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Entry
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- *600011 - EPHRIN RECEPTOR EphB4; EPHB4
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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">*600011</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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFamily">Gene Family</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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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/600011">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000196411;t=ENST00000358173" 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=2050" 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=600011" 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=ENSG00000196411;t=ENST00000358173" 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_004444,XM_017011816" 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_004444" 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=600011" 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=02481&isoform_id=02481_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/EPHB4" 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/495473,13279062,13383505,16209618,16209620,19860819,31127085,32528301,51094568,62088868,119596874,119596875,119596876,194318512,194318514,194318516,194375369,218055944,1034654374,2462612791" 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/P54760" 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=2050" 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=ENSG00000196411;t=ENST00000358173" 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=EPHB4" 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=EPHB4" 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+2050" 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/EPHB4" 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:2050" 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/2050" 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=chr7&hgg_gene=ENST00000358173.8&hgg_start=100802565&hgg_end=100827523&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/genes/HGNC:3395" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600011[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=600011[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/EPHB4/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/ENSG00000196411" 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=EPHB4" 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=EPHB4" 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=EPHB4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EPHB4&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/PA27827" 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:3395" 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/FBgn0025936.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:104757" 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/EPHB4#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:104757" 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/2050/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=2050" 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=WBGene00006868;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-990415-62" 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:2050" 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=EPHB4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600011
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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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EPHRIN RECEPTOR EphB4; EPHB4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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HEPATOMA TRANSMEMBRANE KINASE; HTK<br />
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MYK, MOUSE, HOMOLOG OF; MYK1<br />
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TYRO11
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EPHB4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EPHB4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/7/517?start=-3&limit=10&highlight=517">7q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:100802565-100827523&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'})">7:100,802,565-100,827,523</a> </span>
|
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
|
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=618196,617300" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
|
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
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|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/517?start=-3&limit=10&highlight=517">
|
|
7q22.1
|
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</a>
|
|
</span>
|
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</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Capillary malformation-arteriovenous malformation 2
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618196"> 618196 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Lymphatic malformation 7
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/617300"> 617300 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600011" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>In CD34+ human bone marrow cells and a human hepatocellular carcinoma cell line, <a href="#2" class="mim-tip-reference" title="Bennett, B. D., Wang, Z., Kuang, W.-J., Wang, A., Groopman, J. E., Goeddel, D. V., Scadden, D. T. <strong>Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily.</strong> J. Biol. Chem. 269: 14211-14218, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188704</a>]" pmid="8188704">Bennett et al. (1994)</a> identified a novel transmembrane tyrosine kinase, which they called hepatoma transmembrane kinase, or HTK. They reported that the predicted 987-amino acid sequence of HTK includes a transmembrane region and signal sequence. The predicted extracellular domain contains a cysteine-rich region and tandem fibronectin type III repeats, while the intracellular domain contains the catalytic domain. Northern blot analysis demonstrated a single HTK transcript abundantly expressed in placenta and in a range of primary tissues and malignant cell lines. It is expressed in fetal, but not adult, brain, and in primitive and myeloid, but not lymphoid, hematopoietic cells. The protein shared amino acid similarity with the Eph subfamily of tyrosine kinases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others. <strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong> J. Clin. Invest. 126: 3080-3088, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27400125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27400125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27400125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27400125">Martin-Almedina et al. (2016)</a> found expression of Ephb4 in embryonic venous and lymphatic endothelial cells in the skin and mesenteries of mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27400125" 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 2 independent sets of primers specific for human HTK to amplify DNA from a panel of human-hamster hybrid cell lines, <a href="#2" class="mim-tip-reference" title="Bennett, B. D., Wang, Z., Kuang, W.-J., Wang, A., Groopman, J. E., Goeddel, D. V., Scadden, D. T. <strong>Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily.</strong> J. Biol. Chem. 269: 14211-14218, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188704</a>]" pmid="8188704">Bennett et al. (1994)</a> demonstrated that the human EPHB4 gene is located on chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By sequencing genomic clones and database analysis, <a href="#13" class="mim-tip-reference" title="Wilson, M. D., Riemer, C., Martindale, D. W., Schnupf, P., Boright, A. P., Cheung, T. L., Hardy, D. M., Schwartz, S., Scherer, S. W., Tsui, L.-C., Miller, W., Koop, B. F. <strong>Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5.</strong> Nucleic Acids Res. 29: 1352-1365, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239002</a>] [<a href="https://doi.org/10.1093/nar/29.6.1352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239002">Wilson et al. (2001)</a> mapped the EPHB4 gene to chromosome 7q22. They mapped the mouse Ephb4 gene to a region of conserved synteny on mouse chromosome 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 8/31/2017."None>Hartz (2017)</a> mapped the EPHB4 gene to chromosome 7q22.1 based on an alignment of the EPHB4 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AY056048" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AY056048</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#3" class="mim-tip-reference" title="Berclaz, G., Andres, A.-C., Albrecht, D., Dreher, E., Ziemiecki, A., Gusterson, B. A., Crompton, M. R. <strong>Expression of the receptor protein tyrosine kinase myk-1/htk in normal and malignant mammary epithelium.</strong> Biochem. Biophys. Res. Commun. 226: 869-875, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8831703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8831703</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8831703">Berclaz et al. (1996)</a> examined the expression of HTK in normal and malignant breast tissue. They found that in normal breast, expression is confined to secretory luminal epithelial cells. They found elevated expression of HTK in several human breast carcinoma cell lines as well as in primary ductal carcinomas of the breast. The authors suggested that HTK may have a role in the differentiation or maintenance of secretory epithelia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8831703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse and human erythroleukemia cell lines, <a href="#10" class="mim-tip-reference" title="Sakamoto, H., Zhang, X.-Q., Suenobu, S., Ohbo, K., Ogawa, M., Suda, T. <strong>Cell adhesion to ephrinb2 is induced by EphB4 independently of its kinase activity.</strong> Biochem. Biophys. Res. Commun. 321: 681-687, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15358160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15358160</a>] [<a href="https://doi.org/10.1016/j.bbrc.2004.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15358160">Sakamoto et al. (2004)</a> showed that interaction of EPHB4 with ephrin B2 (EFNB2; <a href="/entry/600527">600527</a>) did not require EPHB4 kinase activity. Activation of EPHB4 via ligation to ephrin B2 resulted in formation of filopodia, phosphorylation of the signal transduction protein CBL (<a href="/entry/165360">165360</a>), and recruitment of CRKL (<a href="/entry/602007">602007</a>) to CBL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15358160" 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>EPHB4 and ephrin B2 show bidirectional signaling, whereby activation of EPHB4 results in forward signaling in the receptor-expressing cell, and activation of ephrin B2 results in reverse signaling in the ligand-expressing cell. <a href="#4" class="mim-tip-reference" title="Erber, R., Eichelsbacher, U., Powajbo, V., Korn, T., Djonov, V., Lin, J., Hammes, H.-P., Grobholz, R., Ullrich, A., Vajkoczy, P. <strong>EphB4 controls blood vascular morphogenesis during postnatal angiogenesis.</strong> EMBO J. 25: 628-641, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16424904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16424904</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16424904">Erber et al. (2006)</a> found that overexpression of wildtype or kinase-dead EPHB4 in human SF126 glioblastoma cells resulted in phosphorylation of endogenous ephrin B2 and reverse signaling. SF126 xenograft tumors expressed ectopic EPHB4 and endogenous ephrin B2 in the same blood vessels, and reverse signaling resulted in abnormally large and dense vessels with reduced permeability. The apparent switch from sprouting angiogenesis to circumferential vessel growth and tightening of the permeability barrier was accompanied by elevated expression of Ang1 (ANGPT1; <a href="/entry/601667">601667</a>) relative to Ang2 (ANGPT2; <a href="/entry/601922">601922</a>) and elevated activation of the Ang1 receptor Tie2 (TEK; <a href="/entry/600221">600221</a>). A similar phenomenon was detected in retinas of newborn mice overexpressing Ephb4. <a href="#4" class="mim-tip-reference" title="Erber, R., Eichelsbacher, U., Powajbo, V., Korn, T., Djonov, V., Lin, J., Hammes, H.