4146 lines
329 KiB
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4146 lines
329 KiB
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Entry
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- *600275 - NOTCH RECEPTOR 2; NOTCH2
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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">*600275</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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="#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/600275">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=ENSG00000134250;t=ENST00000256646" 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=4853" 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=600275" 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=ENSG00000134250;t=ENST00000256646" 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_001200001,NM_024408" 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_024408" 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=600275" 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=02606&isoform_id=02606_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/NOTCH2" 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/1293643,1679774,6453442,11275978,11527997,14042857,24041035,55665845,71052163,119577122,119577123,143811429,283138049,317008611" 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/Q04721" 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=4853" 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=ENSG00000134250;t=ENST00000256646" 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=NOTCH2" 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=NOTCH2" 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+4853" 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/NOTCH2" 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:4853" 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/4853" 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=chr1&hgg_gene=ENST00000256646.7&hgg_start=119911553&hgg_end=120069662&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7882" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/notch2" 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=600275[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=600275[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/NOTCH2/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/ENSG00000134250" 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=NOTCH2" 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=NOTCH2" 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=NOTCH2" 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/NOTCH2" 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=NOTCH2&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/PA31684" 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:7882" 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:97364" 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/NOTCH2#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:97364" 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/4853/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=4853" 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-000329-4" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4853" 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=NOTCH2&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 63122002<br />
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">ICD+</a>
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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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600275
|
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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 2; NOTCH2
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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>
|
|
</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
NOTCH, DROSOPHILA, HOMOLOG OF, 2
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NOTCH2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NOTCH2</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/1/981?start=-3&limit=10&highlight=981">1p12</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:119911553-120069662&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'})">1:119,911,553-120,069,662</a> </span>
|
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</em>
|
|
</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>
|
|
<br />
|
|
</div>
|
|
<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">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=610205,102500" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/981?start=-3&limit=10&highlight=981">
|
|
1p12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Alagille syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/610205"> 610205 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
</span>
|
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</td>
|
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|
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hajdu-Cheney syndrome
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/102500"> 102500 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p>The NOTCH2 gene encodes a single pass transmembrane protein belonging to an evolutionarily conserved NOTCH receptor family (see, e.g., NOTCH1; 190198). NOTCH signaling is activated through cell-cell contact: ligand binding induces cleavage of NOTCH and translocation of the intracellular domain to the nucleus where it regulates gene expression in association with transcriptional cofactors (summary by <a href="#5" class="mim-tip-reference" title="Isidor, B., Lindenbaum, P., Pichon, O., Bezieau, S., Dina, C., Jacquemont, S., Martin-Coignard, D., Thauvin-Robinet, C., Le Merrer, M., Mandel, J.-L., David, A., Faivre, L., Cormier-Daire, V., Redon, R., Le Caignec, C. <strong>Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.</strong> Nature Genet. 43: 306-308, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378989</a>] [<a href="https://doi.org/10.1038/ng.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378989">Isidor et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378989" 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>Using probes designed from the amino acid sequence of purified human Notch2 protein, and by homology to the rat Notch2 cDNA sequence, <a href="#2" class="mim-tip-reference" title="Blaumueller, C. M., Qi, H., Zagouras, P., Artavanis-Tsakonas, S. <strong>Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.</strong> Cell 90: 281-291, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244302</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80336-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244302">Blaumueller et al. (1997)</a> cloned Notch2 from a fetal brain cDNA library. The deduced 2,471-amino acid protein contains multiple EGF (<a href="/entry/131530">131530</a>) repeats, lin-12/Notch repeats, a transmembrane domain, and ankyrin (<a href="/entry/612641">612641</a>) repeats. It also contains a PEST sequence for proteolytic processing, a nuclear localization signal, and several putative phosphorylation sites. Western blot analysis of a neuroblastoma cell line revealed a mature processed protein with an apparent molecular mass of about 110 kD and a full-length precursor with an apparent molecular mass of about 300 kD. Western blot analysis of lysates from brain, heart, kidney, lung, skeletal muscle, and liver revealed both forms in each tissue, but there were differences in the ratio between the full-length protein and the processed form. <a href="#2" class="mim-tip-reference" title="Blaumueller, C. M., Qi, H., Zagouras, P., Artavanis-Tsakonas, S. <strong>Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.</strong> Cell 90: 281-291, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244302</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80336-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244302">Blaumueller et al. (1997)</a> determined that proteolytic processing of Notch2 occurs in the trans-Golgi network as the protein traffics toward the plasma membrane. Cleavage results in a C-terminal fragment that retains the transmembrane domain and an N-terminal fragment that contains most of the extracellular region. The authors determined that these fragments are tethered together by disulfide linkages at the plasma membrane, and they form a heterodimeric receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9244302" 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="Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., Trembath, R. C. <strong>Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.</strong> Nature Genet. 43: 303-305, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378985</a>] [<a href="https://doi.org/10.1038/ng.779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378985">Simpson et al. (2011)</a> stated that the NOTCH2 gene contains 34 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378985" 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="#9" 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> identified cosmid clones for 3 human NOTCH genes, NOTCH1, NOTCH2, and NOTCH3 (<a href="/entry/600276">600276</a>). Using these clones as probes in fluorescence in situ hybridization to human metaphase chromosomes, they obtained results which, combined with data from somatic cell hybrid panels, demonstrated that NOTCH2 is located on 1p13-p11 and NOTCH3 on 19p13.2-p13.1, which are regions of neoplasia-associated translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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><p>As part of a study of a triplication of several Mb occurring on chromosomes 1, 6, and 9, <a href="#7" class="mim-tip-reference" title="Katsanis, N., Fitzgibbon, J., Fisher, E. M. C. <strong>Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci.