 cells, TBR1 and CASK were readily coprecipitated by antibodies directed against either individual protein. <a href="#9" class="mim-tip-reference" title="Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M. <strong>Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.</strong> Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749215</a>] [<a href="https://doi.org/10.1038/35005118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749215">Hsueh et al. (2000)</a> demonstrated that CASK enters the nucleus and binds to a specific DNA sequence (the T element) in a complex with TBR1. CASK acts as a coactivator of TBR1 to induce transcription of T element-containing genes, including reelin, a gene that is essential for cerebrocortical development. On the basis of their findings, <a href="#9" class="mim-tip-reference" title="Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M. <strong>Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.</strong> Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749215</a>] [<a href="https://doi.org/10.1038/35005118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749215">Hsueh et al. (2000)</a> concluded that a membrane-associated guanylate kinase, which is usually associated with cell junctions, has a transcription regulation function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749215" 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>Experiments with vesicles containing NMDA receptor 2B (NR2B subunit; <a href="/entry/138252">138252</a>) showed that they are transported along microtubules by KIF17 (<a href="/entry/605037">605037</a>), a neuron-specific molecular motor in neuronal dendrites. <a href="#19" class="mim-tip-reference" title="Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N. <strong>Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.</strong> Science 288: 1796-1802, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846156</a>] [<a href="https://doi.org/10.1126/science.288.5472.1796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10846156">Setou et al. (2000)</a> demonstrated that selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of Lin10 (<a href="/entry/602414">602414</a>), which is a constituent of a large protein complex including Lin2 (CASK), Lin7 (<a href="/entry/603380">603380</a>), and the NR2B subunit. <a href="#19" class="mim-tip-reference" title="Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N. <strong>Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.</strong> Science 288: 1796-1802, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846156</a>] [<a href="https://doi.org/10.1126/science.288.5472.1796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10846156">Setou et al. (2000)</a> concluded that this interaction, which is specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10846156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Lu, C. S., Hodge, J. J. L., Mehren, J., Sun, X. X., Griffith, L. C. <strong>Regulation of the Ca(2+)/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation.</strong> Neuron 40: 1185-1197, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14687552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14687552</a>] [<a href="https://doi.org/10.1016/s0896-6273(03)00786-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14687552">Lu et al. (2003)</a> showed that Cmg, the Drosophila homolog of CASK, associated with Camk2 (CAMK2A; <a href="/entry/114078">114078</a>) in an ATP-regulated manner. In the presence of Ca(2+)/calmodulin (CALM1; <a href="/entry/114180">114180</a>), Camk2 complexed to Cmg autophosphorylated at thr287 and became constitutively active. In the absence of Ca(2+)/calmodulin, Camk2 inactivated itself by autophosphorylation on thr306 and required a phosphatase to become reactivated. <a href="#12" class="mim-tip-reference" title="Lu, C. S., Hodge, J. J. L., Mehren, J., Sun, X. X., Griffith, L. C. <strong>Regulation of the Ca(2+)/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation.</strong> Neuron 40: 1185-1197, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14687552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14687552</a>] [<a href="https://doi.org/10.1016/s0896-6273(03)00786-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14687552">Lu et al. (2003)</a> concluded that interaction between Cmg and Camk2 provides a postsynaptic pool of Camk2 that can be controlled locally to differentiate active and inactive synapses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14687552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Hsueh, Y.-P. <strong>Calcium/calmodulin-dependent serine protein kinase and mental retardation.</strong> Ann. Neurol. 66: 438-443, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847910</a>] [<a href="https://doi.org/10.1002/ana.21755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19847910">Hsueh (2009)</a> reviewed the synaptic functions of the CASK protein, noting that it has 3 main roles: it regulates presynaptic termini formation and interactions at the presynaptic site; maintains the morphology of dendritic spines at the postsynaptic site; and regulates ion channels at the postsynaptic site. These functions of CASK can explain, at least in part, the mental retardation and brain developmental defects in patients with CASK mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19847910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Intellectual Developmental Disorder with Microcephaly and Pontine and Cerebellar Hypoplasia</em></strong></p><p>
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<a href="#15" class="mim-tip-reference" title="Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K. <strong>Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.</strong> Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165920</a>] [<a href="https://doi.org/10.1038/ng.194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19165920">Najm et al. (2008)</a> found heterozygous loss-of-function mutations in CASK in 4 girls and a partly penetrant splice mutation in a severely affected boy with a syndrome of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH, MRXSNA; <a href="/entry/300749">300749</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165920" 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 20 girls with MICPCH, <a href="#14" class="mim-tip-reference" title="Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others. <strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong> J. Med. Genet. 48: 741-751, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21954287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21954287</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21954287">Moog et al. (2011)</a> identified different loss-of-function mutations or deletions/duplications in the CASK gene (see, e.g., <a href="#0010">300172.0010</a>-<a href="#0012">300172.0012</a>). High-resolution molecular karyotyping of 8 girls found that 6 had intragenic deletions and 2 had intragenic duplications. The smallest deletion was a de novo 60-kb deletion; 1 patient had a 4.24-Mb deletion encompassing the entire gene. Sequence analysis in 12 patients identified 10 heterozygous mutations in 9 patients. The remaining 3 patients were found to have deletions involving CASK using FISH or RT-PCR. All mutations in patients with parental information were shown to occur de novo. All mutations were predicted or demonstrated to result in a null allele. The 20 patients, as well as 5 previously reported patients, had a remarkably similar phenotype, including moderate to severe psychomotor development with poor growth, hypotonia, lack of speech, and lack of ambulation. There was also a distinctive dysmorphic phenotype, with severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism. Brain MRI showed varying degrees of proportionate pontocerebellar hypoplasia, normal corpus callosum, and simplified gyration pattern in some. <a href="#14" class="mim-tip-reference" title="Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others. <strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong> J. Med. Genet. 48: 741-751, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21954287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21954287</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21954287">Moog et al. (2011)</a> emphasized that the brain malformation phenotype in females caused by loss-of-function mutations in CASK is different from the milder phenotype caused by hypomorphic mutations in CASK in males, which results in variable intellectual disability with or without nystagmus (FGS4; <a href="/entry/300422">300422</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21954287" 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 targeted analysis of the CASK gene in 10 unrelated Japanese girls with clinical features suggestive of MICPCH, <a href="#8" class="mim-tip-reference" title="Hayashi, S., Okamoto, N., Chinen, Y., Takanashi, J., Makita, Y., Hata, A., Imoto, I., Inazawa, J. <strong>Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).</strong> Hum. Genet. 131: 99-110, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21735175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21735175</a>] [<a href="https://doi.org/10.1007/s00439-011-1047-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21735175">Hayashi et al. (2012)</a> found genomic aberrations of the CASK gene resulting in a null mutation in all. Three had nonsense mutations, 1 had a 1-bp deletion, 2 had splice site mutations, 2 had heterozygous deletions encompassing the CASK gene, and 2 had intragenic duplications affecting the CASK gene. All patients for whom parental DNA was available were found to carry de novo mutations. There were no molecular hotspots, and the phenotypes were similar regardless of the mutation. The findings extended the variety of genetic alterations causing CASK null mutations, including copy number variations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21735175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 8 male patients (7 with MICPCH with or without severe epilepsy and 1 (patient 8) with microcephaly with developmental delay), <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> identified CASK alterations by Sanger sequencing, copy number analysis (MLPA and/or FISH), and array CGH. Sequence analysis revealed 3 pathogenic mutations: a nonsense mutation (R27X; <a href="#0016">300172.0016</a>) in patient 4, a 5-bp deletion (<a href="#0017">300172.0017</a>) in patient 1, and a transition affecting the start codon (<a href="#0018">300172.0018</a>) in patient 3. All of these patients exhibited MICPCH with the severe epileptic encephalopathy phenotype. In the 2 patients with MICPCH without epilepsy, MLPA identified mosaic deletions of the CASK gene, including a mosaic deletion of exon 1 (<a href="#0019">300172.0019</a>) in patient 6. <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> proposed that CASK mutation-positive males could be distinguished into 3 phenotypic groups that represent a clinical continuum, with inactivating CASK germline mutations associated with the most severe phenotype (MICPCH with severe epileptic encephalopathy); CASK mutations in the mosaic state or partly penetrant CASK mutations associated with the attenuated phenotype (MICPCH); and CASK missense and splice site mutations that leave the CASK protein intact but likely alter function or reduce the amount of normal protein, associated with intellectual disability with or without nystagmus (see <a href="/entry/300422">300422</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25886057" 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 9-year-old girl with MICPCH, <a href="#11" class="mim-tip-reference" title="LaConte, L. E. W., Chavan, V., DeLuca, S., Rubin, K., Malc, J., Berry, S., Gail Summers, C., Mukherjee, K. <strong>An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.</strong> Am. J. Med. Genet. 179A: 94-103, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30549415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30549415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30549415[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.60687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30549415">LaConte et al. (2019)</a> identified a heterozygous missense mutation in the CASK gene (L209P; <a href="/entry/602414#0013">602414.0013</a>). Overexpression of the L209P mutation in HEK293 cells resulted in abnormal cytoplasmic aggregates. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see NRXN1, <a href="/entry/600565">600565</a>) and VELI (see LIN7A, <a href="/entry/603380">603380</a>) but disrupted interaction with MINT1 (APBA1; <a href="/entry/602414">602414</a>). Accordingly, MINT1 interacts with CASK's CaMK binding domain, where the mutation is located. <a href="#11" class="mim-tip-reference" title="LaConte, L. E. W., Chavan, V., DeLuca, S., Rubin, K., Malc, J., Berry, S., Gail Summers, C., Mukherjee, K. <strong>An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.</strong> Am. J. Med. Genet. 179A: 94-103, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30549415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30549415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30549415[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.60687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30549415">LaConte et al. (2019)</a> concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1. Clinical features in the patient included microcephaly, cerebellar hypoplasia, and bilateral retinal dystrophy. It had initially been reported that mutations in the C terminus of CASK were responsible for nystagmus, but this patient also had nystagmus and the L209P mutation is in the N terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30549415" 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>FG Syndrome 4</em></strong></p><p>
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In affected members of an Italian family with FG syndrome-4 (<a href="/entry/300422">300422</a>), <a href="#16" class="mim-tip-reference" title="Piluso, G., D'Amico, F., Saccone, V., Bismuto, E., Rotundo, I. L., Di Domenico, M., Aurino, S., Schwartz, C. E., Neri, G., Nigro, V. <strong>A missense mutation in CASK causes FG syndrome in an Italian family.</strong> Am. J. Hum. Genet. 84: 162-177, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19200522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19200522</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19200522[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.2008.12.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19200522">Piluso et al. (2009)</a> identified a missense mutation (<a href="#0003">300172.0003</a>) in the CASK gene that segregated fully with the disease and was not found in 1,000 ethnically matched control X chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19200522" 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 boy with FG syndrome-4 and nystagmus, <a href="#5" class="mim-tip-reference" title="Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others. <strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong> Am. J. Med. Genet. 173A: 611-617, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28139025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28139025</a>] [<a href="https://doi.org/10.1002/ajmg.a.38069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28139025">Dunn et al. (2017)</a> identified a homozygous splice mutation in the CASK gene (<a href="#0014">300172.0014</a>). Sanger sequencing in the parents demonstrated that this mutation was de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28139025" 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>Impaired Intellectual Development with or without Nystagmus</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a> sequenced the coding exons of the X chromosome in 208 families with X-linked impaired intellectual development (see <a href="/entry/300422">300422</a>). They identified 4 families with missense mutations in the CASK gene. In 2 of the families, the X-linked mental retardation segregated with nystagmus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 additional families with X-linked impaired intellectual development and nystagmus, <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a> identified 2 different mutations in the CASK gene (<a href="#0008">300172.0008</a> and <a href="#0009">300172.0009</a>, respectively). In conjunction with the report of <a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a>, CASK mutations were found in 1.5% of individuals with XLMR who were screened. Families with mutations in the C-terminal part of the gene had nystagmus, suggesting a possible genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20029458+19377476" 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 next-generation sequencing in a 5-year-old boy with impaired intellectual development, autism spectrum disorder, and microcephaly, who did not have nystagmus, <a href="#18" class="mim-tip-reference" title="Seto, T., Hamazaki, T., Nishigaki, S., Kudo, S., Shintaku, H., Ondo, Y., Shimojima, K., Yamamoto, T. <strong>A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly.</strong> Intractable Rare Dis. Res. 6: 177-182, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28944139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28944139</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28944139[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/10.5582/irdr.2017.01031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28944139">Seto et al. (2017)</a> identified a missense mutation in the CASK gene (S475I; <a href="#0015">300172.0015</a>). The mutation was identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she shared autistic symptoms with her brother. The mother showed an almost completely skewed X-chromosome inactivation pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28944139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Atasoy, D., Schoch, S., Ho, A., Nadasy, K. A., Liu, X., Zhang, W., Mukherjee, K., Nosyreva, E. D., Fernandez-Chacon, R., Missler, M., Kavalali, E. T., Sudhof, T. C. <strong>Deletion of CASK in mice is lethal and impairs synaptic function.