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Entry
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- *136352 - FMS-LIKE TYROSINE KINASE 4; FLT4
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- OMIM
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<p>
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<span class="h4">*136352</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/136352">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li 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 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=ENSG00000037280;t=ENST00000261937" 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=2324" 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=136352" 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 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="small">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000037280;t=ENST00000261937" 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_001354989,NM_002020,NM_182925,XM_011534478,XM_011534484,XM_017009263,XM_017009266,XM_017009268,XM_047417002,XM_047417003" 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_182925" 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=136352" 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=00636&isoform_id=00636_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/FLT4" 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/297050,388522,435774,1150991,29691195,29691197,62088854,62820047,77019363,77019397,77157035,77157400,103472027,104294888,119574134,119574135,158256790,194318424,194318426,194318428,262266194,262266301,357529070,395805728,395805730,395805732,698975669,698975671,727346945,727346947,727346949,727346951,727346954,727346956,727346958,727346960,727346962,727346964,727346966,727346968,727346970,767938191,767938204,849238250,849238252,849238254,849238256,849238258,849238260,849238262,1034644328,1034644334,1034644338,1238789368,2217355273,2217355275,2462601675,2462601677,2462601679,2462601681,2462601683,2462601685,2462601687" 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/P35916" 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 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=2324" 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=ENSG00000037280;t=ENST00000261937" 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=FLT4" 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=FLT4" 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+2324" 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/FLT4" 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:2324" 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/2324" 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=chr5&hgg_gene=ENST00000261937.11&hgg_start=180601506&hgg_end=180650298&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:3767" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/flt4" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=136352[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=136352[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/FLT4/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/ENSG00000037280" 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=FLT4" 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=FLT4" 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=FLT4" 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=FLT4&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/PA28183" 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:3767" 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/FBgn0032006.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:95561" 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/FLT4#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:95561" 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/2324/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=2324" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006894;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006894 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006897;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006897 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-980526-326" 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:2324" 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=FLT4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 399889006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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136352
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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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FMS-LIKE TYROSINE KINASE 4; FLT4
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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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VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3; VEGFR3
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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=FLT4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FLT4</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/5/845?start=-3&limit=10&highlight=845">5q35.3</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:180601506-180650298&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'})">5:180,601,506-180,650,298</a> </span>
