4239 lines
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Entry
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- *605908 - MODULATOR OF VRAC CURRENT 1; MLC1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605908</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605908">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000100427;t=ENST00000311597" 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=23209" 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=605908" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000100427;t=ENST00000311597" 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_001376472,NM_001376473,NM_001376474,NM_001376475,NM_001376476,NM_001376477,NM_001376478,NM_001376479,NM_001376480,NM_001376481,NM_001376482,NM_001376483,NM_001376484,NM_015166,NM_139202,NR_164811,NR_164812,NR_164813" 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_015166" 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=605908" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05800&isoform_id=05800_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/MLC1" 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/14326004,14589896,20141590,20306686,21237732,47123290,47678451,119593896,119593897,193784870,221039788,221040596,221041756,221042936,929653968,1775678309,1775678313,1775678339,1775678379,1775678425,1775678447,1775678457,1775678515,1775678525,1775678527,1775678535,1775678584,1775678586" 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/Q15049" 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=23209" 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=ENSG00000100427;t=ENST00000311597" 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=MLC1" 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=MLC1" 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+23209" 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/MLC1" 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:23209" 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/23209" 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=chr22&hgg_gene=ENST00000311597.10&hgg_start=50059391&hgg_end=50085875&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:17082" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:17082" 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/mlc1" 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=605908[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 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=605908[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000100427" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=MLC1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=MLC1" 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=MLC1" 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=MLC1&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/PA38199" 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:17082" 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:2157910" 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/MLC1#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:2157910" 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/23209/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=23209" 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-050419-145" 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=MLC1&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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605908
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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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MODULATOR OF VRAC CURRENT 1; MLC1
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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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KIAA0027
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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=MLC1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MLC1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/22/401?start=-3&limit=10&highlight=401">22q13.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:50059391-50085875&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'})">22:50,059,391-50,085,875</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
|
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<a href="/geneMap/22/401?start=-3&limit=10&highlight=401">
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22q13.33
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Megalencephalic leukoencephalopathy with subcortical cysts 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604004"> 604004 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/605908" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/605908" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<p>MLC1 encodes a transmembrane protein that associates with the Na,K-ATPase beta-1 subunit (ATP1B1; <a href="/entry/182330">182330</a>) in a multiprotein complex. MLC1 regulates the assembly and response of this Na,K-ATPase complex to osmotic stress (<a href="#5" 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>). <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>
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<p><a href="#12" class="mim-tip-reference" title="Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayasi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S. <strong>Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly samples cDNA clones from human immature myeloid cell line KG-1.</strong> DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7584026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7584026</a>] [<a href="https://doi.org/10.1093/dnares/1.1.27" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7584026">Nomura et al. (1994)</a> identified MLC1, which they designated KIAA0027, by analysis of randomly sampled cDNA clones from a human immature myeloid cell line. Northern blot analysis showed that expression of KIAA0027 was relatively high in brain. It was also expressed in peripheral white blood cells and spleen, with relatively low expression in ovary, prostate, placenta, thymus, and lung. No expression was observed in heart, liver, skeletal muscle, and several other tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7584026" 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="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> confirmed that MLC1 is expressed in brain, and they did not detect alternative splice products. MLC1 was predicted to have 8 transmembrane domains. <a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> hypothesized that MLC1 encodes a membrane protein that may have a transport function for a specific substrate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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="#16" class="mim-tip-reference" title="Teijido, O., Martinez, A., Pusch, M., Zorzano, A., Soriano, E., del Rio, J. A., Palacin, M., Estevez, R. <strong>Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 13: 2581-2594, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367490</a>] [<a href="https://doi.org/10.1093/hmg/ddh291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367490">Teijido et al. (2004)</a> showed that human MLC1 localized to the plasma membrane in Xenopus oocytes. Mouse Mlc1 showed similar localization in HeLa cells. MLC1 was found to be an oligomeric protein. In adult mouse brain, Mlc1 was detected preferentially in particular axonal tracts and in some astrocytes, concentrating in Bergmann glia, the astrocyte end-feet membranes adjacent to blood vessels, and in astrocyte-astrocyte membrane contact regions, as well as the ependyma and the pia mater. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15367490" 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="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> stated that the MLC1 protein contains 377 amino acids. <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>
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<p><a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> determined that the MLC1 gene contains 12 exons with a start codon in exon 2 and an untranslated 3-prime end of 2.2 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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 radiation hybrid analysis, <a href="#12" class="mim-tip-reference" title="Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayasi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S. <strong>Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly samples cDNA clones from human immature myeloid cell line KG-1.</strong> DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7584026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7584026</a>] [<a href="https://doi.org/10.1093/dnares/1.1.27" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7584026">Nomura et al. (1994)</a> mapped the MLC1 gene, or KIAA0027, to chromosome 22. <a href="#3" class="mim-tip-reference" title="Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others. <strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong> Nature Genet. 39: 25-27, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17173049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17173049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17173049[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/ng1933" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17173049">Durand et al. (2007)</a> mapped the MLC1 gene to chromosome 22q13.33 by study of a translocation, t(14;22)(p11.2;q13.33). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7584026+17173049" 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 quantitative proteomic analysis of affinity-purified MLC1, <a href="#8" 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 (<a href="/entry/611642">611642</a>) 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="#9" 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, as well as 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="#5" 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 interacted directly with ATP1B1 as part of an Na,K-ATPase multiprotein complex that mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmosis in rat and human astrocyte cell lines. Other components of this complex included the potassium channel Kir4.1 (KCNJ10; <a href="/entry/602208">602208</a>), syntrophin (see <a href="/entry/601017">601017</a>), caveolin-1 (CAV1; <a href="/entry/601047">601047</a>), HEPACAM, and the calcium channel TRPV4 (<a href="/entry/605427">605427</a>). AQP4 (<a href="/entry/600308">600308</a>) was recruited to the complex following hyposmotic shock. Association of MLC1 with ATPB1 was favored by hyposmotic shock. Membrane expression of MLC1 potentiated complex assembly and agonist- or hyposmotic shock-induced TRPV4 activation and calcium influx. <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>
