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Entry
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- *600276 - NOTCH RECEPTOR 3; NOTCH3
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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">*600276</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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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/600276">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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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 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=ENSG00000074181;t=ENST00000263388" 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=4854" 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=600276" 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=ENSG00000074181;t=ENST00000263388" 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_000435,XM_005259924" 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_000435" 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=600276" 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=02607&isoform_id=02607_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/NOTCH3" 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/763116,2668592,2924763,3065951,3108187,62088474,119604872,134244285,219882321,322510053,530414885,2462565587,2783942060" 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/Q9UM47" 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=4854" 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=ENSG00000074181;t=ENST00000263388" 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=NOTCH3" 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=NOTCH3" 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+4854" 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/NOTCH3" 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:4854" 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/4854" 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=chr19&hgg_gene=ENST00000263388.7&hgg_start=15159038&hgg_end=15200995&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7883" 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/notch3" 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=600276[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600276[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/NOTCH3/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000074181" 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=NOTCH3" 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=NOTCH3" 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=NOTCH3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.LOVD.nl/NOTCH3" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NOTCH3&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/PA31685" 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:7883" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0004647.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:99460" 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/NOTCH3#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:99460" 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/4854/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=4854" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001609;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-000329-5" 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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:600276" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4854" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=NOTCH3&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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600276
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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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NOTCH RECEPTOR 3; NOTCH3
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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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NOTCH, DROSOPHILA, HOMOLOG OF, 3
|
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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=NOTCH3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NOTCH3</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/19/392?start=-3&limit=10&highlight=392">19p13.12</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:15159038-15200995&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'})">19:15,159,038-15,200,995</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615293,125310,130720" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/392?start=-3&limit=10&highlight=392">
|
|
19p13.12
|
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</a>
|
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</span>
|
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</td>
|
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|
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<td>
|
|
<span class="mim-font">
|
|
?Myofibromatosis, infantile 2
|
|
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/615293"> 615293 </a>
|
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</span>
|
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</td>
|
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<p>The NOTCH3 gene encodes a single pass transmembrane protein belonging to an evolutionarily conserved NOTCH receptor family (see, e.g., NOTCH1; <a href="/entry/190198">190198</a>). After ligand binding, the intracellular domain translocates to the nucleus and activates transcription factors. The Notch signaling pathway plays a central role in the development and maturation of most vertebrate organs, with pleiotropic effects depending on dose and context (summary by <a href="#26" class="mim-tip-reference" title="Monet-Lepretre, M., Bardot, B., Lemaire, B., Domenga, V., Godin, O., Dichgans, M., Tournier-Lasserve, E., Cohen-Tannoudji, M., Chabriat, H., Joutel, A. <strong>Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain.</strong> Brain 132: 1601-1612, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19293235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19293235</a>] [<a href="https://doi.org/10.1093/brain/awp049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19293235">Monet-Lepretre et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19293235" 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="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> mapped the NOTCH3 gene positionally as part of a search for the gene mutant in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; <a href="/entry/125310">125310</a>). The authors narrowed the critical region to a small interval bracketed by D19S253 centromerically and D19S929 telomerically. The investigators constructed YAC and BAC contigs encompassing the critical region, the size of which was estimated to be approximately 800 kb. Of the candidate transcripts identified through direct selection of cDNA, one showed strong homology with the 5-prime-coding end of the mouse Notch3 gene. They assembled a contiguous stretch of 5,615 bp of human NOTCH3 coding sequence that was highly homologous to its murine coding counterpart. The human and mouse proteins were found to be 90% identical along the available overall sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8878478" 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="Joutel, A., Andreux, F., Gaulis, S., Domenga, V., Cecilon, M., Battail, N., Piga, N., Chapon, F., Godfrain, C., Tournier-Lasserve, E. <strong>The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients.</strong> J. Clin. Invest. 105: 597-605, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712431[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/10.1172/JCI8047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712431">Joutel et al. (2000)</a> showed that NOTCH3 expression was restricted to vascular smooth muscle cells at the cytoplasmic membrane in close vicinity to but not within the granular osmiophilic material. NOTCH3 underwent proteolytic cleavage leading to a 210-kD extracellular fragment and a 97-kD intracellular fragment. In CADASIL brains, they found evidence of accumulation of the 210-kD NOTCH3 cleavage product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712431" 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 immunofluorescence analysis of embryonic day-15.5 mouse epidermis, <a href="#10" class="mim-tip-reference" title="Ezratty, E. J., Stokes, N., Chai, S., Shah, A. S., Williams, S. E., Fuchs, E. <strong>A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.</strong> Cell 145: 1129-1141, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21703454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21703454</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21703454[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.cell.2011.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21703454">Ezratty et al. (2011)</a> found that Notch3 was expressed along the length of primary cilia in differentiated suprabasal keratinocytes. Processed Notch3 intracellular domain also localized to nuclei of ciliated suprabasal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21703454" 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 alignment of available genomic sequence to a cDNA contig, <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> identified at least 29 exons in the NOTCH3 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8878478" 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="#19" class="mim-tip-reference" title="Joutel, A., Favrole, P., Labauge, P., Chabriat, H., Lescoat, C., Andreux, F., Domenga, V., Cecillon, M., Vahedi, K., Ducros, A., Cave-Riant, F., Bousser, M. G., Tournier-Lasserve, E. <strong>Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.</strong> Lancet 358: 2049-2051, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11755616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11755616</a>] [<a href="https://doi.org/10.1016/S0140-6736(01)07142-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11755616">Joutel et al. (2001)</a> stated that the NOTCH3 gene contains 33 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11755616" 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="#22" class="mim-tip-reference" title="Larsson, C., Lardelli, M., White, I., Lendahl, U. <strong>The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.</strong> Genomics 24: 253-258, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7698746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7698746</a>] [<a href="https://doi.org/10.1006/geno.1994.1613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7698746">Larsson et al. (1994)</a> used somatic cell hybrid analyses and FISH to map the NOTCH2 (<a href="/entry/600275">600275</a>) and NOTCH3 genes to 1p13-p11 and 19p13.2-p13.1, respectively, which are regions of neoplasia-associated translocation. <a href="#11" class="mim-tip-reference" title="Gao, X., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Gridley, T. <strong>Assignment of the murine Notch2 and Notch3 genes to chromosomes 3 and 17.</strong> Genomics 49: 160-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570965</a>] [<a href="https://doi.org/10.1006/geno.1997.5211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570965">Gao et al. (1998)</a> mapped the mouse Notch3 gene to chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9570965+7698746" 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="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> stated that Notch is known for its role in specifying cell fate during Drosophila development. They stated that the only human disorder implicating a Notch gene before the identification of mutations in NOTCH3 as the cause of CADASIL was an adult T-cell leukemia, which is associated with truncation of the NOTCH1 (<a href="/entry/190198">190198</a>) transcript. No developmental abnormality or neoplasia is associated with CADASIL. On the basis of an analysis of Drosophila mutants, it had been proposed by <a href="#31" class="mim-tip-reference" title="Rebay, I., Fehon, R. G., Artavanis-Tsakonas, S. <strong>Specific truncations of Drosophila Notch define dominant activated and dominant negative forms of the receptor.</strong> Cell 74: 319-329, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8343959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8343959</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90423-n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8343959">Rebay et al. (1993)</a> that Notch may be a receptor with different functional domains, the intracellular domain having the signal-transducing activity of the intact protein and the extracellular domain possessing a ligand-binding and regulatory activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8878478+8343959" 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="#38" class="mim-tip-reference" title="Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T. <strong>Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.</strong> Neuron 29: 45-55, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182080</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00179-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11182080">Tanigaki et al. (2001)</a> presented evidence that activated NOTCH1 and NOTCH3 promote the differentiation of astroglia from rat adult hippocampus-derived multipotent progenitors. Transient activation of Notch can direct commitment of adult hippocampal-derived progenitors irreversibly to astroglia. Astroglial induction by Notch signaling was shown to be independent of STAT3 (<a href="/entry/102582">102582</a>), which is a key regulatory transcriptional factor when ciliary neurotrophic factor (CNTF; <a href="/entry/118945">118945</a>) induces astroglia. <a href="#38" class="mim-tip-reference" title="Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T. <strong>Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.</strong> Neuron 29: 45-55, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182080</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00179-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11182080">Tanigaki et al. (2001)</a> concluded that their data suggests that Notch provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182080" 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="#23" class="mim-tip-reference" title="Li, X., Zhang, X., Leathers, R., Makino, A., Huang, C., Parsa, P., Macias, J., Yuan, J. X.-J., Jamieson, S. W., Thistlethwaite, P. A. <strong>Notch3 signaling promotes the development of pulmonary arterial hypertension.</strong> Nature Med. 15: 1289-1297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19855400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19855400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19855400[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/nm.2021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19855400">Li et al. (2009)</a> demonstrated that human pulmonary hypertension (PPH; see <a href="/entry/178600">178600</a>) is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells (SMCs) and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. Notch3 -/- mice did not develop pulmonary hypertension in response to hypoxic stimulation, and both pulmonary hypertension and right ventricular hypertrophy were ameliorated in mice by treatment with DAPT, a gamma-secretase (see <a href="/entry/104311">104311</a>) inhibitor that blocks activation of NOTCH3 in SMCs. The authors demonstrated a mechanistic link from NOTCH3 receptor signaling through the HES5 protein (<a href="/entry/607348">607348</a>) to SMC proliferation and a shift to an undifferentiated SMC phenotype. <a href="#23" class="mim-tip-reference" title="Li, X., Zhang, X., Leathers, R., Makino, A., Huang, C., Parsa, P., Macias, J., Yuan, J. X.-J., Jamieson, S. W., Thistlethwaite, P. A. <strong>Notch3 signaling promotes the development of pulmonary arterial hypertension.</strong> Nature Med. 15: 1289-1297, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19855400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19855400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19855400[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/nm.2021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19855400">Li et al. (2009)</a> suggested that the NOTCH3-HES5 signaling pathway is crucial for the development of pulmonary arterial hypertension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19855400" 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="#39" class="mim-tip-reference" title="Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M. <strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong> Nature 565: 505-510, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30651639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30651639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30651639[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0858-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30651639">Wimmer et al. (2019)</a> reported the development of self-organizing 3-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice formed a stable, perfused vascular tree, including arteries, arterioles, and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the vascular basement membrane. Human blood vessels exposed in vivo to a diabetic milieu in mice also mimicked the microvascular changes found in patients with diabetes. DLL4 (<a href="/entry/605185">605185</a>) and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. <a href="#39" class="mim-tip-reference" title="Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M. <strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong> Nature 565: 505-510, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30651639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30651639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30651639[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0858-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30651639">Wimmer et al. (2019)</a> concluded that organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modeling and identifying the regulators of diabetic vasculopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30651639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, Type 1</em></strong></p><p>