-P., Grobholz, R., Ullrich, A., Vajkoczy, P. <strong>EphB4 controls blood vascular morphogenesis during postnatal angiogenesis.</strong> EMBO J. 25: 628-641, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16424904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16424904</a>] [<a href="https://doi.org/10.1038/sj.emboj.7600949" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16424904">Erber et al. (2006)</a> concluded that activation of ephrin B2 by reverse signaling in turn activates the ANG1/TIE2 axis between endothelial cells and perivascular mural cells and pericytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16424904" 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>Blood vessels form de novo (vasculogenesis) or upon sprouting of capillaries from preexisting blood vessels (angiogenesis). Using high-resolution imaging of zebrafish vascular development, <a href="#7" class="mim-tip-reference" title="Herbert, S. P., Huisken, J., Kim, T. N., Feldman, M. E., Houseman, B. T., Wang, R. A., Shokat, K. M., Stainier, D. Y. R. <strong>Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.</strong> Science 326: 294-298, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19815777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19815777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19815777[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/10.1126/science.1178577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19815777">Herbert et al. (2009)</a> uncovered a third mode of blood vessel formation whereby the first embryonic artery and vein, 2 unconnected blood vessels, arise from a common precursor vessel. The first embryonic vein formed by selective sprouting of progenitor cells from the precursor vessel, followed by vessel segregation. <a href="#7" class="mim-tip-reference" title="Herbert, S. P., Huisken, J., Kim, T. N., Feldman, M. E., Houseman, B. T., Wang, R. A., Shokat, K. M., Stainier, D. Y. R. <strong>Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.</strong> Science 326: 294-298, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19815777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19815777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19815777[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/10.1126/science.1178577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19815777">Herbert et al. (2009)</a> found that these processes were regulated by the ligand ephrin B2 and its receptor Ephb4, which are expressed in arterial-fated and venous-fated progenitors, respectively, and interact to orient the direction of progenitor migration. Thus, <a href="#7" class="mim-tip-reference" title="Herbert, S. P., Huisken, J., Kim, T. N., Feldman, M. E., Houseman, B. T., Wang, R. A., Shokat, K. M., Stainier, D. Y. R. <strong>Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.</strong> Science 326: 294-298, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19815777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19815777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19815777[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/10.1126/science.1178577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19815777">Herbert et al. (2009)</a> concluded that directional control of progenitor migration drives arterial-venous segregation and generation of separate parallel vessels from a single precursor vessel, a process essential for vascular development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19815777" 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>Lymphatic Malformation 7</em></strong></p><p>
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In 11 members of 2 unrelated families with nonimmune hydrops fetalis and postnatal lymphatic dysfunction (LMPHM7; <a href="/entry/617300">617300</a>), <a href="#9" class="mim-tip-reference" title="Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others. <strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong> J. Clin. Invest. 126: 3080-3088, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27400125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27400125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27400125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27400125">Martin-Almedina et al. (2016)</a> identified different heterozygous missense mutations in the EPHB4 gene (<a href="#0001">600011.0001</a> and <a href="#0002">600011.0002</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was variable expressivity of the phenotype. Both mutations occurred at highly conserved residues in the tyrosine kinase domain, and in vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant proteins were devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutations had a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27400125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large 4-generation family with hydrops fetalis, lymphedema, and central conduction lymphatic anomalies, <a href="#8" class="mim-tip-reference" title="Li, D., Wenger, T. L., Seiler, C., March, M. E., Gutierrez-Uzquiza, A., Kao, C., Bhoj, E., Tian, L., Rosenbach, M., Liu, Y., Robinson, N., Behr, M., and 12 others. <strong>Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.</strong> Hum. Molec. Genet. 27: 3233-3245, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29905864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29905864</a>] [<a href="https://doi.org/10.1093/hmg/ddy218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29905864">Li et al. (2018)</a> performed whole-exome sequencing and identified heterozygosity for a splice site mutation in the EPHB4 gene (<a href="#0013">600011.0013</a>) that segregated fully with disease in the family and was not found in in-house control samples or in public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29905864" 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>Capillary Malformation-Arteriovenous Malformation 2</em></strong></p><p>
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In an 8-year-old white boy with multiple capillary malformations (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#14" class="mim-tip-reference" title="Yu, J.,Streicher, J. L., Medne, L., Krantz, I. D., Yan, A. C. <strong>EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: a case report.</strong> Pediat. Derm. 34: e227-e230, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28730721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28730721</a>] [<a href="https://doi.org/10.1111/pde.13208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28730721">Yu et al. (2017)</a> identified a de novo heterozygous missense mutation in the EPHB4 gene (D802G; <a href="#0003">600011.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28730721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>From a cohort of 365 index patients with CMAVM, <a href="#1" class="mim-tip-reference" title="Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others. <strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong> Circulation 136: 1037-1048, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28687708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28687708</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28687708">Amyere et al. (2017)</a> identified 47 distinct heterozygous mutations in the EPHB4 gene in 54 probands (see, e.g., <a href="#0004">600011.0004</a>-<a href="#0008">600011.0008</a>). The authors noted that the mutations were located throughout the gene and they found no genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28687708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 51 patients with vein of Galen aneurysmal malformation, <a href="#11" class="mim-tip-reference" title="Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J. <strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong> Brain 141: 979-988, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>] [<a href="https://doi.org/10.1093/brain/awy020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29444212">Vivanti et al. (2018)</a> identified 5 with heterozygous mutations in the EPHB4 gene (see, e.g., <a href="#0009">600011.0009</a>-<a href="#0012">600011.0012</a>). Two of the patients also exhibited capillary malformations. Reduced penetrance was observed, with unaffected carrier parents in 3 of the families, and the authors suggested that other genes play a role in the clinical expression of the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" 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="#5" class="mim-tip-reference" title="Gerety, S. S., Wang, H. U., Chen, Z.-F., Anderson, D. J. <strong>Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development.</strong> Molec. Cell 4: 403-414, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518221</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80342-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10518221">Gerety et al. (1999)</a> generated mice with a targeted disruption of Ephb4 by introducing a tau-lacZ marker into the gene. Unlike the broadly expressed ephrin B2 gene (EFNB2; <a href="/entry/600527">600527</a>), Ephb4 is uniquely expressed in vascular endothelial and endocardial cells. The authors' analysis also confirmed that Ephb4 is preferentially expressed on veins. Remarkably, the phenotype of homozygous Ephb4 mutants was virtually symmetric to that of Efnb2 mutants. These data identified EPHB4 as the major essential interaction partner of EFNB2 in angiogenesis and further indicated that the requisite function of this receptor is intrinsic to the circulatory system. In addition, these data indicated that EFNB2 and EPHB4 mediate reciprocal interactions between arteries and veins that are essential for proper angiogenic remodeling of the capillary beds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518221" 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="Wang, Y., Thorin, E., Luo, H., Tremblay, J., Lavoie, J. L., Wu, Z., Peng, J., Qi, S., Wu, J. <strong>EPHB4 protein expression in vascular smooth muscle cells regulates their contractility, and EPHB4 deletion leads to hypotension in mice.</strong> J. Biol. Chem. 290: 14235-14244, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25903126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25903126</a>] [<a href="https://doi.org/10.1074/jbc.M114.621615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25903126">Wang et al. (2015)</a> developed a line of mice with targeted deletion of Ephb4 in smooth muscle cells (SMCs). Mutant mice showed sex differences in the vascular effects of SMC-specific Ephb4 deletion. Mutant males, but not females, showed significantly reduced systolic blood pressure and mean arterial pressure compared with wildtype, whereas mutant females, but not males, showed significantly reduced heart rate compared with wildtype. Male Ephb4 -/- mesenteric arteries showed abnormally low contractility in response to phenylephrin when grown on substrate containing Ephb4 or ephrin B2, suggesting that both forward and reverse signaling between Ephb4 and ephrin B2 are involved in blood pressure regulation. Male Ephb4 -/- vascular SMCs showed reduced Mlc (see <a href="/entry/609931">609931</a>) phosphorylation and elevated Mlck (MYLK; <a href="/entry/600922">600922</a>) and CAMKII (see <a href="/entry/114078">114078</a>) phosphorylation. <a href="#12" class="mim-tip-reference" title="Wang, Y., Thorin, E., Luo, H., Tremblay, J., Lavoie, J. L., Wu, Z., Peng, J., Qi, S., Wu, J. <strong>EPHB4 protein expression in vascular smooth muscle cells regulates their contractility, and EPHB4 deletion leads to hypotension in mice.