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<p><a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> identified 12 different mutations in the MLC1 gene (see, e.g., <a href="#0001">605908.0001</a>-<a href="#0004">605908.0004</a>) in individuals with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; <a href="/entry/604004">604004</a>) in 13 separate families, 7 of which were informative for linkage to 22qtel. The patients in 1 family were compound heterozygotes for mutations that introduced stop codons. The others were homozygous for frameshifts, splice acceptor mutations, a splice donor mutation, and amino acid substitutions of residues in predicted transmembrane domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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="#6" class="mim-tip-reference" title="Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935341</a>] [<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935341">Leegwater et al. (2002)</a> described 14 new mutations in the MLC1 gene (see, e.g., <a href="#0005">605908.0005</a>-<a href="#0008">605908.0008</a>) in 18 patients with MLC. They found no MLC1 mutations in 14 families; however, 4 of these families were informative for linkage, and 3 families did not display linkage to 22qter, which strongly suggested the presence of a second locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11935341" 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 Israel, MLC is found in an increased frequency among Libyan Jews. <a href="#1" class="mim-tip-reference" title="Ben-Zeev, B., Levy-Nissenbaum, E., Lahat, H., Anikster, Y., Shinar, Y., Brand, N., Gross-Tzur, V., MacGregor, D., Sidi, R., Kleta, R., Frydman, M., Pras, E. <strong>Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.</strong> Hum. Genet. 111: 214-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189496</a>] [<a href="https://doi.org/10.1007/s00439-002-0770-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189496">Ben-Zeev et al. (2002)</a> described 3 novel mutations in affected members of 7 MLC families: gly59 to glu (G59E; <a href="#0009">605908.0009</a>), pro92 to ser (P92S; <a href="#0007">605908.0007</a>), and 135insC (<a href="#0011">605908.0011</a>). The G59E mutation was found in a great majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the mutation revealed a carrier rate of 1 in 40 compared with an expected carrier rate of 1 in 81. Several explanations were offered for this observation, the most likely one being an admixture of the Libyan Jewish population reducing the number of homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189496" 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 13 of 18 patients with MLC, <a href="#13" class="mim-tip-reference" title="Patrono, C., Di Giacinto, G., Eymard-Pierre, E., Santorelli, F. M., Rodriguez, D., De Stefano, N., Federico, A., Gatti, R., Benigno, V., Megarbane, A., Tabarki, B., Boespflug-Tanguy, O., Bertini, E. <strong>Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.</strong> Neurology 61: 534-537, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12939431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12939431</a>] [<a href="https://doi.org/10.1212/01.wnl.0000076184.21183.ca" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12939431">Patrono et al. (2003)</a> identified 11 mutations in the MLC1 gene, 9 of which were novel. There was no apparent genotype/phenotype correlation. Five patients did not show mutations, indicating genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12939431" 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="#17" class="mim-tip-reference" title="Tsujino, S., Kanazawa, N., Yoneyama, H., Shimono, M., Kawakami, A., Hatanaka, Y., Shimizu, T., Oba, H. <strong>A common mutation and a novel mutation in Japanese patients with van der Knaap disease.</strong> J. Hum. Genet. 48: 605-608, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615938</a>] [<a href="https://doi.org/10.1007/s10038-003-0085-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615938">Tsujino et al. (2003)</a> studied 3 Japanese patients with megalencephalic leukoencephalopathy, also known as van der Knaap disease. Two of them were homozygous for a previously described mutation, S93L (<a href="#0002">605908.0002</a>), and 1 was a compound heterozygote for S93L and a novel mutation (<a href="#0012">605908.0012</a>). Combining their data with previous reports, they determined that S93L had been observed in 6 of 7 (85.7%) patients in at least 1 allele, and 10 of 14 (71.4%) alleles had this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14615938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Ilja Boor, P. K., de Groot, K., Mejaski-Bosnjak, V., Brenner, C., van der Knaap, M. S., Scheper, G. C., Pronk, J. C. <strong>Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1.</strong> Hum. Mutat. 27: 505-512, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16652334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16652334</a>] [<a href="https://doi.org/10.1002/humu.20332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16652334">Ilja Boor et al. (2006)</a> demonstrated that in about 20% of patients with a typical clinical and MRI picture of megalencephalic leukoencephalopathy with subcortical cysts, no mutations in the MLC1 gene had been found. Several of these families in which no mutations had been found also do not show linkage with the MLC1 locus, which suggested a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter or 3-prime and 5-prime untranslated regions, and intronic mutations, which may influence the amino acid composition of the end product. <a href="#4" class="mim-tip-reference" title="Ilja Boor, P. K., de Groot, K., Mejaski-Bosnjak, V., Brenner, C., van der Knaap, M. S., Scheper, G. C., Pronk, J. C. <strong>Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1.</strong> Hum. Mutat. 27: 505-512, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16652334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16652334</a>] [<a href="https://doi.org/10.1002/humu.20332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16652334">Ilja Boor et al. (2006)</a> described 13 novel mutations, including those found with extended mutation analysis on MLC patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16652334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Functional Effects of MLC1 Mutations</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Teijido, O., Martinez, A., Pusch, M., Zorzano, A., Soriano, E., del Rio, J. A., Palacin, M., Estevez, R. <strong>Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Molec. Genet. 13: 2581-2594, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367490</a>] [<a href="https://doi.org/10.1093/hmg/ddh291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15367490">Teijido et al. (2004)</a> found that mutant MLC1 had decreased expression and reduced stability compared to wildtype MLC1, suggesting that mutant MLC1 impaired folding. The defect was corrected in vitro by addition of curcumin, a Ca(2+)-ATPase inhibitor. <a href="#2" class="mim-tip-reference" title="Duarri, A., Teijido, O., Lopez-Hernandez, T., Scheper, G. C., Barriere, H., Boor, I., Aguado, F., Zorzano, A., Palacin, M., Martinez, A., Lukacs, G. L., van der Knaap, M. S., Nunes, V., Estevez, R. <strong>Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects.</strong> Hum. Molec. Genet. 17: 3728-3739, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18757878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18757878</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18757878[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18757878">Duarri et al. (2008)</a> demonstrated that disease-causing mutations in MLC1 resulted in a reduction of total MLC1 protein and decreased expression at the plasma membrane in human monocytes, Xenopus oocytes, and rat astrocytes. In vitro analysis in several cell lines showed that the MLC1-mutant proteins had decreased stability, were retained in the endoplasmic reticulum, and were subject to proteosomal or lysosomal degradation, consistent with a defect in protein trafficking. Mutations were classified based on reduction of MLC1 protein levels in plasma membranes as severe (see, e.g., S280L, <a href="#0001">605908.0001</a>; S93L, <a href="#0002">605908.0002</a>; and N141S, <a href="#0006">605908.0006</a>), intermediate (see, e.g., G59E, <a href="#0009">605908.0009</a>; P92S, <a href="#0007">605908.0007</a>), or mild (see, e.g., N141K; <a href="#0006">605908.0006</a>). <a href="#2" class="mim-tip-reference" title="Duarri, A., Teijido, O., Lopez-Hernandez, T., Scheper, G. C., Barriere, H., Boor, I., Aguado, F., Zorzano, A., Palacin, M., Martinez, A., Lukacs, G. L., van der Knaap, M. S., Nunes, V., Estevez, R. <strong>Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects.</strong> Hum. Molec. Genet. 17: 3728-3739, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18757878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18757878</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18757878[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18757878">Duarri et al. (2008)</a> suggested increasing the cellular expression or stability of MLC1 as a therapeutic approach for patients with MLC1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15367490+18757878" 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="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 mutations in MLC1 hindered the response of rat and human astrocytes to hyposmotic stress. Mutations in MLC1 associated with a severe phenotype, including S280L, resulted in absence of MLC1 at the membrane and abrogated assembly of the Na,K-ATPase complex and TRPV4-mediated calcium influx in response to hyposmotic stress. Mutations associated with a less severe phenotype had a milder effect on Na,K-ATPase complex assembly and the response to 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="#15" 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 (HEPACAM; <a href="/entry/611642">611642</a>) in Bergmann glia in the cerebellum of the patient with megalencephalic leukoencephalopathy with subcortical cysts-1 reported by <a href="#9" 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>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21624973+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><strong><em>Exclusion Studies</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Meyer, J., Huberth, A., Ortega, G., Syagailo, Y. V., Jatzke, S., Mossner, R., Strom, T. M., Ulzheimer-Teuber, I., Stober, G., Schmitt, A., Lesch, K. P. <strong>A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree.</strong> Molec. Psychiat. 6: 302-306, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326298</a>] [<a href="https://doi.org/10.1038/sj.mp.4000869" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11326298">Meyer et al. (2001)</a> suggested that KIAA0027/MLC1 is involved in the etiopathogenesis of schizophrenia (<a href="/entry/181500">181500</a>), via a putative dominantly acting rare leu309-to-met (L309M) variant cosegregating in a large pedigree with periodic catatonia. A form of periodic catatonia had been mapped to chromosome 15q15 (SCZD10; <a href="/entry/605419">605419</a>). <a href="#10" class="mim-tip-reference" title="McQuillin, A., Kalsi, G., Moorey, H., Lamb, G., Mayet, S., Quested, D., Baker, P., Curtis, D., Gurling, H. M. <strong>A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia.</strong> Europ. J. Hum. Genet. 