|
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</em>
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618780,602089,153100" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/845?start=-3&limit=10&highlight=845">
|
|
5q35.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Congenital heart defects, multiple types, 7
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618780"> 618780 </a>
|
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|
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</span>
|
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</td>
|
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<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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<p>By screening a placenta cDNA library with a mouse Flt3 probe, <a href="#8" class="mim-tip-reference" title="Galland, F., Karamysheva, A., Mattei, M.-G., Rosnet, O., Marchetto, S., Birnbaum, D. <strong>Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene.</strong> Genomics 13: 475-478, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1319394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1319394</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90277-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1319394">Galland et al. (1992)</a> isolated a human gene encoding a putative receptor-type tyrosine kinase. The deduced amino acid sequence of the intracellular portion of the molecule showed that it was strongly related to FLT1 (<a href="/entry/165070">165070</a>) and KDR (<a href="/entry/191306">191306</a>) and to a lesser degree to members of the class III receptor-type tyrosine kinases: FMS (<a href="/entry/164770">164770</a>), PDGFR (<a href="/entry/173490">173490</a>, <a href="/entry/173410">173410</a>), KIT (<a href="/entry/164920">164920</a>), and FLT3 (<a href="/entry/136351">136351</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1319394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Galland, F., Karamysheva, A., Mattei, M.-G., Rosnet, O., Marchetto, S., Birnbaum, D. <strong>Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene.</strong> Genomics 13: 475-478, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1319394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1319394</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90277-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1319394">Galland et al. (1992)</a> mapped FLT4 to chromosome 5q34-q35, telomeric to the FMS and PDGFRB genes, by in situ hybridization. They assigned the mouse homolog to chromosome 11 by the same method. In the process of creating a radiation hybrid map of 18 genes, <a href="#32" class="mim-tip-reference" title="Warrington, J. A., Bailey, S. K., Armstrong, E., Aprelikova, O., Alitalo, K., Dolganov, G. M., Wilcox, A. S., Sikela, J. M., Wolfe, S. F., Lovett, M., Wasmuth, J. J. <strong>A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5.</strong> Genomics 13: 803-808, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1322355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1322355</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90156-m" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1322355">Warrington et al. (1992)</a> demonstrated that the FLT4 gene is located on distal 5q between GABRA1 (<a href="/entry/137160">137160</a>) at 5q34-q35 and DRD1 (<a href="/entry/126449">126449</a>) at 5q35.1. <a href="#1" class="mim-tip-reference" title="Aprelikova, O., Pajusola, K., Partanen, J., Armstrong, E., Alitalo, R., Bailey, S. K., McMahon, J., Wasmuth, J., Huebner, K., Alitalo, K. <strong>FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter.</strong> Cancer Res. 52: 746-748, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1310071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1310071</a>]" pmid="1310071">Aprelikova et al. (1992)</a> also mapped the FLT4 gene to chromosome 5q33-qter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1322355+1319394+1310071" 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>Among the factors stimulating angiogenesis, the acidic and basic fibroblast growth factors FGF1 (<a href="/entry/131220">131220</a>) and FGF2 (<a href="/entry/134920">134920</a>) and the vascular endothelial growth factor VEGF (<a href="/entry/192240">192240</a>) exert their effects via specific cell surface receptor tyrosine kinases: for FGF1 and FGF2, FGF receptor-1 (FGFR1; <a href="/entry/136350">136350</a>), also known as FLT2, and the endothelial-specific FMS-like tyrosine kinase-1; and for VEGF, the KDR/FLK1 receptor. The protein product of the FLT4 receptor tyrosine kinase cDNA is structurally similar to the FLT1 and KDR/FLK1 receptors (<a href="#24" class="mim-tip-reference" title="Pajusola, K., Aprelikova, O., Korhonen, J., Kaipainen, A., Pertovaara, L., Alitalo, R., Alitalo, K. <strong>FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines.</strong> Cancer Res. 52: 5738-5743, 1992. Note: Erratum: Cancer Res. 53: 3845 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1327515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1327515</a>]" pmid="1327515">Pajusola et al., 1992</a>), but FLT4 does not bind VEGF (<a href="#25" class="mim-tip-reference" title="Pajusola, K., Aprelikova, O., Pelicci, G., Weich, H., Claesson-Welsh, L., Alitalo, K. <strong>Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors.</strong> Oncogene 9: 3545-3555, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7970715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7970715</a>]" pmid="7970715">Pajusola et al., 1994</a>). <a href="#18" class="mim-tip-reference" title="Lee, J., Gray, A., Yuan, J., Luoh, S.-M., Avraham, H., Wood, W. I. <strong>Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4.</strong> Proc. Nat. Acad. Sci. 93: 1988-1992, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8700872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8700872</a>] [<a href="https://doi.org/10.1073/pnas.93.5.1988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8700872">Lee et al. (1996)</a> identified and characterized a vascular endothelial growth factor-related protein (VEGFC; <a href="/entry/601528">601528</a>) that specifically binds to the extracellular domain of Flt4 and stimulates tyrosine phosphorylation and mitogenesis of endothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8700872+7970715+1327515" 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="#14" class="mim-tip-reference" title="Kaipainen, A., Korhonen, J., Mustonen, T., van Hinsbergh, V. W. M., Fang, G.-H., Dumont, D., Breitman, M., Alitalo, K. <strong>Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.</strong> Proc. Nat. Acad. Sci. 92: 3566-3570, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7724599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7724599</a>] [<a href="https://doi.org/10.1073/pnas.92.8.3566" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7724599">Kaipainen et al. (1995)</a> analyzed the expression of FLT4 by in situ hybridization during mouse embryogenesis and in adult human tissues. The FLT4 mRNA signals first became detectable in the angioblasts of head mesenchyme, the cardinal vein, and extraembryonally in the allantois of 8.5-day postcoitus (p.c.) embryos. In 12.5-day p.c. embryos, the FLT4 signal decorated developing venous and presumptive lymphatic endothelia, but arterial endothelia were negative. During later stages of development, FLT4 mRNA became restricted to vascular plexuses devoid of red cells, representing developing lymphatic vessels. In adult human tissues, only the lymphatic endothelia and some high endothelial venules expressed FLT4 mRNA. Increased expression occurred in lymphatic sinuses in metastatic lymph nodes and in lymphangioma. The results suggested that FLT4 is a marker for lymphatic vessels and some high endothelial venules in human adult tissues. They also supported the theory of the venous origin of lymphatic vessels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7724599" 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>Vascular endothelial growth factor is a key regulator of blood vessel development in embryos and angiogenesis in adult tissues. Unlike VEGF, the related VEGFC stimulates the growth of lymphatic vessels through its specific lymphatic endothelial receptor VEGFR3. <a href="#5" class="mim-tip-reference" title="Dumont, D. J., Jussila, L., Taipale, J., Lymboussaki, A., Mustonen, T., Pajusola, K., Breitman, M., Alitalo, K. <strong>Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.</strong> Science 282: 946-949, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9794766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9794766</a>] [<a href="https://doi.org/10.1126/science.282.5390.946" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9794766">Dumont et al. (1998)</a> showed that targeted inactivation of the VEGFR3 gene in mice resulted in defective blood vessel development in early embryos. Vasculogenesis and angiogenesis occurred, but large vessels became abnormally organized with defective lumens, leading to fluid accumulation in the pericardial cavity and cardiovascular failure at embryonic day 9.5. Thus, VEGFR3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9794766" 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 studies of the mouse cornea in vivo, <a href="#4" class="mim-tip-reference" title="Cursiefen, C., Chen, L., Saint-Geniez, M., Hamrah, P., Jin, Y., Rashid, S., Pytowksi, B., Persaud, K., Wu, Y., Streilein, J. W., Dana, R. <strong>Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision.</strong> Proc. Nat. Acad. Sci. 103: 11405-11410, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16849433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16849433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16849433[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0506112103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16849433">Cursiefen et al. (2006)</a> demonstrated that the presence of Vegfr3 in the corneal epithelium is critical for suppressing inflammatory corneal angiogenesis, by acting as a decoy receptor and binding the angiogenic growth factors VEGFC and VEGFD (FIGF; <a href="/entry/300091">300091</a>). <a href="#4" class="mim-tip-reference" title="Cursiefen, C., Chen, L., Saint-Geniez, M., Hamrah, P., Jin, Y., Rashid, S., Pytowksi, B., Persaud, K., Wu, Y., Streilein, J. W., Dana, R. <strong>Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision.</strong> Proc. Nat. Acad. Sci. 103: 11405-11410, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16849433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16849433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16849433[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0506112103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16849433">Cursiefen et al. (2006)</a> concluded that VEGFR3, which provides proangiogenic signaling when expressed on endothelium, may also have antiangiogenic properties when expressed at an avascular site by nonendothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16849433" 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 studies in zebrafish to investigate the role of Notch (see <a href="/entry/190198">190198</a>) signaling in angiogenesis, <a href="#27" class="mim-tip-reference" title="Siekmann, A. F., Lawson, N. D. <strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong> Nature 445: 781-784, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>] [<a href="https://doi.org/10.1038/nature05577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259972">Siekmann and Lawson (2007)</a> found that Flt4 is expressed in segmental artery tip cells and becomes ectopically expressed throughout the sprout in the absence of Notch. Loss of Flt4 could partially restore normal endothelial cell number in Rbpsuh (<a href="/entry/147183">147183</a>)-deficient segmental arteries. Finally, loss of the Notch ligand Dll4 (<a href="/entry/605185">605185</a>) also led to an increased number of endothelial cells within segmental arteries. <a href="#27" class="mim-tip-reference" title="Siekmann, A. F., Lawson, N. D. <strong>Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.</strong> Nature 445: 781-784, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17259972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17259972</a>] [<a href="https://doi.org/10.1038/nature05577" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17259972">Siekmann and Lawson (2007)</a> concluded that their studies taken together indicated that proper specification of cell identity, position, and behavior in a developing blood vessel sprout is required for normal angiogenesis, and implicated the Notch signaling pathway in this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17259972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Tammela, T., Zarkada, G., Wallgard, E., Murtomaki, A., Suchting, S., Wirzenius, M., Waltari, M., Hellstrom, M., Schomber, T., Peltonen, R., Freitas, C., Duarte, A., and 9 others. <strong>Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.</strong> Nature 454: 656-660, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18594512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18594512</a>] [<a href="https://doi.org/10.1038/nature07083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18594512">Tammela et al. (2008)</a> demonstrated that VEGFR3 is highly expressed in angiogenic sprouts, and that genetic targeting of VEGFR3 or blocking of VEGFR3 signaling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching, and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR2 (<a href="/entry/191306">191306</a>) inhibitors, whereas antibodies against VEGFR3 and VEGFR2 in combination resulted in additive inhibition of angiogenesis and tumor growth. Furthermore, genetic or pharmacologic disruption of the Notch signaling pathway led to widespread endothelial VEGFR3 expression and excessive sprouting, which was inhibited by blocking VEGFR3 signals. <a href="#29" class="mim-tip-reference" title="Tammela, T., Zarkada, G., Wallgard, E., Murtomaki, A., Suchting, S., Wirzenius, M., Waltari, M., Hellstrom, M., Schomber, T., Peltonen, R., Freitas, C., Duarte, A., and 9 others. <strong>Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.</strong> Nature 454: 656-660, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18594512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18594512</a>] [<a href="https://doi.org/10.1038/nature07083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18594512">Tammela et al. (2008)</a> concluded that their results implicated VEGFR3 as a regulator of vascular network formation. The authors suggested that targeting VEGFR3 may provide additional efficacy for antiangiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR2 inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18594512" 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="#31" class="mim-tip-reference" title="Wang, Y., Nakayama, M., Pitulescu, M. E., Schmidt, T. S., Bochenek, M. L., Sakakibara, A., Adams, S., Davy, A., Deutsch, U., Luthi, U., Barberis, A., Benjamin, L. E., Makinen, T., Nobes, C. D., Adams, R. H. <strong>Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.</strong> Nature 465: 483-486, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20445537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20445537</a>] [<a href="https://doi.org/10.1038/nature09002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20445537">Wang et al. (2010)</a> demonstrated with genetic experiments in mouse and zebrafish that ephrin-B2 (EFNB2; <a href="/entry/600527">600527</a>), a transmembrane ligand for Ephrin receptor tyrosine kinases, promotes sprouting behavior and motility in the angiogenic endothelium. <a href="#31" class="mim-tip-reference" title="Wang, Y., Nakayama, M., Pitulescu, M. E., Schmidt, T. S., Bochenek, M. L., Sakakibara, A., Adams, S., Davy, A., Deutsch, U., Luthi, U., Barberis, A., Benjamin, L. E., Makinen, T., Nobes, C. D., Adams, R. H. <strong>Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.