</strong> J. Biol. Chem. 290: 14235-14244, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25903126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25903126</a>] [<a href="https://doi.org/10.1074/jbc.M114.621615" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25903126">Wang et al. (2015)</a> concluded that EPHB4 is involved in the CAMKII/MLCK/MLC signaling cascade in vascular SMCs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25903126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others. <strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong> J. Clin. Invest. 126: 3080-3088, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27400125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27400125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27400125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27400125">Martin-Almedina et al. (2016)</a> found that deletion of the Ephb4 gene specifically in the lymphatic vasculature of embryonic mice between days E10 to E12 resulted in subcutaneous edema and abnormal lymphatic development. Tissue from mutant mice showed tortuous and dilated dermal lymphatic vessels associated with defective formation of lymphovenous valves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27400125" 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="#11" class="mim-tip-reference" title="Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J. <strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong> Brain 141: 979-988, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>] [<a href="https://doi.org/10.1093/brain/awy020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29444212">Vivanti et al. (2018)</a> examined different brain layers of transgenic zebrafish embryos with knockdown of ephb4a, the EPHB4 ortholog, and observed marked vascular anomalies of the dorsal cranial vessels including both dorsal longitudinal and mesencephalic veins by 3 days postfertilization. Abnormal number of dorsal longitudinal vein (duplicated or triplicated) was observed in 82% of the mutant embryos, and abnormal morphology of the mesencephalic vein (absent or interrupted, unilaterally or bilaterally) was observed in 76%. Coinjection of wildtype EPHB4 showed significant rescue of both vascular phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 7 affected members of a 3-generation family from the United Kingdom with nonimmune hydrops fetalis and postnatal lymphatic dysfunction (LMPHM7; <a href="/entry/617300">617300</a>), <a href="#9" class="mim-tip-reference" title="Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others. <strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong> J. Clin. Invest. 126: 3080-3088, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27400125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27400125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27400125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27400125">Martin-Almedina et al. (2016)</a> identified a heterozygous c.2216G-A transition (c.2216G-A, NM_004444.4) in exon 13 of the EPHB4 gene, resulting in an arg739-to-glu (R739E) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity of the phenotype. The variant was filtered against the dbSNP (build 135) and 1000 Genomes Project databases and was not found in 900 in-house control exomes. In vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant protein was devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutation has a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27400125" 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">rs1057519264 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519264;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=rs1057519264" 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=rs1057519264" 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=RCV000415536" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000415536" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000415536</a>
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<p>In 4 affected members of a 2-generation Norwegian family with nonimmune hydrops fetalis and postnatal lymphatic dysfunction (LMPHM7; <a href="/entry/617300">617300</a>), <a href="#9" class="mim-tip-reference" title="Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others. <strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong> J. Clin. Invest. 126: 3080-3088, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27400125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27400125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27400125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI85794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27400125">Martin-Almedina et al. (2016)</a> identified a heterozygous c.2345T-G transversion (c.2345T-G, NM_004444.4) in exon 14 of the EPHB4 gene, resulting in an ile782-to-ser (I782S) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity of the phenotype. The variant was filtered against the dbSNP (build 135) and 1000 Genomes Project databases and was not found in 900 in-house control exomes. There were 2 affected mothers, who were monozygotic twins, and each had an affected son. The mothers, whose phenotype was milder than that of the sons, were found to be mosaic for the I782S mutation. In vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant protein was devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutation has a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27400125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs776410552 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs776410552;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs776410552?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs776410552" 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=rs776410552" 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=RCV000722057" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722057" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722057</a>
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<p>In an 8-year-old white boy with multiple capillary malformations (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#14" class="mim-tip-reference" title="Yu, J.,Streicher, J. L., Medne, L., Krantz, I. D., Yan, A. C. <strong>EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: a case report.</strong> Pediat. Derm. 34: e227-e230, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28730721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28730721</a>] [<a href="https://doi.org/10.1111/pde.13208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28730721">Yu et al. (2017)</a> identified heterozygosity for a de novo c.2405A-G transition in the EPHB4 gene, resulting in an asp802-to-gly (D802G) substitution. His unaffected parents did not carry the mutation. The mutation was identified by whole-exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28730721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, 1-BP DEL, 33G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562976493 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562976493;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=rs1562976493" 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=rs1562976493" 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=RCV000722058" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722058" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722058</a>
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<p>In 7 affected members of a 5-generation family (CM-13-HO) with multiple capillary malformations (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#1" class="mim-tip-reference" title="Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others. <strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong> Circulation 136: 1037-1048, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28687708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28687708</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28687708">Amyere et al. (2017)</a> identified heterozygosity for a 1-bp deletion (c.33delG) in exon 1 of the EPHB4 gene, causing a frameshift predicted to result in a premature termination codon (Leu12TrpfsTer10). The mutation segregated fully with disease in the family and was not found in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28687708" 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="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, CYS268ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs201816920 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201816920;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs201816920?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs201816920" 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=rs201816920" 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=RCV000722059" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722059" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722059</a>
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<p>In 2 brothers and their affected father and paternal grandmother (family CM-90) with multiple capillary malformations (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#1" class="mim-tip-reference" title="Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others. <strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong> Circulation 136: 1037-1048, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28687708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28687708</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28687708">Amyere et al. (2017)</a> identified heterozygosity for a c.802T-C transition in exon 4 of the EPHB4 gene, resulting in a cys268-to-arg (C268R) substitution. The mutation segregated fully with disease in the family and was not found in the ExAC database. The 4 mutation carriers all exhibited capillary malformations, and 1 also showed a Parkes Weber lesion on the right leg. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28687708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, 2-BP DEL, 632TG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562973541 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562973541;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=rs1562973541" 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=rs1562973541" 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=RCV000722060" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722060" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722060</a>
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<p>In 2 related patients (family CM-291) with capillary malformations (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#1" class="mim-tip-reference" title="Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others. <strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong> Circulation 136: 1037-1048, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28687708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28687708</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28687708">Amyere et al. (2017)</a> identified heterozygosity for a 2-bp deletion (c.632_633delTG) in exon 4 of the EPHB4 gene, causing a frameshift predicted to result in a premature termination codon (Val211AlafsTer11). The mutation was not found in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28687708" 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="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, GLU664LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562969219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562969219;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=rs1562969219" 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=rs1562969219" 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=RCV000722061 OR RCV004547917 OR RCV004719973" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722061, RCV004547917, RCV004719973" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722061...</a>