10: 491-494, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111645</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111645">McQuillin et al. (2002)</a> screened exon 11 of the MLC1 gene in 174 U.K. patients with schizophrenia, including 22 cases of catatonic schizophrenia, and did not identify any individual with the L309M mutation. They did, however, identify a series of polymorphisms, including an insertion of 11 amino acids at amino acids 351 to 352, which were in complete linkage disequilibrium with each other and which were present in an equal number of schizophrenic and control individuals. <a href="#10" class="mim-tip-reference" title="McQuillin, A., Kalsi, G., Moorey, H., Lamb, G., Mayet, S., Quested, D., Baker, P., Curtis, D., Gurling, H. M. <strong>A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia.</strong> Europ. J. Hum. Genet. 10: 491-494, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111645</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12111645">McQuillin et al. (2002)</a> concluded that the identification of these polymorphisms in healthy individuals suggests that MLC1 exon 11 can withstand a number of changes without producing either the MLC phenotype or schizophrenia. <a href="#14" class="mim-tip-reference" title="Rubie, C., Lichtner, P., Gartner, J., Siekiera, M., Uziel, G., Kohlmann, B., Kohlschutter, A., Meitinger, T., Stober, G., Bettecken, T. <strong>Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?</strong> Hum. Mutat. 21: 45-52, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12497630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12497630</a>] [<a href="https://doi.org/10.1002/humu.10145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12497630">Rubie et al. (2003)</a> screened the MLC1 gene in 140 index cases with periodic catatonia and 5 patients with MLC. The rare L309M variant was found in another multiplex pedigree but did not segregate with periodic catatonia. Furthermore, a complicated 33-bp insertion/deletion polymorphism at the 5-prime end of exon 11 of MLC1 was found at equal frequency among schizophrenic patients and controls. Among the 5 patients with MLC, 4 mutant alleles were detected. <a href="#14" class="mim-tip-reference" title="Rubie, C., Lichtner, P., Gartner, J., Siekiera, M., Uziel, G., Kohlmann, B., Kohlschutter, A., Meitinger, T., Stober, G., Bettecken, T. <strong>Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?</strong> Hum. Mutat. 21: 45-52, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12497630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12497630</a>] [<a href="https://doi.org/10.1002/humu.10145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12497630">Rubie et al. (2003)</a> concluded that their findings excluded MLC1 as a susceptibility locus for schizophrenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12111645+11326298+12497630" 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="#15" 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 (HEPACAM; <a href="/entry/611642">611642</a>) 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908341 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908341;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908341?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908341" 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=rs121908341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Japanese family with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; <a href="/entry/604004">604004</a>), <a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> identified a homozygous C-to-T transition at nucleotide 954 in exon 10 of the MLC1 gene, resulting in a ser280-to-leu substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80358245 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358245;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80358245?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80358245" 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=rs80358245" 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=RCV000004979 OR RCV001380081 OR RCV003155016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004979, RCV001380081, RCV003155016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004979...</a>
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<p>In a Japanese family and a Turkish family, <a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> identified a homozygous C-to-T transition at nucleotide 393 in exon 4 of the MLC1 gene, resulting in a ser93-to-leu (S93L) substitution and causing megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>). In another Japanese family, the S93L mutation was found in heterozygous state in an affected individual. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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="#17" class="mim-tip-reference" title="Tsujino, S., Kanazawa, N., Yoneyama, H., Shimono, M., Kawakami, A., Hatanaka, Y., Shimizu, T., Oba, H. <strong>A common mutation and a novel mutation in Japanese patients with van der Knaap disease.</strong> J. Hum. Genet. 48: 605-608, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615938</a>] [<a href="https://doi.org/10.1007/s10038-003-0085-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615938">Tsujino et al. (2003)</a> assembled data indicating that of 7 Japanese patients, 6 (85.7%) carried the S93L mutation on at least 1 allele and 10 of the 14 alleles (71.4%) had this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14615938" 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 1</strong>
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<p>In 2 families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>), one from Turkey and the other from the Middle East, <a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> identified a 7-bp deletion in exon 6 of the MLC1 gene, resulting in a frameshift after leu149. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1183818307 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1183818307;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1183818307?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1183818307" 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=rs1183818307" 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=RCV000004981" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004981" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004981</a>
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<p>In a family of Turkish origin with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>), <a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a> identified a homozygous donor splice site mutation causing aberrant splicing of exon 11 of the MLC1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11254442" 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 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908343 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908343;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908343?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908343" 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=rs121908343" 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=RCV000004982" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004982" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004982</a>
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<p>In a family in France, <a href="#6" class="mim-tip-reference" title="Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935341</a>] [<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935341">Leegwater et al. (2002)</a> found megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>) caused by homozygosity for an asn141-to-lys (N141K) missense mutation in exon 5 of the MLC1 gene. The amino acid change resulted from a C-to-A transversion at nucleotide 423. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11935341" 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 1</strong>
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MLC1, ASN141SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908344 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908344;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=rs121908344" 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=rs121908344" 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=RCV000004983" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004983" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004983</a>
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<p>In a family in Turkey, <a href="#6" class="mim-tip-reference" title="Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935341</a>] [<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935341">Leegwater et al. (2002)</a> found that homozygosity for an asn141-to-ser (N141S) missense mutation in exon 5 of the MLC1 gene was responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>). The amino acid change resulted from an A-to-G transition at nucleotide 422. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11935341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span class="mim-font">
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<strong>.0007 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908345 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908345;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908345?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908345" 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=rs121908345" 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=RCV000004984 OR RCV001378687 OR RCV001844006" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004984, RCV001378687, RCV001844006" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004984...</a>
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<p>In 3 unrelated families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>), 2 from Croatia and 1 from U.K./Eastern Europe, <a href="#6" class="mim-tip-reference" title="Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935341</a>] [<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935341">Leegwater et al. (2002)</a> found compound heterozygosity for mutations in the MLC1 gene, with 1 of the alleles carrying a pro92-to-ser (P92S) missense mutation. The amino acid change resulted from a C-to-T transition at nucleotide 274. In the U.K./Eastern Europe case, the second mutation was tyr198-to-ter (<a href="#0008">605908.0008</a>), described by <a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">Leegwater et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11254442+11935341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family of mixed Jewish ancestry (the father a Libyan Jew and the mother an Ashkenazi Jew) with megalencephalic leukoencephalopathy with subcortical cysts, <a href="#1" class="mim-tip-reference" title="Ben-Zeev, B., Levy-Nissenbaum, E., Lahat, H., Anikster, Y., Shinar, Y., Brand, N., Gross-Tzur, V., MacGregor, D., Sidi, R., Kleta, R., Frydman, M., Pras, E. <strong>Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.</strong> Hum. Genet. 111: 214-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189496</a>] [<a href="https://doi.org/10.1007/s00439-002-0770-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189496">Ben-Zeev et al. (2002)</a> identified the P92S substitution. The mutation was not found in 140 unaffected Ashkenazi control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189496" 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 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267607236 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607236;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267607236?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607236" 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=rs267607236" 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=RCV000004985 OR RCV001383177 OR RCV001826417" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004985, RCV001383177, RCV001826417" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004985...</a>
