3611 lines
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Entry
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- *611642 - HEPATOCYTE CELL ADHESION MOLECULE; HEPACAM
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- OMIM
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<p>
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<span class="h4">*611642</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#cloning">Cloning and Expression</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/611642">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<h4 class="panel-title">
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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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<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 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=ENSG00000165478;t=ENST00000298251" 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=220296" 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=611642" 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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<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 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=ENSG00000165478;t=ENST00000298251" 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_001411043,NM_152722,XM_005271449" 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_152722" 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=611642" 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 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 id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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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=08068&isoform_id=08068_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/HEPACAM" 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/21740133,21758400,34527768,45643115,85397344,109731075,119588018,119588019,119588020,121674801,121945515,530397881,2288045764,2462523682" 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/Q14CZ8" 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=220296" 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=ENSG00000165478;t=ENST00000298251" 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=HEPACAM" 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=HEPACAM" 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+220296" 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/HEPACAM" 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:220296" 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/220296" 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=chr11&hgg_gene=ENST00000298251.5&hgg_start=124919205&hgg_end=124936047&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:26361" 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/hepacam" 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=611642[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=611642[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/HEPACAM/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/ENSG00000165478" 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.gwascentral.org/search?q=HEPACAM" 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=HEPACAM" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HEPACAM&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/PA162390830" 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:26361" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1920177" 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/HEPACAM#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:1920177" 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/220296/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=220296" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050522-198" 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=HEPACAM&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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611642
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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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HEPATOCYTE CELL ADHESION MOLECULE; HEPACAM
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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GLIAL CELL ADHESION MOLECULE; GLIALCAM<br />
|
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HEPATOCYTE AND GLIAL CELL ADHESION MOLECULE
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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=HEPACAM" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HEPACAM</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/11/1058?start=-3&limit=10&highlight=1058">11q24.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:124919205-124936047&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'})">11:124,919,205-124,936,047</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
|
|
Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613925,613926" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
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<a href="/geneMap/11/1058?start=-3&limit=10&highlight=1058">
|
|
11q24.2
|
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</a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Megalencephalic leukoencephalopathy with subcortical cysts 2A
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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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|
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<a href="/entry/613925"> 613925 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/613926"> 613926 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
|
</td>
|
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</tr>
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</tbody>
|
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</table>
|
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/611642" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/611642" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<p>HEPACAM is a cell adhesion molecule of the immunoglobulin (Ig) family (<a href="#8" class="mim-tip-reference" title="Sirisi, S., Folgueira, M., Lopez-Hernandez, T., Minieri, L., Perez-Rius, C., Gaitan-Penas, H., Zang, J., Martinez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estevez, R., Barrallo-Gimeno, A. <strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.</strong> Hum. Molec. Genet. 23: 5069-5086, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24824219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24824219</a>] [<a href="https://doi.org/10.1093/hmg/ddu231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24824219">Sirisi et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24824219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By database searching with the sequence of HEPN1 (<a href="/entry/611641">611641</a>) as query, <a href="#6" class="mim-tip-reference" title="Moh, M. C., Lee, L. H., Shen, S. <strong>Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.</strong> J. Hepatol. 42: 833-841, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15885354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15885354</a>] [<a href="https://doi.org/10.1016/j.jhep.2005.01.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15885354">Moh et al. (2005)</a> identified a novel gene, designated HEPACAM, that contains the full-length HEPN1 on its antisense strand in the 3-prime noncoding region. A HEPACAM cDNA, isolated from liver, encodes a deduced 416-amino acid protein with the typical structure of Ig-like adhesion molecules, including 2 extracellular Ig-like domains, a transmembrane segment, and a cytoplasmic tail containing putative SH3 binding sites and potential serine/threonine and tyrosine kinase phosphorylation sites. RT-PCR demonstrated expression of HEPACAM in normal liver tissues, downregulated expression in hepatocellular carcinoma (HCC) tissues, and undetectable expression in HCC cell lines. Western blot analysis demonstrated that HEPACAM is glycosylated. A polyclonal antibody raised against the cytoplasmic domain of HEPACAM indicated that this domain is phosphorylated. <a href="#6" class="mim-tip-reference" title="Moh, M. C., Lee, L. H., Shen, S. <strong>Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.</strong> J. Hepatol. 42: 833-841, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15885354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15885354</a>] [<a href="https://doi.org/10.1016/j.jhep.2005.01.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15885354">Moh et al. (2005)</a> suggested that HEPACAM may be a tumor suppressor in HCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15885354" 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>From a human brain cDNA library, <a href="#1" class="mim-tip-reference" title="Favre-Kontula, L., Rolland, A., Bernasconi, L., Karmirantzou, M., Power, C., Antonsson, B., Boschert, U. <strong>GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system.