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CADASIL1 (<a href="/entry/125310">125310</a>)-associated mutations in the NOTCH3 gene are distributed throughout the 34 epidermal growth factor-like repeats (EGFRs) that comprise the extracellular domain of the NOTCH3 receptor and result in a loss or gain of a cysteine residue in one of these EGFRs. Most mutations are located in EGFR2-5 (<a href="#20" class="mim-tip-reference" title="Joutel, A., Monet, M., Domenga, V., Riant, F., Tournier-Lasserve, E. <strong>Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway.</strong> Am. J. Hum. Genet. 74: 338-347, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14714274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14714274</a>] [<a href="https://doi.org/10.1086/381506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14714274">Joutel et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14714274" 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>CADASIL causes a type of stroke and dementia of which key features include recurrent subcortical ischemic events and vascular dementia associated with diffuse white-matter abnormalities on neuroimaging. <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> stated that pathologic examination revealed multiple small, deep cerebral infarcts, leukoencephalopathy, and nonatherosclerotic, nonamyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth muscle cells are evident on ultrastructural analysis. <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> mapped the CADASIL critical region to an 800-kb interval on 19p and identified the human NOTCH3 gene within this region. The meiotic recombinant defining the telomeric boundary of the critical region was observed in an asymptomatic 40-year-old patient with an inconclusive result from cerebral MRI, but a skin biopsy showed typical alterations in vascular smooth muscle cells. <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> detected no gross rearrangement of genomic DNA in CADASIL patients. A panel of 58 unrelated patients were then checked for point mutations in the NOTCH3 gene. Screening of 14 of the 29 NOTCH3 exons by SSCP revealed 11 conformational variants within 7 exons, 10 of which were observed in 14 unrelated patients and none of 200 control chromosomes. Each was shown by nucleotide sequencing to be due to nucleotide substitutions resulting in an amino acid change. Cosegregation of the abnormal conformer with the affected phenotype as established in 6 pedigrees available in the set of 14 patients. The eleventh variant was seen in patients and in controls, and sequencing showed that it was due to a silent nucleotide change. The partial cDNA contig predicted a content of 33 EGF domains, 3 Notch/Lin-12 repeats, and 3 cdc10 (<a href="/entry/603151">603151</a>) ankyrin (see <a href="/entry/600465">600465</a>)-like repeats. Of the mutations within the EGF-like domains, 2 alter a cysteine residue, 6 others replace a conserved residue with a cysteine (e.g., <a href="#0001">600276.0001</a>, <a href="#0002">600276.0002</a>, and <a href="#0003">600276.0003</a>), and 1 replaces a highly conserved glycine with an alanine. No difference in the phenotypes of the CADASIL patients who carried mutations in EGF-like and cdc10 domains was noted and the phenotypes of patients carrying mutations in distinct EGF domains were identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8878478" 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 SSCP, heteroduplex, and sequence analyses, <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">Joutel et al. (1997)</a> screened the entire NOTCH3 coding sequences of 50 unrelated patients with CADASIL for mutations. Strongly stereotyped missense mutations, located within the EGF-like repeats in the extracellular domain of NOTCH3, were detected in 45 patients. Clustering of mutations within the 2 exons encoding the first 5 EGF-like repeats was observed in 32 patients. All of the mutations lead to loss or gain of a cysteine residue and, therefore, to an unpaired cysteine residue within a given EGF domain. None of the mutations was found in 100 healthy controls. The findings suggested that aberrant dimerization of NOTCH3, due to abnormal disulfide bridging with another NOTCH3 molecule or another protein, may be involved in the pathogenesis of CADASIL. <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">Joutel et al. (1997)</a> pointed out that an easy and reliable diagnostic test for this disorder is feasible because of the strong clustering and highly stereotyped nature of the pathogenetic mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9388399" 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="#13" class="mim-tip-reference" title="Gridley, T. <strong>Notch signaling and inherited disease syndromes.</strong> Hum. Molec. Genet. 12(R1): R9-R13, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668592</a>] [<a href="https://doi.org/10.1093/hmg/ddg052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668592">Gridley (2003)</a> provided a brief review of human disorders due to defects in the Notch signaling pathway: Alagille syndrome (see <a href="/entry/118450">118450</a>), spondylocostal dysostosis (see <a href="/entry/277300">277300</a>), and CADASIL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668592" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Arboleda-Velasquez, J. F., Rampal, R., Fung, E., Darland, D. C., Liu, M., Martinez, M. C., Donahue, C. P., Navarro-Gonzalez, M. F., Libby, P., D'Amore, P. A., Aikawa, M., Haltiwanger, R. S., Kosik, K. S. <strong>CADASIL mutations impair Notch3 glycosylation by Fringe.</strong> Hum. Molec. Genet. 14: 1631-1639, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857853</a>] [<a href="https://doi.org/10.1093/hmg/ddi171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857853">Arboleda-Velasquez et al. (2005)</a> showed that Notch3 mutations in the EGFR2-5 hotspot did not affect the addition of O-fucose but did impair carbohydrate chain elongation by Fringe (LFNG; <a href="/entry/602576">602576</a>). Notch3 mutations induced aberrant Notch3 homodimerization and Notch3/Fringe heterodimerization. <a href="#3" class="mim-tip-reference" title="Arboleda-Velasquez, J. F., Rampal, R., Fung, E., Darland, D. C., Liu, M., Martinez, M. C., Donahue, C. P., Navarro-Gonzalez, M. F., Libby, P., D'Amore, P. A., Aikawa, M., Haltiwanger, R. S., Kosik, K. S. <strong>CADASIL mutations impair Notch3 glycosylation by Fringe.</strong> Hum. Molec. Genet. 14: 1631-1639, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857853</a>] [<a href="https://doi.org/10.1093/hmg/ddi171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15857853">Arboleda-Velasquez et al. (2005)</a> suggested that Fringe may play a role in CADASIL pathophysiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15857853" 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="#29" class="mim-tip-reference" title="Opherk, C., Duering, M., Peters, N., Karpinska, A., Rosner, S., Schneider, E., Bader, B., Giese, A., Dichgans, M. <strong>CADASIL mutations enhance spontaneous multimerization of NOTCH3.</strong> Hum. Molec. Genet. 18: 2761-2767, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19417009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19417009</a>] [<a href="https://doi.org/10.1093/hmg/ddp211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19417009">Opherk et al. (2009)</a> showed that both wildtype and CADASIL-mutated (R133C; <a href="#0008">600276.0008</a>) NOTCH3 receptor spontaneously formed oligomers and higher order multimers in vitro and that multimerization was mediated by disulfide bonds. CADASIL-associated mutations significantly enhanced multimerization compared with wildtype. <a href="#29" class="mim-tip-reference" title="Opherk, C., Duering, M., Peters, N., Karpinska, A., Rosner, S., Schneider, E., Bader, B., Giese, A., Dichgans, M. <strong>CADASIL mutations enhance spontaneous multimerization of NOTCH3.</strong> Hum. Molec. Genet. 18: 2761-2767, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19417009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19417009</a>] [<a href="https://doi.org/10.1093/hmg/ddp211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19417009">Opherk et al. (2009)</a> argued for a neomorphic effect of CADASIL mutations in disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19417009" 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="#37" class="mim-tip-reference" title="Takahashi, K., Adachi, K., Yoshizaki, K., Kunimoto, S., Kalaria, R. N., Watanabe, A. <strong>Mutations in NOTCH3 cause the formation and retention of aggregates in the endoplasmic reticulum, leading to impaired cell proliferation.</strong> Hum. Molec. Genet. 19: 79-89, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19825845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19825845</a>] [<a href="https://doi.org/10.1093/hmg/ddp468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19825845">Takahashi et al. (2010)</a> investigated the cytotoxic properties of mutant NOTCH3 using stable HEK293 cell lines with inducible expression of wildtype or the R133C (<a href="#0008">600276.0008</a>) and C185R mutations. Both mutants were prone to aggregation and were retained in the endoplasmic reticulum (ER). The turnover rates of the mutant proteins were strikingly slow, with half-lives greater than 6 days, whereas wildtype was rapidly degraded, with a half-life of 0.7 days. Expression of mutant NOTCH3 also impaired cell proliferation compared with wildtype. Cell lines expressing mutant NOTCH3 were more sensitive to proteasome inhibition resulting in cell death. <a href="#37" class="mim-tip-reference" title="Takahashi, K., Adachi, K., Yoshizaki, K., Kunimoto, S., Kalaria, R. N., Watanabe, A. <strong>Mutations in NOTCH3 cause the formation and retention of aggregates in the endoplasmic reticulum, leading to impaired cell proliferation.</strong> Hum. Molec. Genet. 19: 79-89, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19825845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19825845</a>] [<a href="https://doi.org/10.1093/hmg/ddp468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19825845">Takahashi et al. (2010)</a> suggested that prolonged retention of mutant NOTCH3 aggregates in the ER may decrease cell growth and increase sensitivity to other stresses; alternatively, the aggregate-prone property of mutant NOTCH3 may contribute to a pathogenic mechanism underlying CADASIL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19825845" 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="#33" class="mim-tip-reference" title="Rutten, J. W., Hack, R. J., Duering, M., Gravesteijn, G., Dauwerse, J. G., Overzier, M., van den Akker, E. B., Slagboom, E., Holstege, H., Nho, K., Saykin, A., Dichgans, M., Malik, R., Oberstein, S. A. J. <strong>Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank.</strong> Neurology 95: e1835, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32732295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32732295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32732295[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/10.1212/WNL.0000000000010525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32732295">Rutten et al. (2020)</a> investigated exome and genome sequencing datasets of the UK Biobank (50,000 individuals) and cohorts of cognitively healthy elderly (751 individuals) to identify cysteine-altering mutations in the NOTCH3 gene in the general population. They identified 108 individuals (2.2 in 1000; average age, 64.9 years), of whom 75% had a NOTCH3 mutation that had previously been reported in patients with CADASIL. In 103 individuals, the cysteine-altering mutations were located in the EGFF domains 7 through 34. Three individuals had cysteine-altering mutations in EGFR domains 1 through 6 and were not studied further. Neuroimaging data in the 103 individuals showed that they had more white matter hyperintensity lesions compared to controls, but fewer white matter hyperintensity lesions compared to patients with CADASIL. About one-half of the unaffected individuals had no neuroimaging abnormalities up to 70 years of age, and no increase in stroke was found. <a href="#33" class="mim-tip-reference" title="Rutten, J. W., Hack, R. J., Duering, M., Gravesteijn, G., Dauwerse, J. G., Overzier, M., van den Akker, E. B., Slagboom, E., Holstege, H., Nho, K., Saykin, A., Dichgans, M., Malik, R., Oberstein, S. A. J. <strong>Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank.</strong> Neurology 95: e1835, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32732295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32732295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32732295[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/10.1212/WNL.0000000000010525" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32732295">Rutten et al. (2020)</a> concluded that CADASIL constitutes the severe and rare end of NOTCH3-associated small vessel disease, and that most individuals with cysteine-altering NOTCH3 mutations have milder and later-onset disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32732295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gravesteijn, G., Dauwerse, J. G., Overzier, M., Brouwer, G., Hegeman, I., Mulder, A. A., Baas, F., Kruit, M. C., Terwindt, G. M., van Duinen, S. G., Jost, C. R., Aartsma-Rus, A., Lesnik Oberstein S. A. J., Rutten, J. W. <strong>Naturally occurring NOTCH3 protein aggregation and disease severity in CADASIL patients.</strong> Hum. Molec. Genet. 29: 1853-1863, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31960911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31960911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31960911[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/ddz285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31960911">Gravesteijn et al. (2020)</a> identified a heterozygous missense mutation (G498C; <a href="#0019">600276.0019</a>) in the NOTCH3 gene in 5 individuals from one family with mild CADASIL. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping, which excluded part of the EGFR11 and EGFR12 regions. The mutant protein was expressed at normal levels on the cell surface; however, ligand-dependent signaling was impaired compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31960911" 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>Infantile Myofibromatosis 2</em></strong></p><p>
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In affected members of a family (IM-9) with autosomal dominant infantile myofibromatosis-2 (IMF2; <a href="/entry/615293">615293</a>), <a href="#25" class="mim-tip-reference" title="Martignetti, J. A., Tian, L., Li, D., Ramirez, M. C. M., Camacho-Vanegas, O., Camacho, S. C., Guo, Y., Zand, D. J., Bernstein, A. M., Masur, S. K., Kim, C. E., Otieno, F. G., and 16 others. <strong>Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.</strong> Am. J. Hum. Genet. 92: 1001-1007, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23731542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23731542</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23731542[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.2013.04.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23731542">Martignetti et al. (2013)</a> identified a heterozygous mutation in the NOTCH3 gene (L1519P; <a href="#0012">600276.0012</a>). The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. No functional studies were performed, but the authors predicted that the mutation would result in hyperactivation of NOTCH3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23731542" 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>Lateral Meningocele Syndrome</em></strong></p><p>
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In 6 unrelated patients with lateral meningocele syndrome (LMNS; <a href="/entry/130720">130720</a>), <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> identified 5 different de novo heterozygous truncating mutations in exon 33 of the NOTCH3 gene (<a href="#0013">600276.0013</a>-<a href="#0017">600276.0017</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of the cells of 1 patient showed decreased expression of the NOTCH3 protein as well as expression of the truncated transcript. The truncated NOTCH3 proteins predicted to result from these mutations would lack a functional PEST domain, which could prolong the half-life and thus increase signaling effects. <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> postulated that the de novo mutations in exon 33 would result in a dominant gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25394726" 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="#20" class="mim-tip-reference" title="Joutel, A., Monet, M., Domenga, V., Riant, F., Tournier-Lasserve, E. <strong>Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway.</strong> Am. J. Hum. Genet. 74: 338-347, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14714274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14714274</a>] [<a href="https://doi.org/10.1086/381506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14714274">Joutel et al. (2004)</a> investigated the effect of CADASIL mutations on NOTCH3 activity. They studied 5 naturally occurring mutations: R90C and C212S, located in the previously identified mutation hotspot EGFR2-5; C428S (<a href="#0011">600276.0011</a>), shown by them to be located in the ligand-binding domain EGFR10-11; and C542Y and R1006C, located in EGFR13 and EGFR26, respectively. They found that all 5 mutant proteins were correctly processed. The C428S and C542Y mutant receptors exhibited a significant reduction in Jagged1 (<a href="/entry/601920">601920</a>)-induced transcriptional activity of an RBPJK (<a href="/entry/147183">147183</a>)-responsive luciferase reporter, relative to wildtype Notch3. Impaired signaling activity of these 2 mutants arose through different mechanisms; the C428S mutant lost its ability to bind Jagged1, whereas C542Y retained it but exhibited an impaired presentation to the cell surface. Thus, these mutations resulted in loss of function. In contrast, the R90C, C212S, and R1006C mutants retained the ability to bind Jagged1 and were associated with apparently normal levels of signaling activity. <a href="#20" class="mim-tip-reference" title="Joutel, A., Monet, M., Domenga, V., Riant, F., Tournier-Lasserve, E. <strong>Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway.</strong> Am. J. Hum. Genet. 74: 338-347, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14714274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14714274</a>] [<a href="https://doi.org/10.1086/381506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14714274">Joutel et al. (2004)</a> concluded that mutations in Notch3 differently affect Jagged1 binding and Notch3 signaling via the RBP/JK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14714274" 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 follow-up to the study of <a href="#20" class="mim-tip-reference" title="Joutel, A., Monet, M., Domenga, V., Riant, F., Tournier-Lasserve, E. <strong>Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway.</strong> Am. J. Hum. Genet. 74: 338-347, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14714274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14714274</a>] [<a href="https://doi.org/10.1086/381506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14714274">Joutel et al. (2004)</a>, <a href="#26" class="mim-tip-reference" title="Monet-Lepretre, M., Bardot, B., Lemaire, B., Domenga, V., Godin, O., Dichgans, M., Tournier-Lasserve, E., Cohen-Tannoudji, M., Chabriat, H., Joutel, A. <strong>Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain.</strong> Brain 132: 1601-1612, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19293235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19293235</a>] [<a href="https://doi.org/10.1093/brain/awp049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19293235">Monet-Lepretre et al. (2009)</a> found that the C428S mutation exerted a dominant-negative effect in transgenic mice, and antagonized the function of wildtype Notch3 when coexpressed. In 350 distinct CADASIL families with 99 different NOTCH3 mutations, they found 11 (11%) different mutations in the EGFR10 or EGFR11 regions in 14 (4%) of 350 families, including 8 mutations with loss of a cysteine residue and 3 mutations with gain of a cysteine residue. A further review of 10 patients with mutations in the ligand-binding domain, including 6 with the C428S mutation, suggested that they had a less severe phenotype, including better preservation of cognitive function. These patients tended to have a lower volume of lacunar infarcts, but they also had a larger volume of white matter hyperintensities compared to CADASIL patients with mutations in the EGFR2-5 region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14714274+19293235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>From a clinical and genetic study in 2 unrelated families, <a href="#32" class="mim-tip-reference" title="Rutten, J. W., Boon, E. M. J., Liem, M. K., Dauwerse, J. G., Pont, M. J., Vollebregt, E., Maat-Kievit, A. J., Ginjaar, H. B., Lakeman, P., van Duinen, S. G., Terwindt, G. M., Lesnik Oberstein, S. A. J. <strong>Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.</strong> Hum. Mutat. 34: 1486-1489, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24000151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24000151</a>] [<a href="https://doi.org/10.1002/humu.22432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24000151">Rutten et al. (2013)</a> provided evidence that loss-of-function NOTCH3 mutations do not cause CADASIL. In the first family, a 55-year-old man with polyneuropathy, migraine with aura, and ischemic strokes between ages 50 and 52 was found to carry a heterozygous truncating variant in the NOTCH3 gene (R103X). Brain MRI showed old large vessel infarctions, but no white matter changes consistent with CADASIL. Skin biopsy was negative for NOTCH3 staining, but there was normal structure of the vessel wall and no electron microscopic deposits characteristic of the disorder. The patient's 50-year-old brother also carried the NOTCH3 variant, but was asymptomatic with a normal brain MRI; family history was negative for stroke and dementia. In a second family, a patient with classic MRI findings of CADASIL was compound heterozygous for a tyr710-to-cys (Y710C) mutation in the NOTCH3 gene and an intragenic frameshift deletion. The Y710C mutation was inherited from his possibly affected mother who had transient functional deficit of the arm at age 40 years without available brain imaging, and the deletion was inherited from his unaffected father whose skin biopsy was negative for CADASIL. Most CADASIL-associated NOTCH3 mutations alter conserved cysteine residues and are postulated to cause a toxic neomorphic effect. <a href="#32" class="mim-tip-reference" title="Rutten, J. W., Boon, E. M. J., Liem, M. K., Dauwerse, J. G., Pont, M. J., Vollebregt, E., Maat-Kievit, A. J., Ginjaar, H. B., Lakeman, P., van Duinen, S. G., Terwindt, G. M., Lesnik Oberstein, S. A. J. <strong>Hypomorphic NOTCH3 alleles do not cause CADASIL in humans.</strong> Hum. Mutat. 34: 1486-1489, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24000151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24000151</a>] [<a href="https://doi.org/10.1002/humu.22432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24000151">Rutten et al. (2013)</a> concluded that hypomorphic NOTCH3 mutations do not cause CADASIL, which has important implications for diagnostic interpretation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24000151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gravesteijn, G., Dauwerse, J. G., Overzier, M., Brouwer, G., Hegeman, I., Mulder, A. A., Baas, F., Kruit, M. C., Terwindt, G. M., van Duinen, S. G., Jost, C. R., Aartsma-Rus, A., Lesnik Oberstein S. A. J., Rutten, J. W. <strong>Naturally occurring NOTCH3 protein aggregation and disease severity in CADASIL patients.</strong> Hum. Molec. Genet. 29: 1853-1863, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31960911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31960911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31960911[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/ddz285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31960911">Gravesteijn et al. (2020)</a> identified a heterozygous G498C (<a href="#0019">600276.0019</a>) mutation in the NOTCH3 gene in 5 individuals from one family with mild CADASIL. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping, which leaves the open reading frame intact but excludes part of the EGFR11 and EGFR12 regions and therefore the putative NOTCH3 ligand-binding domain. The mutant protein was expressed at normal levels on the cell surface; however, ligand-dependent signaling was impaired compared to wildtype. The phenotypes of the family members included only minimal levels of NOTCH3 protein aggregation in skin vasculature, suggesting that the mutant NOTCH3 does not aggregate. The 63-year-old index patient had confluent white matter hyperintensities on brain MRI with no lacunae as well as a history of headaches, vertigo, and tinnitus. She had a normal neuropsychologic examination. All 3 of her affected sibs, aged 63 to 71 years, had confluent white matter hyperintensities on brain MRI. None of the sibs had lacunar strokes or vascular cognitive decline, and all lived independently. An affected nephew of the index patient had a few focal white matter hyperintensities on brain MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31960911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Domenga, V., Fardoux, P., Lacombe, P., Monet, M., Maciazek, J., Krebs, L. T., Klonjkowski, B., Berrou, E., Mericskay, M., Li, Z., Tournier-Lasserve, E., Gridley, T., Joutel, A. <strong>Notch3 is required for arterial identity and maturation of vascular smooth muscle cells.</strong> Genes Dev. 18: 2730-2735, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15545631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15545631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15545631[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/10.1101/gad.308904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15545631">Domenga et al. (2004)</a> found that the postnatal maturation stage of vascular smooth muscle cells (VSMCs) was deficient in Notch3 -/- mice. In adult Notch3 -/- mice, distal arteries were enlarged and exhibited a less festooned elastica lamina. In response to angiotensin II or phenylephrine, Notch3 -/- mice showed normal arterial blood pressure elevations, but cerebral blood flow reactivity and cerebrovascular resistance were impaired. The slight increase in cerebral blood flow elicited by acute induced hypertension in control mice was exacerbated in Notch3 -/- mice. In addition, <a href="#8" class="mim-tip-reference" title="Domenga, V., Fardoux, P., Lacombe, P., Monet, M., Maciazek, J., Krebs, L. T., Klonjkowski, B., Berrou, E., Mericskay, M., Li, Z., Tournier-Lasserve, E., Gridley, T., Joutel, A. <strong>Notch3 is required for arterial identity and maturation of vascular smooth muscle cells.</strong> Genes Dev. 18: 2730-2735, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15545631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15545631</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15545631[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/10.1101/gad.308904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15545631">Domenga et al. (2004)</a> showed that Notch3 was required for arterial specification of VSMCs but not endothelial cells. They concluded that NOTCH3 is required for arterial differentiation and maturation of VSMCs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15545631" 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="Arboleda-Velasquez, J. F., Zhou, Z., Shin, H. K., Louvi, A., Kim, H.-H., Savitz, S. I., Liao, J. K., Salomone, S., Ayata, C., Moskowitz, M. A., Artavanis-Tsakonas, S. <strong>Linking Notch signaling to ischemic stroke.</strong> Proc. Nat. Acad. Sci. 105: 4856-4861, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18347334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18347334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18347334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709867105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18347334">Arboleda-Velasquez et al. (2008)</a> found that smooth muscle cells were virtually the only cell in the adult mouse brain to express Notch3 and that Notch3 knockout increased susceptibility of mice to ischemic challenge. Notch3-null mice showed larger ischemic lesions, more neurologic deficits, increased mortality, more severe cerebral blood flow deficits, and more frequent spontaneous periinfarct depolarizations compared with wildtype mice. Microarray analysis revealed over 600 differentially regulated genes, and all genes that regulate muscle contraction were downregulated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18347334" 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="Eikermann-Haerter, K., Yuzawa, I., Dilekoz, E., Joutel, A., Moskowitz, M. A., Ayata, C. <strong>Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression.</strong> Ann. Neurol. 69: 413-418, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21387384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21387384</a>] [<a href="https://doi.org/10.1002/ana.22281" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21387384">Eikermann-Haerter et al. (2011)</a> found that transgenic mice carrying a CADASIL-associated R90C mutation in the Notch3 gene had a 10-fold lower threshold for cortical spreading depression (CSD) as well as a higher propagation speed of CSD compared to wildtype mice. Female mice tended to have a lower threshold than male mice. These changes were even more apparent in Notch3-null mice. Although these findings implicated the neurovascular unit in the development of migraine with aura, chronic forebrain hypoperfusion induced by carotid artery stenosis in wildtype mice did not enhance potassium-induced CSD susceptibility, arguing against a primary vascular mechanism for the phenomenon in CADASIL. The report was consistent with the increased frequency of migraine with aura in patients with this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21387384" 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>.0001 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
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<p>In patient P56 with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> observed a TGG-to-TGT transversion in exon N2 of the NOTCH3 gene, resulting in substitution of trp by cys (W71C). <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">Joutel et al. (1997)</a> stated that the mutation was of nucleotide 291 in codon 71. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8878478+9388399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 unrelated CADASIL1 (<a href="/entry/125310">125310</a>) patients, <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> observed a CGC-to-TGC transition in exon N3 of the NOTCH3 gene, resulting in substitution of cys for arg (R169C). <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">Joutel et al. (1997)</a> indicated that these 2 mutations were arg169cys and arg182cys (see <a href="#0003">600276.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8878478+9388399" 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> rs28933697 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933697;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/rs28933697?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=rs28933697" 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=rs28933697" 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=RCV000009801 OR RCV000517955 OR RCV004737144" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009801, RCV000517955, RCV004737144" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009801...</a>
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<p>In 2 unrelated CADASIL1 (<a href="/entry/125310">125310</a>) patients, Joutel et al. (<a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">1996</a>, <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">1997</a>) observed a CGC-to-TGC transition in a different codon in exon N3 of the NOTCH3 gene that resulted in substitution of cys for arg (R182C) in the same EGF-like domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8878478+9388399" 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="#18" class="mim-tip-reference" title="Joutel, A., Dodick, D. D., Parisi, J. E., Cecillon, M., Tournier-Lasserve, E., Bousser, M. G. <strong>De novo mutation in the Notch3 gene causing CADASIL.</strong> Ann. Neurol. 47: 388-391, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716263</a>]" pmid="10716263">Joutel et al. (2000)</a> reported a patient who was thought to have CADASIL, although no first-degree relative was affected. The patient was found to carry a heterozygous arg182-to-cys mutation in the NOTCH3 gene; the mutation was absent in his parents, indicating a de novo mutation. They suggested that because of the occurrence of such cases, CADASIL may be more frequent than recognized. The frequency of the condition as a familial disorder is reflected in the fact that <a href="#18" class="mim-tip-reference" title="Joutel, A., Dodick, D. D., Parisi, J. E., Cecillon, M., Tournier-Lasserve, E., Bousser, M. G. <strong>De novo mutation in the Notch3 gene causing CADASIL.</strong> Ann. Neurol. 47: 388-391, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10716263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10716263</a>]" pmid="10716263">Joutel et al. (2000)</a> found that more than 400 families had been identified since 1993. The patient with the arg182-to-cys mutation was a 55-year-old businessman who had experienced recurrent transient focal neurologic episodes, some suggestive of transient ischemic attacks and others of migrainous auras, dating back to the age of 32 years. At 48 years of age, he had a minor ischemic stroke with left facial asymmetry and weakness. Brain MRI showed extensive white matter abnormalities. Multiple sclerosis was suspected. At 53 years, he experienced a pure motor right-sided hemiplegia, which progressed over 5 days. Recovery was only partial, and the patient remained disabled with difficulties in walking and in moving his right hand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10716263" 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">rs864621964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864621964;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=rs864621964" 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=rs864621964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In patient F18 with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#17" class="mim-tip-reference" title="Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E. <strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong> Nature 383: 707-710, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878478</a>] [<a href="https://doi.org/10.1038/383707a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878478">Joutel et al. (1996)</a> identified a GCT-to-ACT transition in exon N25 predicted to cause an ala-to-thr substitution in a cdc10 functional domain of the NOTCH3 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8878478" 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>(This mutation did not appear in the tabulation of mutations found in 45 unrelated patients by <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">Joutel et al. (1997)</a>; all of the tabulated mutations either added or removed a cysteine from the protein product.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9388399" 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">rs864621965 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864621965;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=rs864621965" 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=rs864621965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#7" class="mim-tip-reference" title="Dichgans, M., Herzog, J., Gasser, T. <strong>NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.</strong> Neurology 57: 1714-1717, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11706120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11706120</a>] [<a href="https://doi.org/10.1212/wnl.57.9.1714" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11706120">Dichgans et al. (2001)</a> identified a 45-bp deletion in the NOTCH3 gene, resulting in the deletion of 3 cysteine residues within EGF repeat 6. The clinical manifestations were comparable to those in other CADASIL patients with different NOTCH3 mutations, confirming the hypothesis that an unpaired, reactive cysteine residue is the common and critical molecular event in the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11706120" 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">rs28933698 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933698;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=rs28933698" 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=rs28933698" 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=RCV000009804 OR RCV000517813" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009804, RCV000517813" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009804...</a>
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<p><a href="#2" class="mim-tip-reference" title="Arboleda-Velasquez, J. F., Lopera, F., Lopez, E., Frosch, M. P., Sepulveda-Falla, D., Gutierrez, J. E., Vargas, S., Medina, M., Martinez de Arrieta, C., Lebo, R. V., Slaugenhaupt, S. A., Betensky, R. A., Villegas, A., Arcos-Burgos, M., Rivera, D., Restrepo, J. C., Kosik, K. S. <strong>C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke.</strong> Neurology 59: 277-279, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136071</a>] [<a href="https://doi.org/10.1212/wnl.59.2.277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12136071">Arboleda-Velasquez et al. (2002)</a> reported a Colombian kindred with CADASIL1 (<a href="/entry/125310">125310</a>) characterized by early-onset stroke (median age, 31 years), migraine with aura, and confluent MRI hyperintensities. They identified a heterozygous 1441T-C transition in exon 8 of the NOTCH3 gene, resulting in a cys455-to-arg (C455R) substitution. The mutation abolishes the fourth cysteine residue at EGF-like repeat 11 (EGFR11) and may affect the interaction of the NOTCH3 receptor with its ligands. Despite the early onset of stroke, all patients had relatively well-preserved cognitive and functional status more than 2 decades after onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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">rs137852641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852641;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=rs137852641" 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=rs137852641" 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=RCV000009805 OR RCV000516507 OR RCV002271367" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009805, RCV000516507, RCV002271367" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009805...</a>
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<p>In 2 sibs of an Italian family with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#28" class="mim-tip-reference" title="Oliveri, R. L., Muglia, M., de Stefano, N., Mazzei, R., Labate, A., Conforti, F. L., Patitucci, A., Gabriele, A. L., Tagarelli, G., Magariello, A., Zappia, M., Gambardella, A., Federico, A., Quattrone, A. <strong>A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.</strong> Arch. Neurol. 58: 1418-1422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11559313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11559313</a>] [<a href="https://doi.org/10.1001/archneur.58.9.1418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11559313">Oliveri et al. (2001)</a> identified a C-to-T missense mutation in exon 6 of the NOTCH3 gene, resulting in an arg332-to-cys (R332C) substitution. The mutation was not found in 7 unaffected family members or in 200 control chromosomes. The authors noted that gain of a cysteine residue is common in NOTCH3 mutations causing CADASIL, and that it likely induces inappropriate disulfide bonding of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11559313" 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 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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> rs137852642 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852642;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/rs137852642?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=rs137852642" 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=rs137852642" 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=RCV000009806 OR RCV000415016 OR RCV000516340 OR RCV003996082 OR RCV004532318" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009806, RCV000415016, RCV000516340, RCV003996082, RCV004532318" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009806...</a>
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<p>In 3 unrelated patients with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#21" class="mim-tip-reference" title="Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E. <strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong> Lancet 350: 1511-1515, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9388399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9388399</a>] [<a href="https://doi.org/10.1016/S0140-6736(97)08083-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9388399">Joutel et al. (1997)</a> identified a 475C-T transition in exon N4 of the NOTCH3 gene, resulting in an arg133-to-cys (R133C) substitution in the EGF3 domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9388399" 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="#27" class="mim-tip-reference" title="Mykkanen, K., Savontaus, M.-L., Juvonen, V., Sistonen, P., Tuisku, S., Tuominen, S., Penttinen, M., Lundkvist, J., Viitanen, M., Kalimo, H., Poyhonen, M. <strong>Detection of the founder effect in Finnish CADASIL families.</strong> Europ. J. Hum. Genet. 12: 813-819, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15378071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15378071</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15378071">Mykkanen et al. (2004)</a> performed haplotype analysis in 60 patients from 18 Finnish CADASIL families with the R133C mutation. Using 10 microsatellite markers, the authors found a similar haplotype linked to the mutation in all 18 pedigrees, indicating a single common ancestor for all of the Finnish R133C families. Age analysis of the founder mutation placed the introduction of the mutation in the late 1600s or early 1700s. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15378071" 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="#29" class="mim-tip-reference" title="Opherk, C., Duering, M., Peters, N., Karpinska, A., Rosner, S., Schneider, E., Bader, B., Giese, A., Dichgans, M. <strong>CADASIL mutations enhance spontaneous multimerization of NOTCH3.</strong> Hum. Molec. Genet. 18: 2761-2767, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19417009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19417009</a>] [<a href="https://doi.org/10.1093/hmg/ddp211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19417009">Opherk et al. (2009)</a> showed that both wildtype and CADASIL-mutated (R133C) NOTCH3 receptor spontaneously formed oligomers and higher order multimers in vitro and that multimerization was mediated by disulfide bonds. CADASIL-associated mutations significantly enhanced multimerization compared with wildtype. <a href="#29" class="mim-tip-reference" title="Opherk, C., Duering, M., Peters, N., Karpinska, A., Rosner, S., Schneider, E., Bader, B., Giese, A., Dichgans, M. <strong>CADASIL mutations enhance spontaneous multimerization of NOTCH3.</strong> Hum. Molec. Genet. 18: 2761-2767, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19417009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19417009</a>] [<a href="https://doi.org/10.1093/hmg/ddp211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19417009">Opherk et al. (2009)</a> argued for a neomorphic effect of CADASIL mutations in <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19417009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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">rs864621966 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864621966;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=rs864621966" 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=rs864621966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 6 affected members of a Japanese family with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#34" class="mim-tip-reference" title="Saiki, S., Sakai, K., Saiki, M., Kitagawa, Y., Umemori, T., Murata, K., Matsui, M., Hirose, G. <strong>Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene.</strong> Neurology 67: 337-339, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864835</a>] [<a href="https://doi.org/10.1212/01.wnl.0000224758.52970.19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864835">Saiki et al. (2006)</a> identified a heterozygous 1279G-T transversion in intron 15 of the NOTCH3 gene, resulting in the skipping of exon 16, which includes 8 cysteine residues that would affect EGF repeat domains 20, 21, and 22. In addition to the classic features of CADASIL with ischemic episodes, all affected individuals also had varicose veins that developed between age 14 and 30. Biopsies of varicose veins from 3 individuals showed marked intimal hypertrophy, localized thinning of smooth muscle layers, and infiltrated fibrous tissue. Venous smooth muscle cells were irregularly shaped and contained granular osmiophilic material. No affected individuals had involvement of the anterior temporal lobes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16864835" 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>.0010 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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> rs35769976 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35769976;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/rs35769976?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=rs35769976" 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=rs35769976" 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=RCV000009808 OR RCV000243215 OR RCV001519393 OR RCV002504773" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009808, RCV000243215, RCV001519393, RCV002504773" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009808...</a>