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<p>For discussion of the tyr198-to-ter mutation in the MLC1 gene that was found in compound heterozygous state in a U.K./Eastern Europe patient with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; <a href="/entry/604004">604004</a>) by Leegwater et al. (<a href="#7" class="mim-tip-reference" title="Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S. <strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong> Am. J. Hum. Genet. 68: 831-838, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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/10.1086/319519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11254442">2001</a>, <a href="#6" class="mim-tip-reference" title="Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935341</a>] [<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935341">2002</a>), see <a href="#0007">605908.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11254442+11935341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80358242 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358242;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=rs80358242" 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=rs80358242" 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=RCV000004986 OR RCV000293896 OR RCV001826418" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004986, RCV000293896, RCV001826418" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004986...</a>
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<p><a href="#1" class="mim-tip-reference" title="Ben-Zeev, B., Levy-Nissenbaum, E., Lahat, H., Anikster, Y., Shinar, Y., Brand, N., Gross-Tzur, V., MacGregor, D., Sidi, R., Kleta, R., Frydman, M., Pras, E. <strong>Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.</strong> Hum. Genet. 111: 214-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189496</a>] [<a href="https://doi.org/10.1007/s00439-002-0770-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189496">Ben-Zeev et al. (2002)</a> showed that Libyan Jewish patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>) were homozygous for a G-to-A substitution at nucleotide 176 of the MLC1 gene, resulting in a gly59-to-glu (G59E) change. This sequence variation was found in full segregation with the disease in all of the Libyan Jewish and Turkish Jewish families studied, and in the carrier chromosome inherited from a Libyan Jewish father in a mixed Ashkenazi-Libyan Jewish family. This substitution was not found in 200 unaffected, non-Libyan Jewish individuals, but was found in 5 of 200 unaffected Libyan Jewish individuals, establishing a carrier rate of 1 in 40 in this ethnic group. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80358241 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358241;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80358241?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80358241" 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=rs80358241" 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=RCV000004987 OR RCV000599600 OR RCV001274276" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000004987, RCV000599600, RCV001274276" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000004987...</a>
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<p>In a patient of Indian Agrawali ancestry with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>), <a href="#1" class="mim-tip-reference" title="Ben-Zeev, B., Levy-Nissenbaum, E., Lahat, H., Anikster, Y., Shinar, Y., Brand, N., Gross-Tzur, V., MacGregor, D., Sidi, R., Kleta, R., Frydman, M., Pras, E. <strong>Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.</strong> Hum. Genet. 111: 214-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189496</a>] [<a href="https://doi.org/10.1007/s00439-002-0770-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189496">Ben-Zeev et al. (2002)</a> identified a homozygous insertion of a cytosine at nucleotide 135 at exon 2 of the MLC1 gene. This resulted in a frameshift and the creation of a stop codon 104 bp downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189496" 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="#6" class="mim-tip-reference" title="Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong> Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11935341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11935341</a>] [<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11935341">Leegwater et al. (2002)</a> described this mutation in 3 Agrawali patients. They stated that the disease was probably introduced into the tribe by a single founder, and the mutation is probably shared by all MLC patients of this community. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11935341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2062079566 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2062079566;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=rs2062079566" 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=rs2062079566" 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=RCV001248532 OR RCV002287898" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001248532, RCV002287898" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001248532...</a>
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<p>In a patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; <a href="/entry/604004">604004</a>), <a href="#17" class="mim-tip-reference" title="Tsujino, S., Kanazawa, N., Yoneyama, H., Shimono, M., Kawakami, A., Hatanaka, Y., Shimizu, T., Oba, H. <strong>A common mutation and a novel mutation in Japanese patients with van der Knaap disease.</strong> J. Hum. Genet. 48: 605-608, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615938</a>] [<a href="https://doi.org/10.1007/s10038-003-0085-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14615938">Tsujino et al. (2003)</a> described compound heterozygosity for the common S93L mutation (<a href="#0002">605908.0002</a>) and a novel mutation, 452-468del+G. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14615938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs281875309 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875309;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs281875309?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs281875309" 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=rs281875309" 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=RCV000024319 OR RCV000059741 OR RCV001826507" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024319, RCV000059741, RCV001826507" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024319...</a>
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<p>In a woman with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; <a href="/entry/604004">604004</a>), <a href="#9" 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> identified a homozygous 206C-T transition in the MLC1 gene, resulting in a ser69-to-leu (S69L) substitution in a highly conserved residue in the first transmembrane domain. The mutation was not found in 400 control chromosomes. The patient developed macrocephaly within the first few months of life, and thereafter showed slow motor deterioration, epilepsy, and cognitive decline. Brain MRI at age 40 years showed diffuse signal abnormalities in the cerebral white matter, with global atrophy and subcortical cysts in the anterior temporal region. She died at age 57 years following a cranial trauma. Postmortem brain examination showed reduced cerebral white matter with cavitation in the frontal and parietal lobes. Microscopic examination showed preservation of the cerebral cortex, but lack of myelin in the deep white matter with cavitation in the most affected areas. There was a reduction in the number of astrocytes and oligodendrocytes and loss of axons. Many astrocytes lacking myelin contained alpha-beta-crystallin (CRYAB; <a href="/entry/123590">123590</a>), a stress protein. Patient tissue showed no immunostaining for MLC1, indicating that deficiency of cell surface MLC1 protein expression is the basis for the disorder. The MLC1-interacting protein HEPACAM (<a href="/entry/611642">611642</a>) was present in astrocytic processes, but at a reduced level. In vitro expression of the S69L mutation in HeLa cells showed that the mutant protein was located in intracellular compartments, with reduced surface membrane expression compared to wildtype. The mutant protein also showed reduced stability. The mutant protein was stabilized by overexpression of HEPACAM, but it was still less stable than wildtype. <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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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1007/s00439-002-0770-y" target="_blank">Full Text</a>]
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Duarri, A., Teijido, O., Lopez-Hernandez, T., Scheper, G. C., Barriere, H., Boor, I., Aguado, F., Zorzano, A., Palacin, M., Martinez, A., Lukacs, G. L., van der Knaap, M. S., Nunes, V., Estevez, R.
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[<a href="https://doi.org/10.1093/hmg/ddn269" target="_blank">Full Text</a>]
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<a id="Durand2007" class="mim-anchor"></a>
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Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others.
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<strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong>
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[<a href="https://doi.org/10.1038/ng1933" target="_blank">Full Text</a>]
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<a id="Ilja Boor2006" class="mim-anchor"></a>
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Ilja Boor, P. K., de Groot, K., Mejaski-Bosnjak, V., Brenner, C., van der Knaap, M. S., Scheper, G. C., Pronk, J. C.
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<strong>Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1.</strong>
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Hum. Mutat. 27: 505-512, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16652334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16652334</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16652334" 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/humu.20332" 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="Leegwater2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
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<strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.
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[<a href="https://doi.org/10.1007/s00439-002-0682-x" target="_blank">Full Text</a>]
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<a id="Leegwater2001" class="mim-anchor"></a>
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<div class="">
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Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S.