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<p>In 4 members of a family (CM-397) with capillary malformations and vein of Galen aneurysmal malformations (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#1" class="mim-tip-reference" title="Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others. <strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong> Circulation 136: 1037-1048, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28687708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28687708</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28687708">Amyere et al. (2017)</a> identified heterozygosity for a c.1990G-A transition in exon 12 of the EPHB4 gene, resulting in a glu664-to-lys (E664K) substitution. Three members of the family exhibited cutaneous capillary malformations, and 2 had vein of Galen aneurysmal malformations. The mutation was not found in the ExAC database. Analysis of transfected COS-7 cells showed a low level of mutant protein compared to wildtype EPHB4, and the typical membranous staining was not seen with the mutant on immunofluorescence, indicating that E664K represents a loss-of-function mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28687708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs927772349 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs927772349;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs927772349?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs927772349" 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=rs927772349" 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=RCV000722062 OR RCV001811458" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722062, RCV001811458" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722062...</a>
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<p>In a patient (family CM-490) with capillary malformations and a perimedullary arteriovenous malformation of the spine at D8-L1 (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#1" class="mim-tip-reference" title="Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others. <strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong> Circulation 136: 1037-1048, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28687708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28687708</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28687708">Amyere et al. (2017)</a> identified heterozygosity for a splice site mutation (c.2484+1G-A) in intron 14 of the EPHB4 gene. The mutation was not found in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28687708" 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="0009" class="mim-anchor"></a>
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<strong>.0009 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, IVS14DS, G-T, +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"><span class="text-primary">●</span> rs927772349 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs927772349;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs927772349?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs927772349" 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=rs927772349" 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=RCV000722063" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722063" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722063</a>
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<p>In a male patient (family AA5615) with capillary malformations and vein of Galen aneurysmal malformation (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#11" class="mim-tip-reference" title="Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J. <strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong> Brain 141: 979-988, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>] [<a href="https://doi.org/10.1093/brain/awy020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29444212">Vivanti et al. (2018)</a> identified heterozygosity for a splice site mutation (c.2484+1G-T, NM_004444.4) in intron 14 of the EPHB4 gene, predicted to result in a met814_val829 deletion within the catalytic domain of protein tyrosine kinases. The mutation was inherited from his mother, who exhibited only capillary malformations. The variant was not found in the 1000 Genomes Project or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" 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="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, IVS14, 1-BP INS, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1584653620 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1584653620;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=rs1584653620" 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=rs1584653620" 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=RCV000722064 OR RCV004760757" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722064, RCV004760757" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722064...</a>
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<p>In a male patient (family AA5616) with vein of Galen aneurysmal malformation (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#11" class="mim-tip-reference" title="Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J. <strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong> Brain 141: 979-988, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>] [<a href="https://doi.org/10.1093/brain/awy020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29444212">Vivanti et al. (2018)</a> identified heterozygosity for a splice site insertion (c.2484+2insT, NM_004444.4) in intron 14 of the EPHB4 gene. The mutation, which was inherited from his unaffected father, was not found in the 1000 Genomes Project or ExAC databases. The patient's venous anomaly was discovered at 4 days of life upon evaluation for cardiac failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" 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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<h4>
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<span class="mim-font">
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<strong>.0011 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, 1-BP DUP, 570G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562973614 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562973614;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=rs1562973614" 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=rs1562973614" 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=RCV000722065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722065</a>
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<p>In a female patient (family AA5614) with capillary malformation and vein of Galen aneurysmal malformation (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#11" class="mim-tip-reference" title="Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J. <strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong> Brain 141: 979-988, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>] [<a href="https://doi.org/10.1093/brain/awy020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29444212">Vivanti et al. (2018)</a> identified heterozygosity for a de novo 1-bp duplication (c.570dupG, NM_004444.4) in the EPHB4 gene, causing a frameshift predicted to result in a premature termination codon (His191AlafsTer32). The mutation, which was not present in her unaffected parents, was not found in the 1000 Genomes Project or ExAC databases. In a zebrafish knockdown model (see ANIMAL MODEL), injection with mut-mRNA mimicking the c.570dupG mutation did not rescue the cranial venous malformation phenotype, whereas there was statistically significant rescue with wildtype EPHB4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" 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="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, CYS107ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562974383 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562974383;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=rs1562974383" 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=rs1562974383" 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=RCV000722066 OR RCV004751678" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000722066, RCV004751678" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000722066...</a>
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<p>In a female patient (family AA5718) with vein of Galen aneurysmal malformation (CMAVM2; <a href="/entry/618196">618196</a>), <a href="#11" class="mim-tip-reference" title="Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J. <strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong> Brain 141: 979-988, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>] [<a href="https://doi.org/10.1093/brain/awy020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29444212">Vivanti et al. (2018)</a> identified heterozygosity for a c.319T-C transition (c.319T-C, NM_004444.4) in the EPHB4 gene, resulting in a cys107-to-arg (C107R) substitution within the ligand-binding domain. The mutation, which was inherited from her unaffected mother, was not found in the 1000 Genomes Project or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 LYMPHATIC MALFORMATION 7</strong>
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EPHB4, IVS13DS, G-C, +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">rs1562967463 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562967463;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=rs1562967463" 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=rs1562967463" 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=RCV000735638" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000735638" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000735638</a>
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<p>In 6 affected members of a large 4-generation family with hydrops fetalis, lymphedema, and central conduction lymphatic anomalies (LMPHM7; <a href="/entry/617300">617300</a>), <a href="#8" class="mim-tip-reference" title="Li, D., Wenger, T. L., Seiler, C., March, M. E., Gutierrez-Uzquiza, A., Kao, C., Bhoj, E., Tian, L., Rosenbach, M., Liu, Y., Robinson, N., Behr, M., and 12 others. <strong>Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.</strong> Hum. Molec. Genet. 27: 3233-3245, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29905864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29905864</a>] [<a href="https://doi.org/10.1093/hmg/ddy218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29905864">Li et al. (2018)</a> identified heterozygosity for a splice site mutation (c.2334+1G-C, NM_004444.4) in intron 13 of the EPHB4 gene. The mutation was not found in 9 unaffected family members, in more than 4,000 in-house control samples, or in the 1000 Genomes Project, COSMIC v80, ESP6500SI, or gnomAD databases. RNAseq with skin biopsies from the proband demonstrated use of a cryptic splice donor site, causing retention of the intervening 12 bp of the intron, resulting in an in-frame insertion of 4 amino acids (Leu778_Gly779insLeuMetLeuGly) within the highly conserved catalytic loop of the protein kinase domain. Transfection of wildtype EPHB4 into HEK293T cells resulted in constitutive tyrosine phosphorylation of the protein, whereas markedly reduced phosphorylation occurred with the mutant EPHB4. In transfected A375 cells, stimulation by the EPHB4 ligand ephrin-B2 induced phosphorylation of wildtype but not mutant EPHB4, consistent with a loss-of-function effect. Injection into zebrafish of an ephb4a morpholino inhibiting the same splice junction of exon 13 resulted in vessel misbranching and deformities in lymphatic vessel development, indicating possible differentiation defects in lymphatic vessels and mimicking the lymphatic presentations of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29905864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong>
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[<a href="https://doi.org/10.1161/CIRCULATIONAHA.116.026886" target="_blank">Full Text</a>]
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<a id="Berclaz1996" class="mim-anchor"></a>
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Berclaz, G., Andres, A.-C., Albrecht, D., Dreher, E., Ziemiecki, A., Gusterson, B. A., Crompton, M. R.