</strong> Proc. Nat. Acad. Sci. 104: 2525-2530, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17287346[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0611003104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17287346">Atasoy et al. (2007)</a> found that Cask-null mice died within hours of birth and exhibited a partially penetrant cleft palate phenotype and increased apoptosis in the thalamus, but no other major developmental changes. Neurons cultured from Cask-null mice showed no changes in electrical properties or evoked release, formed structurally normal synapses, but did show increased glutamatergic spontaneous release events. The findings indicated that Cask is required for mouse survival without being required for core neuronal activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17287346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a Cre/lox expression system, <a href="#20" class="mim-tip-reference" title="Srivastava, S., McMillan, R., Willis, J., Clark, H., Chavan, V., Liang, C., Zhang, H., Hulver, M., Mukherjee, K. <strong>X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner.</strong> Acta Neuropath. Commun. 4: 30, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27036546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27036546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27036546[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s40478-016-0295-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27036546">Srivastava et al. (2016)</a> generated mouse models with absence of Cask expression first in Purkinje cells and then in cerebellar granule cells. No specific motor or other deficits were identified in either mutant mouse model. Complete Cask knockout of neurons in mice did not result in neonatal lethality; however, the mutant mice developed seizures that were fatal before 23 to 24 days of life. Female mice with a heterozygous neuronal-specific CASK knockout did not have an observable abnormal phenotype, but, conversely, female mice with a full-body constitutive heterozygous knockout of Cask had microcephaly, decreased cerebellar size, optic nerve hypoplasia, and signs of ataxia. Examination of individual brain cells in the heterozygous mutant female mice demonstrated that CASK null cells were equally viable compared to CASK-positive cells. Thus the microcephaly in the mice was not due to a cell-autonomous loss of Cask null cells, but rather another postnatal non-cell autonomous mechanism. <a href="#20" class="mim-tip-reference" title="Srivastava, S., McMillan, R., Willis, J., Clark, H., Chavan, V., Liang, C., Zhang, H., Hulver, M., Mukherjee, K. <strong>X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner.</strong> Acta Neuropath. Commun. 4: 30, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27036546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27036546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27036546[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s40478-016-0295-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27036546">Srivastava et al. (2016)</a> then identified reduced mitochondrial respiration in brain homogenates of the heterozygous mutant female mice and lower oxidation of fatty acid and glucose in the muscles, although how this related to the neuronal phenotype of CASK loss in the heterozygous mutant female mice was not determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27036546" 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 female heterozygote CASK knockout mice (Cask +/-), <a href="#6" class="mim-tip-reference" title="Guo, Q., Kouyama-Suzuki, E., Shirai, Y., Cao, X., Yanagawa, T., Mori, T., Tabuchi, K. <strong>Structural analysis implicates CASK-liprin-alpha-2 interaction in cerebellar granular cell death in MICPCH syndrome.</strong> Cells 12: 1177, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37190086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37190086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37190086[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/10.3390/cells12081177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37190086">Guo et al. (2023)</a> found that the overall size of cerebellum was reduced compared to wildtype due to the death of cerebellar granule (CG) cells. Analysis of homozygous Cask knockout CG cells showed that cell death was apoptotic and was independent of Bdnf (<a href="/entry/113505">113505</a>) secretion mediated by neurexins (<a href="/entry/600565">600565</a>). Rescue analysis in cultured CG cells showed that the CaMK, PDZ, and SH3 domains of Cask were required for the survival of CG cells. Accordingly, in human patients manifesting neurologic symptoms, the authors identified CASK missense mutations in the CaMK, PDZ, or SH3 domains that affected the survival of CG cells. Three of the mutations, R106P, R255C, and Y268H (<a href="#0004">300172.0004</a>), were located in the CaMK domain and resided on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (<a href="/entry/603143">603143</a>), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain was involved in the molecular mechanism by which CASK maintained CG cell survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37190086" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Tello, J. A., Jiang, L., Zohar, Y., Restifo, L. L. <strong>Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery.</strong> Neural Dev. 18: 6, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37805506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37805506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37805506[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13064-023-00174-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37805506">Tello et al. (2023)</a> found a Cask loss-of-function mutation caused microcephaly, microencephaly, and a form of short stature in Drosophila. Cultured neurons from mutant Drosophila had disrupted neurite-arbor morphogenesis, leading to a bushy phenotype. The severity of the busy phenotype was inversely related to Cask gene dosage, and the phenotype improved by transgenic expression of Cask. The authors developed a microfluidic system for standardized, automated dissociation of Drosophila central nervous system tissue into individual viable neurons, and this microfluidic system reproduced the bushy phenotype of Cask mutant neurons with high fidelity. Moreover, this automated dissociation method was also effective for rodent CNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37805506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a female with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH, MRXSNA; <a href="/entry/300749">300749</a>), <a href="#15" class="mim-tip-reference" title="Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K. <strong>Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.</strong> Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165920</a>] [<a href="https://doi.org/10.1038/ng.194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19165920">Najm et al. (2008)</a> identified a C-to-T transition at nucleotide 1915 in exon 21 of the CASK gene, resulting in a premature termination codon replacing the arginine at codon 639 (R639X). This mutation was not identified in the parents of the individual or in 150 control X chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000012287" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012287" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012287</a>
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<p>In a boy with microcephaly and disproportionate pontine and cerebellar hypoplasia (<a href="/entry/300749">300749</a>), <a href="#15" class="mim-tip-reference" title="Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K. <strong>Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.</strong> Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165920</a>] [<a href="https://doi.org/10.1038/ng.194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19165920">Najm et al. (2008)</a> identified a G-to-A transition at nucleotide 915 of the CASK gene, resulting in a synonymous mutation (K305K) located in the last nucleotide of exon 9. In vitro splicing analyses using minigene constructs identified skipping of exon 9 in about 20% of mutant transcripts, suggesting a defect in splicing. The affected individual was male and died at 2 weeks of age, thus being more severely affected than females described by <a href="#15" class="mim-tip-reference" title="Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K. <strong>Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.</strong> Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165920</a>] [<a href="https://doi.org/10.1038/ng.194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19165920">Najm et al. (2008)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852816 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852816;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=rs137852816" 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=rs137852816" 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=RCV000012288" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012288" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012288</a>
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<p>In affected members of an Italian family with FG syndrome-4 (<a href="/entry/300422">300422</a>), <a href="#16" class="mim-tip-reference" title="Piluso, G., D'Amico, F., Saccone, V., Bismuto, E., Rotundo, I. L., Di Domenico, M., Aurino, S., Schwartz, C. E., Neri, G., Nigro, V. <strong>A missense mutation in CASK causes FG syndrome in an Italian family.</strong> Am. J. Hum. Genet. 84: 162-177, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19200522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19200522</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19200522[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.2008.12.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19200522">Piluso et al. (2009)</a> identified a hemizygous 83G-T transversion in exon 2 of the CASK gene, resulting in an arg28-to-leu (R28L) substitution at a highly conserved residue in the CaM-kinase domain. There were 3 affected males and 2 carrier females; 1 of the females had a milder phenotype, with mild mental retardation, hypertelorism, and long philtrum. The mutation segregated fully with disease in the family and was not found in 1,000 ethnically matched control X chromosomes. Functional, structural, and dynamic studies did not reveal significant alterations induced by the R28L substitution; however, the authors observed partial skipping of exon 2 of CASK, suggesting improper recognition of an exonic splicing enhancer (ESE) motif induced by the mutation. RT-PCR analysis confirmed that the exon 2-skipped transcript was differently expressed in affected males and carrier females and was not detectable in either unaffected family members or controls, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19200522" 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 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</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">rs137852817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852817;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=rs137852817" 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=rs137852817" 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=RCV000012289 OR RCV002512982 OR RCV003313028" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012289, RCV002512982, RCV003313028" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012289...</a>
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<p>In a 3-generation pedigree segregating X-linked intellectual developmental disorder with nystagmus (see <a href="/entry/300422">300422</a>), <a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a> identified a C-to-T transition at nucleotide 829 of the CASK gene, resulting in a tyr-to-his substitution at codon 268 (Y268H). The mutation segregated with the phenotype in the family and was not identified in any unaffected male family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Variant Function</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Guo, Q., Kouyama-Suzuki, E., Shirai, Y., Cao, X., Yanagawa, T., Mori, T., Tabuchi, K. <strong>Structural analysis implicates CASK-liprin-alpha-2 interaction in cerebellar granular cell death in MICPCH syndrome.</strong> Cells 12: 1177, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37190086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37190086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37190086[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/10.3390/cells12081177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37190086">Guo et al. (2023)</a> showed that the Y268H mutation in CASK affects the survival of cerebellar granule (CG) cells, is located in the CaMK domain, and resides on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (<a href="/entry/603143">603143</a>), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain is involved in the molecular mechanism by which CASK maintained CG cell survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37190086" 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 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</strong>
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CASK, ASP710GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852818 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852818;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=rs137852818" 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=rs137852818" 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=RCV000012290 OR RCV000760252" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012290, RCV000760252" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012290...</a>
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<p>In a large family segregating X-linked intellectual developmental disorder with nystagmus (see <a href="/entry/300422">300422</a>), <a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a> identified an A-to-G transition at nucleotide 2129 of the CASK gene, predicted to result in an asp-to-gly substitution at codon 710 (D710G). However, RT-PCR analysis showed that the 2129A-G change introduces a splice site affecting exon 22 that removes 27 bp of the coding sequence and thus 9 amino acids of the protein at the C-terminal end of the 'Hook Motif.' This mutation segregated with intellectual developmental disorder and nystagmus in affected family members. An additional family member who had mental retardation without nystagmus was not found to carry this mutation. This individual was considered to have milder mental retardation than other affected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</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">rs137852819 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852819;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=rs137852819" 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=rs137852819" 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=RCV000012291" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012291" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012291</a>
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<p>In a family (family 123) in which 3 sons had X-linked intellectual developmental disorder and nystagmus (see <a href="/entry/300422">300422</a>), <a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a> identified a c.2767C-T transition in the CASK gene, resulting in a trp914-to-arg substitution. The mutation segregated with the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an erratum of <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a>, the authors corrected the mutation in family 123, originally reported by <a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a>, to a c.2755T-C transition, resulting in a trp919-to-arg (W919R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20029458+19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs137852820 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852820;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/rs137852820?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=rs137852820" 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=rs137852820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a pedigree segregating X-linked intellectual developmental disorder without nystagmus (see <a href="/entry/300422">300422</a>), <a href="#23" class="mim-tip-reference" title="Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. <strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong> Nature Genet. 41: 535-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>] [<a href="https://doi.org/10.1038/ng.367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19377476">Tarpey et al. (2009)</a> identified a C-to-T transition at nucleotide 1186 in the CASK gene, resulting in a pro-to-ser substitution at codon 396 (P396S). The mutation was found in affected family members only. This mutation was not associated with nystagmus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</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">rs398122844 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122844;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=rs398122844" 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=rs398122844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 brothers with X-linked intellectual developmental disorder and nystagmus (see <a href="/entry/300422">300422</a>), <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a> identified a 2183A-G transition in exon 23 of the CASK gene, resulting in a tyr728-to-cys (Y728C) substitution in a highly conserved residue. A sister of the brothers, who was affected and also carried the mutation, showed skewed X inactivation. The proband, who had severely impaired intellectual development , also showed cerebellar hypoplasia and pachygyria. He had congenital nystagmus, strabismus, and mild optic disc pallor. He also had dysmorphic features, including synophrys, high nasal bridge, upslanting palpebral fissures, and short columella. His brother had similar features. The sister had normal brain MRI, mildly impaired intellectual development, congenital nystagmus, and no dysmorphic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20029458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</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">rs398122845 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122845;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=rs398122845" 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=rs398122845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with X-linked intellectual developmental disorder and nystagmus (see <a href="/entry/300422">300422</a>), <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a> identified an A-to-T transversion affecting the 3-prime acceptor splice site of exon 26, resulting in the production of 2 aberrant transcripts: one lacking exon 26 and 1 lacking 3 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20029458" 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>See <a href="#0014">300172.0014</a> for discussion of an A-to-G substitution at the same nucleotide.</p>