</strong> Glia 56: 633-645, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18293412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18293412</a>] [<a href="https://doi.org/10.1002/glia.20640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18293412">Favre-Kontula et al. (2008)</a> isolated a clone corresponding to HEPACAM, which they called glial cell adhesion molecule (GlialCAM). The protein was predominantly expressed in the mouse and human nervous system. Expression in the liver was very low in humans, and liver expression was absent in mice. Detailed studies in mice showed expression of GlialCAM in ependymal cells of the brain ventricular zones and the central canal of the spinal cord, with predominant expression in glial cells. GlialCAM was upregulated in postnatal mouse brain development and showed concomitant expression with myelin basic protein (MBP; <a href="/entry/159430">159430</a>). In vitro, GlialCAM was observed at various developmental stages of oligodendrocytes and in astrocytic processes and at cell contact sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18293412" 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="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> preferred the name GlialCAM above HEPACAM and noted that the protein is predominantly expressed in the central nervous system and that mutation in the gene results in a neurologic phenotype without sign of liver involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#6" class="mim-tip-reference" title="Moh, M. C., Lee, L. H., Shen, S. <strong>Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.</strong> J. Hepatol. 42: 833-841, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15885354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15885354</a>] [<a href="https://doi.org/10.1016/j.jhep.2005.01.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15885354">Moh et al. (2005)</a> mapped the HEPACAM gene to chromosome 11q24. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15885354" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Moh, M. C., Lee, L. H., Shen, S. <strong>Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.</strong> J. Hepatol. 42: 833-841, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15885354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15885354</a>] [<a href="https://doi.org/10.1016/j.jhep.2005.01.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15885354">Moh et al. (2005)</a> demonstrated that the HEPACAM gene contains 7 exons ranging in size from 71 to 2,252 basepairs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15885354" 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="#7" class="mim-tip-reference" title="Moh, M. C., Zhang, C., Luo, C., Lee, L. H., Shen, S. <strong>Structural and functional analyses of a novel Ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells.</strong> J. Biol. Chem. 280: 27366-27374, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917256</a>] [<a href="https://doi.org/10.1074/jbc.M500852200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917256">Moh et al. (2005)</a> evaluated the cytoplasmic domain of HEPACAM by transfecting wildtype and cytoplasmic domain-truncated constructs of HEPACAM into breast carcinoma MCF7 cells and analyzing their effects on HEPACAM function. Biochemical analysis revealed that HEPACAM is a glycosylated protein that forms a cis-homodimer on the cell surface. Deletion of the cytoplasmic domain did not interfere with dimer formation, suggesting that this domain is not required for dimerization. Subcellular localization of HEPACAM in nonpolarized MCF7 cells showed that HEPACAM molecules were recruited to the cytoplasmic membranes at sites of cell-cell attachment. In polarized cells, HEPACAM was preferentially expressed in the lateral and basal membranes. Colocalization analysis demonstrated that HEPACAM colocalized laterally with E-cadherin (<a href="/entry/192090">192090</a>), but no direct contact between the 2 molecules was detected. Partial truncation and complete deletion of the cytoplasmic domain did not alter the plasma membrane location. <a href="#7" class="mim-tip-reference" title="Moh, M. C., Zhang, C., Luo, C., Lee, L. H., Shen, S. <strong>Structural and functional analyses of a novel Ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells.</strong> J. Biol. Chem. 280: 27366-27374, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917256</a>] [<a href="https://doi.org/10.1074/jbc.M500852200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15917256">Moh et al. (2005)</a> found that HEPACAM is capable of modulating cell-matrix interaction and of mediating substrate affinity and cell motility. Deletion of the cytoplasmic domain reduced, but did not completely abrogate, cell-matrix adhesion, but was essential for wound healing, suggesting that cell-matrix adhesion and cell motility are controlled separately, and that phosphorylation of the cytoplasmic domain may be involved in the regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917256" 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 quantitative proteomic analysis of affinity-purified MLC1 (<a href="/entry/605908">605908</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified HEPACAM as a direct MLC1-binding partner. Immunohistochemistry of human brain tissue showed HEPACAM expression mainly around blood vessels. Double immunostaining with a monoclonal antibody against HEPACAM and a polyclonal antibody against human MLC1 showed that MLC1 and HEPACAM colocalized at astrocytic end-feet in astrocyte-astrocyte junctions. The HEPACAM protein was localized inside axons, in contact regions between myelin and axons, and in cells that surrounded myelin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R. <strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 20: 3266-3277, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>] [<a href="https://doi.org/10.1093/hmg/ddr238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21624973">Lopez-Hernandez et al. (2011)</a> found no changes in endogenous HEPACAM protein in primary astrocyte culture that had been depleted of MLC1 by RNA interference: HEPACAM was detected in astrocyte-astrocyte processes in MLC1-depleted astrocytes. The studies suggested that HEPACAM subcellular localization is independent of MLC1 expression. Additional in vitro studies showed that both HEPACAM and MLC1 homooligomerize and also heterooligomerize with each other. When coexpressed, both proteins were localized in astrocyte-astrocyte cell junctions. However, MLC1 expressed alone was detected at the plasma membrane, but was not particularly enriched in cell junctions. In contrast, HEPACAM expressed alone was clearly detected in cell junctions. The findings indicated that HEPACAM acts as an escort molecule, necessary to bring MLC1 to cell-cell junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21624973" 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 various methods, <a href="#2" class="mim-tip-reference" title="Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E. <strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations.</strong> Hum. Molec. Genet. 21: 2166-2180, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22328087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22328087</a>] [<a href="https://doi.org/10.1093/hmg/dds032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22328087">Lanciotti et al. (2012)</a> found that MLC1, TRPV4 (<a href="/entry/605427">605427</a>), HEPACAM, syntrophin (see <a href="/entry/601017">601017</a>), caveolin-1 (CAV1; <a href="/entry/601047">601047</a>), Kir4.1 (KCNJ10; <a href="/entry/602208">602208</a>), and AQP4 (<a href="/entry/600308">600308</a>) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; <a href="/entry/182330">182330</a>), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22328087" 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 immunohistochemical analysis, <a href="#8" class="mim-tip-reference" title="Sirisi, S., Folgueira, M., Lopez-Hernandez, T., Minieri, L., Perez-Rius, C., Gaitan-Penas, H., Zang, J., Martinez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estevez, R., Barrallo-Gimeno, A. <strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.</strong> Hum. Molec. Genet. 23: 5069-5086, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24824219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24824219</a>] [<a href="https://doi.org/10.1093/hmg/ddu231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24824219">Sirisi et al. (2014)</a> observed mislocalization of GLIALCAM in Bergmann glia in the cerebellum of a patient with megalencephalic leukoencephalopathy with subcortical cysts-1 (<a href="/entry/604004">604004</a>) due to mutation in MLC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24824219" 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="#3" class="mim-tip-reference" title="Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J.-S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G.