</strong> Genomics 35: 101-108, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661110</a>] [<a href="https://doi.org/10.1006/geno.1996.0328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661110">Katsanis et al. (1996)</a> confirmed the presence of a NOTCH locus on chromosome 1. <a href="#3" 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 Notch2 gene to chromosome 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9570965+8661110" 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="#10" class="mim-tip-reference" title="Loomes, K. M., Taichman, D. B., Glover, C. L., Williams, P. T., Markowitz, J. E., Piccoli, D. A., Baldwin, H. S., Oakey, R. J. <strong>Characterization of Notch receptor expression in the developing mammalian heart and liver.</strong> Am. J. Med. Genet. 112: 181-189, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12244553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12244553</a>] [<a href="https://doi.org/10.1002/ajmg.10592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12244553">Loomes et al. (2002)</a> characterized Notch receptor expression in the developing mouse heart and liver. In the developing mouse heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, and in specific cell populations previously shown to express Jag1 (<a href="/entry/601920">601920</a>) by <a href="#11" class="mim-tip-reference" title="Loomes, K. M., Underkoffler, L. A., Morabito, J., Gottlieb, S., Piccoli, D. A., Spinner, N. B., Baldwin, H. S., Oakey, R. J. <strong>The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome.</strong> Hum. Molec. Genet. 8: 2443-2449, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10556292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10556292</a>] [<a href="https://doi.org/10.1093/hmg/8.13.2443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10556292">Loomes et al. (1999)</a>. These cells are destined to undergo transformation from epithelial to mesenchymal cells. In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development. Jag1 is also expressed in cells adjacent to those expressing Notch2, suggesting a possible ligand-receptor interaction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12244553+10556292" 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="#15" class="mim-tip-reference" title="Mitsiadis, T. A., Romeas, A., Lendahl, U., Sharpe, P. T., Farges, J. C. <strong>Notch2 protein distribution in human teeth under normal and pathological conditions.</strong> Exp. Cell Res. 282: 101-109, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531696</a>] [<a href="https://doi.org/10.1016/s0014-4827(02)00012-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531696">Mitsiadis et al. (2003)</a> determined that Notch2 is involved in tooth development. During early stages, Notch2 was expressed in the epithelium and, at more advanced stages of development, it was expressed in the enamel-producing ameloblasts. Notch2 was not expressed in the pulp of adult intact teeth, but was reexpressed during dentin repair in odontoblasts and in subdontoblastic cells. TGFB1 (<a href="/entry/190180">190180</a>), which stimulated odontoblast differentiation and hard tissue formation after dental injury, downregulated Notch2 expressed in cultured human dental slices. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531696" 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>Ligand binding in Notch receptors triggers a conformational change in the receptor-negative regulatory region (NRR) that enables ADAM protease (see <a href="/entry/601533">601533</a>) cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalyzed by the gamma-secretase complex liberates the intracellular domain to initiate downstream Notch transcriptional program. Aberrant signaling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for drugs (summary by <a href="#21" class="mim-tip-reference" title="Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others. <strong>Therapeutic antibody targeting of individual Notch receptors.</strong> Nature 464: 1052-1057, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393564</a>] [<a href="https://doi.org/10.1038/nature08878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20393564">Wu et al., 2010</a>). Although gamma-secretase inhibitors (GSIs) had progressed into the clinic, GSIs failed to distinguish individual Notch receptors, inhibited other signaling pathways, and caused intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (<a href="#17" class="mim-tip-reference" title="Riccio, O., van Gijn, M. E., Bezdek, A. C., Pellegrinet, L., van Es, J. H., Zimber-Strobl, U., Strobl, L. J., Honjo, T., Clevers, H., Radtke, F. <strong>Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied y derepression of CDK inhibitors p27Kip1 and p57Kip2.</strong> EMBO Rep. 9: 377-383, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18274550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18274550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18274550[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/embor.2008.7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18274550">Riccio et al., 2008</a>). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, <a href="#21" class="mim-tip-reference" title="Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others. <strong>Therapeutic antibody targeting of individual Notch receptors.</strong> Nature 464: 1052-1057, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393564</a>] [<a href="https://doi.org/10.1038/nature08878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20393564">Wu et al. (2010)</a> used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralog and yet crossreact with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. The cocrystal structure showed that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibited tumor growth in preclinical models through 2 mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20393564+18274550" 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="Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C. <strong>Neural crest regulates myogenesis through the transient activation of NOTCH.</strong> Nature 473: 532-535, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21572437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21572437</a>] [<a href="https://doi.org/10.1038/nature09970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21572437">Rios et al. (2011)</a> characterized the signaling events taking place during morphogenesis of chick skeletal muscle, and showed that muscle progenitors present in somites require the transient activation of NOTCH signaling to undergo terminal differentiation. The NOTCH ligand Delta1 (<a href="/entry/606582">606582</a>) is expressed in a mosaic pattern in neural crest cells that migrate past the somites. Gain and loss of Delta1 function in neural crest modifies NOTCH signaling in somites, which results in delayed or premature myogenesis. <a href="#18" class="mim-tip-reference" title="Rios, A. C., Serralbo, O., Salgado, D., Marcelle, C. <strong>Neural crest regulates myogenesis through the transient activation of NOTCH.</strong> Nature 473: 532-535, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21572437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21572437</a>] [<a href="https://doi.org/10.1038/nature09970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21572437">Rios et al. (2011)</a> concluded that the neural crest regulates early muscle formation by a unique mechanism that relies on the migration of Delta1-expressing neural crest cells to trigger the transient activation of NOTCH signaling in selected muscle progenitors. This dynamic signaling guarantees a balanced and progressive differentiation of the muscle progenitor pool. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21572437" 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>Alagille Syndrome</em></strong></p><p>
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Alagille syndrome (ALGS; see <a href="/entry/118450">118450</a>) is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. In about 94% of patients with ALGS, mutations in the gene encoding the NOTCH signaling pathway ligand Jagged-1 (JAG1; <a href="/entry/601920">601920</a>) had been identified. To identify the cause of disease in patients without JAG1 mutations, <a href="#14" class="mim-tip-reference" title="McDaniell, R., Warthen, D. M., Sanchez-Lara, P. A., Pai, A., Krantz, I. D., Piccoli, D. A., Spinner, N. B. <strong>NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway.</strong> Am. J. Hum. Genet. 79: 169-173, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773578[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773578">McDaniell et al. (2006)</a> screened 11 JAG1 mutation-negative probands with ALGS for alterations in the gene for the NOTCH2 receptor. They found NOTCH2 mutations segregating in 2 families with Alagille syndrome (ALGS2; <a href="/entry/610205">610205</a>) and identified 5 affected individuals. Renal manifestations, a minor feature of ALGS, were present in all affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773578" 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>Hajdu-Cheney Syndrome</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., Trembath, R. C. <strong>Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.</strong> Nature Genet. 