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<strong>.0010 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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">rs387906704 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906704;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=rs387906704" 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=rs387906704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 3.5-year-old girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; <a href="/entry/300749">300749</a>), <a href="#14" class="mim-tip-reference" title="Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others. <strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong> J. Med. Genet. 48: 741-751, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21954287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21954287</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21954287">Moog et al. (2011)</a> identified a de novo heterozygous 316C-T transition in exon 4 of the CASK gene, resulting in an arg106-to-ter (R106X) substitution. The child had microcephaly (-6.3 SD), poor growth, severe developmental delay, hypotonia, sensorineural hearing loss, and myopia. She had never achieved walking. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. Dysmorphic facial features included flat occiput, almond-shaped eyes, beaked nose, broad and prominent nasal bridge and tip, smooth philtrum, and large ears. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21954287" 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>.0011 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
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<p>In a 4-year-old Moroccan girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; <a href="/entry/300749">300749</a>), <a href="#14" class="mim-tip-reference" title="Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others. <strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong> J. Med. Genet. 48: 741-751, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21954287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21954287</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21954287">Moog et al. (2011)</a> identified a de novo heterozygous 100-kb deletion affecting exon 1 of the CASK gene, predicted to result in a null allele. The child had microcephaly (-6 SD), severe developmental delay, hypotonia, dyskinesia, and pale optic disc; she could not walk. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. She had a broad nasal bridge, full lips, small chin, and large ears. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21954287" 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>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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">rs387906705 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906705;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=rs387906705" 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=rs387906705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old American girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; <a href="/entry/300749">300749</a>), <a href="#14" class="mim-tip-reference" title="Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others. <strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong> J. Med. Genet. 48: 741-751, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21954287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21954287</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21954287">Moog et al. (2011)</a> identified a heterozygous 1639C-T transition in exon 17 of the CASK gene, resulting in a gln547-to-ter (Q547X) substitution. The patient had microcephaly (-5 SD), severe developmental delay, hypotonia, seizures, strabismus, and scoliosis. She could not walk. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21954287" 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>.0013 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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">rs1556014749 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1556014749;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=rs1556014749" 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=rs1556014749" 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=RCV000498072 OR RCV000621770" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000498072, RCV000621770" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000498072...</a>
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<p>In a 9-year-old girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; <a href="/entry/300749">300749</a>), <a href="#11" class="mim-tip-reference" title="LaConte, L. E. W., Chavan, V., DeLuca, S., Rubin, K., Malc, J., Berry, S., Gail Summers, C., Mukherjee, K. <strong>An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.</strong> Am. J. Med. Genet. 179A: 94-103, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30549415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30549415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30549415[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.60687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30549415">LaConte et al. (2019)</a> identified a heterozygous c.626T-C transition (c.626T-C, NM_003688.3) in the CASK gene, resulting in a leu209-to-pro (L209P) substitution in the CaMK protein domain. The mutation was identified by whole-exome sequencing and was shown to be de novo. Transient overexpression of mutant L209P CASK in HEK293 cells resulted in abnormal cytoplasmic aggregates and lower solubility compared to wildtype CASK protein. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see <a href="/entry/600565">600565</a>) and VELI (see <a href="/entry/603380">603380</a>) but disrupted interaction with MINT1 (<a href="/entry/602414">602414</a>). <a href="#11" class="mim-tip-reference" title="LaConte, L. E. W., Chavan, V., DeLuca, S., Rubin, K., Malc, J., Berry, S., Gail Summers, C., Mukherjee, K. <strong>An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.</strong> Am. J. Med. Genet. 179A: 94-103, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30549415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30549415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30549415[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.60687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30549415">LaConte et al. (2019)</a> concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30549415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122845 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122845;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=rs398122845" 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=rs398122845" 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=RCV000255115 OR RCV000626851 OR RCV003227734" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000255115, RCV000626851, RCV003227734" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000255115...</a>
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<p>In a boy with nystagmus and FG syndrome-4 (FGS4; <a href="/entry/300422">300422</a>), <a href="#5" class="mim-tip-reference" title="Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others. <strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong> Am. J. Med. Genet. 173A: 611-617, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28139025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28139025</a>] [<a href="https://doi.org/10.1002/ajmg.a.38069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28139025">Dunn et al. (2017)</a> identified a de novo hemizygous 3-prime acceptor splice site mutation in the CASK gene (IVS25-2A-G). The mutation was found by genome sequencing and confirmed by Sanger sequencing. <a href="#5" class="mim-tip-reference" title="Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others. <strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong> Am. J. Med. Genet. 173A: 611-617, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28139025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28139025</a>] [<a href="https://doi.org/10.1002/ajmg.a.38069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28139025">Dunn et al. (2017)</a> identified 3 different transcripts in the patient, including the wildtype transcript and 2 mutant transcripts. Mutant transcripts included the expected skipping of exon 26 as well as a 9-bp deletion associated with a cryptic splice site, leading to a 28-amino acid and a 3-amino acid in-frame deletion, respectively (Ala841_Lys843del and Ala841_Glu868del), in the C terminus. RNA-seq of the patient's RNA demonstrated exon skipping in 48% of the reads in the CASK gene and the use of a cryptic splice site in 52% of the reads. Wildtype RNA CASK was amplified only by RT-PCR and was not detected by RNA-seq. The predominant mutant transcripts contain an aberrant guanylate kinase domain and are thus predicted to degrade the ability of CASK to interact with important neuronal and ocular development proteins. <a href="#5" class="mim-tip-reference" title="Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others. <strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong> Am. J. Med. Genet. 173A: 611-617, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28139025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28139025</a>] [<a href="https://doi.org/10.1002/ajmg.a.38069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28139025">Dunn et al. (2017)</a> noted that patients reported by <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a> with a pathogenic allele at the same position c.2521-2A-T (<a href="#0009">300172.0009</a>) as their patient resulted in a different phenotype. The 4 patients reported by <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a> presented with nystagmus, other ocular defects, and mild developmental/intellectual delay; 3 of them had childhood epilepsy or absence seizures and none had feeding issues. <a href="#5" class="mim-tip-reference" title="Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others. <strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong> Am. J. Med. Genet. 173A: 611-617, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28139025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28139025</a>] [<a href="https://doi.org/10.1002/ajmg.a.38069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28139025">Dunn et al. (2017)</a> proposed that different levels of expression of the 3 transcripts in their patient compared to the patients described by <a href="#7" class="mim-tip-reference" title="Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others. <strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong> Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20029458">Hackett et al. (2010)</a> might explain the difference in some of the phenotypic characteristics. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20029458+28139025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2147201250 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2147201250;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=rs2147201250" 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=rs2147201250" 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=RCV001761582 OR RCV003238468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001761582, RCV003238468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001761582...</a>
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<p><a href="#18" class="mim-tip-reference" title="Seto, T., Hamazaki, T., Nishigaki, S., Kudo, S., Shintaku, H., Ondo, Y., Shimojima, K., Yamamoto, T. <strong>A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly.</strong> Intractable Rare Dis. Res. 6: 177-182, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28944139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28944139</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28944139[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/10.5582/irdr.2017.01031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28944139">Seto et al. (2017)</a> performed next-generation sequencing in a boy with intellectual developmental disorder without nystagmus (see <a href="/entry/300422">300422</a>), who also had microcephaly and autism spectrum disorder, and identified a G-T transversion in exon 15 of the CASK gene, resulting in a ser475-to-ile (S475I) substitution. The variant was confirmed by Sanger sequencing and identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she did share autism spectrum disorder symptoms with her brother. Their mother showed an almost completely skewed X-inactivation (XCI) pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28944139" 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>.0016 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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">rs794727270 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs794727270;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=rs794727270" 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=rs794727270" 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=RCV000175755 OR RCV000723984 OR RCV001257954 OR RCV005089881" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000175755, RCV000723984, RCV001257954, RCV005089881" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000175755...</a>
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<p>In a male infant (patient 4) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; <a href="/entry/300749">300749</a>), <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> detected a de novo c.79C-T transition (c.79C-T, NM_003688) in exon 2 of the CASK gene, resulting in an arg27-to-ter (R27X) substitution. The patient was born at 34 weeks' gestation with intrauterine growth retardation and primary microcephaly (-2.57 SD). Medical history was significant for a ventricular septal defect, apnea-bradycardia syndrome, severe hypotonia, and seizures with onset at 2 months of life. MRI demonstrated severe pontocerebellar hypoplasia (especially the cerebellar hemispheres), progressive cerebral atrophy, and progressive hypomyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25886057" 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>.0017 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
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<p>In a male infant (patient 1) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; <a href="/entry/300749">300749</a>), <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> detected a de novo 5-bp deletion (c.704_708delATAAG, NM_003688) in exon 7 of the CASK gene, causing a frameshift predicted to result in a premature termination (Lys236GlufsTer10). RT-PCR on RNA isolated from patient fibroblasts revealed 5 different CASK transcript variants including a major transcript form that skipped exon 7. Immunoblot analysis did not detect CASK protein. The patient was born at 37 weeks' gestation with primary microcephaly and bilateral clubfeet. He had a severe neurologic disorder with hypotonia, abnormal movements, inability to swallow, and intractable seizures. MRI revealed severe hypoplasia of the medulla, pons, and cerebellum (especially the cerebellar hemispheres), progressive cortical atrophy, simplified gyri, and hypomyelination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25886057" 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>.0018 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002417108 OR RCV003624490" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002417108, RCV003624490" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002417108...</a>