-S., Bartley, C. M., Schubert, R. D., Hawes, I. A., and 18 others. <strong>Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.</strong> Nature 603: 321-327, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35073561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35073561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35073561[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/s41586-022-04432-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35073561">Lanz et al. (2022)</a> demonstrated high-affinity molecular mimicry between the Epstein-Barr virus (EBV) transcription factor EBV nuclear antigen-1 (EBNA1) and the central nervous system protein GlialCAM and provided structural and in vivo functional evidence for its relevance. A crossreactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of blood and CSF from patients with multiple sclerosis (MS; <a href="/entry/126200">126200</a>), followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1 peptide epitope in complex with the autoreactive antigen-binding fragment (Fab) enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM crossreactive antibody. Molecular mimicry was facilitated by phosphorylation of GlialCAM. EBNA1 immunization exacerbated disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies were prevalent in patients with MS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35073561" 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 10 patients from 8 families with autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; <a href="/entry/613925">613925</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified homozygous or compound heterozygous mutations in the HEPACAM gene (see, e g., <a href="#0001">611642.0001</a>-<a href="#0005">611642.0005</a>). The phenotype was characterized by infantile-onset macrocephaly followed by slowly progressive motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. Brain MRI showed typical white matter abnormalities, including cerebral white matter swelling and subcortical cysts, in all stages of the disease. All 16 heterozygous parents were unaffected, but 2 of them had macrocephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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 18 patients from 16 families with autosomal dominant remitting megalencephalic leukoencephalopathy with subcortical cysts-2B with or without impaired intellectual development (MLC2B; <a href="/entry/613926">613926</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified a heterozygous mutation in the HEPACAM gene (see, e.g., <a href="#0006">611642.0006</a>-<a href="#0008">611642.0008</a>). All the mutations were located in a putative interface of the first immunoglobulin domain. The phenotype was characterized by early-onset macrocephaly associated with cerebral white matter swelling and subcortical cysts. With time, however, the MRI changes improved, and patients had relatively normal motor function, with only some residual hypotonia or clumsiness. About 40% of patients had mental retardation. Eight of 11 parents with a mutant mutated allele had macrocephaly, 1 had transient macrocephaly as a child, and 2 reportedly never had macrocephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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 in vitro studies, <a href="#5" class="mim-tip-reference" title="Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R. <strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 20: 3266-3277, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>] [<a href="https://doi.org/10.1093/hmg/ddr238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21624973">Lopez-Hernandez et al. (2011)</a> showed that mutant HEPACAM proteins, except S196Y (<a href="#0001">611642.0001</a>), showed a reduced tendency to homooligomerize compared to wildtype. Mutant HEPACAM proteins showed an altered trafficking, and were located preferentially at the plasma membrane but not in cell junctions, suggesting that homooligomerization is a prerequisite for correct targeting. The recessive pathogenic variants R92Q (<a href="#0003">611642.0003</a>) and R98C (<a href="#0005">611642.0005</a>) showed a reduced ability to heterooligomerize with MLC1. In contrast, the recessive mutation S196Y or the dominant mutations R92W (<a href="#0008">611642.0008</a>) and G89D (<a href="#0007">611642.0007</a>) retained the capacity to oligomerize with MLC1. Mutant HEPACAM proteins also resulted in mislocalization of MLC1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21624973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Sirisi, S., Folgueira, M., Lopez-Hernandez, T., Minieri, L., Perez-Rius, C., Gaitan-Penas, H., Zang, J., Martinez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estevez, R., Barrallo-Gimeno, A. <strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.</strong> Hum. Molec. Genet. 23: 5069-5086, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24824219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24824219</a>] [<a href="https://doi.org/10.1093/hmg/ddu231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24824219">Sirisi et al. (2014)</a> found that the zebrafish genome contains 2 GLIALCAM paralogs, glialcama and glialcamb, of which only glialcama exhibited subcellular localization and modulation of the chloride channel Clc2 (CLCN2; <a href="/entry/600570">600570</a>) similar to that of mammalian GLIALCAM. Similar to findings in mouse, mlc1 and glialcama colocalized in zebrafish glial cells, especially around brain barriers, radial glia processes and endfeet, and in retinal Muller glia. Mlc1 -/- zebrafish showed minor lesions and megalencephaly in brain, but not myelin vacuolization. However, absence of mlc1 in zebrafish brain, as in mice, led to mislocalization of glialcama. Glialcama mislocalization was not found in cultured Mlc1 -/- mouse astrocytes unless they were exposed to high extracellular potassium, a condition that mimicked neuronal activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24824219" 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 2 sisters with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; <a href="/entry/613925">613925</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified compound heterozygosity for 2 mutations in the HEPACAM gene: a 587C-A transversion in exon 3, resulting in a ser196-to-tyr (S196Y) substitution, and a 789G-A transition in exon 4, resulting in a trp263-to-ter (W263X; <a href="#0002">611642.0002</a>) substitution. Both mutations occurred in conserved residues in the extracellular domain, and were not found in 400 control chromosomes. Both girls had onset of macrocephaly in the first year of life, followed by neurologic decline in early childhood, manifest as ataxia, spasticity, and cognitive decline. They became wheelchair-bound at ages 7 and 14 years, respectively. Both also developed epilepsy. As adults, they had dysarthria, dysphagia, mental retardation, spasticity, and ataxia. Brain MRI, first performed in adulthood, showed diffuse cerebral white matter swelling, involvement of the posterior limb of the internal capsule, the external capsule, thin corpus callosum, and ventriculomegaly. Both also had subcortical cysts and cerebellar atrophy. Coexpression of wildtype MLC1 and mutant S196Y HEPACAM in rat astrocytes did not show mislocalization of MLC1 or HEPACAM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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>For discussion of the 789G-A transition in the HEPACAM gene, resulting in a trp263-to-ter (W263X) substitution, that was identified in compound heterozygous state in 2 sisters with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; <a href="/entry/613925">613925</a>) by <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a>, see <a href="#0001">611642.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</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">rs387907050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907050;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=rs387907050" 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=rs387907050" 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=RCV000023904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023904</a>
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<p>In a girl with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; <a href="/entry/613925">613925</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified compound heterozygosity for 2 mutations in the HEPACAM gene: a 275G-A transition in exon 2, resulting in an arg92-to-gln (R92Q) substitution, and a 631G-A transition in exon 3, resulting in an asp211-to-asn (D211N; <a href="#0004">611642.0004</a>) substitution. Both mutations occurred in conserved residues in the extracellular domain and were not found in 400 control chromosomes. The patient had onset of macrocephaly at age 3 months, developed seizures at age 3 years, and ataxia and dysarthria beginning at age 4 years. She became wheelchair-bound at age 7. At age 10, she was mentally retarded with spasticity and ataxia. Brain MRI showed diffuse cerebral white matter swelling and subcortical cysts. Coexpression of wildtype MLC1 (<a href="/entry/605908">605908</a>) and mutant R92Q HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM rescued the defect of the R92Q mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</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">rs387907051 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907051;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=rs387907051" 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=rs387907051" 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=RCV000023905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023905</a>