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[<a href="https://doi.org/10.1006/bbrc.1996.1442" target="_blank">Full Text</a>]
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Erber, R., Eichelsbacher, U., Powajbo, V., Korn, T., Djonov, V., Lin, J., Hammes, H.-P., Grobholz, R., Ullrich, A., Vajkoczy, P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16424904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16424904</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16424904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.emboj.7600949" target="_blank">Full Text</a>]
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Gerety, S. S., Wang, H. U., Chen, Z.-F., Anderson, D. J.
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<strong>Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development.</strong>
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Molec. Cell 4: 403-414, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518221/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518221</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518221" 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/s1097-2765(00)80342-1" target="_blank">Full Text</a>]
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<a id="Hartz2017" class="mim-anchor"></a>
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 8/31/2017.
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Herbert, S. P., Huisken, J., Kim, T. N., Feldman, M. E., Houseman, B. T., Wang, R. A., Shokat, K. M., Stainier, D. Y. R.
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Science 326: 294-298, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19815777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19815777</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19815777[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19815777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1178577" target="_blank">Full Text</a>]
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Li, D., Wenger, T. L., Seiler, C., March, M. E., Gutierrez-Uzquiza, A., Kao, C., Bhoj, E., Tian, L., Rosenbach, M., Liu, Y., Robinson, N., Behr, M., and 12 others.
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<strong>Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.</strong>
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Hum. Molec. Genet. 27: 3233-3245, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29905864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29905864</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29905864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy218" target="_blank">Full Text</a>]
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Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others.
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<strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong>
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J. Clin. Invest. 126: 3080-3088, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27400125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27400125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27400125[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27400125" 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/10.1172/JCI85794" target="_blank">Full Text</a>]
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Sakamoto, H., Zhang, X.-Q., Suenobu, S., Ohbo, K., Ogawa, M., Suda, T.
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<strong>Cell adhesion to ephrinb2 is induced by EphB4 independently of its kinase activity.</strong>
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Biochem. Biophys. Res. Commun. 321: 681-687, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15358160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15358160</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15358160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.bbrc.2004.07.016" target="_blank">Full Text</a>]
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<a id="Vivanti2018" class="mim-anchor"></a>
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Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J.
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<strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong>
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Brain 141: 979-988, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29444212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29444212</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29444212" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awy020" target="_blank">Full Text</a>]
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</p>
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<a id="12" class="mim-anchor"></a>
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<a id="Wang2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, Y., Thorin, E., Luo, H., Tremblay, J., Lavoie, J. L., Wu, Z., Peng, J., Qi, S., Wu, J.
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<strong>EPHB4 protein expression in vascular smooth muscle cells regulates their contractility, and EPHB4 deletion leads to hypotension in mice.</strong>
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J. Biol. Chem. 290: 14235-14244, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25903126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25903126</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25903126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M114.621615" target="_blank">Full Text</a>]
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</p>
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<a id="13" class="mim-anchor"></a>
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<a id="Wilson2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wilson, M. D., Riemer, C., Martindale, D. W., Schnupf, P., Boright, A. P., Cheung, T. L., Hardy, D. M., Schwartz, S., Scherer, S. W., Tsui, L.-C., Miller, W., Koop, B. F.
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<strong>Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5.</strong>
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Nucleic Acids Res. 29: 1352-1365, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239002</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239002" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/nar/29.6.1352" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Yu2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yu, J.,Streicher, J. L., Medne, L., Krantz, I. D., Yan, A. C.
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<strong>EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: a case report.</strong>
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Pediat. Derm. 34: e227-e230, 2017. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28730721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28730721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28730721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/pde.13208" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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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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Marla J. F. O'Neill - updated : 12/19/2018
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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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Marla J. F. O'Neill - updated : 11/21/2018<br>Patricia A. Hartz - updated : 08/31/2017<br>Cassandra L. Kniffin - updated : 01/10/2017<br>Ada Hamosh - updated : 11/10/2009<br>Stylianos E. Antonarakis - updated : 10/6/1999<br>Jennifer P. Macke - updated : 5/30/1997
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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 : 6/28/1994
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</span>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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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 : 12/19/2018
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</span>
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</div>
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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 : 11/27/2018<br>carol : 11/26/2018<br>carol : 11/21/2018<br>mgross : 09/01/2017<br>mgross : 08/31/2017<br>carol : 01/13/2017<br>ckniffin : 01/10/2017<br>alopez : 11/11/2009<br>terry : 11/10/2009<br>alopez : 4/8/2009<br>mgross : 10/6/1999<br>psherman : 4/23/1998<br>psherman : 4/20/1998<br>alopez : 7/24/1997<br>alopez : 7/23/1997<br>mimadm : 7/30/1994<br>jason : 6/28/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600011
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<div>
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<h3>
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<span class="mim-font">
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EPHRIN RECEPTOR EphB4; EPHB4
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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HEPATOMA TRANSMEMBRANE KINASE; HTK<br />
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MYK, MOUSE, HOMOLOG OF; MYK1<br />
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TYRO11
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</span>
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</h4>
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</div>
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</div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EPHB4</em></strong>
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</span>
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</p>
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</div>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:100,802,565-100,827,523 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<td rowspan="2">
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<span class="mim-font">
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7q22.1
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<td>
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<span class="mim-font">
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Capillary malformation-arteriovenous malformation 2
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</td>
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<td>
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<span class="mim-font">
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618196
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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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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<tr>
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<td>
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<span class="mim-font">
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Lymphatic malformation 7
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</td>
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<td>
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<span class="mim-font">
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617300