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<p>In a male infant (patient 3) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; <a href="/entry/300749">300749</a>), <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> detected a de novo c.1A-G transition (c.1A-G, NM_003688) in the CASK gene. The patient was born with a normal head circumference but head growth rapidly decelerated to -2.5 SD by age 3 months. He exhibited severe intractable seizures, severe hypotonia, feeding difficulties necessitating PEG tube, and optic hypoplasia, and demonstrated virtually no motor or cognitive development. MRI revealed significant hypoplasia of the pons and cerebellum. <a href="#17" class="mim-tip-reference" title="Saitsu, H., Kato, M., Osaka, H., Moriyama, N., Horita, H., Nishiyama, K., Yoneda, Y., Kondo, Y., Tsurusaki, Y., Doi, H., Miyake, N., Hayasaka, K., Matsumoto, N. <strong>CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia.</strong> Epilepsia 53: 1441-1449, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22709267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22709267</a>] [<a href="https://doi.org/10.1111/j.1528-1167.2012.03548.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22709267">Saitsu et al. (2012)</a> had previously described the same c.1A-G mutation in the start codon in a male patient (patient 2) with a diagnosis of Ohtahara syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22709267+25886057" 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>.0019 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
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<p>In a male patient (patient 6) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; <a href="/entry/300749">300749</a>), <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> detected a mosaic deletion of exon 1. MLPA demonstrated that the relative peak area of the 2 probes for exon 1 was reduced by 50 to 60%, indicating a mosaic deletion. Somatic mosaicism of the exon 1 deletion was confirmed in buccal cell-derived DNA by MLPA as dosage of this exon was reduced by 60%. <a href="#13" class="mim-tip-reference" title="Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K. <strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong> Orphanet J. Rare Dis. 10: 44, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-015-0256-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25886057">Moog et al. (2015)</a> suggested that somatic mosaicism of the CASK gene produces wildtype protein in a significant percentage of the cells, most likely reducing clinical severity. Patient 6 showed progressive microcephaly during his first year of life and global developmental delay. He had a history of an afebrile seizure but otherwise had a normal EEG. MRI showed moderate pontocerebellar hypoplasia affecting the cerebellar hemispheres and vermis equally. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25886057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Atasoy2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Atasoy, D., Schoch, S., Ho, A., Nadasy, K. A., Liu, X., Zhang, W., Mukherjee, K., Nosyreva, E. D., Fernandez-Chacon, R., Missler, M., Kavalali, E. T., Sudhof, T. C.
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<strong>Deletion of CASK in mice is lethal and impairs synaptic function.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17287346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17287346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17287346[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=17287346" 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/10.1073/pnas.0611003104" target="_blank">Full Text</a>]
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<a id="Butz1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Butz, S., Okamoto, M., Sudhof, T. C.
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<strong>A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.</strong>
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Cell 94: 773-782, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753324</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753324" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81736-5" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Cohen1998" class="mim-anchor"></a>
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<div class="">
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Cohen, A. R., Woods, D. F., Marfatia, S. M., Walther, Z., Chishti, A. H., Anderson, J. M.
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<strong>Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.</strong>
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J. Cell Biol. 142: 129-138, 1998. Note: Erratum: J. Cell Biol. 142: following 1156, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660868</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9660868[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=9660868" 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/10.1083/jcb.142.1.129" target="_blank">Full Text</a>]
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</p>
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<a id="4" class="mim-anchor"></a>
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<a id="Dimitratos1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Dimitratos, S. D., Stathakis, D. G., Nelson, C. A., Woods, D. F., Bryant, P. J.
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<strong>The location of human CASK at Xp11.4 identifies this gene as a candidate for X-linked optic atrophy.</strong>
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Genomics 51: 308-309, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9722958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9722958</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9722958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1998.5404" target="_blank">Full Text</a>]
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</p>
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<a id="5" class="mim-anchor"></a>
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<a id="Dunn2017" class="mim-anchor"></a>
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<div class="">
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Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others.
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<strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong>
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Am. J. Med. Genet. 173A: 611-617, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28139025/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28139025</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28139025" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.38069" target="_blank">Full Text</a>]
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<a id="Guo2023" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Guo, Q., Kouyama-Suzuki, E., Shirai, Y., Cao, X., Yanagawa, T., Mori, T., Tabuchi, K.
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<strong>Structural analysis implicates CASK-liprin-alpha-2 interaction in cerebellar granular cell death in MICPCH syndrome.</strong>
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Cells 12: 1177, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37190086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37190086</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37190086[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=37190086" 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/10.3390/cells12081177" target="_blank">Full Text</a>]
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</p>
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<a id="7" class="mim-anchor"></a>
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<a id="Hackett2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others.
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<strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong>
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Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20029458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20029458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20029458[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=20029458" 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/ejhg.2009.220" target="_blank">Full Text</a>]
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</p>
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<a id="Hayashi2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hayashi, S., Okamoto, N., Chinen, Y., Takanashi, J., Makita, Y., Hata, A., Imoto, I., Inazawa, J.
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<strong>Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).</strong>
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Hum. Genet. 131: 99-110, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21735175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21735175</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21735175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-011-1047-0" target="_blank">Full Text</a>]
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</p>
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<a id="Hsueh2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M.
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<strong>Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.</strong>
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Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749215</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749215" 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/10.1038/35005118" target="_blank">Full Text</a>]
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</p>
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<a id="Hsueh2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Hsueh, Y.-P.
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<strong>Calcium/calmodulin-dependent serine protein kinase and mental retardation.</strong>
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Ann. Neurol. 66: 438-443, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19847910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19847910</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19847910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.21755" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="LaConte2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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LaConte, L. E. W., Chavan, V., DeLuca, S., Rubin, K., Malc, J., Berry, S., Gail Summers, C., Mukherjee, K.
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<strong>An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.</strong>
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Am. J. Med. Genet. 179A: 94-103, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30549415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30549415</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30549415[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=30549415" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.60687" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Lu2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lu, C. S., Hodge, J. J. L., Mehren, J., Sun, X. X., Griffith, L. C.
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<strong>Regulation of the Ca(2+)/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation.</strong>
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Neuron 40: 1185-1197, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14687552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14687552</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14687552" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(03)00786-4" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Moog2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K.
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<strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong>
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Orphanet J. Rare Dis. 10: 44, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25886057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25886057</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25886057[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=25886057" 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/10.1186/s13023-015-0256-3" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Moog2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others.
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<strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong>
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J. Med. Genet. 48: 741-751, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21954287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21954287</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21954287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100218" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Najm2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K.
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<strong>Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.</strong>
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Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19165920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19165920</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19165920" 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/ng.194" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Piluso2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Piluso, G., D'Amico, F., Saccone, V., Bismuto, E., Rotundo, I. L., Di Domenico, M., Aurino, S., Schwartz, C. E., Neri, G., Nigro, V.
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<strong>A missense mutation in CASK causes FG syndrome in an Italian family.</strong>
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Am. J. Hum. Genet. 84: 162-177, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19200522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19200522</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19200522[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=19200522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.12.018" target="_blank">Full Text</a>]
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</p>
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<a id="17" class="mim-anchor"></a>
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<a id="Saitsu2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saitsu, H., Kato, M., Osaka, H., Moriyama, N., Horita, H., Nishiyama, K., Yoneda, Y., Kondo, Y., Tsurusaki, Y., Doi, H., Miyake, N., Hayasaka, K., Matsumoto, N.
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<strong>CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia.</strong>
|
|
Epilepsia 53: 1441-1449, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22709267/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22709267</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22709267" 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/10.1111/j.1528-1167.2012.03548.x" target="_blank">Full Text</a>]
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Seto2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Seto, T., Hamazaki, T., Nishigaki, S., Kudo, S., Shintaku, H., Ondo, Y., Shimojima, K., Yamamoto, T.
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<strong>A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly.</strong>
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Intractable Rare Dis. Res. 6: 177-182, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28944139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28944139</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28944139[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=28944139" 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/10.5582/irdr.2017.01031" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Setou2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N.
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<strong>Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.</strong>
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Science 288: 1796-1802, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846156</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10846156" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.288.5472.1796" target="_blank">Full Text</a>]
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</p>
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<a id="20" class="mim-anchor"></a>
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<a id="Srivastava2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Srivastava, S., McMillan, R., Willis, J., Clark, H., Chavan, V., Liang, C., Zhang, H., Hulver, M., Mukherjee, K.
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<strong>X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner.</strong>
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Acta Neuropath. Commun. 4: 30, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27036546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27036546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27036546[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=27036546" 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/10.1186/s40478-016-0295-6" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Stevenson2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stevenson, D., Laverty, H. G., Wenwieser, S., Douglas, M., Wilson, J. B.
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<strong>Mapping and expression analysis of the human CASK gene.</strong>
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Mammalian Genome 11: 934-937, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11003712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11003712</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11003712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s003350010170" target="_blank">Full Text</a>]
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Tabuchi2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tabuchi, K., Biederer, T., Butz, S., Sudhof, T. C.