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<strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Am. J. Hum. Genet. 68: 831-838, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11254442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11254442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11254442[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=11254442" 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/10.1086/319519" target="_blank">Full Text</a>]
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<a id="Lopez-Hernandez2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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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</p>
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<a id="9" class="mim-anchor"></a>
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<a id="Lopez-Hernandez2011" class="mim-anchor"></a>
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<div class="">
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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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<a id="10" class="mim-anchor"></a>
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<a id="McQuillin2002" class="mim-anchor"></a>
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<div class="">
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McQuillin, A., Kalsi, G., Moorey, H., Lamb, G., Mayet, S., Quested, D., Baker, P., Curtis, D., Gurling, H. M.
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<strong>A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia.</strong>
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Europ. J. Hum. Genet. 10: 491-494, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12111645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12111645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12111645" 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/sj.ejhg.5200837" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Meyer2001" class="mim-anchor"></a>
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Meyer, J., Huberth, A., Ortega, G., Syagailo, Y. V., Jatzke, S., Mossner, R., Strom, T. M., Ulzheimer-Teuber, I., Stober, G., Schmitt, A., Lesch, K. P.
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<strong>A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11326298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11326298</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11326298" 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/sj.mp.4000869" target="_blank">Full Text</a>]
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<a id="Nomura1994" class="mim-anchor"></a>
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<div class="">
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Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayasi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S.
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<strong>Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly samples cDNA clones from human immature myeloid cell line KG-1.</strong>
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[<a href="https://doi.org/10.1093/dnares/1.1.27" target="_blank">Full Text</a>]
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<a id="Patrono2003" class="mim-anchor"></a>
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<div class="">
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Patrono, C., Di Giacinto, G., Eymard-Pierre, E., Santorelli, F. M., Rodriguez, D., De Stefano, N., Federico, A., Gatti, R., Benigno, V., Megarbane, A., Tabarki, B., Boespflug-Tanguy, O., Bertini, E.
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<strong>Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.</strong>
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[<a href="https://doi.org/10.1212/01.wnl.0000076184.21183.ca" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Rubie2003" class="mim-anchor"></a>
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<div class="">
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Rubie, C., Lichtner, P., Gartner, J., Siekiera, M., Uziel, G., Kohlmann, B., Kohlschutter, A., Meitinger, T., Stober, G., Bettecken, T.
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<strong>Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?</strong>
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Hum. Mutat. 21: 45-52, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12497630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12497630</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12497630" 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/humu.10145" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Sirisi2014" class="mim-anchor"></a>
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<div class="">
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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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<a id="16" class="mim-anchor"></a>
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<a id="Teijido2004" class="mim-anchor"></a>
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<p class="mim-text-font">
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Teijido, O., Martinez, A., Pusch, M., Zorzano, A., Soriano, E., del Rio, J. A., Palacin, M., Estevez, R.
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<strong>Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts.</strong>
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Hum. Molec. Genet. 13: 2581-2594, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15367490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15367490</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15367490" 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/ddh291" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Tsujino2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tsujino, S., Kanazawa, N., Yoneyama, H., Shimono, M., Kawakami, A., Hatanaka, Y., Shimizu, T., Oba, H.
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<strong>A common mutation and a novel mutation in Japanese patients with van der Knaap disease.</strong>
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J. Hum. Genet. 48: 605-608, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14615938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14615938</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14615938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10038-003-0085-4" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 10/27/2014
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 7/8/2013<br>Cassandra L. Kniffin - updated : 5/30/2012<br>Cassandra L. Kniffin - updated : 8/23/2010<br>George E. Tiller - updated : 6/13/2007<br>Victor A. McKusick - updated : 2/15/2007<br>Victor A. McKusick - updated : 7/12/2006<br>Victor A. McKusick - updated : 4/5/2004<br>Cassandra L. Kniffin - updated : 1/21/2004<br>Michael B. Petersen - updated : 6/16/2003<br>Victor A. McKusick - updated : 1/15/2003<br>Anne M. Stumpf - updated : 11/6/2002<br>Victor A. McKusick - updated : 10/2/2002<br>Victor A. McKusick - updated : 5/10/2002
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/4/2001
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carol : 12/18/2019
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<span class="mim-text-font">
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carol : 09/28/2016<br>mgross : 10/29/2014<br>mcolton : 10/27/2014<br>mgross : 7/8/2013<br>alopez : 4/30/2013<br>terry : 6/4/2012<br>carol : 5/31/2012<br>ckniffin : 5/30/2012<br>wwang : 4/28/2011<br>ckniffin : 4/25/2011<br>joanna : 4/21/2011<br>wwang : 9/17/2010<br>ckniffin : 8/23/2010<br>wwang : 6/14/2007<br>terry : 6/13/2007<br>alopez : 2/19/2007<br>joanna : 2/15/2007<br>alopez : 7/18/2006<br>terry : 7/12/2006<br>terry : 4/9/2004<br>alopez : 4/7/2004<br>terry : 4/5/2004<br>tkritzer : 1/27/2004<br>ckniffin : 1/21/2004<br>cwells : 7/11/2003<br>cwells : 6/16/2003<br>tkritzer : 2/10/2003<br>cwells : 1/15/2003<br>terry : 1/15/2003<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>alopez : 11/6/2002<br>tkritzer : 10/10/2002<br>tkritzer : 10/7/2002<br>terry : 10/2/2002<br>alopez : 5/14/2002<br>terry : 5/10/2002<br>mgross : 5/2/2002<br>mgross : 5/4/2001
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<span class="mim-font">
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<strong>*</strong> 605908
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<h3>
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<span class="mim-font">
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MODULATOR OF VRAC CURRENT 1; MLC1
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</div>
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<div>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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KIAA0027
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MLC1</em></strong>
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<strong>
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<em>
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Cytogenetic location: 22q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 22:50,059,391-50,085,875 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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22q13.33
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<span class="mim-font">
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Megalencephalic leukoencephalopathy with subcortical cysts 1
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<span class="mim-font">
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604004
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>MLC1 encodes a transmembrane protein that associates with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330) in a multiprotein complex. MLC1 regulates the assembly and response of this Na,K-ATPase complex to osmotic stress (Lanciotti et al., 2012). </p>