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<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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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In CD34+ human bone marrow cells and a human hepatocellular carcinoma cell line, Bennett et al. (1994) identified a novel transmembrane tyrosine kinase, which they called hepatoma transmembrane kinase, or HTK. They reported that the predicted 987-amino acid sequence of HTK includes a transmembrane region and signal sequence. The predicted extracellular domain contains a cysteine-rich region and tandem fibronectin type III repeats, while the intracellular domain contains the catalytic domain. Northern blot analysis demonstrated a single HTK transcript abundantly expressed in placenta and in a range of primary tissues and malignant cell lines. It is expressed in fetal, but not adult, brain, and in primitive and myeloid, but not lymphoid, hematopoietic cells. The protein shared amino acid similarity with the Eph subfamily of tyrosine kinases. </p><p>Martin-Almedina et al. (2016) found expression of Ephb4 in embryonic venous and lymphatic endothelial cells in the skin and mesenteries of mice. </p>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Family</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>See 179610 for information on the Eph receptor gene family.</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>Using 2 independent sets of primers specific for human HTK to amplify DNA from a panel of human-hamster hybrid cell lines, Bennett et al. (1994) demonstrated that the human EPHB4 gene is located on chromosome 7. </p><p>By sequencing genomic clones and database analysis, Wilson et al. (2001) mapped the EPHB4 gene to chromosome 7q22. They mapped the mouse Ephb4 gene to a region of conserved synteny on mouse chromosome 5. </p><p>Hartz (2017) mapped the EPHB4 gene to chromosome 7q22.1 based on an alignment of the EPHB4 sequence (GenBank AY056048) with the genomic sequence (GRCh38).</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>Berclaz et al. (1996) examined the expression of HTK in normal and malignant breast tissue. They found that in normal breast, expression is confined to secretory luminal epithelial cells. They found elevated expression of HTK in several human breast carcinoma cell lines as well as in primary ductal carcinomas of the breast. The authors suggested that HTK may have a role in the differentiation or maintenance of secretory epithelia. </p><p>Using mouse and human erythroleukemia cell lines, Sakamoto et al. (2004) showed that interaction of EPHB4 with ephrin B2 (EFNB2; 600527) did not require EPHB4 kinase activity. Activation of EPHB4 via ligation to ephrin B2 resulted in formation of filopodia, phosphorylation of the signal transduction protein CBL (165360), and recruitment of CRKL (602007) to CBL. </p><p>EPHB4 and ephrin B2 show bidirectional signaling, whereby activation of EPHB4 results in forward signaling in the receptor-expressing cell, and activation of ephrin B2 results in reverse signaling in the ligand-expressing cell. Erber et al. (2006) found that overexpression of wildtype or kinase-dead EPHB4 in human SF126 glioblastoma cells resulted in phosphorylation of endogenous ephrin B2 and reverse signaling. SF126 xenograft tumors expressed ectopic EPHB4 and endogenous ephrin B2 in the same blood vessels, and reverse signaling resulted in abnormally large and dense vessels with reduced permeability. The apparent switch from sprouting angiogenesis to circumferential vessel growth and tightening of the permeability barrier was accompanied by elevated expression of Ang1 (ANGPT1; 601667) relative to Ang2 (ANGPT2; 601922) and elevated activation of the Ang1 receptor Tie2 (TEK; 600221). A similar phenomenon was detected in retinas of newborn mice overexpressing Ephb4. Erber et al. (2006) concluded that activation of ephrin B2 by reverse signaling in turn activates the ANG1/TIE2 axis between endothelial cells and perivascular mural cells and pericytes. </p><p>Blood vessels form de novo (vasculogenesis) or upon sprouting of capillaries from preexisting blood vessels (angiogenesis). Using high-resolution imaging of zebrafish vascular development, Herbert et al. (2009) uncovered a third mode of blood vessel formation whereby the first embryonic artery and vein, 2 unconnected blood vessels, arise from a common precursor vessel. The first embryonic vein formed by selective sprouting of progenitor cells from the precursor vessel, followed by vessel segregation. Herbert et al. (2009) found that these processes were regulated by the ligand ephrin B2 and its receptor Ephb4, which are expressed in arterial-fated and venous-fated progenitors, respectively, and interact to orient the direction of progenitor migration. Thus, Herbert et al. (2009) concluded that directional control of progenitor migration drives arterial-venous segregation and generation of separate parallel vessels from a single precursor vessel, a process essential for vascular development. </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>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</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>Lymphatic Malformation 7</em></strong></p><p>
|
|
In 11 members of 2 unrelated families with nonimmune hydrops fetalis and postnatal lymphatic dysfunction (LMPHM7; 617300), Martin-Almedina et al. (2016) identified different heterozygous missense mutations in the EPHB4 gene (600011.0001 and 600011.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was variable expressivity of the phenotype. Both mutations occurred at highly conserved residues in the tyrosine kinase domain, and in vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant proteins were devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutations had a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect. </p><p>In a large 4-generation family with hydrops fetalis, lymphedema, and central conduction lymphatic anomalies, Li et al. (2018) performed whole-exome sequencing and identified heterozygosity for a splice site mutation in the EPHB4 gene (600011.0013) that segregated fully with disease in the family and was not found in in-house control samples or in public variant databases. </p><p><strong><em>Capillary Malformation-Arteriovenous Malformation 2</em></strong></p><p>
|
|
In an 8-year-old white boy with multiple capillary malformations (CMAVM2; 618196), Yu et al. (2017) identified a de novo heterozygous missense mutation in the EPHB4 gene (D802G; 600011.0003). </p><p>From a cohort of 365 index patients with CMAVM, Amyere et al. (2017) identified 47 distinct heterozygous mutations in the EPHB4 gene in 54 probands (see, e.g., 600011.0004-600011.0008). The authors noted that the mutations were located throughout the gene and they found no genotype/phenotype correlations. </p><p>In a cohort of 51 patients with vein of Galen aneurysmal malformation, Vivanti et al. (2018) identified 5 with heterozygous mutations in the EPHB4 gene (see, e.g., 600011.0009-600011.0012). Two of the patients also exhibited capillary malformations. Reduced penetrance was observed, with unaffected carrier parents in 3 of the families, and the authors suggested that other genes play a role in the clinical expression of the disease phenotype. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gerety et al. (1999) generated mice with a targeted disruption of Ephb4 by introducing a tau-lacZ marker into the gene. Unlike the broadly expressed ephrin B2 gene (EFNB2; 600527), Ephb4 is uniquely expressed in vascular endothelial and endocardial cells. The authors' analysis also confirmed that Ephb4 is preferentially expressed on veins. Remarkably, the phenotype of homozygous Ephb4 mutants was virtually symmetric to that of Efnb2 mutants. These data identified EPHB4 as the major essential interaction partner of EFNB2 in angiogenesis and further indicated that the requisite function of this receptor is intrinsic to the circulatory system. In addition, these data indicated that EFNB2 and EPHB4 mediate reciprocal interactions between arteries and veins that are essential for proper angiogenic remodeling of the capillary beds. </p><p>Wang et al. (2015) developed a line of mice with targeted deletion of Ephb4 in smooth muscle cells (SMCs). Mutant mice showed sex differences in the vascular effects of SMC-specific Ephb4 deletion. Mutant males, but not females, showed significantly reduced systolic blood pressure and mean arterial pressure compared with wildtype, whereas mutant females, but not males, showed significantly reduced heart rate compared with wildtype. Male Ephb4 -/- mesenteric arteries showed abnormally low contractility in response to phenylephrin when grown on substrate containing Ephb4 or ephrin B2, suggesting that both forward and reverse signaling between Ephb4 and ephrin B2 are involved in blood pressure regulation. Male Ephb4 -/- vascular SMCs showed reduced Mlc (see 609931) phosphorylation and elevated Mlck (MYLK; 600922) and CAMKII (see 114078) phosphorylation. Wang et al. (2015) concluded that EPHB4 is involved in the CAMKII/MLCK/MLC signaling cascade in vascular SMCs. </p><p>Martin-Almedina et al. (2016) found that deletion of the Ephb4 gene specifically in the lymphatic vasculature of embryonic mice between days E10 to E12 resulted in subcutaneous edema and abnormal lymphatic development. Tissue from mutant mice showed tortuous and dilated dermal lymphatic vessels associated with defective formation of lymphovenous valves. </p><p>Vivanti et al. (2018) examined different brain layers of transgenic zebrafish embryos with knockdown of ephb4a, the EPHB4 ortholog, and observed marked vascular anomalies of the dorsal cranial vessels including both dorsal longitudinal and mesencephalic veins by 3 days postfertilization. Abnormal number of dorsal longitudinal vein (duplicated or triplicated) was observed in 82% of the mutant embryos, and abnormal morphology of the mesencephalic vein (absent or interrupted, unilaterally or bilaterally) was observed in 76%. Coinjection of wildtype EPHB4 showed significant rescue of both vascular phenotypes. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 LYMPHATIC MALFORMATION 7</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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EPHB4, ARG739GLU
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<br />
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SNP: rs1057519263,
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ClinVar: RCV000415595, RCV003128798
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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 7 affected members of a 3-generation family from the United Kingdom with nonimmune hydrops fetalis and postnatal lymphatic dysfunction (LMPHM7; 617300), Martin-Almedina et al. (2016) identified a heterozygous c.2216G-A transition (c.2216G-A, NM_004444.4) in exon 13 of the EPHB4 gene, resulting in an arg739-to-glu (R739E) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity of the phenotype. The variant was filtered against the dbSNP (build 135) and 1000 Genomes Project databases and was not found in 900 in-house control exomes. In vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant protein was devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutation has a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 LYMPHATIC MALFORMATION 7</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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EPHB4, ILE782SER
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<br />
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SNP: rs1057519264,
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ClinVar: RCV000415536