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<strong>CASK participates in alternative tripartite complexes in which Mint1 competes for binding with caskin1, a novel CASK-binding protein.</strong>
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J. Neurosci. 22: 4264-4273, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12040031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12040031</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12040031[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=12040031" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1523/JNEUROSCI.22-11-04264.2002" target="_blank">Full Text</a>]
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Tarpey2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others.
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<strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong>
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Nature Genet. 41: 535-543, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19377476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19377476</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19377476" 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/ng.367" target="_blank">Full Text</a>]
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Tello2023" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tello, J. A., Jiang, L., Zohar, Y., Restifo, L. L.
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<strong>Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery.</strong>
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Neural Dev. 18: 6, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37805506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37805506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37805506[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=37805506" 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/10.1186/s13064-023-00174-y" target="_blank">Full Text</a>]
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 07/19/2024
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 03/27/2024<br>Bao Lige - updated : 03/27/2024<br>Hilary J. Vernon - updated : 02/12/2024<br>Kelly A. Przylepa - updated : 05/04/2023<br>Hilary J. Vernon - updated : 11/11/2022<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Cassandra L. Kniffin - updated : 4/17/2012<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 12/21/2011<br>Ada Hamosh - updated : 10/1/2009<br>Marla J. F. O'Neill - updated : 3/26/2009<br>Ada Hamosh - updated : 10/22/2008<br>Carol A. Bocchini - updated : 7/18/2008<br>Patricia A. Hartz - updated : 6/5/2007<br>Cassandra L. Kniffin - updated : 4/12/2007<br>Victor A. McKusick - updated : 10/23/2000<br>Ada Hamosh - updated : 6/8/2000<br>Ada Hamosh - updated : 3/28/2000
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Jennifer P. Macke : 2/22/1999
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 07/19/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 03/27/2024<br>alopez : 03/27/2024<br>carol : 02/12/2024<br>carol : 05/05/2023<br>carol : 05/04/2023<br>carol : 03/20/2023<br>carol : 11/11/2022<br>carol : 11/10/2021<br>carol : 08/21/2021<br>carol : 02/20/2013<br>ckniffin : 2/13/2013<br>alopez : 1/30/2013<br>terry : 7/27/2012<br>carol : 6/6/2012<br>carol : 4/17/2012<br>ckniffin : 4/17/2012<br>carol : 3/28/2012<br>alopez : 3/21/2012<br>terry : 3/19/2012<br>ckniffin : 3/19/2012<br>carol : 12/22/2011<br>ckniffin : 12/21/2011<br>carol : 10/28/2011<br>alopez : 10/6/2009<br>terry : 10/1/2009<br>terry : 6/4/2009<br>wwang : 3/27/2009<br>terry : 3/26/2009<br>alopez : 11/24/2008<br>alopez : 10/30/2008<br>terry : 10/22/2008<br>carol : 7/18/2008<br>carol : 7/18/2008<br>carol : 7/18/2008<br>mgross : 6/22/2007<br>terry : 6/5/2007<br>wwang : 4/19/2007<br>ckniffin : 4/12/2007<br>carol : 10/23/2000<br>terry : 10/23/2000<br>alopez : 6/8/2000<br>carol : 3/28/2000<br>mgross : 6/17/1999<br>terry : 6/7/1999<br>alopez : 2/22/1999
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<h3>
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<span class="mim-font">
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<strong>*</strong> 300172
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<h3>
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<span class="mim-font">
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CALCIUM/CALMODULIN-DEPENDENT SERINE PROTEIN KINASE; CASK
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</span>
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</h3>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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VERTEBRATE LIN2 HOMOLOG; LIN2<br />
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CAMGUK, DROSOPHILA, HOMOLOG OF; CMG
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CASK</em></strong>
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<strong>
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<em>
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Cytogenetic location: Xp11.4
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Genomic coordinates <span class="small">(GRCh38)</span> : X:41,514,934-41,923,554 </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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<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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</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="3">
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<span class="mim-font">
|
|
Xp11.4
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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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FG syndrome 4
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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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|
300422
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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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X-linked recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
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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Intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia
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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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300749
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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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X-linked
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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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Intellectual developmental disorder, with or without nystagmus
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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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300422
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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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X-linked recessive
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
3
|
|
</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 CASK gene encodes a calcium/calmodulin-dependent serine protein kinase that is a member of the membrane-associated guanylate kinase (MAGUK) protein family. MAGUKs are scaffolding proteins associated with intercellular junctions (summary by Atasoy et al., 2007). </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>Cohen et al. (1998) used degenerate PCR to clone human CASK cDNAs from several libraries. CASK encodes a 921-amino acid polypeptide with an N-terminal calcium/calmodulin-dependent protein kinase-like domain, PDZ and SH3 domains, a potential protein 4.1-binding motif, and a domain homologous to guanylate kinase. Human CASK is 99% and 52% identical to rat CASK and C. elegans LIN2, respectively. Northern blot analysis demonstrated that CASK is ubiquitously expressed. Immunofluorescence localized the CASK protein to lateral and/or basal plasma membrane domains in epithelial cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Dimitratos et al. (1998) used radiation hybrid panels to map the CASK gene to human chromosome Xp11.4. Stevenson et al. (2000) confirmed the assignment of the CASK gene to Xp11.4 by inclusion within a YAC contig. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Cohen et al. (1998) determined that CASK interacts with both syndecan-2 (SDC2; 142460) and the actin-binding band 4.1 protein (130500). They suggested that CASK may function as a cytoskeletal membrane scaffold that coordinates signal transduction pathways within the cortical cytoskeleton. </p><p>Butz et al. (1998) identified a complex of 3 proteins in brain that has the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. The 3 proteins are CASK; Mint1 (APBA1; 602414), a putative vesicular trafficking protein; and Veli1 (603380), -2, and -3, vertebrate homologs of C. elegans LIN7. CASK, Mint1, and the Velis form a tight, salt-resistant complex. All of these proteins contain PDZ domains in addition to other modules. Butz et al. (1998) proposed that the tripartite complex acts as a nucleation site for the assembly of proteins involved in synaptic vesicle exocytosis and synaptic junctions. </p><p>Using immunoprecipitation experiments, Tabuchi et al. (2002) determined that Caskin1 (612184), like Mint1, is stably bound to CASK in the brain. Affinity chromatography experiments determined that Caskin1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin-1 (600565), suggesting that CASK and Caskin1 coat the cytoplasmic tails of neurexins and other cell surface proteins. Detailed mapping studies revealed that Caskin1 and Mint1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. GST-pull-down experiments indicated that CASK forms a tripartite complex with Caskin1 and Velis similar to the CASK-Mint1-Veli complex. </p><p>To identify binding partners for the guanylate kinase domain of CASK, Hsueh et al. (2000) carried out a yeast 2-hybrid screen of brain complementary DNA libraries, from which TBR1 (604616) was isolated. By deletion analysis, the C-terminal region of TBR1 (residues 342 to 681) was found to be necessary and sufficient for association with the guanylate kinase domain of CASK. When coexpressed in COS-7 cells, TBR1 and CASK were readily coprecipitated by antibodies directed against either individual protein. Hsueh et al. (2000) demonstrated that CASK enters the nucleus and binds to a specific DNA sequence (the T element) in a complex with TBR1. CASK acts as a coactivator of TBR1 to induce transcription of T element-containing genes, including reelin, a gene that is essential for cerebrocortical development. On the basis of their findings, Hsueh et al. (2000) concluded that a membrane-associated guanylate kinase, which is usually associated with cell junctions, has a transcription regulation function. </p><p>Experiments with vesicles containing NMDA receptor 2B (NR2B subunit; 138252) showed that they are transported along microtubules by KIF17 (605037), a neuron-specific molecular motor in neuronal dendrites. Setou et al. (2000) demonstrated that selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of Lin10 (602414), which is a constituent of a large protein complex including Lin2 (CASK), Lin7 (603380), and the NR2B subunit. Setou et al. (2000) concluded that this interaction, which is specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis. </p><p>Lu et al. (2003) showed that Cmg, the Drosophila homolog of CASK, associated with Camk2 (CAMK2A; 114078) in an ATP-regulated manner. In the presence of Ca(2+)/calmodulin (CALM1; 114180), Camk2 complexed to Cmg autophosphorylated at thr287 and became constitutively active. In the absence of Ca(2+)/calmodulin, Camk2 inactivated itself by autophosphorylation on thr306 and required a phosphatase to become reactivated. Lu et al. (2003) concluded that interaction between Cmg and Camk2 provides a postsynaptic pool of Camk2 that can be controlled locally to differentiate active and inactive synapses. </p><p>Hsueh (2009) reviewed the synaptic functions of the CASK protein, noting that it has 3 main roles: it regulates presynaptic termini formation and interactions at the presynaptic site; maintains the morphology of dendritic spines at the postsynaptic site; and regulates ion channels at the postsynaptic site. These functions of CASK can explain, at least in part, the mental retardation and brain developmental defects in patients with CASK mutations. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Intellectual Developmental Disorder with Microcephaly and Pontine and Cerebellar Hypoplasia</em></strong></p><p>
|
|
Najm et al. (2008) found heterozygous loss-of-function mutations in CASK in 4 girls and a partly penetrant splice mutation in a severely affected boy with a syndrome of mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH, MRXSNA; 300749). </p><p>In 20 girls with MICPCH, Moog et al. (2011) identified different loss-of-function mutations or deletions/duplications in the CASK gene (see, e.g., 300172.0010-300172.0012). High-resolution molecular karyotyping of 8 girls found that 6 had intragenic deletions and 2 had intragenic duplications. The smallest deletion was a de novo 60-kb deletion; 1 patient had a 4.24-Mb deletion encompassing the entire gene. Sequence analysis in 12 patients identified 10 heterozygous mutations in 9 patients. The remaining 3 patients were found to have deletions involving CASK using FISH or RT-PCR. All mutations in patients with parental information were shown to occur de novo. All mutations were predicted or demonstrated to result in a null allele. The 20 patients, as well as 5 previously reported patients, had a remarkably similar phenotype, including moderate to severe psychomotor development with poor growth, hypotonia, lack of speech, and lack of ambulation. There was also a distinctive dysmorphic phenotype, with severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism. Brain MRI showed varying degrees of proportionate pontocerebellar hypoplasia, normal corpus callosum, and simplified gyration pattern in some. Moog et al. (2011) emphasized that the brain malformation phenotype in females caused by loss-of-function mutations in CASK is different from the milder phenotype caused by hypomorphic mutations in CASK in males, which results in variable intellectual disability with or without nystagmus (FGS4; 300422). </p><p>By targeted analysis of the CASK gene in 10 unrelated Japanese girls with clinical features suggestive of MICPCH, Hayashi et al. (2012) found genomic aberrations of the CASK gene resulting in a null mutation in all. Three had nonsense mutations, 1 had a 1-bp deletion, 2 had splice site mutations, 2 had heterozygous deletions encompassing the CASK gene, and 2 had intragenic duplications affecting the CASK gene. All patients for whom parental DNA was available were found to carry de novo mutations. There were no molecular hotspots, and the phenotypes were similar regardless of the mutation. The findings extended the variety of genetic alterations causing CASK null mutations, including copy number variations. </p><p>In 8 male patients (7 with MICPCH with or without severe epilepsy and 1 (patient 8) with microcephaly with developmental delay), Moog et al. (2015) identified CASK alterations by Sanger sequencing, copy number analysis (MLPA and/or FISH), and array CGH. Sequence analysis revealed 3 pathogenic mutations: a nonsense mutation (R27X; 300172.0016) in patient 4, a 5-bp deletion (300172.0017) in patient 1, and a transition affecting the start codon (300172.0018) in patient 3. All of these patients exhibited MICPCH with the severe epileptic encephalopathy phenotype. In the 2 patients with MICPCH without epilepsy, MLPA identified mosaic deletions of the CASK gene, including a mosaic deletion of exon 1 (300172.0019) in patient 6. Moog et al. (2015) proposed that CASK mutation-positive males could be distinguished into 3 phenotypic groups that represent a clinical continuum, with inactivating CASK germline mutations associated with the most severe phenotype (MICPCH with severe epileptic encephalopathy); CASK mutations in the mosaic state or partly penetrant CASK mutations associated with the attenuated phenotype (MICPCH); and CASK missense and splice site mutations that leave the CASK protein intact but likely alter function or reduce the amount of normal protein, associated with intellectual disability with or without nystagmus (see 300422). </p><p>In a 9-year-old girl with MICPCH, LaConte et al. (2019) identified a heterozygous missense mutation in the CASK gene (L209P; 602414.0013). Overexpression of the L209P mutation in HEK293 cells resulted in abnormal cytoplasmic aggregates. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see NRXN1, 600565) and VELI (see LIN7A, 603380) but disrupted interaction with MINT1 (APBA1; 602414). Accordingly, MINT1 interacts with CASK's CaMK binding domain, where the mutation is located. LaConte et al. (2019) concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1. Clinical features in the patient included microcephaly, cerebellar hypoplasia, and bilateral retinal dystrophy. It had initially been reported that mutations in the C terminus of CASK were responsible for nystagmus, but this patient also had nystagmus and the L209P mutation is in the N terminus. </p><p><strong><em>FG Syndrome 4</em></strong></p><p>
|
|
In affected members of an Italian family with FG syndrome-4 (300422), Piluso et al. (2009) identified a missense mutation (300172.0003) in the CASK gene that segregated fully with the disease and was not found in 1,000 ethnically matched control X chromosomes. </p><p>In a boy with FG syndrome-4 and nystagmus, Dunn et al. (2017) identified a homozygous splice mutation in the CASK gene (300172.0014). Sanger sequencing in the parents demonstrated that this mutation was de novo. </p><p><strong><em>Impaired Intellectual Development with or without Nystagmus</em></strong></p><p>
|
|
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked impaired intellectual development (see 300422). They identified 4 families with missense mutations in the CASK gene. In 2 of the families, the X-linked mental retardation segregated with nystagmus. </p><p>In 2 additional families with X-linked impaired intellectual development and nystagmus, Hackett et al. (2010) identified 2 different mutations in the CASK gene (300172.0008 and 300172.0009, respectively). In conjunction with the report of Tarpey et al. (2009), CASK mutations were found in 1.5% of individuals with XLMR who were screened. Families with mutations in the C-terminal part of the gene had nystagmus, suggesting a possible genotype/phenotype correlation. </p><p>By next-generation sequencing in a 5-year-old boy with impaired intellectual development, autism spectrum disorder, and microcephaly, who did not have nystagmus, Seto et al. (2017) identified a missense mutation in the CASK gene (S475I; 300172.0015). The mutation was identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she shared autistic symptoms with her brother. The mother showed an almost completely skewed X-chromosome inactivation pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated. </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>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
|
<p>Atasoy et al. (2007) found that Cask-null mice died within hours of birth and exhibited a partially penetrant cleft palate phenotype and increased apoptosis in the thalamus, but no other major developmental changes. Neurons cultured from Cask-null mice showed no changes in electrical properties or evoked release, formed structurally normal synapses, but did show increased glutamatergic spontaneous release events. The findings indicated that Cask is required for mouse survival without being required for core neuronal activities. </p><p>Using a Cre/lox expression system, Srivastava et al. (2016) generated mouse models with absence of Cask expression first in Purkinje cells and then in cerebellar granule cells. No specific motor or other deficits were identified in either mutant mouse model. Complete Cask knockout of neurons in mice did not result in neonatal lethality; however, the mutant mice developed seizures that were fatal before 23 to 24 days of life. Female mice with a heterozygous neuronal-specific CASK knockout did not have an observable abnormal phenotype, but, conversely, female mice with a full-body constitutive heterozygous knockout of Cask had microcephaly, decreased cerebellar size, optic nerve hypoplasia, and signs of ataxia. Examination of individual brain cells in the heterozygous mutant female mice demonstrated that CASK null cells were equally viable compared to CASK-positive cells. Thus the microcephaly in the mice was not due to a cell-autonomous loss of Cask null cells, but rather another postnatal non-cell autonomous mechanism. Srivastava et al. (2016) then identified reduced mitochondrial respiration in brain homogenates of the heterozygous mutant female mice and lower oxidation of fatty acid and glucose in the muscles, although how this related to the neuronal phenotype of CASK loss in the heterozygous mutant female mice was not determined. </p><p>In female heterozygote CASK knockout mice (Cask +/-), Guo et al. (2023) found that the overall size of cerebellum was reduced compared to wildtype due to the death of cerebellar granule (CG) cells. Analysis of homozygous Cask knockout CG cells showed that cell death was apoptotic and was independent of Bdnf (113505) secretion mediated by neurexins (600565). Rescue analysis in cultured CG cells showed that the CaMK, PDZ, and SH3 domains of Cask were required for the survival of CG cells. Accordingly, in human patients manifesting neurologic symptoms, the authors identified CASK missense mutations in the CaMK, PDZ, or SH3 domains that affected the survival of CG cells. Three of the mutations, R106P, R255C, and Y268H (300172.0004), were located in the CaMK domain and resided on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (603143), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain was involved in the molecular mechanism by which CASK maintained CG cell survival. </p><p>Tello et al. (2023) found a Cask loss-of-function mutation caused microcephaly, microencephaly, and a form of short stature in Drosophila. Cultured neurons from mutant Drosophila had disrupted neurite-arbor morphogenesis, leading to a bushy phenotype. The severity of the busy phenotype was inversely related to Cask gene dosage, and the phenotype improved by transgenic expression of Cask. The authors developed a microfluidic system for standardized, automated dissociation of Drosophila central nervous system tissue into individual viable neurons, and this microfluidic system reproduced the bushy phenotype of Cask mutant neurons with high fidelity. Moreover, this automated dissociation method was also effective for rodent CNS. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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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CASK, ARG639TER
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<br />
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SNP: rs137852815,
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ClinVar: RCV000012286, RCV000255325, RCV004798721
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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 female with intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia (MICPCH, MRXSNA; 300749), Najm et al. (2008) identified a C-to-T transition at nucleotide 1915 in exon 21 of the CASK gene, resulting in a premature termination codon replacing the arginine at codon 639 (R639X). This mutation was not identified in the parents of the individual or in 150 control X 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">
|
|
<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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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CASK, 915G-A, EX9
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<br />
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SNP: rs387906499,
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ClinVar: RCV000012287
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a boy with microcephaly and disproportionate pontine and cerebellar hypoplasia (300749), Najm et al. (2008) identified a G-to-A transition at nucleotide 915 of the CASK gene, resulting in a synonymous mutation (K305K) located in the last nucleotide of exon 9. In vitro splicing analyses using minigene constructs identified skipping of exon 9 in about 20% of mutant transcripts, suggesting a defect in splicing. The affected individual was male and died at 2 weeks of age, thus being more severely affected than females described by Najm et al. (2008). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 FG SYNDROME 4</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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CASK, ARG28LEU
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<br />
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SNP: rs137852816,
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ClinVar: RCV000012288
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of an Italian family with FG syndrome-4 (300422), Piluso et al. (2009) identified a hemizygous 83G-T transversion in exon 2 of the CASK gene, resulting in an arg28-to-leu (R28L) substitution at a highly conserved residue in the CaM-kinase domain. There were 3 affected males and 2 carrier females; 1 of the females had a milder phenotype, with mild mental retardation, hypertelorism, and long philtrum. The mutation segregated fully with disease in the family and was not found in 1,000 ethnically matched control X chromosomes. Functional, structural, and dynamic studies did not reveal significant alterations induced by the R28L substitution; however, the authors observed partial skipping of exon 2 of CASK, suggesting improper recognition of an exonic splicing enhancer (ESE) motif induced by the mutation. RT-PCR analysis confirmed that the exon 2-skipped transcript was differently expressed in affected males and carrier females and was not detectable in either unaffected family members or controls, </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>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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CASK, TYR268HIS
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<br />
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|
|
SNP: rs137852817,
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|
|
ClinVar: RCV000012289, RCV002512982, RCV003313028
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 3-generation pedigree segregating X-linked intellectual developmental disorder with nystagmus (see 300422), Tarpey et al. (2009) identified a C-to-T transition at nucleotide 829 of the CASK gene, resulting in a tyr-to-his substitution at codon 268 (Y268H). The mutation segregated with the phenotype in the family and was not identified in any unaffected male family members. </p><p><strong><em>Variant Function</em></strong></p><p>
|
|
Guo et al. (2023) showed that the Y268H mutation in CASK affects the survival of cerebellar granule (CG) cells, is located in the CaMK domain, and resides on the binding interface between the CASK-CaMK domain and liprin-alpha-2 (603143), disrupting its structure. This result suggested that interaction with liprin-alpha-2 through the CaMK domain is involved in the molecular mechanism by which CASK maintained CG cell survival. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</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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CASK, ASP710GLY
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<br />
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SNP: rs137852818,
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ClinVar: RCV000012290, RCV000760252
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|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a large family segregating X-linked intellectual developmental disorder with nystagmus (see 300422), Tarpey et al. (2009) identified an A-to-G transition at nucleotide 2129 of the CASK gene, predicted to result in an asp-to-gly substitution at codon 710 (D710G). However, RT-PCR analysis showed that the 2129A-G change introduces a splice site affecting exon 22 that removes 27 bp of the coding sequence and thus 9 amino acids of the protein at the C-terminal end of the 'Hook Motif.' This mutation segregated with intellectual developmental disorder and nystagmus in affected family members. An additional family member who had mental retardation without nystagmus was not found to carry this mutation. This individual was considered to have milder mental retardation than other affected family members. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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CASK, TRP919ARG
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<br />
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|
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SNP: rs137852819,
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|
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ClinVar: RCV000012291
|
|
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|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family (family 123) in which 3 sons had X-linked intellectual developmental disorder and nystagmus (see 300422), Tarpey et al. (2009) identified a c.2767C-T transition in the CASK gene, resulting in a trp914-to-arg substitution. The mutation segregated with the phenotype. </p><p>In an erratum of Hackett et al. (2010), the authors corrected the mutation in family 123, originally reported by Tarpey et al. (2009), to a c.2755T-C transition, resulting in a trp919-to-arg (W919R) substitution. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITHOUT NYSTAGMUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
CASK, PRO396SER
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<br />
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|
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SNP: rs137852820,