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<div>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>Nomura et al. (1994) identified MLC1, which they designated KIAA0027, by analysis of randomly sampled cDNA clones from a human immature myeloid cell line. Northern blot analysis showed that expression of KIAA0027 was relatively high in brain. It was also expressed in peripheral white blood cells and spleen, with relatively low expression in ovary, prostate, placenta, thymus, and lung. No expression was observed in heart, liver, skeletal muscle, and several other tissues. </p><p>Leegwater et al. (2001) confirmed that MLC1 is expressed in brain, and they did not detect alternative splice products. MLC1 was predicted to have 8 transmembrane domains. Leegwater et al. (2001) hypothesized that MLC1 encodes a membrane protein that may have a transport function for a specific substrate. </p><p>Teijido et al. (2004) showed that human MLC1 localized to the plasma membrane in Xenopus oocytes. Mouse Mlc1 showed similar localization in HeLa cells. MLC1 was found to be an oligomeric protein. In adult mouse brain, Mlc1 was detected preferentially in particular axonal tracts and in some astrocytes, concentrating in Bergmann glia, the astrocyte end-feet membranes adjacent to blood vessels, and in astrocyte-astrocyte membrane contact regions, as well as the ependyma and the pia mater. </p><p>Lanciotti et al. (2012) stated that the MLC1 protein contains 377 amino acids. </p>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Leegwater et al. (2001) determined that the MLC1 gene contains 12 exons with a start codon in exon 2 and an untranslated 3-prime end of 2.2 kb. </p>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, Nomura et al. (1994) mapped the MLC1 gene, or KIAA0027, to chromosome 22. Durand et al. (2007) mapped the MLC1 gene to chromosome 22q13.33 by study of a translocation, t(14;22)(p11.2;q13.33). </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By quantitative proteomic analysis of affinity-purified MLC1, Lopez-Hernandez et al. (2011) identified HEPACAM (611642) 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, as well as 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 interacted directly with ATP1B1 as part of an Na,K-ATPase multiprotein complex that mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmosis in rat and human astrocyte cell lines. Other components of this complex included the potassium channel Kir4.1 (KCNJ10; 602208), syntrophin (see 601017), caveolin-1 (CAV1; 601047), HEPACAM, and the calcium channel TRPV4 (605427). AQP4 (600308) was recruited to the complex following hyposmotic shock. Association of MLC1 with ATPB1 was favored by hyposmotic shock. Membrane expression of MLC1 potentiated complex assembly and agonist- or hyposmotic shock-induced TRPV4 activation and calcium influx. </p>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Leegwater et al. (2001) identified 12 different mutations in the MLC1 gene (see, e.g., 605908.0001-605908.0004) in individuals with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004) in 13 separate families, 7 of which were informative for linkage to 22qtel. The patients in 1 family were compound heterozygotes for mutations that introduced stop codons. The others were homozygous for frameshifts, splice acceptor mutations, a splice donor mutation, and amino acid substitutions of residues in predicted transmembrane domains. </p><p>Leegwater et al. (2002) described 14 new mutations in the MLC1 gene (see, e.g., 605908.0005-605908.0008) in 18 patients with MLC. They found no MLC1 mutations in 14 families; however, 4 of these families were informative for linkage, and 3 families did not display linkage to 22qter, which strongly suggested the presence of a second locus. </p><p>In Israel, MLC is found in an increased frequency among Libyan Jews. Ben-Zeev et al. (2002) described 3 novel mutations in affected members of 7 MLC families: gly59 to glu (G59E; 605908.0009), pro92 to ser (P92S; 605908.0007), and 135insC (605908.0011). The G59E mutation was found in a great majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the mutation revealed a carrier rate of 1 in 40 compared with an expected carrier rate of 1 in 81. Several explanations were offered for this observation, the most likely one being an admixture of the Libyan Jewish population reducing the number of homozygotes. </p><p>In 13 of 18 patients with MLC, Patrono et al. (2003) identified 11 mutations in the MLC1 gene, 9 of which were novel. There was no apparent genotype/phenotype correlation. Five patients did not show mutations, indicating genetic heterogeneity. </p><p>Tsujino et al. (2003) studied 3 Japanese patients with megalencephalic leukoencephalopathy, also known as van der Knaap disease. Two of them were homozygous for a previously described mutation, S93L (605908.0002), and 1 was a compound heterozygote for S93L and a novel mutation (605908.0012). Combining their data with previous reports, they determined that S93L had been observed in 6 of 7 (85.7%) patients in at least 1 allele, and 10 of 14 (71.4%) alleles had this mutation. </p><p>Ilja Boor et al. (2006) demonstrated that in about 20% of patients with a typical clinical and MRI picture of megalencephalic leukoencephalopathy with subcortical cysts, no mutations in the MLC1 gene had been found. Several of these families in which no mutations had been found also do not show linkage with the MLC1 locus, which suggested a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter or 3-prime and 5-prime untranslated regions, and intronic mutations, which may influence the amino acid composition of the end product. Ilja Boor et al. (2006) described 13 novel mutations, including those found with extended mutation analysis on MLC patients. </p><p><strong><em>Functional Effects of MLC1 Mutations</em></strong></p><p>
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Teijido et al. (2004) found that mutant MLC1 had decreased expression and reduced stability compared to wildtype MLC1, suggesting that mutant MLC1 impaired folding. The defect was corrected in vitro by addition of curcumin, a Ca(2+)-ATPase inhibitor. Duarri et al. (2008) demonstrated that disease-causing mutations in MLC1 resulted in a reduction of total MLC1 protein and decreased expression at the plasma membrane in human monocytes, Xenopus oocytes, and rat astrocytes. In vitro analysis in several cell lines showed that the MLC1-mutant proteins had decreased stability, were retained in the endoplasmic reticulum, and were subject to proteosomal or lysosomal degradation, consistent with a defect in protein trafficking. Mutations were classified based on reduction of MLC1 protein levels in plasma membranes as severe (see, e.g., S280L, 605908.0001; S93L, 605908.0002; and N141S, 605908.0006), intermediate (see, e.g., G59E, 605908.0009; P92S, 605908.0007), or mild (see, e.g., N141K; 605908.0006). Duarri et al. (2008) suggested increasing the cellular expression or stability of MLC1 as a therapeutic approach for patients with MLC1 mutations. </p><p>Lanciotti et al. (2012) found that mutations in MLC1 hindered the response of rat and human astrocytes to hyposmotic stress. Mutations in MLC1 associated with a severe phenotype, including S280L, resulted in absence of MLC1 at the membrane and abrogated assembly of the Na,K-ATPase complex and TRPV4-mediated calcium influx in response to hyposmotic stress. Mutations associated with a less severe phenotype had a milder effect on Na,K-ATPase complex assembly and the response to hyposmotic stress. </p><p>By immunohistochemical analysis, Sirisi et al. (2014) observed mislocalization of GLIALCAM (HEPACAM; 611642) in Bergmann glia in the cerebellum of the patient with megalencephalic leukoencephalopathy with subcortical cysts-1 reported by Lopez-Hernandez et al. (2011). </p><p><strong><em>Exclusion Studies</em></strong></p><p>
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Meyer et al. (2001) suggested that KIAA0027/MLC1 is involved in the etiopathogenesis of schizophrenia (181500), via a putative dominantly acting rare leu309-to-met (L309M) variant cosegregating in a large pedigree with periodic catatonia. A form of periodic catatonia had been mapped to chromosome 15q15 (SCZD10; 605419). McQuillin et al. (2002) screened exon 11 of the MLC1 gene in 174 U.K. patients with schizophrenia, including 22 cases of catatonic schizophrenia, and did not identify any individual with the L309M mutation. They did, however, identify a series of polymorphisms, including an insertion of 11 amino acids at amino acids 351 to 352, which were in complete linkage disequilibrium with each other and which were present in an equal number of schizophrenic and control individuals. McQuillin et al. (2002) concluded that the identification of these polymorphisms in healthy individuals suggests that MLC1 exon 11 can withstand a number of changes without producing either the MLC phenotype or schizophrenia. Rubie et al. (2003) screened the MLC1 gene in 140 index cases with periodic catatonia and 5 patients with MLC. The rare L309M variant was found in another multiplex pedigree but did not segregate with periodic catatonia. Furthermore, a complicated 33-bp insertion/deletion polymorphism at the 5-prime end of exon 11 of MLC1 was found at equal frequency among schizophrenic patients and controls. Among the 5 patients with MLC, 4 mutant alleles were detected. Rubie et al. (2003) concluded that their findings excluded MLC1 as a susceptibility locus for schizophrenia. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Sirisi et al. (2014) found that the zebrafish genome contains 2 GLIALCAM (HEPACAM; 611642) 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>13 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 1</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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MLC1, SER280LEU
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<br />
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SNP: rs121908341,
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gnomAD: rs121908341,
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ClinVar: RCV000004978
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese family with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004), Leegwater et al. (2001) identified a homozygous C-to-T transition at nucleotide 954 in exon 10 of the MLC1 gene, resulting in a ser280-to-leu substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, SER93LEU
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<br />
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SNP: rs80358245,
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gnomAD: rs80358245,
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ClinVar: RCV000004979, RCV001380081, RCV003155016