</strong> Nature 465: 483-486, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20445537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20445537</a>] [<a href="https://doi.org/10.1038/nature09002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20445537">Wang et al. (2010)</a> linked this proangiogenic function to a crucial role of ephrin-B2 in the VEGF signaling pathway, which they studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1 (<a href="/entry/602048">602048</a>), Akt (<a href="/entry/164730">164730</a>), and the mitogen-activated protein kinase Erk (<a href="/entry/601795">601795</a>). <a href="#31" class="mim-tip-reference" title="Wang, Y., Nakayama, M., Pitulescu, M. E., Schmidt, T. S., Bochenek, M. L., Sakakibara, A., Adams, S., Davy, A., Deutsch, U., Luthi, U., Barberis, A., Benjamin, L. E., Makinen, T., Nobes, C. D., Adams, R. H. <strong>Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.</strong> Nature 465: 483-486, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20445537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20445537</a>] [<a href="https://doi.org/10.1038/nature09002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20445537">Wang et al. (2010)</a> concluded that VEGFR3 signaling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20445537" 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="#2" class="mim-tip-reference" title="Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. <strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong> Nature 484: 110-114, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>] [<a href="https://doi.org/10.1038/nature10908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22426001">Benedito et al. (2012)</a> used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 (<a href="/entry/605185">605185</a>) protein expression in retinal tip cells is only weakly modulated by VEGFR2 (<a href="/entry/191306">191306</a>) signaling. Surprisingly, Notch (<a href="/entry/190198">190198</a>) inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA (<a href="/entry/192240">192240</a>) receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGFC (<a href="/entry/601528">601528</a>), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. <a href="#2" class="mim-tip-reference" title="Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H. <strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong> Nature 484: 110-114, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22426001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22426001</a>] [<a href="https://doi.org/10.1038/nature10908" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22426001">Benedito et al. (2012)</a> concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22426001" 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 screening immunity-related proteins and their receptors for bacteria- or LPS-induced expression, <a href="#33" class="mim-tip-reference" title="Zhang, Y., Lu, Y., Ma, L., Cao, X., Xiao, J., Chen, J., Jiao, S., Gao, Y., Liu, C., Duan, Z., Li, D., He, Y., Wei, B., Wang, H. <strong>Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-kappa-beta signaling and protects against endotoxin shock.</strong> Immunity 40: 501-514, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24656836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24656836</a>] [<a href="https://doi.org/10.1016/j.immuni.2014.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24656836">Zhang et al. (2014)</a> detected upregulation of VEGFR3 and VEGFC in macrophages. Serum VEGFC was also increased in patient and mouse models of septic shock. Ligation of VEGFR3 by VEGFC attenuated proinflammatory cytokine production. In the absence of either the ligand-binding domain or tyrosine kinase activity of Vegfr3, mice became more sensitive to septic shock. Vegfr3 restrained Tlr4 (<a href="/entry/603030">603030</a>)-NFKB (see <a href="/entry/164011">164011</a>) activation by regulating the PI3K (see <a href="/entry/601232">601232</a>)-Akt signaling pathway and Socs1 (<a href="/entry/603597">603597</a>) expression. <a href="#33" class="mim-tip-reference" title="Zhang, Y., Lu, Y., Ma, L., Cao, X., Xiao, J., Chen, J., Jiao, S., Gao, Y., Liu, C., Duan, Z., Li, D., He, Y., Wei, B., Wang, H. <strong>Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-kappa-beta signaling and protects against endotoxin shock.</strong> Immunity 40: 501-514, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24656836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24656836</a>] [<a href="https://doi.org/10.1016/j.immuni.2014.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24656836">Zhang et al. (2014)</a> proposed that in addition to targeting lymphatic vessels, VEGFR3 signaling via VEGFC prevents microphagic overreaction to infections complicated by lymphedema. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24656836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Lorenz, L., Axnick, J., Buschmann, T., Henning, C., Urner, S., Fang, S., Nurmi, H., Eichhorst, N., Holtmeier, R., Bodis, K., Hwang, J.-H., Mussig, K., Eberhard, D., Stypmann, J., Kuss, O., Roden, M., Alitalo, K., Haussinger, D., Lammert, E. <strong>Mechanosensing by beta-1 integrin induces angiocrine signals for liver growth and survival.</strong> Nature 562: 128-132, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30258227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30258227</a>] [<a href="https://doi.org/10.1038/s41586-018-0522-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30258227">Lorenz et al. (2018)</a> used the developing liver as a model organ to study angiocrine signals and showed that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, <a href="#19" class="mim-tip-reference" title="Lorenz, L., Axnick, J., Buschmann, T., Henning, C., Urner, S., Fang, S., Nurmi, H., Eichhorst, N., Holtmeier, R., Bodis, K., Hwang, J.-H., Mussig, K., Eberhard, D., Stypmann, J., Kuss, O., Roden, M., Alitalo, K., Haussinger, D., Lammert, E. <strong>Mechanosensing by beta-1 integrin induces angiocrine signals for liver growth and survival.</strong> Nature 562: 128-132, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30258227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30258227</a>] [<a href="https://doi.org/10.1038/s41586-018-0522-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30258227">Lorenz et al. (2018)</a> demonstrated that vessel perfusion activates beta-1 integrin (<a href="/entry/135630">135630</a>) and VEGFR3. Notably, both beta-1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes, and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrated that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. <a href="#19" class="mim-tip-reference" title="Lorenz, L., Axnick, J., Buschmann, T., Henning, C., Urner, S., Fang, S., Nurmi, H., Eichhorst, N., Holtmeier, R., Bodis, K., Hwang, J.-H., Mussig, K., Eberhard, D., Stypmann, J., Kuss, O., Roden, M., Alitalo, K., Haussinger, D., Lammert, E. <strong>Mechanosensing by beta-1 integrin induces angiocrine signals for liver growth and survival.</strong> Nature 562: 128-132, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30258227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30258227</a>] [<a href="https://doi.org/10.1038/s41586-018-0522-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30258227">Lorenz et al. (2018)</a> concluded that their findings uncovered a signaling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30258227" 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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In affected members of a family with lymphatic malformation-1 (LMPHM1; <a href="/entry/153100">153100</a>), <a href="#7" class="mim-tip-reference" title="Ferrell, R. E., Levinson, K. L., Esman, J. H., Kimak, M. A., Lawrence, E. C., Barmada, M. M., Finegold, D. N. <strong>Hereditary lymphedema: evidence for linkage and genetic heterogeneity.</strong> Hum. Molec. Genet. 7: 2073-2078, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817924</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817924">Ferrell et al. (1998)</a> identified a mutation in the FLT4 gene (<a href="#0005">136352.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9817924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al. (2000)</a> identified mutations at the FLT4 locus in several families with hereditary lymphedema. They found that all disease-associated alleles analyzed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. These studies established that vascular endothelial growth factor receptor-3 is important for normal lymphatic vascular function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family with hereditary lymphedema, <a href="#12" class="mim-tip-reference" title="Irrthum, A., Karkkainen, M. J., Devriendt, K., Alitalo, K., Vikkula, M. <strong>Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase.</strong> Am. J. Hum. Genet. 67: 295-301, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10856194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10856194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10856194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10856194">Irrthum et al. (2000)</a> identified a mutation in the FLT4 gene (<a href="#0006">136352.0006</a>) that cosegregated with the disease. In vitro expression showed that this mutation inhibited the autophosphorylation of the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10856194" 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="Evans, A. L., Bell, R., Brice, G., Comeglio, P., Lipede, C., Jeffery, S., Mortimer, P., Sarfarazi, M., Child, A. H. <strong>Identification of eight novel VEGFR-3 mutations in families with primary lymphoedema.</strong> J. Med. Genet. 40: 697-703, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960217</a>] [<a href="https://doi.org/10.1136/jmg.40.9.697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960217">Evans et al. (2003)</a> identified 8 different heterozygous mutations in the FLT4 gene (see, e.g., <a href="#0011">136352.0011</a>) in affected members of 12 different Caucasian families with hereditary lymphedema. All the mutations occurred in the tyrosine kinase domains. Several families showed incomplete penetrance of the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Kim, H., Dumont, D. J. <strong>Molecular mechanisms in lymphangiogenesis: model systems and implications in human disease.