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<p>For discussion of the 631G-A transition in the HEPACAM gene, resulting in an asp211-to-asn (D211N) substitution, that was identified in a patient with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; <a href="/entry/613925">613925</a>) by <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a>, see <a href="#0003">611642.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</strong>
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HEPACAM, ARG98CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907052 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907052;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=rs387907052" 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=rs387907052" 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=RCV000023906 OR RCV005089309" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023906, RCV005089309" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023906...</a>
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<p>In 3 patients, including 2 sibs, with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; <a href="/entry/613925">613925</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified a homozygous 292C-T transition in exon 2 of the HEPACAM gene, resulting in an arg98-to-cys (R98C) substitution in a conserved residue in the extracellular domain. The mutation was not found in 400 control chromosomes. Coexpression of wildtype MLC1 (<a href="/entry/605908">605908</a>) and mutant R98C HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM rescued the defect of the R98C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT</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">rs387907053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907053;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=rs387907053" 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=rs387907053" 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=RCV000023907 OR RCV000055996 OR RCV000390259 OR RCV003407358" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023907, RCV000055996, RCV000390259, RCV003407358" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023907...</a>
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<p>In 7 patients, including 2 sibs, with remitting megalencephalic leukoencephalopathy with subcortical cysts-2B with or without impaired intellectual development (MLC2B; <a href="/entry/613926">613926</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified a heterozygous 265G-A transition in exon 2 of the HEPACAM gene, resulting in a gly89-to-ser (G89S) substitution in the putative interface of the first immunoglobulin domain. The mutation occurred de novo in 2 patients, and haplotype analysis excluded a founder effect in the other families with the G89S mutation. The mutation was not found in 400 control chromosomes. All patients developed macrocephaly in the first year of life, and most showed delayed motor development which subsequently resolved. Two patients had mental retardation associated with autism; the remaining 5 patients had normal intelligence. Three of the parents transmitting the mutation had macrocephaly, and 1 had transient macrocephaly as a child. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH IMPAIRED INTELLECTUAL DEVELOPMENT</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">rs387907054 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907054;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=rs387907054" 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=rs387907054" 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=RCV002280810 OR RCV003314557" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002280810, RCV003314557" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002280810...</a>
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<p>In a patient with remitting megalencephalic leukoencephalopathy with subcortical cysts-2B with impaired intellectual development (MLC2B; <a href="/entry/613926">613926</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified a heterozygous 266G-A transition in exon 2 of the HEPACAM gene, resulting in a gly89-to-asp (G89D) substitution in the putative interface of the first immunoglobulin domain. The mutation was not found in 400 control chromosomes. The patient's father, who also carried the mutation, had macrocephaly. Coexpression of wildtype MLC1 (<a href="/entry/605908">605908</a>) and mutant G89D HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM did not rescue the defect of the G89D mutation. The patient developed macrocephaly in the first year of life and showed delayed motor and language development. At age 5.5 years, she was mentally retarded and showed mild hypotonia and clumsiness of the upper limbs. <a href="#9" class="mim-tip-reference" title="van der Knaap, M. S., Lai, V., Kohler, W., Salih, M. A., Fonseca, M.-J., Benke, T. A., Wilson, C., Jayakar, P., Aine, M., Dom, L., Lynch, B., Kalmanchey, R., Pietsch, P., Errami, A., Scheper, G. C. <strong>Megalencephalic leukoencephalopathy with cysts without MLC1 defect: two phenotypes.</strong> Ann. Neurol. 67: 834-837, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20517947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20517947</a>] [<a href="https://doi.org/10.1002/ana.21980" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20517947">Van der Knaap et al. (2010)</a> reported detailed MRI studies of this patient and noted that she had microcephaly at birth and low birth weight, suggesting preexistent problems. Brain MRI at age 12 months showed diffuse cerebral white matter swelling with involvement of the posterior limb of the internal capsule, the external capsule, and the corpus callosum, as well as temporal cysts. There was much improvement in brain MRI at age 7 years, but she still had mild ventriculomegaly and cysts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21419380+20517947" 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 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT</strong>
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HEPACAM, ARG92TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907055 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907055;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=rs387907055" 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=rs387907055" 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=RCV000023909 OR RCV000055997 OR RCV003556082" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023909, RCV000055997, RCV003556082" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023909...</a>
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<p>In 6 patients, including 2 sibs, with the remitting type of megalencephalic leukoencephalopathy with subcortical cysts-2B with or without impaired intellectual development (MLC2B; <a href="/entry/613926">613926</a>), <a href="#4" class="mim-tip-reference" title="Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. <strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong> Am. J. Hum. Genet. 88: 422-432, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21419380">Lopez-Hernandez et al. (2011)</a> identified a 274C-T transition in exon 2 of the HEPACAM gene, resulting in an arg92-to-trp (R92W) substitution in the putative interface of the first immunoglobulin domain. The mutation was not found in 400 control chromosomes, and haplotype analysis excluded a founder effect. All patients developed macrocephaly in the first year of life, and most showed delayed motor development, which subsequently resolved. The 2 sibs also had impaired intellectual development, and another unrelated patient had impaired intellectual development associated with autism; the remaining 3 patients had normal intelligence. Coexpression of wildtype MLC1 (<a href="/entry/605908">605908</a>) and mutant R92W HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM did not rescue the defect of the R92W mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21419380" 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="Favre-Kontula2008" class="mim-anchor"></a>
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Favre-Kontula, L., Rolland, A., Bernasconi, L., Karmirantzou, M., Power, C., Antonsson, B., Boschert, U.