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<p>In affected members of 2 unrelated German families with a relatively mild form of CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#35" class="mim-tip-reference" title="Scheid, R., Heinritz, W., Leyhe, T., Thal, D. R., Schober, R., Strenge, S., von Cramon, D. Y., Froster, U. G. <strong>Cysteine-sparing NOTCH3 mutations: CADASIL or CADASIL variants?</strong> Neurology 71: 774-776, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18765654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18765654</a>] [<a href="https://doi.org/10.1212/01.wnl.0000324928.44694.f7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18765654">Scheid et al. (2008)</a> identified a heterozygous 3058G-C transversion in the NOTCH3 gene, resulting in an ala1020-to-pro (A1020P) substitution in a highly conserved region within the EGF-like repeat domain 26. The phenotype included later onset milder neurologic signs and later onset of white matter lesions than most cases of CADASIL. Sensorineural hearing loss and arterial hypertension were also prominent features. The mutation was not found in 100 control chromosomes. The authors noted that most CADASIL-associated NOTCH3 mutations affect cysteine residues but that the proline in these patients may also have cysteine-like effects on protein folding, dimerization, or interactions since a proline contains an additional amino group that can alter secondary or tertiary structures. <a href="#35" class="mim-tip-reference" title="Scheid, R., Heinritz, W., Leyhe, T., Thal, D. R., Schober, R., Strenge, S., von Cramon, D. Y., Froster, U. G. <strong>Cysteine-sparing NOTCH3 mutations: CADASIL or CADASIL variants?</strong> Neurology 71: 774-776, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18765654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18765654</a>] [<a href="https://doi.org/10.1212/01.wnl.0000324928.44694.f7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18765654">Scheid et al. (2008)</a> concluded that cysteine-sparing NOTCH3 mutations may result in a more benign CADASIL phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18765654" 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="#30" class="mim-tip-reference" title="Quattrone, A., Mazzei, R. <strong>Cysteine-sparing NOTCH3 mutations: CADASIL or CADASIL variants? (Letter)</strong> Neurology 72: 2135-2136, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19528524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19528524</a>] [<a href="https://doi.org/10.1212/01.wnl.0000349699.12456.06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19528524">Quattrone and Mazzei (2009)</a> noted that the A1020P variant described by <a href="#35" class="mim-tip-reference" title="Scheid, R., Heinritz, W., Leyhe, T., Thal, D. R., Schober, R., Strenge, S., von Cramon, D. Y., Froster, U. G. <strong>Cysteine-sparing NOTCH3 mutations: CADASIL or CADASIL variants?</strong> Neurology 71: 774-776, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18765654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18765654</a>] [<a href="https://doi.org/10.1212/01.wnl.0000324928.44694.f7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18765654">Scheid et al. (2008)</a> is also known as <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35769976;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs35769976</a>. <a href="#30" class="mim-tip-reference" title="Quattrone, A., Mazzei, R. <strong>Cysteine-sparing NOTCH3 mutations: CADASIL or CADASIL variants? (Letter)</strong> Neurology 72: 2135-2136, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19528524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19528524</a>] [<a href="https://doi.org/10.1212/01.wnl.0000349699.12456.06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19528524">Quattrone and Mazzei (2009)</a> identified this variant in 3 of 50 European control individuals, casting doubt on the pathogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19528524+18765654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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">rs267606915 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606915;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=rs267606915" 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=rs267606915" 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 patient with CADASIL1 (<a href="/entry/125310">125310</a>), <a href="#19" class="mim-tip-reference" title="Joutel, A., Favrole, P., Labauge, P., Chabriat, H., Lescoat, C., Andreux, F., Domenga, V., Cecillon, M., Vahedi, K., Ducros, A., Cave-Riant, F., Bousser, M. G., Tournier-Lasserve, E. <strong>Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.</strong> Lancet 358: 2049-2051, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11755616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11755616</a>] [<a href="https://doi.org/10.1016/S0140-6736(01)07142-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11755616">Joutel et al. (2001)</a> identified a heterozygous 1282T-A transversion in exon 8 of the NOTCH3 gene, resulting in a cys428-to-ser (C428S) substitution in EGFR10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11755616" 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 in vitro studies, <a href="#20" class="mim-tip-reference" title="Joutel, A., Monet, M., Domenga, V., Riant, F., Tournier-Lasserve, E. <strong>Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway.</strong> Am. J. Hum. Genet. 74: 338-347, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14714274/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14714274</a>] [<a href="https://doi.org/10.1086/381506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14714274">Joutel et al. (2004)</a> found that the C428S mutant was correctly processed, but resulted in impaired downstream transcriptional activity of an RBPJK (<a href="/entry/147183">147183</a>)-responsive luciferase reporter by losing its ability to bind Jagged1 (<a href="/entry/601920">601920</a>). These findings were consistent with a loss of function. <a href="#26" class="mim-tip-reference" title="Monet-Lepretre, M., Bardot, B., Lemaire, B., Domenga, V., Godin, O., Dichgans, M., Tournier-Lasserve, E., Cohen-Tannoudji, M., Chabriat, H., Joutel, A. <strong>Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain.</strong> Brain 132: 1601-1612, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19293235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19293235</a>] [<a href="https://doi.org/10.1093/brain/awp049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19293235">Monet-Lepretre et al. (2009)</a> found that, although transgenic mice with the C428S mutation did not develop overt brain parenchymal lesions, they did develop the characteristic progressive aggregation of mutant Notch3 extracellular domain in vascular smooth muscle cells. Further animal and cellular studies showed that the mutant C428S protein was nonfunctional in vivo, but exerted a dominant-negative effect when expressed with wildtype Notch3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14714274+19293235" 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">rs367543285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs367543285;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=rs367543285" 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=rs367543285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a family with infantile myofibromatosis-2 (IMF2; <a href="/entry/615293">615293</a>), <a href="#25" class="mim-tip-reference" title="Martignetti, J. A., Tian, L., Li, D., Ramirez, M. C. M., Camacho-Vanegas, O., Camacho, S. C., Guo, Y., Zand, D. J., Bernstein, A. M., Masur, S. K., Kim, C. E., Otieno, F. G., and 16 others. <strong>Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.</strong> Am. J. Hum. Genet. 92: 1001-1007, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23731542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23731542</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23731542[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.2013.04.024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23731542">Martignetti et al. (2013)</a> identified a heterozygous c.4556T-C transition in exon 25 of the NOTCH3 gene, resulting in a leu1519-to-pro (L1519P) substitution at a highly conserved residue in the heterodimerization domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. No functional studies were performed, but the authors predicted that the mutation would result in hyperactivation of NOTCH3. Affected individuals had no evidence of CADASIL (<a href="/entry/125310">125310</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23731542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 27-year-old man, originally reported as patient 2 by <a href="#15" class="mim-tip-reference" title="Gripp, K. W., Scott, C. I., Jr., Hughes, H. E., Wallerstein, R., Nicholson, L., States, L., Bason, L. D., Kaplan, P., Zderic, S. A., Duhaime, A. C., Miller, F., Magnusson, M. R., Zackai, E. H. <strong>Lateral meningocele syndrome: three new patients and review of the literature.</strong> Am. J. Med. Genet. 70: 229-239, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9188658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9188658</a>]" pmid="9188658">Gripp et al. (1997)</a>, with lateral meningocele syndrome (LMNS; <a href="/entry/130720">130720</a>), <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> identified a de novo heterozygous 26-bp deletion (c.6461_6486del, NM_000435) in exon 33 of the NOTCH3 gene, resulting in a frameshift and premature termination (Gly2154fsTer78). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> postulated a dominant gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9188658+25394726" 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>.0014 LATERAL MENINGOCELE SYNDROME</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">rs773656789 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs773656789;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=rs773656789" 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=rs773656789" 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=RCV000210463 OR RCV001268088" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210463, RCV001268088" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210463...</a>
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<p>In 2 unrelated male patients with lateral meningocele syndrome (LMNS; <a href="/entry/130720">130720</a>), <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> identified a de novo heterozygous 1-bp insertion (c.6692_6693insC, NM_000435), in exon 33 of the NOTCH3 gene, resulting in a frameshift and premature termination (Pro2231fsTer11). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> postulated a dominant gain-of-function effect. One of the patients was originally reported as patient 1 by <a href="#15" class="mim-tip-reference" title="Gripp, K. W., Scott, C. I., Jr., Hughes, H. E., Wallerstein, R., Nicholson, L., States, L., Bason, L. D., Kaplan, P., Zderic, S. A., Duhaime, A. C., Miller, F., Magnusson, M. R., Zackai, E. H. <strong>Lateral meningocele syndrome: three new patients and review of the literature.</strong> Am. J. Med. Genet. 70: 229-239, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9188658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9188658</a>]" pmid="9188658">Gripp et al. (1997)</a> and was deceased; DNA was extracted from a formalin-fixed paraffin tissue sample. The other patient was originally reported by <a href="#5" class="mim-tip-reference" title="Avela, K., Valanne, L., Helenius, I., Makitie, O. <strong>Hajdu-Cheney syndrome with severe dural ectasia.</strong> Am. J. Med. Genet. 155A: 595-598, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21337686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21337686</a>] [<a href="https://doi.org/10.1002/ajmg.a.33510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21337686">Avela et al. (2011)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9188658+25394726+21337686" 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">rs869312910 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869312910;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=rs869312910" 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=rs869312910" 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=RCV000210475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210475</a>
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<p>In a 13-year-old boy, originally reported as patient 3 by <a href="#6" class="mim-tip-reference" title="Chen, K. M., Bird, L., Barnes, P., Barth, R., Hudgins, L. <strong>Lateral meningocele syndrome: vertical transmission and expansion of the phenotype.</strong> Am. J. Med. Genet. 133A: 115-121, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15666314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15666314</a>] [<a href="https://doi.org/10.1002/ajmg.a.30526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15666314">Chen et al. (2005)</a>, with lateral meningocele syndrome (LMNS; <a href="/entry/130720">130720</a>), <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> identified a de novo heterozygous c.6732C-A transversion in exon 33 of the NOTCH3 gene (c.6732C-A, NM_000435), resulting in a tyr2244-to-ter (Y2244X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> postulated a dominant gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25394726+15666314" 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">rs869312911 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869312911;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=rs869312911" 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=rs869312911" 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=RCV000210457 OR RCV000426246" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210457, RCV000426246" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210457...</a>
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<p>In a boy, originally reported by <a href="#1" class="mim-tip-reference" title="Alves, D., Sampaio, M., Figueiredo, R., Leao, M. <strong>Lateral meningocele syndrome: additional report and further evidence supporting a connective tissue basis.</strong> Am. J. Med. Genet. 161A: 1768-1772, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23696373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23696373</a>] [<a href="https://doi.org/10.1002/ajmg.a.35968" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23696373">Alves et al. (2013)</a>, with lateral meningocele syndrome (LMNS; <a href="/entry/130720">130720</a>), <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> identified a de novo heterozygous c.6663C-G transversion in exon 33 of the NOTCH3 gene (c.6663C-G, NM_000435), resulting in a tyr2221-to-ter (Y2221X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> postulated a dominant gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23696373+25394726" 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">rs796065045 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065045;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=rs796065045" 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=rs796065045" 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 5-year-old boy (patient 28) with lateral meningocele syndrome (LMNS; <a href="/entry/130720">130720</a>), <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> identified a de novo heterozygous c.6247A-T transversion in exon 33 of the NOTCH3 gene (c.6247A-T, NM_000435), resulting in a lys2083-to-ter (K2083X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Analysis of patient cells showed decreased expression of the NOTCH3 protein as well as expression of the truncated transcript. <a href="#14" class="mim-tip-reference" title="Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K. <strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong> Am. J. Med. Genet. 167A: 271-281, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394726[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394726">Gripp et al. (2015)</a> postulated a dominant gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25394726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
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NOTCH3, ARG141CYS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000850169" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000850169" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000850169</a>
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<p>In 3 affected members of an English family with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 1 (CADASIL1; <a href="/entry/125310">125310</a>), <a href="#24" class="mim-tip-reference" title="Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N. <strong>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.</strong> Brain 130: 357-367, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235124</a>] [<a href="https://doi.org/10.1093/brain/awl360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235124">Low et al. (2007)</a> identified a heterozygous arg141-to-cys (R141C) substitution in exon 4 of the NOTCH3 gene. The mutation, which was found by direct sequencing of the gene, segregated with the disorder in the family. Immunostaining of patient cerebral tissue showed abnormal accumulation of NOTCH3 N-terminal fragments within the walls of the microvasculature. The family had originally been reported by <a href="#36" class="mim-tip-reference" title="Stevens, D. L., Hewlett, R. H., Brownell, B. <strong>Chronic familial vascular encephalopathy. (Letter)</strong> Lancet 309: 1364-1365, 1977. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/69080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">69080</a>] [<a href="https://doi.org/10.1016/s0140-6736(77)92576-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="69080">Stevens et al. (1977)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=69080+17235124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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">rs2145434841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2145434841;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=rs2145434841" 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=rs2145434841" 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=RCV001726685" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001726685" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001726685</a>
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<p>In 5 individuals from 2 generations of a family, including 4 sibs, with mild autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 1 (CADASIL1; <a href="/entry/125310">125310</a>), <a href="#12" class="mim-tip-reference" title="Gravesteijn, G., Dauwerse, J. G., Overzier, M., Brouwer, G., Hegeman, I., Mulder, A. A., Baas, F., Kruit, M. C., Terwindt, G. M., van Duinen, S. G., Jost, C. R., Aartsma-Rus, A., Lesnik Oberstein S. A. J., Rutten, J. W. <strong>Naturally occurring NOTCH3 protein aggregation and disease severity in CADASIL patients.</strong> Hum. Molec. Genet. 29: 1853-1863, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31960911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31960911</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31960911[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/ddz285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31960911">Gravesteijn et al. (2020)</a> identified a heterozygous c.1492G-T transversion (c.1492G-T, NM_000435.2) in the NOTCH3 gene, resulting in a gly498-to-cys (G498C) substitution. The mutation was identified in the index patient by using a gene panel of 28 genes associated with small vessel disease and adult-onset leukodystrophy. The mutation segregated with disease in the family. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping, which excluded part of the EGFR11 and EGFR12 regions. The mutant protein was expressed at normal levels on the cell surface; however, ligand-dependent signaling was impaired compared to wildtype. Fibroblasts from the patients showed only slightly positive NOTCH3 antibody staining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31960911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Alves2013" class="mim-anchor"></a>
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Alves, D., Sampaio, M., Figueiredo, R., Leao, M.