43: 303-305, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378985</a>] [<a href="https://doi.org/10.1038/ng.779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378985">Simpson et al. (2011)</a> performed whole-exome sequencing of 3 unrelated individuals of European origin with Hajdu-Cheney syndrome (HJCYS; <a href="/entry/102500">102500</a>), also known as acroosteolysis with osteoporosis and changes in the skull and mandible, and identified 3 different truncating mutations in exon 34 of the NOTCH2 gene. One of the patients had affected relatives, and the mutation (<a href="#0003">600275.0003</a>) was found to segregate with the disorder in that family. Further analysis of exon 34 of the NOTCH2 gene identified further truncating mutations in 11 additional probands with the disorder, including 8 patients with sporadic disease who had a de novo mutation (see, e.g., <a href="#0004">600275.0004</a>-<a href="#0005">600275.0005</a>). All the mutations occurred in exon 34, the last exon of the NOTCH2 gene, and all were predicted to lead to truncation of the protein product before complete translation of the PEST domain, which mediates proteosomal destruction of the protein. The mutations escaped nonsense-mediated mRNA decay and the truncated proteins were expressed. Thus, the mutations resulted in persistence of the Notch intracellular signal, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378985" 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>Simultaneously and independently, <a href="#5" class="mim-tip-reference" title="Isidor, B., Lindenbaum, P., Pichon, O., Bezieau, S., Dina, C., Jacquemont, S., Martin-Coignard, D., Thauvin-Robinet, C., Le Merrer, M., Mandel, J.-L., David, A., Faivre, L., Cormier-Daire, V., Redon, R., Le Caignec, C. <strong>Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.</strong> Nature Genet. 43: 306-308, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378989</a>] [<a href="https://doi.org/10.1038/ng.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378989">Isidor et al. (2011)</a> identified 5 different truncating mutations in exon 34 of the NOTCH2 gene (see, e.g., <a href="#0006">600275.0006</a>-<a href="#0007">600275.0007</a>) in 5 unrelated probands with Hajdu-Cheney syndrome by exome sequencing. The mutant mRNAs were expected to be stable and result in truncated proteins with constitutively active intracellular domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378989" 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="Majewski, J., Schwartzentruber, J. A., Caqueret, A., Patry, L., Marcadier, J., Fryns, J.-P., Boycott, K. M., Ste-Marie, L.-G., McKiernan, F. E., Marik, I., Van Esch, H., FORGE Canada Consortium, Michaud, J. L., Samuels, M. E. <strong>Mutations in NOTCH2 in families with Hajdu-Cheney syndrome.</strong> Hum. Mutat. 32: 1114-1117, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21681853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21681853</a>] [<a href="https://doi.org/10.1002/humu.21546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21681853">Majewski et al. (2011)</a> identified 6 different heterozygous truncating mutations in the NOTCH2 gene in affected members of 7 families with Hajdu-Cheney syndrome. Mutations in the first 3 families were found by whole-exome sequencing. All of the mutations were clustered in exon 34 near the C terminus. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21681853" 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="Gray, M. J., Kim, C. A., Bertola, D. R., Arantes, P. R., Stewart, H., Simpson, M. A., Irving, M. D., Robertson, S. P. <strong>Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome.</strong> Europ. J. Hum. Genet. 20: 122-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21712856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21712856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21712856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21712856">Gray et al. (2012)</a> identified heterozygous truncating mutations in exon 34 of the NOTCH2 gene (<a href="#0008">600275.0008</a> and <a href="#0009">600275.0009</a>) in 2 unrelated patients with phenotypic features of both serpentine fibula-polycystic kidney syndrome (SFPKS) and Hajdu-Cheney syndrome. The phenotypic overlap between HJCYS and SFPKS had been noted before by <a href="#6" class="mim-tip-reference" title="Kaplan, P., Ramos, F., Zackai, E. H., Bellah, R. D., Kaplan, B. S. <strong>Cystic kidney disease in Hajdu-Cheney syndrome.</strong> Am. J. Med. Genet. 56: 25-30, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7747781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7747781</a>] [<a href="https://doi.org/10.1002/ajmg.1320560108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7747781">Kaplan et al. (1995)</a> and <a href="#16" class="mim-tip-reference" title="Ramos, F. J., Kaplan, B. S., Bellah, R. D., Zackai, E. H., Kaplan, P. <strong>Further evidence that the Hajdu-Cheney syndrome and the 'serpentine fibula-polycystic kidney syndrome' are a single entity.</strong> Am. J. Med. Genet. 78: 474-481, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714016</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980806)78:5<474::aid-ajmg14>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9714016">Ramos et al. (1998)</a>, both of whom had suggested that the 2 disorders may be allelic. The mutations identified by <a href="#4" class="mim-tip-reference" title="Gray, M. J., Kim, C. A., Bertola, D. R., Arantes, P. R., Stewart, H., Simpson, M. A., Irving, M. D., Robertson, S. P. <strong>Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome.</strong> Europ. J. Hum. Genet. 20: 122-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21712856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21712856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21712856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21712856">Gray et al. (2012)</a> were located in the same gene region as mutations that cause HJCYS, with the same activating effect on protein function. The molecular findings indicated that SFPKS should be considered part of the phenotypic spectrum of HJCYS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7747781+9714016+21712856" 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>To assess the in vivo role of the Notch2 gene, <a href="#13" class="mim-tip-reference" title="McCright, B., Gao, X., Shen, L., Lozier, J., Lan, Y., Maguire, M., Herzlinger, D., Weinmaster, G., Jiang, R., Gridley, T. <strong>Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation.</strong> Development 128: 491-502, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11171333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11171333</a>] [<a href="https://doi.org/10.1242/dev.128.4.491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11171333">McCright et al. (2001)</a> constructed a targeted mutation, Notch2(del1). They found that alternative splicing of the Notch2(del1) mutant allele led to the production of 2 different in-frame transcripts that delete either 1 or 2 EGF repeats of the Notch2 protein, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2(del1) mutation died perinatally from defects in glomerular development in the kidney. Notch2(del1)/Notch2(del1) mutant kidneys were hypoplastic and mutant glomeruli lacked a normal capillary tuft. The Notch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells. <a href="#13" class="mim-tip-reference" title="McCright, B., Gao, X., Shen, L., Lozier, J., Lan, Y., Maguire, M., Herzlinger, D., Weinmaster, G., Jiang, R., Gridley, T. <strong>Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation.</strong> Development 128: 491-502, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11171333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11171333</a>] [<a href="https://doi.org/10.1242/dev.128.4.491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11171333">McCright et al. (2001)</a> showed that mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibited a glomerular defect similar to, but less severe than, that of Notch2(del1)/Notch2(del1) homozygotes. The colocalization and genetic interaction of Jag1 and Notch2 implied that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1) homozygotes also displayed myocardial hypoplasia, edema, and hyperplasia of cells associated with the hyaloid vasculature of the eye. <a href="#13" class="mim-tip-reference" title="McCright, B., Gao, X., Shen, L., Lozier, J., Lan, Y., Maguire, M., Herzlinger, D., Weinmaster, G., Jiang, R., Gridley, T. <strong>Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation.</strong> Development 128: 491-502, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11171333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11171333</a>] [<a href="https://doi.org/10.1242/dev.128.4.491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11171333">McCright et al. (2001)</a> concluded that their data identified novel developmental roles for Notch2 in kidney, heart, and eye development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11171333" 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="#8" class="mim-tip-reference" title="Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T. <strong>Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.</strong> Genes Dev. 17: 1207-1212, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730124[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.1084703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730124">Krebs et al. (2003)</a> showed that mouse embryos mutant for the Notch ligand Dll1 (<a href="/entry/606582">606582</a>) or doubly mutant for Notch1 and Notch2 exhibited multiple defects in left-right asymmetry. Dll1 -/- embryos did not express Nodal (<a href="/entry/601265">601265</a>) in the region around the node. Analysis of the enhancer regulating node-specific Nodal expression revealed binding sites for Rbpj (RBPSUH; <a href="/entry/147183">147183</a>). Mutation of these sites destroyed the ability of the enhancer to direct node-specific gene expression in transgenic mice. <a href="#8" class="mim-tip-reference" title="Krebs, L. T., Iwai, N., Nonaka, S., Welsh, I. C., Lan, Y., Jiang, R., Saijoh, Y., O'Brien, T. P., Hamada, H., Gridley, T. <strong>Notch signaling regulates left-right asymmetry determination by inducing Nodal expression.</strong> Genes Dev. 17: 1207-1212, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12730124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12730124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12730124[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.1084703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12730124">Krebs et al. (2003)</a> concluded that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that perinodal expression of Nodal is an essential component of left-right asymmetry determination in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12730124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600275[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 ALAGILLE SYNDROME 2</strong>