</strong> Clin. Genet. 64: 282-292, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12974730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12974730</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00152.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12974730">Kim and Dumont (2003)</a> reviewed molecular mechanisms in lymphangiogenesis and their implications for human disease. In addition to VEGFR3 and FOXC2 (<a href="/entry/602402">602402</a>), 6 'lymphangiogenic markers' were reviewed. The role of some of these lymphangiogenetic mechanisms in cancer and metastasis was also reviewed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12974730" 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="#10" class="mim-tip-reference" title="Ghalamkarpour, A., Morlot, S., Raas-Rothschild, A., Utkus, A., Mulliken, J. B., Boon, L. M., Vikkula, M. <strong>Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.</strong> Clin. Genet. 70: 330-335, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965327</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00687.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965327">Ghalamkarpour et al. (2006)</a> identified mutations in the FLT4 gene (see, e.g., <a href="#0008">136352.0008</a>-<a href="#0009">136352.0009</a>) in affected members from 3 unrelated families with autosomal dominant lymphedema and in a sporadic case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965327" 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 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema, <a href="#28" class="mim-tip-reference" title="Spiegel, R., Ghalamkarpour, A., Daniel-Spiegel, E., Vikkula, M., Shalev, S. A. <strong>Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.</strong> J. Hum. Genet. 51: 846-850, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16924388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16924388</a>] [<a href="https://doi.org/10.1007/s10038-006-0031-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16924388">Spiegel et al. (2006)</a> identified heterozygosity for a missense mutation in the VEGFR3 gene (<a href="#0010">136352.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16924388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Connell, F. C., Ostergaard, P., Carver, C., Brice, G., Williams, N., Mansour, S., Mortimer, P. S., Jeffery, S., Lymphoedema Consortium. <strong>Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas.</strong> Hum. Genet. 124: 625-631, 2009. Note: Erratum: Hum. Genet. 125: 237 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19002718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19002718</a>] [<a href="https://doi.org/10.1007/s00439-008-0586-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19002718">Connell et al. (2009)</a> identified mutations in the FLT4 gene, including 14 novel mutations, in 22 (42%) of 52 patients with primary lymphedema. Mutation prevalence was 75% in patients with a typical Milroy phenotype and a positive family history, and 68% if positive family history was not a diagnostic criterion. No mutations were found outside the kinase domains, showing that analysis of nonkinase domains of FLT4 is not useful for Milroy disease patients. No mutations were identified in the VEGFC gene (<a href="/entry/601528">601528</a>), which encodes the FLT4 ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19002718" 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 Hispanic female with congenital lymphedema who was born of first-cousin parents, <a href="#9" class="mim-tip-reference" title="Ghalamkarpour, A., Holnthoner, W., Saharinen, P., Boon, L. M., Mulliken, J. B., Alitalo, K., Vikkula, M. <strong>Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.</strong> J. Med. Genet. 46: 399-404, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289394</a>] [<a href="https://doi.org/10.1136/jmg.2008.064469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289394">Ghalamkarpour et al. (2009)</a> identified homozygosity for a missense mutation in the ATP-binding domain of the FLT4 gene (<a href="#0012">136352.0012</a>). Her unaffected parents were heterozygous for the hypomorphic mutation, which was not found in 110 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289394" 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>Congenital Heart Defects, Multiple Types, 7</em></strong></p><p>