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<strong>Lateral meningocele syndrome: additional report and further evidence supporting a connective tissue basis.</strong>
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Am. J. Med. Genet. 161A: 1768-1772, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23696373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23696373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23696373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.35968" target="_blank">Full Text</a>]
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Arboleda-Velasquez, J. F., Lopera, F., Lopez, E., Frosch, M. P., Sepulveda-Falla, D., Gutierrez, J. E., Vargas, S., Medina, M., Martinez de Arrieta, C., Lebo, R. V., Slaugenhaupt, S. A., Betensky, R. A., Villegas, A., Arcos-Burgos, M., Rivera, D., Restrepo, J. C., Kosik, K. S.
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<strong>C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke.</strong>
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Neurology 59: 277-279, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12136071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12136071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12136071" 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/10.1212/wnl.59.2.277" target="_blank">Full Text</a>]
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Arboleda-Velasquez, J. F., Rampal, R., Fung, E., Darland, D. C., Liu, M., Martinez, M. C., Donahue, C. P., Navarro-Gonzalez, M. F., Libby, P., D'Amore, P. A., Aikawa, M., Haltiwanger, R. S., Kosik, K. S.
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<strong>CADASIL mutations impair Notch3 glycosylation by Fringe.</strong>
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Hum. Molec. Genet. 14: 1631-1639, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15857853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15857853</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15857853" 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/ddi171" target="_blank">Full Text</a>]
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Arboleda-Velasquez, J. F., Zhou, Z., Shin, H. K., Louvi, A., Kim, H.-H., Savitz, S. I., Liao, J. K., Salomone, S., Ayata, C., Moskowitz, M. A., Artavanis-Tsakonas, S.
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<strong>Linking Notch signaling to ischemic stroke.</strong>
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Proc. Nat. Acad. Sci. 105: 4856-4861, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18347334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18347334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18347334[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=18347334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0709867105" target="_blank">Full Text</a>]
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Avela, K., Valanne, L., Helenius, I., Makitie, O.
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<strong>Hajdu-Cheney syndrome with severe dural ectasia.</strong>
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Am. J. Med. Genet. 155A: 595-598, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21337686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21337686</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21337686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33510" target="_blank">Full Text</a>]
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Chen, K. M., Bird, L., Barnes, P., Barth, R., Hudgins, L.
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<strong>Lateral meningocele syndrome: vertical transmission and expansion of the phenotype.</strong>
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Am. J. Med. Genet. 133A: 115-121, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15666314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15666314</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15666314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30526" target="_blank">Full Text</a>]
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Dichgans, M., Herzog, J., Gasser, T.
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<strong>NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.</strong>
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Neurology 57: 1714-1717, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11706120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11706120</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11706120" 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/10.1212/wnl.57.9.1714" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gad.308904" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.22281" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2011.05.030" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1997.5211" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddz285" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg052" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.36863" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19855400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19855400</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19855400[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=19855400" 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/nm.2021" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awl360" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.04.024" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awp049" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201221" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneur.58.9.1418" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp211" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000349699.12456.06" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.22432" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000010525" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000224758.52970.19" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000324928.44694.f7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp468" target="_blank">Full Text</a>]
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<strong>Human blood vessel organoids as a model of diabetic vasculopathy.</strong>
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Nature 565: 505-510, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30651639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30651639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30651639[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=30651639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-018-0858-8" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 10/01/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/30/2020<br>Cassandra L. Kniffin - updated : 09/03/2019<br>Ada Hamosh - updated : 06/06/2019<br>Cassandra L. Kniffin - updated : 8/3/2015<br>Cassandra L. Kniffin - updated : 12/3/2013<br>Cassandra L. Kniffin - updated : 6/27/2013<br>Patricia A. Hartz - updated : 7/5/2012<br>Cassandra L. Kniffin - updated : 8/3/2011<br>George E. Tiller - updated : 11/12/2010<br>George E. Tiller - updated : 6/23/2010<br>Cassandra L. Kniffin - updated : 3/10/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Marla J. F. O'Neill - updated : 12/2/2009<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Patricia A. Hartz - updated : 9/4/2008<br>George E. Tiller - updated : 6/16/2008<br>Cassandra L. Kniffin - updated : 7/31/2007<br>George E. Tiller - updated : 3/2/2005<br>Patricia A. Hartz - updated : 1/5/2005<br>Marla J. F. O'Neill - updated : 11/8/2004<br>Victor A. McKusick - updated : 2/5/2004<br>Cassandra L. Kniffin - updated : 12/3/2002<br>Cassandra L. Kniffin - updated : 10/8/2002<br>Cassandra L. Kniffin - updated : 6/13/2002<br>Anne M. Stumpf - updated : 5/17/2002<br>Victor A. McKusick - updated : 5/13/2002<br>Ada Hamosh - updated : 4/26/2001<br>Victor A. McKusick - updated : 5/1/2000<br>Alan F. Scott - updated : 6/1/1998<br>Victor A. McKusick - updated : 3/24/1998
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/4/1995
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carol : 10/04/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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carol : 10/01/2021<br>carol : 12/01/2020<br>carol : 11/30/2020<br>alopez : 09/09/2019<br>ckniffin : 09/03/2019<br>carol : 08/07/2019<br>carol : 06/27/2019<br>alopez : 06/06/2019<br>alopez : 09/29/2016<br>carol : 01/29/2016<br>alopez : 8/10/2015<br>mcolton : 8/4/2015<br>ckniffin : 8/3/2015<br>carol : 12/6/2013<br>mcolton : 12/5/2013<br>ckniffin : 12/3/2013<br>carol : 7/8/2013<br>tpirozzi : 7/8/2013<br>tpirozzi : 7/3/2013<br>ckniffin : 6/27/2013<br>mgross : 7/10/2012<br>terry : 7/5/2012<br>alopez : 8/18/2011<br>ckniffin : 8/3/2011<br>wwang : 11/19/2010<br>terry : 11/12/2010<br>wwang : 6/30/2010<br>terry : 6/23/2010<br>alopez : 4/30/2010<br>wwang : 3/18/2010<br>ckniffin : 3/10/2010<br>wwang : 1/11/2010<br>carol : 12/23/2009<br>ckniffin : 12/15/2009<br>wwang : 12/7/2009<br>terry : 12/2/2009<br>wwang : 4/9/2009<br>ckniffin : 3/23/2009<br>wwang : 9/4/2008<br>wwang : 6/19/2008<br>terry : 6/16/2008<br>wwang : 8/16/2007<br>ckniffin : 7/31/2007<br>carol : 8/16/2006<br>wwang : 5/22/2006<br>terry : 5/17/2006<br>terry : 8/3/2005<br>alopez : 3/2/2005<br>mgross : 1/11/2005<br>terry : 1/5/2005<br>tkritzer : 11/8/2004<br>alopez : 2/6/2004<br>terry : 2/5/2004<br>terry : 6/11/2003<br>terry : 2/26/2003<br>cwells : 12/10/2002<br>ckniffin : 12/3/2002<br>carol : 11/1/2002<br>tkritzer : 10/29/2002<br>ckniffin : 10/8/2002<br>carol : 6/17/2002<br>ckniffin : 6/13/2002<br>alopez : 5/17/2002<br>alopez : 5/17/2002<br>alopez : 5/17/2002<br>terry : 5/13/2002<br>mcapotos : 5/7/2001<br>mcapotos : 5/3/2001<br>terry : 4/26/2001<br>carol : 3/26/2001<br>mcapotos : 5/31/2000<br>mcapotos : 5/31/2000<br>mcapotos : 5/26/2000<br>mcapotos : 5/25/2000<br>terry : 5/1/2000<br>alopez : 10/15/1998<br>alopez : 10/15/1998<br>carol : 6/22/1998<br>terry : 6/1/1998<br>psherman : 3/24/1998<br>dholmes : 3/5/1998<br>mark : 1/19/1998<br>jamie : 5/7/1997<br>mark : 10/23/1996<br>mark : 10/22/1996<br>mimadm : 9/23/1995<br>carol : 1/5/1995<br>carol : 1/4/1995
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<span class="mim-font">
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<strong>*</strong> 600276
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<h3>
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<span class="mim-font">
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NOTCH RECEPTOR 3; NOTCH3
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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NOTCH, DROSOPHILA, HOMOLOG OF, 3
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NOTCH3</em></strong>
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Cytogenetic location: 19p13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:15,159,038-15,200,995 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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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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<td rowspan="3">
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<span class="mim-font">
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19p13.12
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<span class="mim-font">
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?Myofibromatosis, infantile 2
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<span class="mim-font">
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615293
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1
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<span class="mim-font">
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125310
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Lateral meningocele syndrome
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<span class="mim-font">
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130720
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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<td>
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<span class="mim-font">
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3
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</div>
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<span class="mim-text-font">
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<p>The NOTCH3 gene encodes a single pass transmembrane protein belonging to an evolutionarily conserved NOTCH receptor family (see, e.g., NOTCH1; 190198). After ligand binding, the intracellular domain translocates to the nucleus and activates transcription factors. The Notch signaling pathway plays a central role in the development and maturation of most vertebrate organs, with pleiotropic effects depending on dose and context (summary by Monet-Lepretre et al., 2009). </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Joutel et al. (1996) mapped the NOTCH3 gene positionally as part of a search for the gene mutant in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310). The authors narrowed the critical region to a small interval bracketed by D19S253 centromerically and D19S929 telomerically. The investigators constructed YAC and BAC contigs encompassing the critical region, the size of which was estimated to be approximately 800 kb. Of the candidate transcripts identified through direct selection of cDNA, one showed strong homology with the 5-prime-coding end of the mouse Notch3 gene. They assembled a contiguous stretch of 5,615 bp of human NOTCH3 coding sequence that was highly homologous to its murine coding counterpart. The human and mouse proteins were found to be 90% identical along the available overall sequence. </p><p>Joutel et al. (2000) showed that NOTCH3 expression was restricted to vascular smooth muscle cells at the cytoplasmic membrane in close vicinity to but not within the granular osmiophilic material. NOTCH3 underwent proteolytic cleavage leading to a 210-kD extracellular fragment and a 97-kD intracellular fragment. In CADASIL brains, they found evidence of accumulation of the 210-kD NOTCH3 cleavage product. </p><p>By immunofluorescence analysis of embryonic day-15.5 mouse epidermis, Ezratty et al. (2011) found that Notch3 was expressed along the length of primary cilia in differentiated suprabasal keratinocytes. Processed Notch3 intracellular domain also localized to nuclei of ciliated suprabasal cells. </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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<strong>Gene Structure</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 alignment of available genomic sequence to a cDNA contig, Joutel et al. (1996) identified at least 29 exons in the NOTCH3 gene. </p><p>Joutel et al. (2001) stated that the NOTCH3 gene contains 33 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Larsson et al. (1994) used somatic cell hybrid analyses and FISH to map the NOTCH2 (600275) and NOTCH3 genes to 1p13-p11 and 19p13.2-p13.1, respectively, which are regions of neoplasia-associated translocation. Gao et al. (1998) mapped the mouse Notch3 gene to chromosome 17. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Joutel et al. (1996) stated that Notch is known for its role in specifying cell fate during Drosophila development. They stated that the only human disorder implicating a Notch gene before the identification of mutations in NOTCH3 as the cause of CADASIL was an adult T-cell leukemia, which is associated with truncation of the NOTCH1 (190198) transcript. No developmental abnormality or neoplasia is associated with CADASIL. On the basis of an analysis of Drosophila mutants, it had been proposed by Rebay et al. (1993) that Notch may be a receptor with different functional domains, the intracellular domain having the signal-transducing activity of the intact protein and the extracellular domain possessing a ligand-binding and regulatory activity. </p><p>Tanigaki et al. (2001) presented evidence that activated NOTCH1 and NOTCH3 promote the differentiation of astroglia from rat adult hippocampus-derived multipotent progenitors. Transient activation of Notch can direct commitment of adult hippocampal-derived progenitors irreversibly to astroglia. Astroglial induction by Notch signaling was shown to be independent of STAT3 (102582), which is a key regulatory transcriptional factor when ciliary neurotrophic factor (CNTF; 118945) induces astroglia. Tanigaki et al. (2001) concluded that their data suggests that Notch provides a CNTF-independent instructive signal of astroglia differentiation in central nervous system multipotent progenitor cells. </p><p>Li et al. (2009) demonstrated that human pulmonary hypertension (PPH; see 178600) is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells (SMCs) and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. Notch3 -/- mice did not develop pulmonary hypertension in response to hypoxic stimulation, and both pulmonary hypertension and right ventricular hypertrophy were ameliorated in mice by treatment with DAPT, a gamma-secretase (see 104311) inhibitor that blocks activation of NOTCH3 in SMCs. The authors demonstrated a mechanistic link from NOTCH3 receptor signaling through the HES5 protein (607348) to SMC proliferation and a shift to an undifferentiated SMC phenotype. Li et al. (2009) suggested that the NOTCH3-HES5 signaling pathway is crucial for the development of pulmonary arterial hypertension. </p><p>Wimmer et al. (2019) reported the development of self-organizing 3-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice formed a stable, perfused vascular tree, including arteries, arterioles, and venules. Exposure of blood vessel organoids to hyperglycemia and inflammatory cytokines in vitro induced thickening of the vascular basement membrane. Human blood vessels exposed in vivo to a diabetic milieu in mice also mimicked the microvascular changes found in patients with diabetes. DLL4 (605185) and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Wimmer et al. (2019) concluded that organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modeling and identifying the regulators of diabetic vasculopathy. </p>