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<strong>GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system.</strong>
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Glia 56: 633-645, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18293412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18293412</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18293412" 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/glia.20640" target="_blank">Full Text</a>]
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<a id="Lanciotti2012" class="mim-anchor"></a>
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Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E.
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<strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations.</strong>
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Hum. Molec. Genet. 21: 2166-2180, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22328087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22328087</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22328087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/dds032" target="_blank">Full Text</a>]
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<a id="Lanz2022" class="mim-anchor"></a>
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Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J.-S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G.-S., Bartley, C. M., Schubert, R. D., Hawes, I. A., and 18 others.
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<strong>Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.</strong>
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Nature 603: 321-327, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35073561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35073561</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35073561[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=35073561" 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/s41586-022-04432-7" target="_blank">Full Text</a>]
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Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S.
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<strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong>
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Am. J. Hum. Genet. 88: 422-432, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21419380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21419380</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21419380[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=21419380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.02.009" target="_blank">Full Text</a>]
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Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R.
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<strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Hum. Molec. Genet. 20: 3266-3277, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21624973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21624973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21624973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddr238" target="_blank">Full Text</a>]
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Moh, M. C., Lee, L. H., Shen, S.
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<strong>Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.</strong>
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J. Hepatol. 42: 833-841, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15885354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15885354</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15885354" 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.jhep.2005.01.025" target="_blank">Full Text</a>]
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Moh, M. C., Zhang, C., Luo, C., Lee, L. H., Shen, S.
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<strong>Structural and functional analyses of a novel Ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells.</strong>
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J. Biol. Chem. 280: 27366-27374, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15917256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15917256</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15917256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M500852200" target="_blank">Full Text</a>]
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<a id="Sirisi2014" class="mim-anchor"></a>
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Sirisi, S., Folgueira, M., Lopez-Hernandez, T., Minieri, L., Perez-Rius, C., Gaitan-Penas, H., Zang, J., Martinez, A., Capdevila-Nortes, X., De La Villa, P., Roy, U., Alia, A., Neuhauss, S., Ferroni, S., Nunes, V., Estevez, R., Barrallo-Gimeno, A.
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<strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.</strong>
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Hum. Molec. Genet. 23: 5069-5086, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24824219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24824219</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24824219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddu231" target="_blank">Full Text</a>]
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van der Knaap, M. S., Lai, V., Kohler, W., Salih, M. A., Fonseca, M.-J., Benke, T. A., Wilson, C., Jayakar, P., Aine, M., Dom, L., Lynch, B., Kalmanchey, R., Pietsch, P., Errami, A., Scheper, G. C.
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<strong>Megalencephalic leukoencephalopathy with cysts without MLC1 defect: two phenotypes.</strong>
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Ann. Neurol. 67: 834-837, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20517947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20517947</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20517947" 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.21980" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 09/01/2022
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Patricia A. Hartz - updated : 10/27/2014<br>Patricia A. Hartz - updated : 7/8/2013<br>Cassandra L. Kniffin - updated : 5/30/2012<br>Cassandra L. Kniffin - updated : 4/25/2011
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Creation Date:
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Jennifer L. Goldstein : 12/3/2007
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carol : 09/02/2022
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alopez : 09/01/2022<br>mgross : 10/29/2014<br>mcolton : 10/27/2014<br>mcolton : 10/27/2014<br>mgross : 7/8/2013<br>carol : 5/31/2012<br>ckniffin : 5/30/2012<br>wwang : 4/28/2011<br>wwang : 4/28/2011<br>ckniffin : 4/25/2011<br>terry : 12/4/2007<br>carol : 12/3/2007
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<strong>*</strong> 611642
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HEPATOCYTE CELL ADHESION MOLECULE; HEPACAM
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GLIAL CELL ADHESION MOLECULE; GLIALCAM<br />
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HEPATOCYTE AND GLIAL CELL ADHESION MOLECULE
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<strong><em>HGNC Approved Gene Symbol: HEPACAM</em></strong>
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Cytogenetic location: 11q24.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:124,919,205-124,936,047 </span>
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<span class="small">(from NCBI)</span>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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11q24.2
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Megalencephalic leukoencephalopathy with subcortical cysts 2A
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<span class="mim-font">
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613925
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Autosomal recessive
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3