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|
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|
|
|
gnomAD: rs137852820,
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|
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|
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ClinVar: RCV000012292, RCV000733420, RCV000990800, RCV001086366, RCV002326675
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a pedigree segregating X-linked intellectual developmental disorder without nystagmus (see 300422), Tarpey et al. (2009) identified a C-to-T transition at nucleotide 1186 in the CASK gene, resulting in a pro-to-ser substitution at codon 396 (P396S). The mutation was found in affected family members only. This mutation was not associated with nystagmus. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, TYR728CYS
|
|
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|
|
<br />
|
|
|
|
SNP: rs398122844,
|
|
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|
|
|
|
|
ClinVar: RCV000022829, RCV000193589, RCV004700270
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with X-linked intellectual developmental disorder and nystagmus (see 300422), Hackett et al. (2010) identified a 2183A-G transition in exon 23 of the CASK gene, resulting in a tyr728-to-cys (Y728C) substitution in a highly conserved residue. A sister of the brothers, who was affected and also carried the mutation, showed skewed X inactivation. The proband, who had severely impaired intellectual development , also showed cerebellar hypoplasia and pachygyria. He had congenital nystagmus, strabismus, and mild optic disc pallor. He also had dysmorphic features, including synophrys, high nasal bridge, upslanting palpebral fissures, and short columella. His brother had similar features. The sister had normal brain MRI, mildly impaired intellectual development, congenital nystagmus, and no dysmorphic features. </p>
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITH NYSTAGMUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, IVS25AS, A-T, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122845,
|
|
|
|
|
|
|
|
ClinVar: RCV000022830, RCV000145403
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with X-linked intellectual developmental disorder and nystagmus (see 300422), Hackett et al. (2010) identified an A-to-T transversion affecting the 3-prime acceptor splice site of exon 26, resulting in the production of 2 aberrant transcripts: one lacking exon 26 and 1 lacking 3 amino acids. </p><p>See 300172.0014 for discussion of an A-to-G substitution at the same nucleotide.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, ARG106TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906704,
|
|
|
|
|
|
|
|
ClinVar: RCV000022831, RCV000522520
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3.5-year-old girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2011) identified a de novo heterozygous 316C-T transition in exon 4 of the CASK gene, resulting in an arg106-to-ter (R106X) substitution. The child had microcephaly (-6.3 SD), poor growth, severe developmental delay, hypotonia, sensorineural hearing loss, and myopia. She had never achieved walking. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. Dysmorphic facial features included flat occiput, almond-shaped eyes, beaked nose, broad and prominent nasal bridge and tip, smooth philtrum, and large ears. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, 100-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000022832
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old Moroccan girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2011) identified a de novo heterozygous 100-kb deletion affecting exon 1 of the CASK gene, predicted to result in a null allele. The child had microcephaly (-6 SD), severe developmental delay, hypotonia, dyskinesia, and pale optic disc; she could not walk. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. She had a broad nasal bridge, full lips, small chin, and large ears. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, GLN547TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906705,
|
|
|
|
|
|
|
|
ClinVar: RCV000022833
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old American girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2011) identified a heterozygous 1639C-T transition in exon 17 of the CASK gene, resulting in a gln547-to-ter (Q547X) substitution. The patient had microcephaly (-5 SD), severe developmental delay, hypotonia, seizures, strabismus, and scoliosis. She could not walk. Brain MRI showed mild brainstem hypoplasia and moderate cerebellar hypoplasia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, LEU209PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1556014749,
|
|
|
|
|
|
|
|
ClinVar: RCV000498072, RCV000621770
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 9-year-old girl with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), LaConte et al. (2019) identified a heterozygous c.626T-C transition (c.626T-C, NM_003688.3) in the CASK gene, resulting in a leu209-to-pro (L209P) substitution in the CaMK protein domain. The mutation was identified by whole-exome sequencing and was shown to be de novo. Transient overexpression of mutant L209P CASK in HEK293 cells resulted in abnormal cytoplasmic aggregates and lower solubility compared to wildtype CASK protein. Pull-down assays with mutant L209P CASK demonstrated normal interaction with neurexin (see 600565) and VELI (see 603380) but disrupted interaction with MINT1 (602414). LaConte et al. (2019) concluded that the L209P mutation likely disrupts the regulatory scaffolding function of CASK, which links neurexin to molecules such as MINT1. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 FG SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, IVS25AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122845,
|
|
|
|
|
|
|
|
ClinVar: RCV000255115, RCV000626851, RCV003227734
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with nystagmus and FG syndrome-4 (FGS4; 300422), Dunn et al. (2017) identified a de novo hemizygous 3-prime acceptor splice site mutation in the CASK gene (IVS25-2A-G). The mutation was found by genome sequencing and confirmed by Sanger sequencing. Dunn et al. (2017) identified 3 different transcripts in the patient, including the wildtype transcript and 2 mutant transcripts. Mutant transcripts included the expected skipping of exon 26 as well as a 9-bp deletion associated with a cryptic splice site, leading to a 28-amino acid and a 3-amino acid in-frame deletion, respectively (Ala841_Lys843del and Ala841_Glu868del), in the C terminus. RNA-seq of the patient's RNA demonstrated exon skipping in 48% of the reads in the CASK gene and the use of a cryptic splice site in 52% of the reads. Wildtype RNA CASK was amplified only by RT-PCR and was not detected by RNA-seq. The predominant mutant transcripts contain an aberrant guanylate kinase domain and are thus predicted to degrade the ability of CASK to interact with important neuronal and ocular development proteins. Dunn et al. (2017) noted that patients reported by Hackett et al. (2010) with a pathogenic allele at the same position c.2521-2A-T (300172.0009) as their patient resulted in a different phenotype. The 4 patients reported by Hackett et al. (2010) presented with nystagmus, other ocular defects, and mild developmental/intellectual delay; 3 of them had childhood epilepsy or absence seizures and none had feeding issues. Dunn et al. (2017) proposed that different levels of expression of the 3 transcripts in their patient compared to the patients described by Hackett et al. (2010) might explain the difference in some of the phenotypic characteristics. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, WITHOUT NYSTAGMUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
CASK, SER475ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2147201250,
|
|
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|
|
|
|
|
ClinVar: RCV001761582, RCV003238468
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
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<p>Seto et al. (2017) performed next-generation sequencing in a boy with intellectual developmental disorder without nystagmus (see 300422), who also had microcephaly and autism spectrum disorder, and identified a G-T transversion in exon 15 of the CASK gene, resulting in a ser475-to-ile (S475I) substitution. The variant was confirmed by Sanger sequencing and identified in his mother and younger sister. Although the sister did not demonstrate impaired intellectual development, she did share autism spectrum disorder symptoms with her brother. Their mother showed an almost completely skewed X-inactivation (XCI) pattern, whereas the sister demonstrated a paradoxical XCI pattern, with the paternally derived allele predominantly inactivated. </p>
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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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<h4>
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<span class="mim-font">
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<strong>.0016 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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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CASK, ARG27TER
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<br />
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SNP: rs794727270,
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ClinVar: RCV000175755, RCV000723984, RCV001257954, RCV005089881
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</span>
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<span class="mim-text-font">
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<p>In a male infant (patient 4) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; 300749), Moog et al. (2015) detected a de novo c.79C-T transition (c.79C-T, NM_003688) in exon 2 of the CASK gene, resulting in an arg27-to-ter (R27X) substitution. The patient was born at 34 weeks' gestation with intrauterine growth retardation and primary microcephaly (-2.57 SD). Medical history was significant for a ventricular septal defect, apnea-bradycardia syndrome, severe hypotonia, and seizures with onset at 2 months of life. MRI demonstrated severe pontocerebellar hypoplasia (especially the cerebellar hemispheres), progressive cerebral atrophy, and progressive hypomyelination. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0017 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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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CASK, 5-BP DEL, 704ATAAG
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<br />
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ClinVar: RCV003625105
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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 male infant (patient 1) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; 300749), Moog et al. (2015) detected a de novo 5-bp deletion (c.704_708delATAAG, NM_003688) in exon 7 of the CASK gene, causing a frameshift predicted to result in a premature termination (Lys236GlufsTer10). RT-PCR on RNA isolated from patient fibroblasts revealed 5 different CASK transcript variants including a major transcript form that skipped exon 7. Immunoblot analysis did not detect CASK protein. The patient was born at 37 weeks' gestation with primary microcephaly and bilateral clubfeet. He had a severe neurologic disorder with hypotonia, abnormal movements, inability to swallow, and intractable seizures. MRI revealed severe hypoplasia of the medulla, pons, and cerebellum (especially the cerebellar hemispheres), progressive cortical atrophy, simplified gyri, and hypomyelination. </p>
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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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<h4>
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<span class="mim-font">
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<strong>.0018 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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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CASK, MET1?
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<br />
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ClinVar: RCV002417108, RCV003624490
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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 male infant (patient 3) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia and severe epilepsy (MICPCH; 300749), Moog et al. (2015) detected a de novo c.1A-G transition (c.1A-G, NM_003688) in the CASK gene. The patient was born with a normal head circumference but head growth rapidly decelerated to -2.5 SD by age 3 months. He exhibited severe intractable seizures, severe hypotonia, feeding difficulties necessitating PEG tube, and optic hypoplasia, and demonstrated virtually no motor or cognitive development. MRI revealed significant hypoplasia of the pons and cerebellum. Saitsu et al. (2012) had previously described the same c.1A-G mutation in the start codon in a male patient (patient 2) with a diagnosis of Ohtahara syndrome. </p>
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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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<h4>
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<span class="mim-font">
|
|
<strong>.0019 INTELLECTUAL DEVELOPMENTAL DISORDER WITH MICROCEPHALY AND PONTINE AND CEREBELLAR HYPOPLASIA</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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CASK, EX1DEL
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<br />
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ClinVar: RCV003625106
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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 male patient (patient 6) with intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH; 300749), Moog et al. (2015) detected a mosaic deletion of exon 1. MLPA demonstrated that the relative peak area of the 2 probes for exon 1 was reduced by 50 to 60%, indicating a mosaic deletion. Somatic mosaicism of the exon 1 deletion was confirmed in buccal cell-derived DNA by MLPA as dosage of this exon was reduced by 60%. Moog et al. (2015) suggested that somatic mosaicism of the CASK gene produces wildtype protein in a significant percentage of the cells, most likely reducing clinical severity. Patient 6 showed progressive microcephaly during his first year of life and global developmental delay. He had a history of an afebrile seizure but otherwise had a normal EEG. MRI showed moderate pontocerebellar hypoplasia affecting the cerebellar hemispheres and vermis equally. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Atasoy, D., Schoch, S., Ho, A., Nadasy, K. A., Liu, X., Zhang, W., Mukherjee, K., Nosyreva, E. D., Fernandez-Chacon, R., Missler, M., Kavalali, E. T., Sudhof, T. C.
|
|
<strong>Deletion of CASK in mice is lethal and impairs synaptic function.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 2525-2530, 2007.