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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 2-generation Norwegian family with nonimmune hydrops fetalis and postnatal lymphatic dysfunction (LMPHM7; 617300), Martin-Almedina et al. (2016) identified a heterozygous c.2345T-G transversion (c.2345T-G, NM_004444.4) in exon 14 of the EPHB4 gene, resulting in an ile782-to-ser (I782S) substitution at a highly conserved residue in the tyrosine kinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity of the phenotype. The variant was filtered against the dbSNP (build 135) and 1000 Genomes Project databases and was not found in 900 in-house control exomes. There were 2 affected mothers, who were monozygotic twins, and each had an affected son. The mothers, whose phenotype was milder than that of the sons, were found to be mosaic for the I782S mutation. In vitro functional expression studies in HEK293 cells and lymphatic endothelial cells showed that the mutant protein was devoid of tyrosine kinase activity, suggesting altered EPHB4 signaling. The findings indicated that the mutation has a negative effect on receptor activity after ligand stimulation. There was no evidence of a dominant-negative effect. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 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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EPHB4, ASP802GLY
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<br />
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SNP: rs776410552,
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gnomAD: rs776410552,
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ClinVar: RCV000722057
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In an 8-year-old white boy with multiple capillary malformations (CMAVM2; 618196), Yu et al. (2017) identified heterozygosity for a de novo c.2405A-G transition in the EPHB4 gene, resulting in an asp802-to-gly (D802G) substitution. His unaffected parents did not carry the mutation. The mutation was identified by whole-exome sequencing. </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>.0004 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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EPHB4, 1-BP DEL, 33G
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<br />
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SNP: rs1562976493,
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ClinVar: RCV000722058
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</span>
|
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</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 7 affected members of a 5-generation family (CM-13-HO) with multiple capillary malformations (CMAVM2; 618196), Amyere et al. (2017) identified heterozygosity for a 1-bp deletion (c.33delG) in exon 1 of the EPHB4 gene, causing a frameshift predicted to result in a premature termination codon (Leu12TrpfsTer10). The mutation segregated fully with disease in the family and was not found in the ExAC database. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EPHB4, CYS268ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs201816920,
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|
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|
|
|
gnomAD: rs201816920,
|
|
|
|
|
|
ClinVar: RCV000722059
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers and their affected father and paternal grandmother (family CM-90) with multiple capillary malformations (CMAVM2; 618196), Amyere et al. (2017) identified heterozygosity for a c.802T-C transition in exon 4 of the EPHB4 gene, resulting in a cys268-to-arg (C268R) substitution. The mutation segregated fully with disease in the family and was not found in the ExAC database. The 4 mutation carriers all exhibited capillary malformations, and 1 also showed a Parkes Weber lesion on the right leg. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EPHB4, 2-BP DEL, 632TG
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs1562973541,
|
|
|
|
|
|
|
|
ClinVar: RCV000722060
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 related patients (family CM-291) with capillary malformations (CMAVM2; 618196), Amyere et al. (2017) identified heterozygosity for a 2-bp deletion (c.632_633delTG) in exon 4 of the EPHB4 gene, causing a frameshift predicted to result in a premature termination codon (Val211AlafsTer11). The mutation was not found in the ExAC database. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EPHB4, GLU664LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1562969219,
|
|
|
|
|
|
|
|
ClinVar: RCV000722061, RCV004547917, RCV004719973
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 members of a family (CM-397) with capillary malformations and vein of Galen aneurysmal malformations (CMAVM2; 618196), Amyere et al. (2017) identified heterozygosity for a c.1990G-A transition in exon 12 of the EPHB4 gene, resulting in a glu664-to-lys (E664K) substitution. Three members of the family exhibited cutaneous capillary malformations, and 2 had vein of Galen aneurysmal malformations. The mutation was not found in the ExAC database. Analysis of transfected COS-7 cells showed a low level of mutant protein compared to wildtype EPHB4, and the typical membranous staining was not seen with the mutant on immunofluorescence, indicating that E664K represents a loss-of-function mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
EPHB4, IVS14DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs927772349,
|
|
|
|
|
|
gnomAD: rs927772349,
|
|
|
|
|
|
ClinVar: RCV000722062, RCV001811458
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient (family CM-490) with capillary malformations and a perimedullary arteriovenous malformation of the spine at D8-L1 (CMAVM2; 618196), Amyere et al. (2017) identified heterozygosity for a splice site mutation (c.2484+1G-A) in intron 14 of the EPHB4 gene. The mutation was not found in the ExAC database. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EPHB4, IVS14DS, G-T, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs927772349,
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|
|
|
|
|
gnomAD: rs927772349,
|
|
|
|
|
|
ClinVar: RCV000722063
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient (family AA5615) with capillary malformations and vein of Galen aneurysmal malformation (CMAVM2; 618196), Vivanti et al. (2018) identified heterozygosity for a splice site mutation (c.2484+1G-T, NM_004444.4) in intron 14 of the EPHB4 gene, predicted to result in a met814_val829 deletion within the catalytic domain of protein tyrosine kinases. The mutation was inherited from his mother, who exhibited only capillary malformations. The variant was not found in the 1000 Genomes Project or ExAC databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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EPHB4, IVS14, 1-BP INS, +2
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<br />
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|
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SNP: rs1584653620,
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|
|
ClinVar: RCV000722064, RCV004760757
|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient (family AA5616) with vein of Galen aneurysmal malformation (CMAVM2; 618196), Vivanti et al. (2018) identified heterozygosity for a splice site insertion (c.2484+2insT, NM_004444.4) in intron 14 of the EPHB4 gene. The mutation, which was inherited from his unaffected father, was not found in the 1000 Genomes Project or ExAC databases. The patient's venous anomaly was discovered at 4 days of life upon evaluation for cardiac failure. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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|
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EPHB4, 1-BP DUP, 570G
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<br />
|
|
|
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SNP: rs1562973614,
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ClinVar: RCV000722065
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<p>In a female patient (family AA5614) with capillary malformation and vein of Galen aneurysmal malformation (CMAVM2; 618196), Vivanti et al. (2018) identified heterozygosity for a de novo 1-bp duplication (c.570dupG, NM_004444.4) in the EPHB4 gene, causing a frameshift predicted to result in a premature termination codon (His191AlafsTer32). The mutation, which was not present in her unaffected parents, was not found in the 1000 Genomes Project or ExAC databases. In a zebrafish knockdown model (see ANIMAL MODEL), injection with mut-mRNA mimicking the c.570dupG mutation did not rescue the cranial venous malformation phenotype, whereas there was statistically significant rescue with wildtype EPHB4. </p>
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<span class="mim-font">
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<strong>.0012 CAPILLARY MALFORMATION-ARTERIOVENOUS MALFORMATION 2</strong>
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EPHB4, CYS107ARG
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<br />
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SNP: rs1562974383,
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ClinVar: RCV000722066, RCV004751678
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<p>In a female patient (family AA5718) with vein of Galen aneurysmal malformation (CMAVM2; 618196), Vivanti et al. (2018) identified heterozygosity for a c.319T-C transition (c.319T-C, NM_004444.4) in the EPHB4 gene, resulting in a cys107-to-arg (C107R) substitution within the ligand-binding domain. The mutation, which was inherited from her unaffected mother, was not found in the 1000 Genomes Project or ExAC databases. </p>
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<span class="mim-font">
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<strong>.0013 LYMPHATIC MALFORMATION 7</strong>
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<span class="mim-text-font">
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EPHB4, IVS13DS, G-C, +1
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<br />
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SNP: rs1562967463,
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ClinVar: RCV000735638
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<p>In 6 affected members of a large 4-generation family with hydrops fetalis, lymphedema, and central conduction lymphatic anomalies (LMPHM7; 617300), Li et al. (2018) identified heterozygosity for a splice site mutation (c.2334+1G-C, NM_004444.4) in intron 13 of the EPHB4 gene. The mutation was not found in 9 unaffected family members, in more than 4,000 in-house control samples, or in the 1000 Genomes Project, COSMIC v80, ESP6500SI, or gnomAD databases. RNAseq with skin biopsies from the proband demonstrated use of a cryptic splice donor site, causing retention of the intervening 12 bp of the intron, resulting in an in-frame insertion of 4 amino acids (Leu778_Gly779insLeuMetLeuGly) within the highly conserved catalytic loop of the protein kinase domain. Transfection of wildtype EPHB4 into HEK293T cells resulted in constitutive tyrosine phosphorylation of the protein, whereas markedly reduced phosphorylation occurred with the mutant EPHB4. In transfected A375 cells, stimulation by the EPHB4 ligand ephrin-B2 induced phosphorylation of wildtype but not mutant EPHB4, consistent with a loss-of-function effect. Injection into zebrafish of an ephb4a morpholino inhibiting the same splice junction of exon 13 resulted in vessel misbranching and deformities in lymphatic vessel development, indicating possible differentiation defects in lymphatic vessels and mimicking the lymphatic presentations of the patients. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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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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Amyere, M., Revencu, N., Helaers, R., Pairet, E., Baselga, E., Cordisco, M., Chung, W., Dubois, J., Lacour, J.-P., Martorell, L., Mazereeuw-Hautier, J., Pyeritz, R. E., and 33 others.