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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><strong><em>Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, Type 1</em></strong></p><p>
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CADASIL1 (125310)-associated mutations in the NOTCH3 gene are distributed throughout the 34 epidermal growth factor-like repeats (EGFRs) that comprise the extracellular domain of the NOTCH3 receptor and result in a loss or gain of a cysteine residue in one of these EGFRs. Most mutations are located in EGFR2-5 (Joutel et al., 2004). </p><p>CADASIL causes a type of stroke and dementia of which key features include recurrent subcortical ischemic events and vascular dementia associated with diffuse white-matter abnormalities on neuroimaging. Joutel et al. (1996) stated that pathologic examination revealed multiple small, deep cerebral infarcts, leukoencephalopathy, and nonatherosclerotic, nonamyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth muscle cells are evident on ultrastructural analysis. Joutel et al. (1996) mapped the CADASIL critical region to an 800-kb interval on 19p and identified the human NOTCH3 gene within this region. The meiotic recombinant defining the telomeric boundary of the critical region was observed in an asymptomatic 40-year-old patient with an inconclusive result from cerebral MRI, but a skin biopsy showed typical alterations in vascular smooth muscle cells. Joutel et al. (1996) detected no gross rearrangement of genomic DNA in CADASIL patients. A panel of 58 unrelated patients were then checked for point mutations in the NOTCH3 gene. Screening of 14 of the 29 NOTCH3 exons by SSCP revealed 11 conformational variants within 7 exons, 10 of which were observed in 14 unrelated patients and none of 200 control chromosomes. Each was shown by nucleotide sequencing to be due to nucleotide substitutions resulting in an amino acid change. Cosegregation of the abnormal conformer with the affected phenotype as established in 6 pedigrees available in the set of 14 patients. The eleventh variant was seen in patients and in controls, and sequencing showed that it was due to a silent nucleotide change. The partial cDNA contig predicted a content of 33 EGF domains, 3 Notch/Lin-12 repeats, and 3 cdc10 (603151) ankyrin (see 600465)-like repeats. Of the mutations within the EGF-like domains, 2 alter a cysteine residue, 6 others replace a conserved residue with a cysteine (e.g., 600276.0001, 600276.0002, and 600276.0003), and 1 replaces a highly conserved glycine with an alanine. No difference in the phenotypes of the CADASIL patients who carried mutations in EGF-like and cdc10 domains was noted and the phenotypes of patients carrying mutations in distinct EGF domains were identical. </p><p>By SSCP, heteroduplex, and sequence analyses, Joutel et al. (1997) screened the entire NOTCH3 coding sequences of 50 unrelated patients with CADASIL for mutations. Strongly stereotyped missense mutations, located within the EGF-like repeats in the extracellular domain of NOTCH3, were detected in 45 patients. Clustering of mutations within the 2 exons encoding the first 5 EGF-like repeats was observed in 32 patients. All of the mutations lead to loss or gain of a cysteine residue and, therefore, to an unpaired cysteine residue within a given EGF domain. None of the mutations was found in 100 healthy controls. The findings suggested that aberrant dimerization of NOTCH3, due to abnormal disulfide bridging with another NOTCH3 molecule or another protein, may be involved in the pathogenesis of CADASIL. Joutel et al. (1997) pointed out that an easy and reliable diagnostic test for this disorder is feasible because of the strong clustering and highly stereotyped nature of the pathogenetic mutations. </p><p>Gridley (2003) provided a brief review of human disorders due to defects in the Notch signaling pathway: Alagille syndrome (see 118450), spondylocostal dysostosis (see 277300), and CADASIL. </p><p>Arboleda-Velasquez et al. (2005) showed that Notch3 mutations in the EGFR2-5 hotspot did not affect the addition of O-fucose but did impair carbohydrate chain elongation by Fringe (LFNG; 602576). Notch3 mutations induced aberrant Notch3 homodimerization and Notch3/Fringe heterodimerization. Arboleda-Velasquez et al. (2005) suggested that Fringe may play a role in CADASIL pathophysiology. </p><p>Opherk et al. (2009) showed that both wildtype and CADASIL-mutated (R133C; 600276.0008) NOTCH3 receptor spontaneously formed oligomers and higher order multimers in vitro and that multimerization was mediated by disulfide bonds. CADASIL-associated mutations significantly enhanced multimerization compared with wildtype. Opherk et al. (2009) argued for a neomorphic effect of CADASIL mutations in disease pathogenesis. </p><p>Takahashi et al. (2010) investigated the cytotoxic properties of mutant NOTCH3 using stable HEK293 cell lines with inducible expression of wildtype or the R133C (600276.0008) and C185R mutations. Both mutants were prone to aggregation and were retained in the endoplasmic reticulum (ER). The turnover rates of the mutant proteins were strikingly slow, with half-lives greater than 6 days, whereas wildtype was rapidly degraded, with a half-life of 0.7 days. Expression of mutant NOTCH3 also impaired cell proliferation compared with wildtype. Cell lines expressing mutant NOTCH3 were more sensitive to proteasome inhibition resulting in cell death. Takahashi et al. (2010) suggested that prolonged retention of mutant NOTCH3 aggregates in the ER may decrease cell growth and increase sensitivity to other stresses; alternatively, the aggregate-prone property of mutant NOTCH3 may contribute to a pathogenic mechanism underlying CADASIL. </p><p>Rutten et al. (2020) investigated exome and genome sequencing datasets of the UK Biobank (50,000 individuals) and cohorts of cognitively healthy elderly (751 individuals) to identify cysteine-altering mutations in the NOTCH3 gene in the general population. They identified 108 individuals (2.2 in 1000; average age, 64.9 years), of whom 75% had a NOTCH3 mutation that had previously been reported in patients with CADASIL. In 103 individuals, the cysteine-altering mutations were located in the EGFF domains 7 through 34. Three individuals had cysteine-altering mutations in EGFR domains 1 through 6 and were not studied further. Neuroimaging data in the 103 individuals showed that they had more white matter hyperintensity lesions compared to controls, but fewer white matter hyperintensity lesions compared to patients with CADASIL. About one-half of the unaffected individuals had no neuroimaging abnormalities up to 70 years of age, and no increase in stroke was found. Rutten et al. (2020) concluded that CADASIL constitutes the severe and rare end of NOTCH3-associated small vessel disease, and that most individuals with cysteine-altering NOTCH3 mutations have milder and later-onset disease. </p><p>Gravesteijn et al. (2020) identified a heterozygous missense mutation (G498C; 600276.0019) in the NOTCH3 gene in 5 individuals from one family with mild CADASIL. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping, which excluded part of the EGFR11 and EGFR12 regions. The mutant protein was expressed at normal levels on the cell surface; however, ligand-dependent signaling was impaired compared to wildtype. </p><p><strong><em>Infantile Myofibromatosis 2</em></strong></p><p>
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In affected members of a family (IM-9) with autosomal dominant infantile myofibromatosis-2 (IMF2; 615293), Martignetti et al. (2013) identified a heterozygous mutation in the NOTCH3 gene (L1519P; 600276.0012). The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. No functional studies were performed, but the authors predicted that the mutation would result in hyperactivation of NOTCH3. </p><p><strong><em>Lateral Meningocele Syndrome</em></strong></p><p>
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In 6 unrelated patients with lateral meningocele syndrome (LMNS; 130720), Gripp et al. (2015) identified 5 different de novo heterozygous truncating mutations in exon 33 of the NOTCH3 gene (600276.0013-600276.0017). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of the cells of 1 patient showed decreased expression of the NOTCH3 protein as well as expression of the truncated transcript. The truncated NOTCH3 proteins predicted to result from these mutations would lack a functional PEST domain, which could prolong the half-life and thus increase signaling effects. Gripp et al. (2015) postulated that the de novo mutations in exon 33 would result in a dominant gain-of-function effect. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Joutel et al. (2004) investigated the effect of CADASIL mutations on NOTCH3 activity. They studied 5 naturally occurring mutations: R90C and C212S, located in the previously identified mutation hotspot EGFR2-5; C428S (600276.0011), shown by them to be located in the ligand-binding domain EGFR10-11; and C542Y and R1006C, located in EGFR13 and EGFR26, respectively. They found that all 5 mutant proteins were correctly processed. The C428S and C542Y mutant receptors exhibited a significant reduction in Jagged1 (601920)-induced transcriptional activity of an RBPJK (147183)-responsive luciferase reporter, relative to wildtype Notch3. Impaired signaling activity of these 2 mutants arose through different mechanisms; the C428S mutant lost its ability to bind Jagged1, whereas C542Y retained it but exhibited an impaired presentation to the cell surface. Thus, these mutations resulted in loss of function. In contrast, the R90C, C212S, and R1006C mutants retained the ability to bind Jagged1 and were associated with apparently normal levels of signaling activity. Joutel et al. (2004) concluded that mutations in Notch3 differently affect Jagged1 binding and Notch3 signaling via the RBP/JK pathway. </p><p>In a follow-up to the study of Joutel et al. (2004), Monet-Lepretre et al. (2009) found that the C428S mutation exerted a dominant-negative effect in transgenic mice, and antagonized the function of wildtype Notch3 when coexpressed. In 350 distinct CADASIL families with 99 different NOTCH3 mutations, they found 11 (11%) different mutations in the EGFR10 or EGFR11 regions in 14 (4%) of 350 families, including 8 mutations with loss of a cysteine residue and 3 mutations with gain of a cysteine residue. A further review of 10 patients with mutations in the ligand-binding domain, including 6 with the C428S mutation, suggested that they had a less severe phenotype, including better preservation of cognitive function. These patients tended to have a lower volume of lacunar infarcts, but they also had a larger volume of white matter hyperintensities compared to CADASIL patients with mutations in the EGFR2-5 region. </p><p>From a clinical and genetic study in 2 unrelated families, Rutten et al. (2013) provided evidence that loss-of-function NOTCH3 mutations do not cause CADASIL. In the first family, a 55-year-old man with polyneuropathy, migraine with aura, and ischemic strokes between ages 50 and 52 was found to carry a heterozygous truncating variant in the NOTCH3 gene (R103X). Brain MRI showed old large vessel infarctions, but no white matter changes consistent with CADASIL. Skin biopsy was negative for NOTCH3 staining, but there was normal structure of the vessel wall and no electron microscopic deposits characteristic of the disorder. The patient's 50-year-old brother also carried the NOTCH3 variant, but was asymptomatic with a normal brain MRI; family history was negative for stroke and dementia. In a second family, a patient with classic MRI findings of CADASIL was compound heterozygous for a tyr710-to-cys (Y710C) mutation in the NOTCH3 gene and an intragenic frameshift deletion. The Y710C mutation was inherited from his possibly affected mother who had transient functional deficit of the arm at age 40 years without available brain imaging, and the deletion was inherited from his unaffected father whose skin biopsy was negative for CADASIL. Most CADASIL-associated NOTCH3 mutations alter conserved cysteine residues and are postulated to cause a toxic neomorphic effect. Rutten et al. (2013) concluded that hypomorphic NOTCH3 mutations do not cause CADASIL, which has important implications for diagnostic interpretation. </p><p>Gravesteijn et al. (2020) identified a heterozygous G498C (600276.0019) mutation in the NOTCH3 gene in 5 individuals from one family with mild CADASIL. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping, which leaves the open reading frame intact but excludes part of the EGFR11 and EGFR12 regions and therefore the putative NOTCH3 ligand-binding domain. The mutant protein was expressed at normal levels on the cell surface; however, ligand-dependent signaling was impaired compared to wildtype. The phenotypes of the family members included only minimal levels of NOTCH3 protein aggregation in skin vasculature, suggesting that the mutant NOTCH3 does not aggregate. The 63-year-old index patient had confluent white matter hyperintensities on brain MRI with no lacunae as well as a history of headaches, vertigo, and tinnitus. She had a normal neuropsychologic examination. All 3 of her affected sibs, aged 63 to 71 years, had confluent white matter hyperintensities on brain MRI. None of the sibs had lacunar strokes or vascular cognitive decline, and all lived independently. An affected nephew of the index patient had a few focal white matter hyperintensities on brain MRI. </p>
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</span>
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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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<span class="mim-text-font">
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<p>Domenga et al. (2004) found that the postnatal maturation stage of vascular smooth muscle cells (VSMCs) was deficient in Notch3 -/- mice. In adult Notch3 -/- mice, distal arteries were enlarged and exhibited a less festooned elastica lamina. In response to angiotensin II or phenylephrine, Notch3 -/- mice showed normal arterial blood pressure elevations, but cerebral blood flow reactivity and cerebrovascular resistance were impaired. The slight increase in cerebral blood flow elicited by acute induced hypertension in control mice was exacerbated in Notch3 -/- mice. In addition, Domenga et al. (2004) showed that Notch3 was required for arterial specification of VSMCs but not endothelial cells. They concluded that NOTCH3 is required for arterial differentiation and maturation of VSMCs. </p><p>Arboleda-Velasquez et al. (2008) found that smooth muscle cells were virtually the only cell in the adult mouse brain to express Notch3 and that Notch3 knockout increased susceptibility of mice to ischemic challenge. Notch3-null mice showed larger ischemic lesions, more neurologic deficits, increased mortality, more severe cerebral blood flow deficits, and more frequent spontaneous periinfarct depolarizations compared with wildtype mice. Microarray analysis revealed over 600 differentially regulated genes, and all genes that regulate muscle contraction were downregulated. </p><p>Eikermann-Haerter et al. (2011) found that transgenic mice carrying a CADASIL-associated R90C mutation in the Notch3 gene had a 10-fold lower threshold for cortical spreading depression (CSD) as well as a higher propagation speed of CSD compared to wildtype mice. Female mice tended to have a lower threshold than male mice. These changes were even more apparent in Notch3-null mice. Although these findings implicated the neurovascular unit in the development of migraine with aura, chronic forebrain hypoperfusion induced by carotid artery stenosis in wildtype mice did not enhance potassium-induced CSD susceptibility, arguing against a primary vascular mechanism for the phenomenon in CADASIL. The report was consistent with the increased frequency of migraine with aura in patients with this disorder. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</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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NOTCH3, TRP71CYS
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<br />
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SNP: rs28937321,
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ClinVar: RCV000009799, RCV001659689
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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 patient P56 with CADASIL1 (125310), Joutel et al. (1996) observed a TGG-to-TGT transversion in exon N2 of the NOTCH3 gene, resulting in substitution of trp by cys (W71C). Joutel et al. (1997) stated that the mutation was of nucleotide 291 in codon 71. </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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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NOTCH3, ARG169CYS
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<br />
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SNP: rs28933696,
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ClinVar: RCV000009800, RCV000518159, RCV001003548, RCV002482849, RCV004532317
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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 3 unrelated CADASIL1 (125310) patients, Joutel et al. (1996) observed a CGC-to-TGC transition in exon N3 of the NOTCH3 gene, resulting in substitution of cys for arg (R169C). Joutel et al. (1997) indicated that these 2 mutations were arg169cys and arg182cys (see 600276.0003). </p>
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</span>
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</div>
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<div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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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NOTCH3, ARG182CYS
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<br />
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SNP: rs28933697,
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gnomAD: rs28933697,
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ClinVar: RCV000009801, RCV000517955, RCV004737144