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Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development
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613926
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>HEPACAM is a cell adhesion molecule of the immunoglobulin (Ig) family (Sirisi et al., 2014). </p>
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<strong>Cloning and Expression</strong>
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<p>By database searching with the sequence of HEPN1 (611641) as query, Moh et al. (2005) identified a novel gene, designated HEPACAM, that contains the full-length HEPN1 on its antisense strand in the 3-prime noncoding region. A HEPACAM cDNA, isolated from liver, encodes a deduced 416-amino acid protein with the typical structure of Ig-like adhesion molecules, including 2 extracellular Ig-like domains, a transmembrane segment, and a cytoplasmic tail containing putative SH3 binding sites and potential serine/threonine and tyrosine kinase phosphorylation sites. RT-PCR demonstrated expression of HEPACAM in normal liver tissues, downregulated expression in hepatocellular carcinoma (HCC) tissues, and undetectable expression in HCC cell lines. Western blot analysis demonstrated that HEPACAM is glycosylated. A polyclonal antibody raised against the cytoplasmic domain of HEPACAM indicated that this domain is phosphorylated. Moh et al. (2005) suggested that HEPACAM may be a tumor suppressor in HCC. </p><p>From a human brain cDNA library, Favre-Kontula et al. (2008) isolated a clone corresponding to HEPACAM, which they called glial cell adhesion molecule (GlialCAM). The protein was predominantly expressed in the mouse and human nervous system. Expression in the liver was very low in humans, and liver expression was absent in mice. Detailed studies in mice showed expression of GlialCAM in ependymal cells of the brain ventricular zones and the central canal of the spinal cord, with predominant expression in glial cells. GlialCAM was upregulated in postnatal mouse brain development and showed concomitant expression with myelin basic protein (MBP; 159430). In vitro, GlialCAM was observed at various developmental stages of oligodendrocytes and in astrocytic processes and at cell contact sites. </p>
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<strong>Nomenclature</strong>
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<p>Lopez-Hernandez et al. (2011) preferred the name GlialCAM above HEPACAM and noted that the protein is predominantly expressed in the central nervous system and that mutation in the gene results in a neurologic phenotype without sign of liver involvement. </p>
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<strong>Mapping</strong>
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<p>By genomic sequence analysis, Moh et al. (2005) mapped the HEPACAM gene to chromosome 11q24. </p>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Moh et al. (2005) demonstrated that the HEPACAM gene contains 7 exons ranging in size from 71 to 2,252 basepairs. </p>
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<strong>Gene Function</strong>
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<p>Moh et al. (2005) evaluated the cytoplasmic domain of HEPACAM by transfecting wildtype and cytoplasmic domain-truncated constructs of HEPACAM into breast carcinoma MCF7 cells and analyzing their effects on HEPACAM function. Biochemical analysis revealed that HEPACAM is a glycosylated protein that forms a cis-homodimer on the cell surface. Deletion of the cytoplasmic domain did not interfere with dimer formation, suggesting that this domain is not required for dimerization. Subcellular localization of HEPACAM in nonpolarized MCF7 cells showed that HEPACAM molecules were recruited to the cytoplasmic membranes at sites of cell-cell attachment. In polarized cells, HEPACAM was preferentially expressed in the lateral and basal membranes. Colocalization analysis demonstrated that HEPACAM colocalized laterally with E-cadherin (192090), but no direct contact between the 2 molecules was detected. Partial truncation and complete deletion of the cytoplasmic domain did not alter the plasma membrane location. Moh et al. (2005) found that HEPACAM is capable of modulating cell-matrix interaction and of mediating substrate affinity and cell motility. Deletion of the cytoplasmic domain reduced, but did not completely abrogate, cell-matrix adhesion, but was essential for wound healing, suggesting that cell-matrix adhesion and cell motility are controlled separately, and that phosphorylation of the cytoplasmic domain may be involved in the regulation. </p><p>By quantitative proteomic analysis of affinity-purified MLC1 (605908), Lopez-Hernandez et al. (2011) identified HEPACAM as a direct MLC1-binding partner. Immunohistochemistry of human brain tissue showed HEPACAM expression mainly around blood vessels. Double immunostaining with a monoclonal antibody against HEPACAM and a polyclonal antibody against human MLC1 showed that MLC1 and HEPACAM colocalized at astrocytic end-feet in astrocyte-astrocyte junctions. The HEPACAM protein was localized inside axons, in contact regions between myelin and axons, and in cells that surrounded myelin. </p><p>Lopez-Hernandez et al. (2011) found no changes in endogenous HEPACAM protein in primary astrocyte culture that had been depleted of MLC1 by RNA interference: HEPACAM was detected in astrocyte-astrocyte processes in MLC1-depleted astrocytes. The studies suggested that HEPACAM subcellular localization is independent of MLC1 expression. Additional in vitro studies showed that both HEPACAM and MLC1 homooligomerize and also heterooligomerize with each other. When coexpressed, both proteins were localized in astrocyte-astrocyte cell junctions. However, MLC1 expressed alone was detected at the plasma membrane, but was not particularly enriched in cell junctions. In contrast, HEPACAM expressed alone was clearly detected in cell junctions. The findings indicated that HEPACAM acts as an escort molecule, necessary to bring MLC1 to cell-cell junctions. </p><p>Using various methods, Lanciotti et al. (2012) found that MLC1, TRPV4 (605427), HEPACAM, syntrophin (see 601017), caveolin-1 (CAV1; 601047), Kir4.1 (KCNJ10; 602208), and AQP4 (600308) assembled into an Na,K-ATPase-associated multiprotein complex. In rat and human astrocyte cell lines, this Na,K-ATPase complex mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmotic stress. MLC1 associated directly with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330), and plasma membrane expression of MLC1 was required for assembly of the Na,K-ATPase complex. TRPV4 was required for calcium influx, and AQP4 was recruited to the complex following hyposmotic stress. </p><p>By immunohistochemical analysis, Sirisi et al. (2014) observed mislocalization of GLIALCAM in Bergmann glia in the cerebellum of a patient with megalencephalic leukoencephalopathy with subcortical cysts-1 (604004) due to mutation in MLC1. </p><p>Lanz et al. (2022) demonstrated high-affinity molecular mimicry between the Epstein-Barr virus (EBV) transcription factor EBV nuclear antigen-1 (EBNA1) and the central nervous system protein GlialCAM and provided structural and in vivo functional evidence for its relevance. A crossreactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of blood and CSF from patients with multiple sclerosis (MS; 126200), followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1 peptide epitope in complex with the autoreactive antigen-binding fragment (Fab) enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM crossreactive antibody. Molecular mimicry was facilitated by phosphorylation of GlialCAM. EBNA1 immunization exacerbated disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies were prevalent in patients with MS. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In 10 patients from 8 families with autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; 613925), Lopez-Hernandez et al. (2011) identified homozygous or compound heterozygous mutations in the HEPACAM gene (see, e g., 611642.0001-611642.0005). The phenotype was characterized by infantile-onset macrocephaly followed by slowly progressive motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. Brain MRI showed typical white matter abnormalities, including cerebral white matter swelling and subcortical cysts, in all stages of the disease. All 16 heterozygous parents were unaffected, but 2 of them had macrocephaly. </p><p>In 18 patients from 16 families with autosomal dominant remitting megalencephalic leukoencephalopathy with subcortical cysts-2B with or without impaired intellectual development (MLC2B; 613926), Lopez-Hernandez et al. (2011) identified a heterozygous mutation in the HEPACAM gene (see, e.g., 611642.0006-611642.0008). All the mutations were located in a putative interface of the first immunoglobulin domain. The phenotype was characterized by early-onset macrocephaly associated with cerebral white matter swelling and subcortical cysts. With time, however, the MRI changes improved, and patients had relatively normal motor function, with only some residual hypotonia or clumsiness. About 40% of patients had mental retardation. Eight of 11 parents with a mutant mutated allele had macrocephaly, 1 had transient macrocephaly as a child, and 2 reportedly never had macrocephaly. </p><p>In in vitro studies, Lopez-Hernandez et al. (2011) showed that mutant HEPACAM proteins, except S196Y (611642.0001), showed a reduced tendency to homooligomerize compared to wildtype. Mutant HEPACAM proteins showed an altered trafficking, and were located preferentially at the plasma membrane but not in cell junctions, suggesting that homooligomerization is a prerequisite for correct targeting. The recessive pathogenic variants R92Q (611642.0003) and R98C (611642.0005) showed a reduced ability to heterooligomerize with MLC1. In contrast, the recessive mutation S196Y or the dominant mutations R92W (611642.0008) and G89D (611642.0007) retained the capacity to oligomerize with MLC1. Mutant HEPACAM proteins also resulted in mislocalization of MLC1. </p>
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sirisi et al. (2014) found that the zebrafish genome contains 2 GLIALCAM paralogs, glialcama and glialcamb, of which only glialcama exhibited subcellular localization and modulation of the chloride channel Clc2 (CLCN2; 600570) similar to that of mammalian GLIALCAM. Similar to findings in mouse, mlc1 and glialcama colocalized in zebrafish glial cells, especially around brain barriers, radial glia processes and endfeet, and in retinal Muller glia. Mlc1 -/- zebrafish showed minor lesions and megalencephaly in brain, but not myelin vacuolization. However, absence of mlc1 in zebrafish brain, as in mice, led to mislocalization of glialcama. Glialcama mislocalization was not found in cultured Mlc1 -/- mouse astrocytes unless they were exposed to high extracellular potassium, a condition that mimicked neuronal activity. </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>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</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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HEPACAM, SER196TYR
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<br />
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SNP: rs387907049,
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gnomAD: rs387907049,
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ClinVar: RCV000023902, RCV001092301
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; 613925), Lopez-Hernandez et al. (2011) identified compound heterozygosity for 2 mutations in the HEPACAM gene: a 587C-A transversion in exon 3, resulting in a ser196-to-tyr (S196Y) substitution, and a 789G-A transition in exon 4, resulting in a trp263-to-ter (W263X; 611642.0002) substitution. Both mutations occurred in conserved residues in the extracellular domain, and were not found in 400 control chromosomes. Both girls had onset of macrocephaly in the first year of life, followed by neurologic decline in early childhood, manifest as ataxia, spasticity, and cognitive decline. They became wheelchair-bound at ages 7 and 14 years, respectively. Both also developed epilepsy. As adults, they had dysarthria, dysphagia, mental retardation, spasticity, and ataxia. Brain MRI, first performed in adulthood, showed diffuse cerebral white matter swelling, involvement of the posterior limb of the internal capsule, the external capsule, thin corpus callosum, and ventriculomegaly. Both also had subcortical cysts and cerebellar atrophy. Coexpression of wildtype MLC1 and mutant S196Y HEPACAM in rat astrocytes did not show mislocalization of MLC1 or HEPACAM. </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>.0002 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</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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HEPACAM, TRP263TER
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<br />
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ClinVar: RCV000023903
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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>For discussion of the 789G-A transition in the HEPACAM gene, resulting in a trp263-to-ter (W263X) substitution, that was identified in compound heterozygous state in 2 sisters with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; 613925) by Lopez-Hernandez et al. (2011), see 611642.0001. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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HEPACAM, ARG92GLN
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|
<br />
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|
|
SNP: rs387907050,
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|
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|
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|
|
ClinVar: RCV000023904
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; 613925), Lopez-Hernandez et al. (2011) identified compound heterozygosity for 2 mutations in the HEPACAM gene: a 275G-A transition in exon 2, resulting in an arg92-to-gln (R92Q) substitution, and a 631G-A transition in exon 3, resulting in an asp211-to-asn (D211N; 611642.0004) substitution. Both mutations occurred in conserved residues in the extracellular domain and were not found in 400 control chromosomes. The patient had onset of macrocephaly at age 3 months, developed seizures at age 3 years, and ataxia and dysarthria beginning at age 4 years. She became wheelchair-bound at age 7. At age 10, she was mentally retarded with spasticity and ataxia. Brain MRI showed diffuse cerebral white matter swelling and subcortical cysts. Coexpression of wildtype MLC1 (605908) and mutant R92Q HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM rescued the defect of the R92Q mutation. </p>
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEPACAM, ASP211ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907051,
|
|
|
|
|
|
|
|
ClinVar: RCV000023905
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 631G-A transition in the HEPACAM gene, resulting in an asp211-to-asn (D211N) substitution, that was identified in a patient with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; 613925) by Lopez-Hernandez et al. (2011), see 611642.0003. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2A</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEPACAM, ARG98CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907052,
|
|
|
|
|
|
|
|
ClinVar: RCV000023906, RCV005089309
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 patients, including 2 sibs, with megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A; 613925), Lopez-Hernandez et al. (2011) identified a homozygous 292C-T transition in exon 2 of the HEPACAM gene, resulting in an arg98-to-cys (R98C) substitution in a conserved residue in the extracellular domain. The mutation was not found in 400 control chromosomes. Coexpression of wildtype MLC1 (605908) and mutant R98C HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM rescued the defect of the R98C mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEPACAM, GLY89SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907053,
|
|
|
|
|
|
|
|