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese family and a Turkish family, Leegwater et al. (2001) identified a homozygous C-to-T transition at nucleotide 393 in exon 4 of the MLC1 gene, resulting in a ser93-to-leu (S93L) substitution and causing megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004). In another Japanese family, the S93L mutation was found in heterozygous state in an affected individual. </p><p>Tsujino et al. (2003) assembled data indicating that of 7 Japanese patients, 6 (85.7%) carried the S93L mutation on at least 1 allele and 10 of the 14 alleles (71.4%) had this mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, 7-BP DEL, NT564
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<br />
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SNP: rs1057517090,
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gnomAD: rs1057517090,
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ClinVar: RCV000412051, RCV002523869
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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 families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), one from Turkey and the other from the Middle East, Leegwater et al. (2001) identified a 7-bp deletion in exon 6 of the MLC1 gene, resulting in a frameshift after leu149. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, IVS10AS, A-G, -2
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<br />
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SNP: rs1183818307,
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gnomAD: rs1183818307,
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ClinVar: RCV000004981
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a family of Turkish origin with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Leegwater et al. (2001) identified a homozygous donor splice site mutation causing aberrant splicing of exon 11 of the MLC1 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
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MLC1, ASN141LYS
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<br />
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SNP: rs121908343,
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gnomAD: rs121908343,
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ClinVar: RCV000004982
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family in France, Leegwater et al. (2002) found megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004) caused by homozygosity for an asn141-to-lys (N141K) missense mutation in exon 5 of the MLC1 gene. The amino acid change resulted from a C-to-A transversion at nucleotide 423. </p>
|
|
</span>
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</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
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MLC1, ASN141SER
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<br />
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|
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SNP: rs121908344,
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|
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ClinVar: RCV000004983
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family in Turkey, Leegwater et al. (2002) found that homozygosity for an asn141-to-ser (N141S) missense mutation in exon 5 of the MLC1 gene was responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004). The amino acid change resulted from an A-to-G transition at nucleotide 422. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
MLC1, PRO92SER
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<br />
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|
|
SNP: rs121908345,
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|
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gnomAD: rs121908345,
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|
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ClinVar: RCV000004984, RCV001378687, RCV001844006
|
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 3 unrelated families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), 2 from Croatia and 1 from U.K./Eastern Europe, Leegwater et al. (2002) found compound heterozygosity for mutations in the MLC1 gene, with 1 of the alleles carrying a pro92-to-ser (P92S) missense mutation. The amino acid change resulted from a C-to-T transition at nucleotide 274. In the U.K./Eastern Europe case, the second mutation was tyr198-to-ter (605908.0008), described by Leegwater et al. (2001). </p><p>In a family of mixed Jewish ancestry (the father a Libyan Jew and the mother an Ashkenazi Jew) with megalencephalic leukoencephalopathy with subcortical cysts, Ben-Zeev et al. (2002) identified the P92S substitution. The mutation was not found in 140 unaffected Ashkenazi control chromosomes. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, TYR198TER
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<br />
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SNP: rs267607236,
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gnomAD: rs267607236,
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ClinVar: RCV000004985, RCV001383177, RCV001826417
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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 tyr198-to-ter mutation in the MLC1 gene that was found in compound heterozygous state in a U.K./Eastern Europe patient with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004) by Leegwater et al. (2001, 2002), see 605908.0007. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, GLY59GLU
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<br />
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SNP: rs80358242,
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ClinVar: RCV000004986, RCV000293896, RCV001826418
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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>Ben-Zeev et al. (2002) showed that Libyan Jewish patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004) were homozygous for a G-to-A substitution at nucleotide 176 of the MLC1 gene, resulting in a gly59-to-glu (G59E) change. This sequence variation was found in full segregation with the disease in all of the Libyan Jewish and Turkish Jewish families studied, and in the carrier chromosome inherited from a Libyan Jewish father in a mixed Ashkenazi-Libyan Jewish family. This substitution was not found in 200 unaffected, non-Libyan Jewish individuals, but was found in 5 of 200 unaffected Libyan Jewish individuals, establishing a carrier rate of 1 in 40 in this ethnic group. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0010 REMOVED FROM DATABASE</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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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0011 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, 1-BP INS, 135C
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<br />
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SNP: rs80358241,
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gnomAD: rs80358241,
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ClinVar: RCV000004987, RCV000599600, RCV001274276
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient of Indian Agrawali ancestry with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Ben-Zeev et al. (2002) identified a homozygous insertion of a cytosine at nucleotide 135 at exon 2 of the MLC1 gene. This resulted in a frameshift and the creation of a stop codon 104 bp downstream. </p><p>Leegwater et al. (2002) described this mutation in 3 Agrawali patients. They stated that the disease was probably introduced into the tribe by a single founder, and the mutation is probably shared by all MLC patients of this community. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, 17-BP DEL, G INS
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<br />
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SNP: rs2062079566,
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ClinVar: RCV001248532, RCV002287898
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Tsujino et al. (2003) described compound heterozygosity for the common S93L mutation (605908.0002) and a novel mutation, 452-468del+G. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS 1</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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MLC1, SER69LEU
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<br />
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SNP: rs281875309,
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gnomAD: rs281875309,
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ClinVar: RCV000024319, RCV000059741, RCV001826507
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004), Lopez-Hernandez et al. (2011) identified a homozygous 206C-T transition in the MLC1 gene, resulting in a ser69-to-leu (S69L) substitution in a highly conserved residue in the first transmembrane domain. The mutation was not found in 400 control chromosomes. The patient developed macrocephaly within the first few months of life, and thereafter showed slow motor deterioration, epilepsy, and cognitive decline. Brain MRI at age 40 years showed diffuse signal abnormalities in the cerebral white matter, with global atrophy and subcortical cysts in the anterior temporal region. She died at age 57 years following a cranial trauma. Postmortem brain examination showed reduced cerebral white matter with cavitation in the frontal and parietal lobes. Microscopic examination showed preservation of the cerebral cortex, but lack of myelin in the deep white matter with cavitation in the most affected areas. There was a reduction in the number of astrocytes and oligodendrocytes and loss of axons. Many astrocytes lacking myelin contained alpha-beta-crystallin (CRYAB; 123590), a stress protein. Patient tissue showed no immunostaining for MLC1, indicating that deficiency of cell surface MLC1 protein expression is the basis for the disorder. The MLC1-interacting protein HEPACAM (611642) was present in astrocytic processes, but at a reduced level. In vitro expression of the S69L mutation in HeLa cells showed that the mutant protein was located in intracellular compartments, with reduced surface membrane expression compared to wildtype. The mutant protein also showed reduced stability. The mutant protein was stabilized by overexpression of HEPACAM, but it was still less stable than wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Ben-Zeev, B., Levy-Nissenbaum, E., Lahat, H., Anikster, Y., Shinar, Y., Brand, N., Gross-Tzur, V., MacGregor, D., Sidi, R., Kleta, R., Frydman, M., Pras, E.
|
|
<strong>Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.</strong>
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Hum. Genet. 111: 214-218, 2002.