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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 unrelated CADASIL1 (125310) patients, Joutel et al. (1996, 1997) observed a CGC-to-TGC transition in a different codon in exon N3 of the NOTCH3 gene that resulted in substitution of cys for arg (R182C) in the same EGF-like domain. </p><p>Joutel et al. (2000) reported a patient who was thought to have CADASIL, although no first-degree relative was affected. The patient was found to carry a heterozygous arg182-to-cys mutation in the NOTCH3 gene; the mutation was absent in his parents, indicating a de novo mutation. They suggested that because of the occurrence of such cases, CADASIL may be more frequent than recognized. The frequency of the condition as a familial disorder is reflected in the fact that Joutel et al. (2000) found that more than 400 families had been identified since 1993. The patient with the arg182-to-cys mutation was a 55-year-old businessman who had experienced recurrent transient focal neurologic episodes, some suggestive of transient ischemic attacks and others of migrainous auras, dating back to the age of 32 years. At 48 years of age, he had a minor ischemic stroke with left facial asymmetry and weakness. Brain MRI showed extensive white matter abnormalities. Multiple sclerosis was suspected. At 53 years, he experienced a pure motor right-sided hemiplegia, which progressed over 5 days. Recovery was only partial, and the patient remained disabled with difficulties in walking and in moving his right hand. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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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NOTCH3, ALA-THR
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<br />
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SNP: rs864621964,
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ClinVar: RCV000009802
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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 patient F18 with CADASIL1 (125310), Joutel et al. (1996) identified a GCT-to-ACT transition in exon N25 predicted to cause an ala-to-thr substitution in a cdc10 functional domain of the NOTCH3 protein. </p><p>(This mutation did not appear in the tabulation of mutations found in 45 unrelated patients by Joutel et al. (1997); all of the tabulated mutations either added or removed a cysteine from the protein product.) </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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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NOTCH3, 45-BP DEL
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<br />
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SNP: rs864621965,
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ClinVar: RCV000009803
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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 affected members of a family with CADASIL1 (125310), Dichgans et al. (2001) identified a 45-bp deletion in the NOTCH3 gene, resulting in the deletion of 3 cysteine residues within EGF repeat 6. The clinical manifestations were comparable to those in other CADASIL patients with different NOTCH3 mutations, confirming the hypothesis that an unpaired, reactive cysteine residue is the common and critical molecular event in the disease. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
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</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, CYS455ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28933698,
|
|
|
|
|
|
|
|
ClinVar: RCV000009804, RCV000517813
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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|
<p>Arboleda-Velasquez et al. (2002) reported a Colombian kindred with CADASIL1 (125310) characterized by early-onset stroke (median age, 31 years), migraine with aura, and confluent MRI hyperintensities. They identified a heterozygous 1441T-C transition in exon 8 of the NOTCH3 gene, resulting in a cys455-to-arg (C455R) substitution. The mutation abolishes the fourth cysteine residue at EGF-like repeat 11 (EGFR11) and may affect the interaction of the NOTCH3 receptor with its ligands. Despite the early onset of stroke, all patients had relatively well-preserved cognitive and functional status more than 2 decades after onset. </p>
|
|
</span>
|
|
</div>
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|
<div>
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|
<br />
|
|
</div>
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|
</div>
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|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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|
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|
NOTCH3, ARG332CYS
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|
|
<br />
|
|
|
|
SNP: rs137852641,
|
|
|
|
|
|
|
|
ClinVar: RCV000009805, RCV000516507, RCV002271367
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs of an Italian family with CADASIL1 (125310), Oliveri et al. (2001) identified a C-to-T missense mutation in exon 6 of the NOTCH3 gene, resulting in an arg332-to-cys (R332C) substitution. The mutation was not found in 7 unaffected family members or in 200 control chromosomes. The authors noted that gain of a cysteine residue is common in NOTCH3 mutations causing CADASIL, and that it likely induces inappropriate disulfide bonding of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, ARG133CYS
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs137852642,
|
|
|
|
|
|
gnomAD: rs137852642,
|
|
|
|
|
|
ClinVar: RCV000009806, RCV000415016, RCV000516340, RCV003996082, RCV004532318
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 unrelated patients with CADASIL1 (125310), Joutel et al. (1997) identified a 475C-T transition in exon N4 of the NOTCH3 gene, resulting in an arg133-to-cys (R133C) substitution in the EGF3 domain. </p><p>Mykkanen et al. (2004) performed haplotype analysis in 60 patients from 18 Finnish CADASIL families with the R133C mutation. Using 10 microsatellite markers, the authors found a similar haplotype linked to the mutation in all 18 pedigrees, indicating a single common ancestor for all of the Finnish R133C families. Age analysis of the founder mutation placed the introduction of the mutation in the late 1600s or early 1700s. </p><p>Opherk et al. (2009) showed that both wildtype and CADASIL-mutated (R133C) NOTCH3 receptor spontaneously formed oligomers and higher order multimers in vitro and that multimerization was mediated by disulfide bonds. CADASIL-associated mutations significantly enhanced multimerization compared with wildtype. Opherk et al. (2009) argued for a neomorphic effect of CADASIL mutations in </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, IVS15AS, G-T, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs864621966,
|
|
|
|
|
|
|
|
ClinVar: RCV000009807
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected members of a Japanese family with CADASIL1 (125310), Saiki et al. (2006) identified a heterozygous 1279G-T transversion in intron 15 of the NOTCH3 gene, resulting in the skipping of exon 16, which includes 8 cysteine residues that would affect EGF repeat domains 20, 21, and 22. In addition to the classic features of CADASIL with ischemic episodes, all affected individuals also had varicose veins that developed between age 14 and 30. Biopsies of varicose veins from 3 individuals showed marked intimal hypertrophy, localized thinning of smooth muscle layers, and infiltrated fibrous tissue. Venous smooth muscle cells were irregularly shaped and contained granular osmiophilic material. No affected individuals had involvement of the anterior temporal lobes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, ALA1020PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs35769976,
|
|
|
|
|
|
gnomAD: rs35769976,
|
|
|
|
|
|
ClinVar: RCV000009808, RCV000243215, RCV001519393, RCV002504773
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated German families with a relatively mild form of CADASIL1 (125310), Scheid et al. (2008) identified a heterozygous 3058G-C transversion in the NOTCH3 gene, resulting in an ala1020-to-pro (A1020P) substitution in a highly conserved region within the EGF-like repeat domain 26. The phenotype included later onset milder neurologic signs and later onset of white matter lesions than most cases of CADASIL. Sensorineural hearing loss and arterial hypertension were also prominent features. The mutation was not found in 100 control chromosomes. The authors noted that most CADASIL-associated NOTCH3 mutations affect cysteine residues but that the proline in these patients may also have cysteine-like effects on protein folding, dimerization, or interactions since a proline contains an additional amino group that can alter secondary or tertiary structures. Scheid et al. (2008) concluded that cysteine-sparing NOTCH3 mutations may result in a more benign CADASIL phenotype. </p><p>Quattrone and Mazzei (2009) noted that the A1020P variant described by Scheid et al. (2008) is also known as rs35769976. Quattrone and Mazzei (2009) identified this variant in 3 of 50 European control individuals, casting doubt on the pathogenicity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, CYS428SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606915,
|
|
|
|
|
|
|
|
ClinVar: RCV000009809
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CADASIL1 (125310), Joutel et al. (2001) identified a heterozygous 1282T-A transversion in exon 8 of the NOTCH3 gene, resulting in a cys428-to-ser (C428S) substitution in EGFR10. </p><p>Using in vitro studies, Joutel et al. (2004) found that the C428S mutant was correctly processed, but resulted in impaired downstream transcriptional activity of an RBPJK (147183)-responsive luciferase reporter by losing its ability to bind Jagged1 (601920). These findings were consistent with a loss of function. Monet-Lepretre et al. (2009) found that, although transgenic mice with the C428S mutation did not develop overt brain parenchymal lesions, they did develop the characteristic progressive aggregation of mutant Notch3 extracellular domain in vascular smooth muscle cells. Further animal and cellular studies showed that the mutant C428S protein was nonfunctional in vivo, but exerted a dominant-negative effect when expressed with wildtype Notch3. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MYOFIBROMATOSIS, INFANTILE, 2 (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, LEU1519PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs367543285,
|
|
|
|
|
|
|
|
ClinVar: RCV000049266, RCV000049572
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with infantile myofibromatosis-2 (IMF2; 615293), Martignetti et al. (2013) identified a heterozygous c.4556T-C transition in exon 25 of the NOTCH3 gene, resulting in a leu1519-to-pro (L1519P) substitution at a highly conserved residue in the heterodimerization domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. No functional studies were performed, but the authors predicted that the mutation would result in hyperactivation of NOTCH3. Affected individuals had no evidence of CADASIL (125310). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 LATERAL MENINGOCELE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, 26-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869312909,
|
|
|
|
|
|
|
|
ClinVar: RCV000210456
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 27-year-old man, originally reported as patient 2 by Gripp et al. (1997), with lateral meningocele syndrome (LMNS; 130720), Gripp et al. (2015) identified a de novo heterozygous 26-bp deletion (c.6461_6486del, NM_000435) in exon 33 of the NOTCH3 gene, resulting in a frameshift and premature termination (Gly2154fsTer78). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but Gripp et al. (2015) postulated a dominant gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 LATERAL MENINGOCELE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, 1-BP INS, 6692C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs773656789,
|
|
|
|
|
|
|
|
ClinVar: RCV000210463, RCV001268088
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated male patients with lateral meningocele syndrome (LMNS; 130720), Gripp et al. (2015) identified a de novo heterozygous 1-bp insertion (c.6692_6693insC, NM_000435), in exon 33 of the NOTCH3 gene, resulting in a frameshift and premature termination (Pro2231fsTer11). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but Gripp et al. (2015) postulated a dominant gain-of-function effect. One of the patients was originally reported as patient 1 by Gripp et al. (1997) and was deceased; DNA was extracted from a formalin-fixed paraffin tissue sample. The other patient was originally reported by Avela et al. (2011). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LATERAL MENINGOCELE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, TYR2244TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869312910,
|
|
|
|
|
|
|
|
ClinVar: RCV000210475
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 13-year-old boy, originally reported as patient 3 by Chen et al. (2005), with lateral meningocele syndrome (LMNS; 130720), Gripp et al. (2015) identified a de novo heterozygous c.6732C-A transversion in exon 33 of the NOTCH3 gene (c.6732C-A, NM_000435), resulting in a tyr2244-to-ter (Y2244X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but Gripp et al. (2015) postulated a dominant gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 LATERAL MENINGOCELE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, TYR2221TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869312911,
|
|
|
|
|
|
|
|
ClinVar: RCV000210457, RCV000426246
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy, originally reported by Alves et al. (2013), with lateral meningocele syndrome (LMNS; 130720), Gripp et al. (2015) identified a de novo heterozygous c.6663C-G transversion in exon 33 of the NOTCH3 gene (c.6663C-G, NM_000435), resulting in a tyr2221-to-ter (Y2221X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Functional studies of the variant or of patient cells were not performed, but Gripp et al. (2015) postulated a dominant gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 LATERAL MENINGOCELE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NOTCH3, LYS2083TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs796065045,
|
|
|
|
|
|
|
|
ClinVar: RCV000190331
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old boy (patient 28) with lateral meningocele syndrome (LMNS; 130720), Gripp et al. (2015) identified a de novo heterozygous c.6247A-T transversion in exon 33 of the NOTCH3 gene (c.6247A-T, NM_000435), resulting in a lys2083-to-ter (K2083X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 126, 129, and 131) database and was not found in the Exome Variant Server or 1000 Genomes Project databases. Analysis of patient cells showed decreased expression of the NOTCH3 protein as well as expression of the truncated transcript. Gripp et al. (2015) postulated a dominant gain-of-function effect. </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>.0018 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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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NOTCH3, ARG141CYS
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<br />
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ClinVar: RCV000850169
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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 3 affected members of an English family with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 1 (CADASIL1; 125310), Low et al. (2007) identified a heterozygous arg141-to-cys (R141C) substitution in exon 4 of the NOTCH3 gene. The mutation, which was found by direct sequencing of the gene, segregated with the disorder in the family. Immunostaining of patient cerebral tissue showed abnormal accumulation of NOTCH3 N-terminal fragments within the walls of the microvasculature. The family had originally been reported by Stevens et al. (1977). </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>.0019 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 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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NOTCH3, GLY498CYS
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<br />
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SNP: rs2145434841,
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ClinVar: RCV001726685
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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 5 individuals from 2 generations of a family, including 4 sibs, with mild autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 1 (CADASIL1; 125310), Gravesteijn et al. (2020) identified a heterozygous c.1492G-T transversion (c.1492G-T, NM_000435.2) in the NOTCH3 gene, resulting in a gly498-to-cys (G498C) substitution. The mutation was identified in the index patient by using a gene panel of 28 genes associated with small vessel disease and adult-onset leukodystrophy. The mutation segregated with disease in the family. Studies in patient fibroblasts showed that the mutation resulted in highly efficient exon 9 skipping, which excluded part of the EGFR11 and EGFR12 regions. The mutant protein was expressed at normal levels on the cell surface; however, ligand-dependent signaling was impaired compared to wildtype. Fibroblasts from the patients showed only slightly positive NOTCH3 antibody staining. </p>
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</span>
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</div>
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<div>
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</div>
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</div>
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</div>
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<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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Alves, D., Sampaio, M., Figueiredo, R., Leao, M.