ClinVar: RCV000023907, RCV000055996, RCV000390259, RCV003407358
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 7 patients, including 2 sibs, with remitting megalencephalic leukoencephalopathy with subcortical cysts-2B with or without impaired intellectual development (MLC2B; 613926), Lopez-Hernandez et al. (2011) identified a heterozygous 265G-A transition in exon 2 of the HEPACAM gene, resulting in a gly89-to-ser (G89S) substitution in the putative interface of the first immunoglobulin domain. The mutation occurred de novo in 2 patients, and haplotype analysis excluded a founder effect in the other families with the G89S mutation. The mutation was not found in 400 control chromosomes. All patients developed macrocephaly in the first year of life, and most showed delayed motor development which subsequently resolved. Two patients had mental retardation associated with autism; the remaining 5 patients had normal intelligence. Three of the parents transmitting the mutation had macrocephaly, and 1 had transient macrocephaly as a child. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH IMPAIRED INTELLECTUAL DEVELOPMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEPACAM, GLY89ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907054,
|
|
|
|
|
|
|
|
ClinVar: RCV002280810, RCV003314557
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with remitting megalencephalic leukoencephalopathy with subcortical cysts-2B with impaired intellectual development (MLC2B; 613926), Lopez-Hernandez et al. (2011) identified a heterozygous 266G-A transition in exon 2 of the HEPACAM gene, resulting in a gly89-to-asp (G89D) substitution in the putative interface of the first immunoglobulin domain. The mutation was not found in 400 control chromosomes. The patient's father, who also carried the mutation, had macrocephaly. Coexpression of wildtype MLC1 (605908) and mutant G89D HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM did not rescue the defect of the G89D mutation. The patient developed macrocephaly in the first year of life and showed delayed motor and language development. At age 5.5 years, she was mentally retarded and showed mild hypotonia and clumsiness of the upper limbs. Van der Knaap et al. (2010) reported detailed MRI studies of this patient and noted that she had microcephaly at birth and low birth weight, suggesting preexistent problems. Brain MRI at age 12 months showed diffuse cerebral white matter swelling with involvement of the posterior limb of the internal capsule, the external capsule, and the corpus callosum, as well as temporal cysts. There was much improvement in brain MRI at age 7 years, but she still had mild ventriculomegaly and cysts. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 2B, REMITTING, WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
HEPACAM, ARG92TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387907055,
|
|
|
|
|
|
|
|
ClinVar: RCV000023909, RCV000055997, RCV003556082
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 patients, including 2 sibs, with the remitting type of megalencephalic leukoencephalopathy with subcortical cysts-2B with or without impaired intellectual development (MLC2B; 613926), Lopez-Hernandez et al. (2011) identified a 274C-T transition in exon 2 of the HEPACAM gene, resulting in an arg92-to-trp (R92W) substitution in the putative interface of the first immunoglobulin domain. The mutation was not found in 400 control chromosomes, and haplotype analysis excluded a founder effect. All patients developed macrocephaly in the first year of life, and most showed delayed motor development, which subsequently resolved. The 2 sibs also had impaired intellectual development, and another unrelated patient had impaired intellectual development associated with autism; the remaining 3 patients had normal intelligence. Coexpression of wildtype MLC1 (605908) and mutant R92W HEPACAM in rat astrocytes resulted in diffuse intracellular MLC1 and HEPACAM mislocalization with partial enrichment in cell membranes, but not specifically in cell junctions. Expression of wildtype HEPACAM did not rescue the defect of the R92W mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Favre-Kontula, L., Rolland, A., Bernasconi, L., Karmirantzou, M., Power, C., Antonsson, B., Boschert, U.
|
|
<strong>GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system.</strong>
|
|
Glia 56: 633-645, 2008.
|
|
|
|
|
|
[PubMed: 18293412]
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|
|
|
[Full Text: https://doi.org/10.1002/glia.20640]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lanciotti, A., Brignone, M. S., Molinari, P., Visentin, S., De Nuccio, C., Macchia, G., Aiello, C., Bertini, E., Aloisi, F., Petrucci, T. C., Ambrosini, E.
|
|
<strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 functionally cooperates with the TRPV4 cation channel to activate the response of astrocytes to osmotic stress: dysregulation by pathological mutations.</strong>
|
|
Hum. Molec. Genet. 21: 2166-2180, 2012.
|
|
|
|
|
|
[PubMed: 22328087]
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|
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|
|
[Full Text: https://doi.org/10.1093/hmg/dds032]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J.-S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G.-S., Bartley, C. M., Schubert, R. D., Hawes, I. A., and 18 others.
|
|
<strong>Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.</strong>
|
|
Nature 603: 321-327, 2022.
|
|
|
|
|
|
[PubMed: 35073561]
|
|
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|
|
[Full Text: https://doi.org/10.1038/s41586-022-04432-7]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S.
|
|
<strong>Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.</strong>
|
|
Am. J. Hum. Genet. 88: 422-432, 2011.
|
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|
|
[PubMed: 21419380]
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|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2011.02.009]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lopez-Hernandez, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G. C., van der Knaap, M. S., Casquero, P., Ciruela, F., Ferrer, I., Nunes, V., Estevez, R.
|
|
<strong>Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.</strong>
|
|
Hum. Molec. Genet. 20: 3266-3277, 2011.
|
|
|
|
|
|
[PubMed: 21624973]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddr238]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Moh, M. C., Lee, L. H., Shen, S.
|
|
<strong>Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma.</strong>
|
|
J. Hepatol. 42: 833-841, 2005.
|
|
|
|
|
|
[PubMed: 15885354]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.jhep.2005.01.025]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Moh, M. C., Zhang, C., Luo, C., Lee, L. H., Shen, S.
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<strong>Structural and functional analyses of a novel Ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells.</strong>
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<strong>Megalencephalic leukoencephalopathy with subcortical cysts protein 1 regulates glial surface localization of GLIALCAM from fish to humans.</strong>
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Hum. Molec. Genet. 23: 5069-5086, 2014.
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[PubMed: 24824219]
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[Full Text: https://doi.org/10.1093/hmg/ddu231]
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van der Knaap, M. S., Lai, V., Kohler, W., Salih, M. A., Fonseca, M.-J., Benke, T. A., Wilson, C., Jayakar, P., Aine, M., Dom, L., Lynch, B., Kalmanchey, R., Pietsch, P., Errami, A., Scheper, G. C.
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<strong>Megalencephalic leukoencephalopathy with cysts without MLC1 defect: two phenotypes.</strong>
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Ann. Neurol. 67: 834-837, 2010.
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[PubMed: 20517947]
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[Full Text: https://doi.org/10.1002/ana.21980]
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