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NOTCH2, IVS33AS, G-A, -1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs312262798 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs312262798;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=rs312262798" 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=rs312262798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009810" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009810" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009810</a>
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<p><a href="#14" class="mim-tip-reference" title="McDaniell, R., Warthen, D. M., Sanchez-Lara, P. A., Pai, A., Krantz, I. D., Piccoli, D. A., Spinner, N. B. <strong>NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway.</strong> Am. J. Hum. Genet. 79: 169-173, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773578[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773578">McDaniell et al. (2006)</a> described a mother and son with Alagille syndrome (<a href="/entry/610205">610205</a>), both of whom had a splice acceptor mutation (5930-1G-A) in exon 33 of the NOTCH2 gene. The proband had cholestatic liver disease, cardiac disease characteristic facial features, and severe infantile renal disease. He died of cardiopulmonary arrest at age 2. His mother had valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant. The maternal grandparents and 3 of the mother's sibs did not carry the mutation, indicating it was a de novo change in the proband's mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0002" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0002 ALAGILLE SYNDROME 2</strong>
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<span class="mim-text-font">
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NOTCH2, CYS444TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs111033632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs111033632;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=rs111033632" 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=rs111033632" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009811" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009811" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009811</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a proband, her mother, and her grandmother with Alagille syndrome (<a href="/entry/610205">610205</a>), <a href="#14" class="mim-tip-reference" title="McDaniell, R., Warthen, D. M., Sanchez-Lara, P. A., Pai, A., Krantz, I. D., Piccoli, D. A., Spinner, N. B. <strong>NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway.</strong> Am. J. Hum. Genet. 79: 169-173, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16773578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16773578</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16773578[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16773578">McDaniell et al. (2006)</a> identified a 1331G-A transition in exon 8 of the NOTCH2 gene that resulted in a cys444-to-tyr (C444Y) substitution in the eleventh EGF-like repeat of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16773578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 HAJDU-CHENEY SYNDROME</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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<div style="float: left;">
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NOTCH2, 1-BP DEL, 6272T
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1557802353 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1557802353;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=rs1557802353" 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=rs1557802353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022957" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022957" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022957</a>
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</span>
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<span class="mim-text-font">
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<p>In 3 affected members of a family with autosomal dominant Hajdu-Cheney syndrome, also known as acroosteolysis with osteoporosis and changes in the skull and mandible (<a href="/entry/102500">102500</a>), <a href="#20" class="mim-tip-reference" title="Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., Trembath, R. C. <strong>Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.</strong> Nature Genet. 43: 303-305, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378985</a>] [<a href="https://doi.org/10.1038/ng.779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378985">Simpson et al. (2011)</a> identified a heterozygous 1-bp deletion (6272delT) in exon 34 of the NOTCH2 gene, resulting in a frameshift and premature termination. The mutation occurred in the last exon of the NOTCH2 gene and escaped nonsense-mediated mRNA decay. RT-PCR studies showed that the truncated protein was expressed in patient fibroblasts. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 HAJDU-CHENEY SYNDROME</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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<div style="float: left;">
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NOTCH2, 1-BP DEL, 6460T
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022958" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022958" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022958</a>
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</span>
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<span class="mim-text-font">
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<p>In 3 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (<a href="/entry/102500">102500</a>), <a href="#20" class="mim-tip-reference" title="Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., Trembath, R. C. <strong>Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.</strong> Nature Genet. 43: 303-305, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378985</a>] [<a href="https://doi.org/10.1038/ng.779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378985">Simpson et al. (2011)</a> identified a heterozygous 1-bp deletion (6460delT) in exon 34 of the NOTCH2 gene, resulting in a frameshift and premature termination. The mutation occurred in the last exon of the NOTCH2 gene and likely escaped nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 HAJDU-CHENEY SYNDROME</strong>
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</span>
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</h4>
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</div>
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NOTCH2, GLN2208TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906746 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906746;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=rs387906746" 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=rs387906746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022959" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022959" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022959</a>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (<a href="/entry/102500">102500</a>), <a href="#20" class="mim-tip-reference" title="Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., Trembath, R. C. <strong>Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.</strong> Nature Genet. 43: 303-305, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378985</a>] [<a href="https://doi.org/10.1038/ng.779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378985">Simpson et al. (2011)</a> identified a heterozygous 6622C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2208-to-ter (Q2208X) substitution. The Q2208X mutation was also found in 2 affected members of a second unrelated family with Hajdu-Cheney syndrome. The mutation occurred in the last exon of the NOTCH2 gene and likely escaped nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 HAJDU-CHENEY SYNDROME</strong>
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</h4>
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NOTCH2, TYR2373TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1557801639 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1557801639;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=rs1557801639" 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=rs1557801639" 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=RCV000022960" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022960" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022960</a>