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[PubMed: 17287346]
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[Full Text: https://doi.org/10.1073/pnas.0611003104]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Butz, S., Okamoto, M., Sudhof, T. C.
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<strong>A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain.</strong>
|
|
Cell 94: 773-782, 1998.
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[PubMed: 9753324]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81736-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Cohen, A. R., Woods, D. F., Marfatia, S. M., Walther, Z., Chishti, A. H., Anderson, J. M.
|
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<strong>Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.</strong>
|
|
J. Cell Biol. 142: 129-138, 1998. Note: Erratum: J. Cell Biol. 142: following 1156, 1998.
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[PubMed: 9660868]
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[Full Text: https://doi.org/10.1083/jcb.142.1.129]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Dimitratos, S. D., Stathakis, D. G., Nelson, C. A., Woods, D. F., Bryant, P. J.
|
|
<strong>The location of human CASK at Xp11.4 identifies this gene as a candidate for X-linked optic atrophy.</strong>
|
|
Genomics 51: 308-309, 1998.
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[PubMed: 9722958]
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[Full Text: https://doi.org/10.1006/geno.1998.5404]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Dunn, P., Prigatano, G. P., Szelinger, S., Roth, J., Siniard, A. L., Claasen, A. M., Richholt, R. F., De Both, M., Corneveaux, J. J., Moskowitz, A. M., Balak, C., Piras, I. S., and 10 others.
|
|
<strong>A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus.</strong>
|
|
Am. J. Med. Genet. 173A: 611-617, 2017.
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[PubMed: 28139025]
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[Full Text: https://doi.org/10.1002/ajmg.a.38069]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Guo, Q., Kouyama-Suzuki, E., Shirai, Y., Cao, X., Yanagawa, T., Mori, T., Tabuchi, K.
|
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<strong>Structural analysis implicates CASK-liprin-alpha-2 interaction in cerebellar granular cell death in MICPCH syndrome.</strong>
|
|
Cells 12: 1177, 2023.
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[PubMed: 37190086]
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[Full Text: https://doi.org/10.3390/cells12081177]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hackett, A., Tarpey, P. S., Licata, A., Cox, J., Whibley, A., Boyle, J., Rogers, C., Grigg, J., Partington, M., Stevenson, R. E., Tolmie, J., Yates, J. R. W., and 10 others.
|
|
<strong>CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.</strong>
|
|
Europ. J. Hum. Genet. 18: 544-552, 2010. Note: Erratum: Europ. J. Hum. Genet. 552 only, 2010.
|
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[PubMed: 20029458]
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[Full Text: https://doi.org/10.1038/ejhg.2009.220]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hayashi, S., Okamoto, N., Chinen, Y., Takanashi, J., Makita, Y., Hata, A., Imoto, I., Inazawa, J.
|
|
<strong>Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH).</strong>
|
|
Hum. Genet. 131: 99-110, 2012.
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[PubMed: 21735175]
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[Full Text: https://doi.org/10.1007/s00439-011-1047-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng, M.
|
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<strong>Nuclear transcription and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.</strong>
|
|
Nature 404: 298-302, 2000. Note: Erratum: Nature 417: 205 only, 2002.
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[PubMed: 10749215]
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[Full Text: https://doi.org/10.1038/35005118]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hsueh, Y.-P.
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<strong>Calcium/calmodulin-dependent serine protein kinase and mental retardation.</strong>
|
|
Ann. Neurol. 66: 438-443, 2009.
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[PubMed: 19847910]
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[Full Text: https://doi.org/10.1002/ana.21755]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
LaConte, L. E. W., Chavan, V., DeLuca, S., Rubin, K., Malc, J., Berry, S., Gail Summers, C., Mukherjee, K.
|
|
<strong>An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.</strong>
|
|
Am. J. Med. Genet. 179A: 94-103, 2019.
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[PubMed: 30549415]
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[Full Text: https://doi.org/10.1002/ajmg.a.60687]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Lu, C. S., Hodge, J. J. L., Mehren, J., Sun, X. X., Griffith, L. C.
|
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<strong>Regulation of the Ca(2+)/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation.</strong>
|
|
Neuron 40: 1185-1197, 2003.
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[PubMed: 14687552]
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[Full Text: https://doi.org/10.1016/s0896-6273(03)00786-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Moog, U., Bierhals, T., Brand, K., Bautsch, J., Biskup, S., Brune, T., Denecke, J., de Die-Smulders, C. E., Evers, C., Hempel, M., Henneke, M., Yntema, H., Menten, B., Pietz, J., Pfundt, R., Schmidtke, J., Steinemann, D., Stumpel, C. T., Van Maldergem, L., Kutsche, K.
|
|
<strong>Phenotypic and molecular insights into CASK-related disorders in males.</strong>
|
|
Orphanet J. Rare Dis. 10: 44, 2015.
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|
[PubMed: 25886057]
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[Full Text: https://doi.org/10.1186/s13023-015-0256-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Moog, U., Kutsche, K., Kortum, F., Chilian, B., Bierhals, T., Apeshiotis, N., Balg, S., Chassaing, N., Coubes, C., Das, S., Engels, H., Van Esch, H., and 20 others.
|
|
<strong>Phenotypic spectrum associated with CASK loss-of-function mutations.</strong>
|
|
J. Med. Genet. 48: 741-751, 2011.
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[PubMed: 21954287]
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[Full Text: https://doi.org/10.1136/jmedgenet-2011-100218]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Najm, J., Horn, D., Wimplinger, I., Golden, J. A., Chizhikov, V. V., Sudi, J., Christian, S. L., Ullmann, R., Kuechler, A., Haas, C. A., Flubacher, A., Charnas, L. R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W. B., Kutsche, K.
|
|
<strong>Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum.</strong>
|
|
Nature Genet. 40: 1065-1067, 2008. Note: Erratum: Nature Genet. 40: 1384 only, 2008.
|
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|
[PubMed: 19165920]
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[Full Text: https://doi.org/10.1038/ng.194]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Piluso, G., D'Amico, F., Saccone, V., Bismuto, E., Rotundo, I. L., Di Domenico, M., Aurino, S., Schwartz, C. E., Neri, G., Nigro, V.
|
|
<strong>A missense mutation in CASK causes FG syndrome in an Italian family.</strong>
|
|
Am. J. Hum. Genet. 84: 162-177, 2009.
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|
|
[PubMed: 19200522]
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[Full Text: https://doi.org/10.1016/j.ajhg.2008.12.018]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Saitsu, H., Kato, M., Osaka, H., Moriyama, N., Horita, H., Nishiyama, K., Yoneda, Y., Kondo, Y., Tsurusaki, Y., Doi, H., Miyake, N., Hayasaka, K., Matsumoto, N.
|
|
<strong>CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia.</strong>
|
|
Epilepsia 53: 1441-1449, 2012.
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|
|
[PubMed: 22709267]
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[Full Text: https://doi.org/10.1111/j.1528-1167.2012.03548.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Seto, T., Hamazaki, T., Nishigaki, S., Kudo, S., Shintaku, H., Ondo, Y., Shimojima, K., Yamamoto, T.
|
|
<strong>A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly.</strong>
|
|
Intractable Rare Dis. Res. 6: 177-182, 2017.
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[PubMed: 28944139]
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[Full Text: https://doi.org/10.5582/irdr.2017.01031]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Setou, M., Nakagawa, T., Seog, D.-H., Hirokawa, N.
|
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<strong>Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.</strong>
|
|
Science 288: 1796-1802, 2000.
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|
|
[PubMed: 10846156]
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[Full Text: https://doi.org/10.1126/science.288.5472.1796]
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</p>
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</li>
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Srivastava, S., McMillan, R., Willis, J., Clark, H., Chavan, V., Liang, C., Zhang, H., Hulver, M., Mukherjee, K.
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<strong>X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner.</strong>
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Acta Neuropath. Commun. 4: 30, 2016.
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[PubMed: 27036546]
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[Full Text: https://doi.org/10.1186/s40478-016-0295-6]
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Stevenson, D., Laverty, H. G., Wenwieser, S., Douglas, M., Wilson, J. B.
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<strong>Mapping and expression analysis of the human CASK gene.</strong>
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Mammalian Genome 11: 934-937, 2000.
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[PubMed: 11003712]
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[Full Text: https://doi.org/10.1007/s003350010170]
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Tabuchi, K., Biederer, T., Butz, S., Sudhof, T. C.
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<strong>CASK participates in alternative tripartite complexes in which Mint1 competes for binding with caskin1, a novel CASK-binding protein.</strong>
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J. Neurosci. 22: 4264-4273, 2002.
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[PubMed: 12040031]
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[Full Text: https://doi.org/10.1523/JNEUROSCI.22-11-04264.2002]
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Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others.
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<strong>A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.</strong>
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Nature Genet. 41: 535-543, 2009.
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[PubMed: 19377476]
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[Full Text: https://doi.org/10.1038/ng.367]
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Tello, J. A., Jiang, L., Zohar, Y., Restifo, L. L.
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<strong>Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery.</strong>
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Neural Dev. 18: 6, 2023.
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[PubMed: 37805506]
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[Full Text: https://doi.org/10.1186/s13064-023-00174-y]
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Bao Lige - updated : 07/19/2024<br>Anne M. Stumpf - updated : 03/27/2024<br>Bao Lige - updated : 03/27/2024<br>Hilary J. Vernon - updated : 02/12/2024<br>Kelly A. Przylepa - updated : 05/04/2023<br>Hilary J. Vernon - updated : 11/11/2022<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Cassandra L. Kniffin - updated : 4/17/2012<br>Cassandra L. Kniffin - updated : 3/19/2012<br>Cassandra L. Kniffin - updated : 12/21/2011<br>Ada Hamosh - updated : 10/1/2009<br>Marla J. F. O'Neill - updated : 3/26/2009<br>Ada Hamosh - updated : 10/22/2008<br>Carol A. Bocchini - updated : 7/18/2008<br>Patricia A. Hartz - updated : 6/5/2007<br>Cassandra L. Kniffin - updated : 4/12/2007<br>Victor A. McKusick - updated : 10/23/2000<br>Ada Hamosh - updated : 6/8/2000<br>Ada Hamosh - updated : 3/28/2000
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Jennifer P. Macke : 2/22/1999
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