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<strong>Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling.</strong>
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Circulation 136: 1037-1048, 2017.
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[PubMed: 28687708]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.116.026886]
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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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Bennett, B. D., Wang, Z., Kuang, W.-J., Wang, A., Groopman, J. E., Goeddel, D. V., Scadden, D. T.
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<strong>Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily.</strong>
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J. Biol. Chem. 269: 14211-14218, 1994.
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[PubMed: 8188704]
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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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Berclaz, G., Andres, A.-C., Albrecht, D., Dreher, E., Ziemiecki, A., Gusterson, B. A., Crompton, M. R.
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<strong>Expression of the receptor protein tyrosine kinase myk-1/htk in normal and malignant mammary epithelium.</strong>
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Biochem. Biophys. Res. Commun. 226: 869-875, 1996.
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[PubMed: 8831703]
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[Full Text: https://doi.org/10.1006/bbrc.1996.1442]
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<p class="mim-text-font">
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Erber, R., Eichelsbacher, U., Powajbo, V., Korn, T., Djonov, V., Lin, J., Hammes, H.-P., Grobholz, R., Ullrich, A., Vajkoczy, P.
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<strong>EphB4 controls blood vascular morphogenesis during postnatal angiogenesis.</strong>
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EMBO J. 25: 628-641, 2006.
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[PubMed: 16424904]
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[Full Text: https://doi.org/10.1038/sj.emboj.7600949]
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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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Gerety, S. S., Wang, H. U., Chen, Z.-F., Anderson, D. J.
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<strong>Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development.</strong>
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Molec. Cell 4: 403-414, 1999.
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[PubMed: 10518221]
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[Full Text: https://doi.org/10.1016/s1097-2765(00)80342-1]
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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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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 8/31/2017.
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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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Herbert, S. P., Huisken, J., Kim, T. N., Feldman, M. E., Houseman, B. T., Wang, R. A., Shokat, K. M., Stainier, D. Y. R.
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<strong>Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.</strong>
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Science 326: 294-298, 2009.
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[PubMed: 19815777]
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[Full Text: https://doi.org/10.1126/science.1178577]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Li, D., Wenger, T. L., Seiler, C., March, M. E., Gutierrez-Uzquiza, A., Kao, C., Bhoj, E., Tian, L., Rosenbach, M., Liu, Y., Robinson, N., Behr, M., and 12 others.
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<strong>Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly.</strong>
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Hum. Molec. Genet. 27: 3233-3245, 2018.
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[PubMed: 29905864]
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[Full Text: https://doi.org/10.1093/hmg/ddy218]
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<li>
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Martin-Almedina, S., Martinez-Corral, I., Holdhus, R., Vicente, A., Fotiou, E., Lin, S., Petersen, K., Simpson, M. A., Hoischen, A., Gilissen, C., Jeffery, H., Atton, G., and 13 others.
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<strong>EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.</strong>
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J. Clin. Invest. 126: 3080-3088, 2016.
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[PubMed: 27400125]
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[Full Text: https://doi.org/10.1172/JCI85794]
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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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Sakamoto, H., Zhang, X.-Q., Suenobu, S., Ohbo, K., Ogawa, M., Suda, T.
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<strong>Cell adhesion to ephrinb2 is induced by EphB4 independently of its kinase activity.</strong>
|
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Biochem. Biophys. Res. Commun. 321: 681-687, 2004.
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[PubMed: 15358160]
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[Full Text: https://doi.org/10.1016/j.bbrc.2004.07.016]
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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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Vivanti, A., Ozanne, A., Grondin, C., Saliou, G., Quevarec, L., Maurey, H., Aubourg, P., Benachi, A., Gut, M., Gut, I., Martinovic, J., Senat, M. C., Tawk, M., Melki, J.
|
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<strong>Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation.</strong>
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Brain 141: 979-988, 2018.
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[PubMed: 29444212]
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[Full Text: https://doi.org/10.1093/brain/awy020]
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</li>
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<li>
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<p class="mim-text-font">
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Wang, Y., Thorin, E., Luo, H., Tremblay, J., Lavoie, J. L., Wu, Z., Peng, J., Qi, S., Wu, J.
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<strong>EPHB4 protein expression in vascular smooth muscle cells regulates their contractility, and EPHB4 deletion leads to hypotension in mice.</strong>
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J. Biol. Chem. 290: 14235-14244, 2015.
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[PubMed: 25903126]
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[Full Text: https://doi.org/10.1074/jbc.M114.621615]
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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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Wilson, M. D., Riemer, C., Martindale, D. W., Schnupf, P., Boright, A. P., Cheung, T. L., Hardy, D. M., Schwartz, S., Scherer, S. W., Tsui, L.-C., Miller, W., Koop, B. F.
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<strong>Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5.</strong>
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Nucleic Acids Res. 29: 1352-1365, 2001.
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[PubMed: 11239002]
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[Full Text: https://doi.org/10.1093/nar/29.6.1352]
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</li>
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<li>
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<p class="mim-text-font">
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Yu, J.,Streicher, J. L., Medne, L., Krantz, I. D., Yan, A. C.
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<strong>EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: a case report.</strong>
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Pediat. Derm. 34: e227-e230, 2017. Note: Electronic Article.
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[PubMed: 28730721]
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[Full Text: https://doi.org/10.1111/pde.13208]
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Marla J. F. O'Neill - updated : 12/19/2018<br>Marla J. F. O'Neill - updated : 11/21/2018<br>Patricia A. Hartz - updated : 08/31/2017<br>Cassandra L. Kniffin - updated : 01/10/2017<br>Ada Hamosh - updated : 11/10/2009<br>Stylianos E. Antonarakis - updated : 10/6/1999<br>Jennifer P. Macke - updated : 5/30/1997
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carol : 12/19/2018<br>carol : 11/27/2018<br>carol : 11/26/2018<br>carol : 11/21/2018<br>mgross : 09/01/2017<br>mgross : 08/31/2017<br>carol : 01/13/2017<br>ckniffin : 01/10/2017<br>alopez : 11/11/2009<br>terry : 11/10/2009<br>alopez : 4/8/2009<br>mgross : 10/6/1999<br>psherman : 4/23/1998<br>psherman : 4/20/1998<br>alopez : 7/24/1997<br>alopez : 7/23/1997<br>mimadm : 7/30/1994<br>jason : 6/28/1994
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accessible. Unfortunately, it is not free to produce. Expert curators
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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