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<p>In 4 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (<a href="/entry/102500">102500</a>), <a href="#5" class="mim-tip-reference" title="Isidor, B., Lindenbaum, P., Pichon, O., Bezieau, S., Dina, C., Jacquemont, S., Martin-Coignard, D., Thauvin-Robinet, C., Le Merrer, M., Mandel, J.-L., David, A., Faivre, L., Cormier-Daire, V., Redon, R., Le Caignec, C. <strong>Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.</strong> Nature Genet. 43: 306-308, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378989</a>] [<a href="https://doi.org/10.1038/ng.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378989">Isidor et al. (2011)</a> identified a heterozygous 7119T-G transversion in exon 34 of the NOTCH2 gene, resulting in a tyr2373-to-ter (Y2373X) substitution. The mutation occurred in the last exon of the NOTCH2 gene and was expected to escape nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378989" 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">rs387906747 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906747;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=rs387906747" 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=rs387906747" 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=RCV000022961" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022961" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022961</a>
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<p>In 2 affected members of a family with autosomal dominant acroosteolysis with osteoporosis and changes in the skull and mandible (<a href="/entry/102500">102500</a>), <a href="#5" class="mim-tip-reference" title="Isidor, B., Lindenbaum, P., Pichon, O., Bezieau, S., Dina, C., Jacquemont, S., Martin-Coignard, D., Thauvin-Robinet, C., Le Merrer, M., Mandel, J.-L., David, A., Faivre, L., Cormier-Daire, V., Redon, R., Le Caignec, C. <strong>Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.</strong> Nature Genet. 43: 306-308, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378989</a>] [<a href="https://doi.org/10.1038/ng.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21378989">Isidor et al. (2011)</a> identified a heterozygous 6949C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2317-to-ter (Q2317X) substitution. The mutation occurred in the last exon of the NOTCH2 gene and was expected to escape nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378989" 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">rs387906748 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906748;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=rs387906748" 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=rs387906748" 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=RCV000022962" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022962" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022962</a>
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<p>In a girl with Hajdu-Cheney syndrome (<a href="/entry/102500">102500</a>), <a href="#4" class="mim-tip-reference" title="Gray, M. J., Kim, C. A., Bertola, D. R., Arantes, P. R., Stewart, H., Simpson, M. A., Irving, M. D., Robertson, S. P. <strong>Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome.</strong> Europ. J. Hum. Genet. 20: 122-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21712856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21712856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21712856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21712856">Gray et al. (2012)</a> identified a heterozygous 6895G-T transversion in exon 34 of the NOTCH2 gene, resulting in a glu2299-to-ter (E2299X) substitution. The truncated protein was predicted to lack the PEST domain, leading to an increased level of NOTCH signaling in multiple tissues. The patient had originally been reported by <a href="#19" class="mim-tip-reference" title="Rosser, E. M., Mann, N. P., Hall, C. M., Winter, R. M. <strong>Serpentine fibula syndrome: expansion of the phenotype with three affected siblings.</strong> Clin. Dysmorph. 5: 105-113, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8723560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8723560</a>] [<a href="https://doi.org/10.1097/00019605-199604000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8723560">Rosser et al. (1996)</a> as having serpentine fibula-polycystic kidney syndrome. On follow-up by <a href="#4" class="mim-tip-reference" title="Gray, M. J., Kim, C. A., Bertola, D. R., Arantes, P. R., Stewart, H., Simpson, M. A., Irving, M. D., Robertson, S. P. <strong>Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome.</strong> Europ. J. Hum. Genet. 20: 122-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21712856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21712856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21712856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21712856">Gray et al. (2012)</a> between ages 8 and 12 years, she showed mild developmental delay and progressive pulmonary disease requiring supplemental oxygen and corticosteroid treatment. Facial dysmorphism included narrow hirsute forehead, low posterior hairline, shallow supraorbital ridges, horizontal palpebral fissures, a convergent squint, a pinched nasal bridge with a wide nose, a small mouth, dental malocclusion, low-set posteriorly rotated ears, and prominent maxillae. She had short stature, acroosteolysis, osteoporosis, and stress fractures of the metatarsals bilaterally. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8723560+21712856" 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">rs387906749 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906749;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=rs387906749" 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=rs387906749" 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=RCV000022963" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022963" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022963</a>
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<p>In a girl with Hajdu-Cheney syndrome (<a href="/entry/102500">102500</a>), <a href="#4" class="mim-tip-reference" title="Gray, M. J., Kim, C. A., Bertola, D. R., Arantes, P. R., Stewart, H., Simpson, M. A., Irving, M. D., Robertson, S. P. <strong>Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome.</strong> Europ. J. Hum. Genet. 20: 122-124, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21712856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21712856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21712856[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21712856">Gray et al. (2012)</a> identified a heterozygous 7165C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2389-to-ter (Q2389X) substitution. The truncated protein was predicted to lack the PEST domain, leading to an increased level of NOTCH signaling in multiple tissues. The patient was originally reported by <a href="#1" class="mim-tip-reference" title="Albano, L. M., Bertola, D. R., Barba, M. F., Valente, M., Robertson, S. P., Kim, C A. <strong>Phenotypic overlap in Melnick-Needles, serpentine fibula-polycystic kidney and Hajdu-Cheney syndromes: a clinical and molecular study in three patients.</strong> Clin. Dysmorph. 16: 27-33, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159511</a>] [<a href="https://doi.org/10.1097/01.mcd.0000228418.74413.52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159511">Albano et al. (2007)</a> as having serpentine fibula-polycystic kidney syndrome. At age 8 years, she had persistent ductus arteriosus, ventricular septal defect, and facial dysmorphism, including a thin upper lip, downturned mouth, wide nasal tip, long and flat philtrum, dysplastic and posteriorly rotated ears, and short neck. She had bilateral sensorineural hearing loss. Skeletal studies showed wormian bones, vertebral abnormalities, and serpentine fibulae. Ultrasound examination showed polycystic kidneys, but renal function was normal. At age 18 years, she had short stature, hypothyroidism, bathrocephaly, and irregular tooth positioning. There was no significant acroosteolysis of the hands or feet, but she had mild thinning of the distal phalanges. Brain MRI scan showed basilar invagination and abnormal curvature of the cervical spine without cord compression. Intelligence was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21712856+17159511" 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>Phenotypic overlap in Melnick-Needles, serpentine fibula-polycystic kidney and Hajdu-Cheney syndromes: a clinical and molecular study in three patients.</strong>
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Clin. Dysmorph. 16: 27-33, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159511" 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/10.1097/01.mcd.0000228418.74413.52" target="_blank">Full Text</a>]
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Blaumueller, C. M., Qi, H., Zagouras, P., Artavanis-Tsakonas, S.
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<strong>Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.</strong>
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Cell 90: 281-291, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244302</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9244302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80336-0" target="_blank">Full Text</a>]
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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: <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://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9570965" 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.1320560108" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0328" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1613" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21546" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/00019605-199604000-00002" target="_blank">Full Text</a>]
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</p>
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<a id="20" class="mim-anchor"></a>
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<a id="Simpson2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., Trembath, R. C.