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<strong>Lateral meningocele syndrome: additional report and further evidence supporting a connective tissue basis.</strong>
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[Full Text: https://doi.org/10.1002/ajmg.a.35968]
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Arboleda-Velasquez, J. F., Lopera, F., Lopez, E., Frosch, M. P., Sepulveda-Falla, D., Gutierrez, J. E., Vargas, S., Medina, M., Martinez de Arrieta, C., Lebo, R. V., Slaugenhaupt, S. A., Betensky, R. A., Villegas, A., Arcos-Burgos, M., Rivera, D., Restrepo, J. C., Kosik, K. S.
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<strong>C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke.</strong>
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Arboleda-Velasquez, J. F., Rampal, R., Fung, E., Darland, D. C., Liu, M., Martinez, M. C., Donahue, C. P., Navarro-Gonzalez, M. F., Libby, P., D'Amore, P. A., Aikawa, M., Haltiwanger, R. S., Kosik, K. S.
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<strong>CADASIL mutations impair Notch3 glycosylation by Fringe.</strong>
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Hum. Molec. Genet. 14: 1631-1639, 2005.
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Arboleda-Velasquez, J. F., Zhou, Z., Shin, H. K., Louvi, A., Kim, H.-H., Savitz, S. I., Liao, J. K., Salomone, S., Ayata, C., Moskowitz, M. A., Artavanis-Tsakonas, S.
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<strong>Linking Notch signaling to ischemic stroke.</strong>
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Proc. Nat. Acad. Sci. 105: 4856-4861, 2008.
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Avela, K., Valanne, L., Helenius, I., Makitie, O.
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<strong>Hajdu-Cheney syndrome with severe dural ectasia.</strong>
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Am. J. Med. Genet. 155A: 595-598, 2011.
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[PubMed: 21337686]
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[Full Text: https://doi.org/10.1002/ajmg.a.33510]
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Chen, K. M., Bird, L., Barnes, P., Barth, R., Hudgins, L.
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<strong>Lateral meningocele syndrome: vertical transmission and expansion of the phenotype.</strong>
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Am. J. Med. Genet. 133A: 115-121, 2005.
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[PubMed: 15666314]
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[Full Text: https://doi.org/10.1002/ajmg.a.30526]
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Dichgans, M., Herzog, J., Gasser, T.
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<strong>NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.</strong>
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Neurology 57: 1714-1717, 2001.
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[PubMed: 11706120]
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[Full Text: https://doi.org/10.1212/wnl.57.9.1714]
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<p class="mim-text-font">
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Domenga, V., Fardoux, P., Lacombe, P., Monet, M., Maciazek, J., Krebs, L. T., Klonjkowski, B., Berrou, E., Mericskay, M., Li, Z., Tournier-Lasserve, E., Gridley, T., Joutel, A.
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<strong>Notch3 is required for arterial identity and maturation of vascular smooth muscle cells.</strong>
|
|
Genes Dev. 18: 2730-2735, 2004.
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[PubMed: 15545631]
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[Full Text: https://doi.org/10.1101/gad.308904]
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<p class="mim-text-font">
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Eikermann-Haerter, K., Yuzawa, I., Dilekoz, E., Joutel, A., Moskowitz, M. A., Ayata, C.
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<strong>Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression.</strong>
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Ann. Neurol. 69: 413-418, 2011.
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[PubMed: 21387384]
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[Full Text: https://doi.org/10.1002/ana.22281]
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Ezratty, E. J., Stokes, N., Chai, S., Shah, A. S., Williams, S. E., Fuchs, E.
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<strong>A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.</strong>
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|
Cell 145: 1129-1141, 2011.
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[PubMed: 21703454]
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[Full Text: https://doi.org/10.1016/j.cell.2011.05.030]
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</p>
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Gao, X., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Gridley, T.
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<strong>Assignment of the murine Notch2 and Notch3 genes to chromosomes 3 and 17.</strong>
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Genomics 49: 160-161, 1998.
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[PubMed: 9570965]
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[Full Text: https://doi.org/10.1006/geno.1997.5211]
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<p class="mim-text-font">
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Gravesteijn, G., Dauwerse, J. G., Overzier, M., Brouwer, G., Hegeman, I., Mulder, A. A., Baas, F., Kruit, M. C., Terwindt, G. M., van Duinen, S. G., Jost, C. R., Aartsma-Rus, A., Lesnik Oberstein S. A. J., Rutten, J. W.
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<strong>Naturally occurring NOTCH3 protein aggregation and disease severity in CADASIL patients.</strong>
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Hum. Molec. Genet. 29: 1853-1863, 2020.
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[PubMed: 31960911]
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[Full Text: https://doi.org/10.1093/hmg/ddz285]
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Gridley, T.
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Hum. Molec. Genet. 12(R1): R9-R13, 2003.
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[Full Text: https://doi.org/10.1093/hmg/ddg052]
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<p class="mim-text-font">
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Gripp, K. W., Robbins, K. M., Sobreira, N. L., Witmer, P. D., Bird, L. M., Avela, K., Makitie, O., Alves, D., Hogue, J. S., Zackai, E. H., Doheny, K. F., Stabley, D. L., Sol-Church, K.
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<strong>Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.</strong>
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Am. J. Med. Genet. 167A: 271-281, 2015.
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[PubMed: 25394726]
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[Full Text: https://doi.org/10.1002/ajmg.a.36863]
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<p class="mim-text-font">
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Gripp, K. W., Scott, C. I., Jr., Hughes, H. E., Wallerstein, R., Nicholson, L., States, L., Bason, L. D., Kaplan, P., Zderic, S. A., Duhaime, A. C., Miller, F., Magnusson, M. R., Zackai, E. H.
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<strong>Lateral meningocele syndrome: three new patients and review of the literature.</strong>
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Am. J. Med. Genet. 70: 229-239, 1997.
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[PubMed: 9188658]
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<p class="mim-text-font">
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Joutel, A., Andreux, F., Gaulis, S., Domenga, V., Cecilon, M., Battail, N., Piga, N., Chapon, F., Godfrain, C., Tournier-Lasserve, E.
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<strong>The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients.</strong>
|
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J. Clin. Invest. 105: 597-605, 2000.
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[PubMed: 10712431]
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<li>
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<p class="mim-text-font">
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Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.-A., Ruchoux, M. M., Weissenbach, J., Bach, J. F., Bousser, M. G., Tournier-Lasserve, E.
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<strong>Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.</strong>
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Nature 383: 707-710, 1996.
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[PubMed: 8878478]
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[Full Text: https://doi.org/10.1038/383707a0]
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</p>
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<li>
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<p class="mim-text-font">
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Joutel, A., Dodick, D. D., Parisi, J. E., Cecillon, M., Tournier-Lasserve, E., Bousser, M. G.
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<strong>De novo mutation in the Notch3 gene causing CADASIL.</strong>
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Ann. Neurol. 47: 388-391, 2000.
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[PubMed: 10716263]
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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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Joutel, A., Favrole, P., Labauge, P., Chabriat, H., Lescoat, C., Andreux, F., Domenga, V., Cecillon, M., Vahedi, K., Ducros, A., Cave-Riant, F., Bousser, M. G., Tournier-Lasserve, E.
|
|
<strong>Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.</strong>
|
|
Lancet 358: 2049-2051, 2001.
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[PubMed: 11755616]
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[Full Text: https://doi.org/10.1016/S0140-6736(01)07142-2]
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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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Joutel, A., Monet, M., Domenga, V., Riant, F., Tournier-Lasserve, E.
|
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<strong>Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway.</strong>
|
|
Am. J. Hum. Genet. 74: 338-347, 2004.
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|
[PubMed: 14714274]
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[Full Text: https://doi.org/10.1086/381506]
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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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Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssiere, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.-G., Bach, J.-F., Tournier-Lasserve, E.
|
|
<strong>Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.</strong>
|
|
Lancet 350: 1511-1515, 1997.
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[PubMed: 9388399]
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[Full Text: https://doi.org/10.1016/S0140-6736(97)08083-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Larsson, C., Lardelli, M., White, I., Lendahl, U.
|
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<strong>The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.</strong>
|
|
Genomics 24: 253-258, 1994.
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[PubMed: 7698746]
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[Full Text: https://doi.org/10.1006/geno.1994.1613]
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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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Li, X., Zhang, X., Leathers, R., Makino, A., Huang, C., Parsa, P., Macias, J., Yuan, J. X.-J., Jamieson, S. W., Thistlethwaite, P. A.
|
|
<strong>Notch3 signaling promotes the development of pulmonary arterial hypertension.</strong>
|
|
Nature Med. 15: 1289-1297, 2009.
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[PubMed: 19855400]
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[Full Text: https://doi.org/10.1038/nm.2021]
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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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Low, W. C., Junna, M., Borjesson-Hanson, A., Morris, C. M., Moss, T. H., Stevens, D. L., St Clair, D., Mizuno, T., Zhang, W. W., Mykkanen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R. N.
|
|
<strong>Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.</strong>
|
|
Brain 130: 357-367, 2007.
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[PubMed: 17235124]
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[Full Text: https://doi.org/10.1093/brain/awl360]
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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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<strong>Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank.</strong>
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Saiki, S., Sakai, K., Saiki, M., Kitagawa, Y., Umemori, T., Murata, K., Matsui, M., Hirose, G.
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<strong>Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene.</strong>
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<strong>Chronic familial vascular encephalopathy. (Letter)</strong>
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Takahashi, K., Adachi, K., Yoshizaki, K., Kunimoto, S., Kalaria, R. N., Watanabe, A.
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<strong>Mutations in NOTCH3 cause the formation and retention of aggregates in the endoplasmic reticulum, leading to impaired cell proliferation.</strong>
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Tanigaki, K., Nogaki, F., Takahashi, J., Tashiro, K., Kurooka, H., Honjo, T.
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Wimmer, R. A., Leopoldi, A., Aichinger, M., Wick, N., Hantusch, B., Novatchkova, M., Taubenschmid, J., Hammerle, M., Esk, C., Bagley, J. A., Lindenhofer, D., Chen, G., Boehm, M., Agu, C. A., Yang, F., Fu, B., Zuber, J., Knoblich, J. A., Kerjaschki, D., Penninger, J. M.
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Hilary J. Vernon - updated : 10/01/2021<br>Hilary J. Vernon - updated : 11/30/2020<br>Cassandra L. Kniffin - updated : 09/03/2019<br>Ada Hamosh - updated : 06/06/2019<br>Cassandra L. Kniffin - updated : 8/3/2015<br>Cassandra L. Kniffin - updated : 12/3/2013<br>Cassandra L. Kniffin - updated : 6/27/2013<br>Patricia A. Hartz - updated : 7/5/2012<br>Cassandra L. Kniffin - updated : 8/3/2011<br>George E. Tiller - updated : 11/12/2010<br>George E. Tiller - updated : 6/23/2010<br>Cassandra L. Kniffin - updated : 3/10/2010<br>Cassandra L. Kniffin - updated : 12/15/2009<br>Marla J. F. O'Neill - updated : 12/2/2009<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Patricia A. Hartz - updated : 9/4/2008<br>George E. Tiller - updated : 6/16/2008<br>Cassandra L. Kniffin - updated : 7/31/2007<br>George E. Tiller - updated : 3/2/2005<br>Patricia A. Hartz - updated : 1/5/2005<br>Marla J. F. O'Neill - updated : 11/8/2004<br>Victor A. McKusick - updated : 2/5/2004<br>Cassandra L. Kniffin - updated : 12/3/2002<br>Cassandra L. Kniffin - updated : 10/8/2002<br>Cassandra L. Kniffin - updated : 6/13/2002<br>Anne M. Stumpf - updated : 5/17/2002<br>Victor A. McKusick - updated : 5/13/2002<br>Ada Hamosh - updated : 4/26/2001<br>Victor A. McKusick - updated : 5/1/2000<br>Alan F. Scott - updated : 6/1/1998<br>Victor A. McKusick - updated : 3/24/1998
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</div>
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<div class="modal-footer">
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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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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</body>
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</html>
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