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[PubMed: 12189496]
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[Full Text: https://doi.org/10.1007/s00439-002-0770-y]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Duarri, A., Teijido, O., Lopez-Hernandez, T., Scheper, G. C., Barriere, H., Boor, I., Aguado, F., Zorzano, A., Palacin, M., Martinez, A., Lukacs, G. L., van der Knaap, M. S., Nunes, V., Estevez, R.
|
|
<strong>Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects.</strong>
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Hum. Molec. Genet. 17: 3728-3739, 2008.
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[PubMed: 18757878]
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[Full Text: https://doi.org/10.1093/hmg/ddn269]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., and 11 others.
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<strong>Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.</strong>
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Nature Genet. 39: 25-27, 2007.
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[PubMed: 17173049]
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[Full Text: https://doi.org/10.1038/ng1933]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ilja Boor, P. K., de Groot, K., Mejaski-Bosnjak, V., Brenner, C., van der Knaap, M. S., Scheper, G. C., Pronk, J. C.
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<strong>Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1.</strong>
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Hum. Mutat. 27: 505-512, 2006.
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[PubMed: 16652334]
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[Full Text: https://doi.org/10.1002/humu.20332]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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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: 22328087]
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[Full Text: https://doi.org/10.1093/hmg/dds032]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Leegwater, P. A. J., Boor, P. K. I., Yuan, B. Q., van der Steen, J., Visser, A., Konst, A. A. M., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
|
|
<strong>Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts.</strong>
|
|
Hum. Genet. 110: 279-283, 2002. Note: Erratum: Hum. Genet. 111: 114 only, 2002.
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[PubMed: 11935341]
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[Full Text: https://doi.org/10.1007/s00439-002-0682-x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Leegwater, P. A. J., Yuan, B. Q., van der Steen, J., Mulders, J., Konst, A. A. M., Ilja Boor, P. K., Mejaski-Bosnjak, V., van der Maarel, S. M., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knapp, M. S.
|
|
<strong>Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts.</strong>
|
|
Am. J. Hum. Genet. 68: 831-838, 2001.
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[PubMed: 11254442]
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[Full Text: https://doi.org/10.1086/319519]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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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>
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</li>
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<li>
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<p class="mim-text-font">
|
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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.
|
|
<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: 21624973]
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[Full Text: https://doi.org/10.1093/hmg/ddr238]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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McQuillin, A., Kalsi, G., Moorey, H., Lamb, G., Mayet, S., Quested, D., Baker, P., Curtis, D., Gurling, H. M.
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<strong>A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia.</strong>
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Europ. J. Hum. Genet. 10: 491-494, 2002.
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[PubMed: 12111645]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200837]
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</p>
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<li>
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<p class="mim-text-font">
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Meyer, J., Huberth, A., Ortega, G., Syagailo, Y. V., Jatzke, S., Mossner, R., Strom, T. M., Ulzheimer-Teuber, I., Stober, G., Schmitt, A., Lesch, K. P.
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<strong>A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree.</strong>
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Molec. Psychiat. 6: 302-306, 2001.
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[PubMed: 11326298]
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[Full Text: https://doi.org/10.1038/sj.mp.4000869]
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<li>
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<p class="mim-text-font">
|
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Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayasi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S.
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|
<strong>Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly samples cDNA clones from human immature myeloid cell line KG-1.</strong>
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|
DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995.
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[PubMed: 7584026]
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[Full Text: https://doi.org/10.1093/dnares/1.1.27]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Patrono, C., Di Giacinto, G., Eymard-Pierre, E., Santorelli, F. M., Rodriguez, D., De Stefano, N., Federico, A., Gatti, R., Benigno, V., Megarbane, A., Tabarki, B., Boespflug-Tanguy, O., Bertini, E.
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<strong>Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.</strong>
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Neurology 61: 534-537, 2003.
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[Full Text: https://doi.org/10.1212/01.wnl.0000076184.21183.ca]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Rubie, C., Lichtner, P., Gartner, J., Siekiera, M., Uziel, G., Kohlmann, B., Kohlschutter, A., Meitinger, T., Stober, G., Bettecken, T.
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<strong>Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?</strong>
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|
Hum. Mutat. 21: 45-52, 2003.
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[PubMed: 12497630]
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[Full Text: https://doi.org/10.1002/humu.10145]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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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: 24824219]
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[Full Text: https://doi.org/10.1093/hmg/ddu231]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Teijido, O., Martinez, A., Pusch, M., Zorzano, A., Soriano, E., del Rio, J. A., Palacin, M., Estevez, R.
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<strong>Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts.</strong>
|
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Hum. Molec. Genet. 13: 2581-2594, 2004.
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[PubMed: 15367490]
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[Full Text: https://doi.org/10.1093/hmg/ddh291]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Tsujino, S., Kanazawa, N., Yoneyama, H., Shimono, M., Kawakami, A., Hatanaka, Y., Shimizu, T., Oba, H.
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<strong>A common mutation and a novel mutation in Japanese patients with van der Knaap disease.</strong>
|
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J. Hum. Genet. 48: 605-608, 2003.
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[PubMed: 14615938]
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[Full Text: https://doi.org/10.1007/s10038-003-0085-4]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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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 : 8/23/2010<br>George E. Tiller - updated : 6/13/2007<br>Victor A. McKusick - updated : 2/15/2007<br>Victor A. McKusick - updated : 7/12/2006<br>Victor A. McKusick - updated : 4/5/2004<br>Cassandra L. Kniffin - updated : 1/21/2004<br>Michael B. Petersen - updated : 6/16/2003<br>Victor A. McKusick - updated : 1/15/2003<br>Anne M. Stumpf - updated : 11/6/2002<br>Victor A. McKusick - updated : 10/2/2002<br>Victor A. McKusick - updated : 5/10/2002
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</span>
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</div>
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</div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/4/2001
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</div>
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<span class="text-nowrap mim-text-font">
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Edit History:
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carol : 12/18/2019<br>carol : 09/28/2016<br>mgross : 10/29/2014<br>mcolton : 10/27/2014<br>mgross : 7/8/2013<br>alopez : 4/30/2013<br>terry : 6/4/2012<br>carol : 5/31/2012<br>ckniffin : 5/30/2012<br>wwang : 4/28/2011<br>ckniffin : 4/25/2011<br>joanna : 4/21/2011<br>wwang : 9/17/2010<br>ckniffin : 8/23/2010<br>wwang : 6/14/2007<br>terry : 6/13/2007<br>alopez : 2/19/2007<br>joanna : 2/15/2007<br>alopez : 7/18/2006<br>terry : 7/12/2006<br>terry : 4/9/2004<br>alopez : 4/7/2004<br>terry : 4/5/2004<br>tkritzer : 1/27/2004<br>ckniffin : 1/21/2004<br>cwells : 7/11/2003<br>cwells : 6/16/2003<br>tkritzer : 2/10/2003<br>cwells : 1/15/2003<br>terry : 1/15/2003<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>alopez : 11/6/2002<br>tkritzer : 10/10/2002<br>tkritzer : 10/7/2002<br>terry : 10/2/2002<br>alopez : 5/14/2002<br>terry : 5/10/2002<br>mgross : 5/2/2002<br>mgross : 5/4/2001
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