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<strong>Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.</strong>
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Nature Genet. 43: 303-305, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21378985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21378985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21378985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.779" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Wu2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., Wu, X., Ridgway, J., Schahin-Reed, D., Dow, G. J., and 12 others.
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<strong>Therapeutic antibody targeting of individual Notch receptors.</strong>
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Nature 464: 1052-1057, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20393564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20393564</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20393564" 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/nature08878" target="_blank">Full Text</a>]
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</p>
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</ol>
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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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Cassandra L. Kniffin - updated : 5/13/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Ada Hamosh - updated : 6/22/2011<br>Cassandra L. Kniffin - updated : 4/25/2011<br>Ada Hamosh - updated : 5/27/2010<br>Patricia A. Hartz - updated : 7/10/2007<br>Victor A. McKusick - updated : 6/16/2006<br>Patricia A. Hartz - updated : 4/21/2003<br>Deborah L. Stone - updated : 3/26/2003<br>Alan F. Scott - updated : 6/1/1998<br>Alan F. Scott- updated : 8/29/1996
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/4/1995
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/07/2019
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 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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carol : 03/01/2016<br>ckniffin : 5/13/2015<br>carol : 9/10/2013<br>terry : 7/27/2012<br>carol : 3/20/2012<br>ckniffin : 3/19/2012<br>alopez : 3/8/2012<br>carol : 7/6/2011<br>alopez : 6/24/2011<br>terry : 6/22/2011<br>wwang : 4/28/2011<br>ckniffin : 4/25/2011<br>alopez : 6/1/2010<br>terry : 5/27/2010<br>wwang : 5/27/2009<br>carol : 2/26/2009<br>wwang : 6/19/2008<br>mgross : 9/27/2007<br>terry : 7/10/2007<br>carol : 8/16/2006<br>wwang : 8/10/2006<br>alopez : 6/22/2006<br>alopez : 6/22/2006<br>terry : 6/16/2006<br>cwells : 4/23/2003<br>terry : 4/21/2003<br>carol : 3/26/2003<br>carol : 3/26/2003<br>terry : 6/1/1998<br>mark : 1/19/1998<br>terry : 8/29/1996<br>marlene : 8/20/1996<br>mimadm : 9/23/1995<br>carol : 1/5/1995<br>carol : 1/4/1995
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600275
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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NOTCH RECEPTOR 2; NOTCH2
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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NOTCH, DROSOPHILA, HOMOLOG OF, 2
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NOTCH2</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 63122002;
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<strong>
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<em>
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Cytogenetic location: 1p12
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:119,911,553-120,069,662 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<td rowspan="2">
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<span class="mim-font">
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1p12
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<td>
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<span class="mim-font">
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Alagille syndrome 2
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</td>
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<td>
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<span class="mim-font">
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610205
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<td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Hajdu-Cheney syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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102500
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<td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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</tbody>
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</table>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The NOTCH2 gene encodes a single pass transmembrane protein belonging to an evolutionarily conserved NOTCH receptor family (see, e.g., NOTCH1; 190198). NOTCH signaling is activated through cell-cell contact: ligand binding induces cleavage of NOTCH and translocation of the intracellular domain to the nucleus where it regulates gene expression in association with transcriptional cofactors (summary by Isidor et al., 2011). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using probes designed from the amino acid sequence of purified human Notch2 protein, and by homology to the rat Notch2 cDNA sequence, Blaumueller et al. (1997) cloned Notch2 from a fetal brain cDNA library. The deduced 2,471-amino acid protein contains multiple EGF (131530) repeats, lin-12/Notch repeats, a transmembrane domain, and ankyrin (612641) repeats. It also contains a PEST sequence for proteolytic processing, a nuclear localization signal, and several putative phosphorylation sites. Western blot analysis of a neuroblastoma cell line revealed a mature processed protein with an apparent molecular mass of about 110 kD and a full-length precursor with an apparent molecular mass of about 300 kD. Western blot analysis of lysates from brain, heart, kidney, lung, skeletal muscle, and liver revealed both forms in each tissue, but there were differences in the ratio between the full-length protein and the processed form. Blaumueller et al. (1997) determined that proteolytic processing of Notch2 occurs in the trans-Golgi network as the protein traffics toward the plasma membrane. Cleavage results in a C-terminal fragment that retains the transmembrane domain and an N-terminal fragment that contains most of the extracellular region. The authors determined that these fragments are tethered together by disulfide linkages at the plasma membrane, and they form a heterodimeric receptor. </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 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>Simpson et al. (2011) stated that the NOTCH2 gene contains 34 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) identified cosmid clones for 3 human NOTCH genes, NOTCH1, NOTCH2, and NOTCH3 (600276). Using these clones as probes in fluorescence in situ hybridization to human metaphase chromosomes, they obtained results which, combined with data from somatic cell hybrid panels, demonstrated that NOTCH2 is located on 1p13-p11 and NOTCH3 on 19p13.2-p13.1, which are regions of neoplasia-associated translocation. </p><p>As part of a study of a triplication of several Mb occurring on chromosomes 1, 6, and 9, Katsanis et al. (1996) confirmed the presence of a NOTCH locus on chromosome 1. Gao et al. (1998) mapped the mouse Notch2 gene to chromosome 3. </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>Loomes et al. (2002) characterized Notch receptor expression in the developing mouse heart and liver. In the developing mouse heart, both Notch1 and Notch2 are expressed in the outflow tracts and the epicardium, and in specific cell populations previously shown to express Jag1 (601920) by Loomes et al. (1999). These cells are destined to undergo transformation from epithelial to mesenchymal cells. In the newborn mouse liver, Notch2 and Notch3 are expressed in opposing cell populations, suggesting they play different roles in cell fate determination during bile duct development. Jag1 is also expressed in cells adjacent to those expressing Notch2, suggesting a possible ligand-receptor interaction. </p><p>Mitsiadis et al. (2003) determined that Notch2 is involved in tooth development. During early stages, Notch2 was expressed in the epithelium and, at more advanced stages of development, it was expressed in the enamel-producing ameloblasts. Notch2 was not expressed in the pulp of adult intact teeth, but was reexpressed during dentin repair in odontoblasts and in subdontoblastic cells. TGFB1 (190180), which stimulated odontoblast differentiation and hard tissue formation after dental injury, downregulated Notch2 expressed in cultured human dental slices. </p><p>Ligand binding in Notch receptors triggers a conformational change in the receptor-negative regulatory region (NRR) that enables ADAM protease (see 601533) cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalyzed by the gamma-secretase complex liberates the intracellular domain to initiate downstream Notch transcriptional program. Aberrant signaling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for drugs (summary by Wu et al., 2010). Although gamma-secretase inhibitors (GSIs) had progressed into the clinic, GSIs failed to distinguish individual Notch receptors, inhibited other signaling pathways, and caused intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (Riccio et al., 2008). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, Wu et al. (2010) used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralog and yet crossreact with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. The cocrystal structure showed that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibited tumor growth in preclinical models through 2 mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. </p><p>Rios et al. (2011) characterized the signaling events taking place during morphogenesis of chick skeletal muscle, and showed that muscle progenitors present in somites require the transient activation of NOTCH signaling to undergo terminal differentiation. The NOTCH ligand Delta1 (606582) is expressed in a mosaic pattern in neural crest cells that migrate past the somites. Gain and loss of Delta1 function in neural crest modifies NOTCH signaling in somites, which results in delayed or premature myogenesis. Rios et al. (2011) concluded that the neural crest regulates early muscle formation by a unique mechanism that relies on the migration of Delta1-expressing neural crest cells to trigger the transient activation of NOTCH signaling in selected muscle progenitors. This dynamic signaling guarantees a balanced and progressive differentiation of the muscle progenitor pool. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Alagille Syndrome</em></strong></p><p>
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Alagille syndrome (ALGS; see 118450) is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. In about 94% of patients with ALGS, mutations in the gene encoding the NOTCH signaling pathway ligand Jagged-1 (JAG1; 601920) had been identified. To identify the cause of disease in patients without JAG1 mutations, McDaniell et al. (2006) screened 11 JAG1 mutation-negative probands with ALGS for alterations in the gene for the NOTCH2 receptor. They found NOTCH2 mutations segregating in 2 families with Alagille syndrome (ALGS2; 610205) and identified 5 affected individuals. Renal manifestations, a minor feature of ALGS, were present in all affected individuals. </p><p><strong><em>Hajdu-Cheney Syndrome</em></strong></p><p>
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Simpson et al. (2011) performed whole-exome sequencing of 3 unrelated individuals of European origin with Hajdu-Cheney syndrome (HJCYS; 102500), also known as acroosteolysis with osteoporosis and changes in the skull and mandible, and identified 3 different truncating mutations in exon 34 of the NOTCH2 gene. One of the patients had affected relatives, and the mutation (600275.0003) was found to segregate with the disorder in that family. Further analysis of exon 34 of the NOTCH2 gene identified further truncating mutations in 11 additional probands with the disorder, including 8 patients with sporadic disease who had a de novo mutation (see, e.g., 600275.0004-600275.0005). All the mutations occurred in exon 34, the last exon of the NOTCH2 gene, and all were predicted to lead to truncation of the protein product before complete translation of the PEST domain, which mediates proteosomal destruction of the protein. The mutations escaped nonsense-mediated mRNA decay and the truncated proteins were expressed. Thus, the mutations resulted in persistence of the Notch intracellular signal, consistent with a gain of function. </p><p>Simultaneously and independently, Isidor et al. (2011) identified 5 different truncating mutations in exon 34 of the NOTCH2 gene (see, e.g., 600275.0006-600275.0007) in 5 unrelated probands with Hajdu-Cheney syndrome by exome sequencing. The mutant mRNAs were expected to be stable and result in truncated proteins with constitutively active intracellular domains. </p><p>Majewski et al. (2011) identified 6 different heterozygous truncating mutations in the NOTCH2 gene in affected members of 7 families with Hajdu-Cheney syndrome. Mutations in the first 3 families were found by whole-exome sequencing. All of the mutations were clustered in exon 34 near the C terminus. Functional studies of the variants were not performed. </p><p>Gray et al. (2012) identified heterozygous truncating mutations in exon 34 of the NOTCH2 gene (600275.0008 and 600275.0009) in 2 unrelated patients with phenotypic features of both serpentine fibula-polycystic kidney syndrome (SFPKS) and Hajdu-Cheney syndrome. The phenotypic overlap between HJCYS and SFPKS had been noted before by Kaplan et al. (1995) and Ramos et al. (1998), both of whom had suggested that the 2 disorders may be allelic. The mutations identified by Gray et al. (2012) were located in the same gene region as mutations that cause HJCYS, with the same activating effect on protein function. The molecular findings indicated that SFPKS should be considered part of the phenotypic spectrum of HJCYS. </p>
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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>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To assess the in vivo role of the Notch2 gene, McCright et al. (2001) constructed a targeted mutation, Notch2(del1). They found that alternative splicing of the Notch2(del1) mutant allele led to the production of 2 different in-frame transcripts that delete either 1 or 2 EGF repeats of the Notch2 protein, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2(del1) mutation died perinatally from defects in glomerular development in the kidney. Notch2(del1)/Notch2(del1) mutant kidneys were hypoplastic and mutant glomeruli lacked a normal capillary tuft. The Notch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells. McCright et al. (2001) showed that mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibited a glomerular defect similar to, but less severe than, that of Notch2(del1)/Notch2(del1) homozygotes. The colocalization and genetic interaction of Jag1 and Notch2 implied that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1) homozygotes also displayed myocardial hypoplasia, edema, and hyperplasia of cells associated with the hyaloid vasculature of the eye. McCright et al. (2001) concluded that their data identified novel developmental roles for Notch2 in kidney, heart, and eye development. </p><p>Krebs et al. (2003) showed that mouse embryos mutant for the Notch ligand Dll1 (606582) or doubly mutant for Notch1 and Notch2 exhibited multiple defects in left-right asymmetry. Dll1 -/- embryos did not express Nodal (601265) in the region around the node. Analysis of the enhancer regulating node-specific Nodal expression revealed binding sites for Rbpj (RBPSUH; 147183). Mutation of these sites destroyed the ability of the enhancer to direct node-specific gene expression in transgenic mice. Krebs et al. (2003) concluded that Dll1-mediated Notch signaling is essential for generation of left-right asymmetry, and that perinodal expression of Nodal is an essential component of left-right asymmetry determination in mice. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 ALAGILLE SYNDROME 2</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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NOTCH2, IVS33AS, G-A, -1
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<br />
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SNP: rs312262798,
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ClinVar: RCV000009810
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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>McDaniell et al. (2006) described a mother and son with Alagille syndrome (610205), both of whom had a splice acceptor mutation (5930-1G-A) in exon 33 of the NOTCH2 gene. The proband had cholestatic liver disease, cardiac disease characteristic facial features, and severe infantile renal disease. He died of cardiopulmonary arrest at age 2. His mother had valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant. The maternal grandparents and 3 of the mother's sibs did not carry the mutation, indicating it was a de novo change in the proband's mother. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 ALAGILLE SYNDROME 2</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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NOTCH2, CYS444TYR
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<br />
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SNP: rs111033632,
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ClinVar: RCV000009811
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a proband, her mother, and her grandmother with Alagille syndrome (610205), McDaniell et al. (2006) identified a 1331G-A transition in exon 8 of the NOTCH2 gene that resulted in a cys444-to-tyr (C444Y) substitution in the eleventh EGF-like repeat of the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HAJDU-CHENEY SYNDROME</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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NOTCH2, 1-BP DEL, 6272T
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<br />
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SNP: rs1557802353,
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ClinVar: RCV000022957
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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 a family with autosomal dominant Hajdu-Cheney syndrome, also known as acroosteolysis with osteoporosis and changes in the skull and mandible (102500), Simpson et al. (2011) identified a heterozygous 1-bp deletion (6272delT) in exon 34 of the NOTCH2 gene, resulting in a frameshift and premature termination. The mutation occurred in the last exon of the NOTCH2 gene and escaped nonsense-mediated mRNA decay. RT-PCR studies showed that the truncated protein was expressed in patient fibroblasts. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 HAJDU-CHENEY SYNDROME</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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NOTCH2, 1-BP DEL, 6460T
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<br />
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ClinVar: RCV000022958
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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 a family with autosomal dominant Hajdu-Cheney syndrome (102500), Simpson et al. (2011) identified a heterozygous 1-bp deletion (6460delT) in exon 34 of the NOTCH2 gene, resulting in a frameshift and premature termination. The mutation occurred in the last exon of the NOTCH2 gene and likely escaped nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. </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>.0005 HAJDU-CHENEY SYNDROME</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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NOTCH2, GLN2208TER
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<br />
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SNP: rs387906746,
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ClinVar: RCV000022959
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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 a family with autosomal dominant Hajdu-Cheney syndrome (102500), Simpson et al. (2011) identified a heterozygous 6622C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2208-to-ter (Q2208X) substitution. The Q2208X mutation was also found in 2 affected members of a second unrelated family with Hajdu-Cheney syndrome. The mutation occurred in the last exon of the NOTCH2 gene and likely escaped nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 HAJDU-CHENEY SYNDROME</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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NOTCH2, TYR2373TER
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<br />
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SNP: rs1557801639,
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ClinVar: RCV000022960
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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 4 affected members of a family with autosomal dominant Hajdu-Cheney syndrome (102500), Isidor et al. (2011) identified a heterozygous 7119T-G transversion in exon 34 of the NOTCH2 gene, resulting in a tyr2373-to-ter (Y2373X) substitution. The mutation occurred in the last exon of the NOTCH2 gene and was expected to escape nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 HAJDU-CHENEY SYNDROME</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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NOTCH2, GLN2317TER
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<br />
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SNP: rs387906747,
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ClinVar: RCV000022961
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 affected members of a family with autosomal dominant acroosteolysis with osteoporosis and changes in the skull and mandible (102500), Isidor et al. (2011) identified a heterozygous 6949C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2317-to-ter (Q2317X) substitution. The mutation occurred in the last exon of the NOTCH2 gene and was expected to escape nonsense-mediated mRNA decay. The truncated protein was predicted to have a disrupted or absent proteolytic PEST sequence, which would result in persistence of the Notch intracellular signal, consistent with a gain of function. </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>.0008 HAJDU-CHENEY SYNDROME</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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NOTCH2, GLU2299TER
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<br />
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SNP: rs387906748,
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ClinVar: RCV000022962
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a girl with Hajdu-Cheney syndrome (102500), Gray et al. (2012) identified a heterozygous 6895G-T transversion in exon 34 of the NOTCH2 gene, resulting in a glu2299-to-ter (E2299X) substitution. The truncated protein was predicted to lack the PEST domain, leading to an increased level of NOTCH signaling in multiple tissues. The patient had originally been reported by Rosser et al. (1996) as having serpentine fibula-polycystic kidney syndrome. On follow-up by Gray et al. (2012) between ages 8 and 12 years, she showed mild developmental delay and progressive pulmonary disease requiring supplemental oxygen and corticosteroid treatment. Facial dysmorphism included narrow hirsute forehead, low posterior hairline, shallow supraorbital ridges, horizontal palpebral fissures, a convergent squint, a pinched nasal bridge with a wide nose, a small mouth, dental malocclusion, low-set posteriorly rotated ears, and prominent maxillae. She had short stature, acroosteolysis, osteoporosis, and stress fractures of the metatarsals bilaterally. </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>.0009 HAJDU-CHENEY SYNDROME</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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NOTCH2, GLN2389TER
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<br />
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SNP: rs387906749,
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ClinVar: RCV000022963
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a girl with Hajdu-Cheney syndrome (102500), Gray et al. (2012) identified a heterozygous 7165C-T transition in exon 34 of the NOTCH2 gene, resulting in a gln2389-to-ter (Q2389X) substitution. The truncated protein was predicted to lack the PEST domain, leading to an increased level of NOTCH signaling in multiple tissues. The patient was originally reported by Albano et al. (2007) as having serpentine fibula-polycystic kidney syndrome. At age 8 years, she had persistent ductus arteriosus, ventricular septal defect, and facial dysmorphism, including a thin upper lip, downturned mouth, wide nasal tip, long and flat philtrum, dysplastic and posteriorly rotated ears, and short neck. She had bilateral sensorineural hearing loss. Skeletal studies showed wormian bones, vertebral abnormalities, and serpentine fibulae. Ultrasound examination showed polycystic kidneys, but renal function was normal. At age 18 years, she had short stature, hypothyroidism, bathrocephaly, and irregular tooth positioning. There was no significant acroosteolysis of the hands or feet, but she had mild thinning of the distal phalanges. Brain MRI scan showed basilar invagination and abnormal curvature of the cervical spine without cord compression. Intelligence was normal. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Albano, L. M., Bertola, D. R., Barba, M. F., Valente, M., Robertson, S. P., Kim, C A.
|
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<strong>Phenotypic overlap in Melnick-Needles, serpentine fibula-polycystic kidney and Hajdu-Cheney syndromes: a clinical and molecular study in three patients.</strong>
|
|
Clin. Dysmorph. 16: 27-33, 2007.
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[PubMed: 17159511]
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[Full Text: https://doi.org/10.1097/01.mcd.0000228418.74413.52]
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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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Blaumueller, C. M., Qi, H., Zagouras, P., Artavanis-Tsakonas, S.
|
|
<strong>Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.</strong>
|
|
Cell 90: 281-291, 1997.
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[PubMed: 9244302]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80336-0]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
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>
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