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In a cohort of 2,871 probands with congenital heart disease, comprising 2,645 parent-offspring trios and 226 singletons, <a href="#13" class="mim-tip-reference" title="Jin, S. C., Homsy, J., Zaidi, S., Lu, Q., Morton, S., DePalma, S. R., Zeng, X., Qi, H., Chang, W., Sierant, M. C., Hung, W.-C., Haider, S., and 33 others. <strong>Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.</strong> Nature Genet. 49: 1593-1601, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28991257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28991257</a>] [<a href="https://doi.org/10.1038/ng.3970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28991257">Jin et al. (2017)</a> performed whole-exome sequencing and identified 10 probands who were heterozygous for frameshift or nonsense mutations in the FLT4 gene. In 2 probands the mutations appeared to have arisen de novo and in 2 probands the mutations were inherited from an affected parent; however, in 6 probands, the mutation was inherited from an unaffected parent. Cardiac diagnoses in affected individuals included tetralogy of Fallot, pulmonary stenosis or atresia, absent pulmonary valve, right aortic arch, double aortic arch, and major aortopulmonary collateral arteries. The authors stated that FLT4 mutation carriers had no extracardiac malformations (unspecified), but elsewhere in the text stated that 1 proband had an extracardiac congenital anomaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28991257" 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="#26" class="mim-tip-reference" title="Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. <strong>Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.</strong> Genet. Med. 21: 1001-1007, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232381</a>] [<a href="https://doi.org/10.1038/s41436-018-0260-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232381">Reuter et al. (2019)</a> sequenced 175 adult patients with tetralogy of Fallot and 56 with other congenital cardiac anomalies for loss-of-function and deleterious mutations in FLT4 and other VEGF pathway genes. They identified 9 (5.1%) probands with novel FLT4 variants, all of whom came from the group of individuals with tetralogy of Fallot. Seven of the variants were predicted to have a loss-of-function effect, implicating haploinsufficiency, and comprised 2 stopgain, 3 frameshift, 1 splice site, and 1 multiexon deletion mutation; the other 2 mutations, a missense and an in-frame deletion, were predicted to be deleterious. In addition to variants in FLT4, multiple variants were also identified in the KDR (<a href="/entry/191306">191306</a>) gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232381" 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>The Chy mouse mutant, characterized by accumulation of chylous ascites and swelling of the limbs, was obtained by ethylnitrosourea-induced mutagenesis (Lyon and Glenister (<a href="#20" class="mim-tip-reference" title="Lyon, M. F., Glenister, P. H. <strong>New Mutants.</strong> Mouse Newsletter 71: 26 only, 1984."None>1984</a>, <a href="#21" class="mim-tip-reference" title="Lyon, M. F., Glenister, P. H. <strong>Gene order of Chy-vt-Re on chromosome 11.</strong> Mouse Newsletter 74: 96 only, 1986."None>1986</a>)). The phenotype is linked to mouse chromosome 11. <a href="#16" class="mim-tip-reference" title="Karkkainen, M. J., Saaristo, A., Jussila, L., Karila, K. A., Lawrence, E. C., Pajusola, K., Bueler, H., Eichmann, A., Kauppinen, R., Kettunen, M. I., Yla-Herttuala, S., Finegold, D. N., Ferrell, R. E., Alitalo, K. <strong>A model for gene therapy of human hereditary lymphedema.</strong> Proc. Nat. Acad. Sci. 98: 12677-12682, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592985</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11592985[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.221449198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592985">Karkkainen et al. (2001)</a> sequenced the Vegfr3 candidate gene on chromosome 11 in Chy mice and found a heterozygous 3157A-T mutation resulting in an ile1053-to-phe (I1053F) substitution in the tyrosine kinase domain. This mutation was located in a highly conserved catalytic domain of the receptor, in close proximity to the VEGFR3 mutations in human primary lymphedema. The I1053F mutant receptor was tyrosine kinase inactive. Although lymphedema patients with heterozygous missense mutations of VEGFR3 retain some receptor activity because of the presence of the wildtype allele (<a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al., 2000</a>), the mutant VEGFR3 can be classified as a dominant-negative receptor similar to certain mutant KIT receptors in piebaldism (<a href="/entry/172800">172800</a>) and RET receptors (<a href="/entry/164761">164761</a>) in Hirschsprung disease (<a href="/entry/142623">142623</a>). <a href="#16" class="mim-tip-reference" title="Karkkainen, M. J., Saaristo, A., Jussila, L., Karila, K. A., Lawrence, E. C., Pajusola, K., Bueler, H., Eichmann, A., Kauppinen, R., Kettunen, M. I., Yla-Herttuala, S., Finegold, D. N., Ferrell, R. E., Alitalo, K. <strong>A model for gene therapy of human hereditary lymphedema.</strong> Proc. Nat. Acad. Sci. 98: 12677-12682, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592985</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11592985[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.221449198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592985">Karkkainen et al. (2001)</a> found that neuropilin-2 (NRP2; <a href="/entry/602070">602070</a>) bound VEGFC and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia. This may explain why hypoplastic cutaneous, but not visceral, lymphatic vessels were found in the Chy mice. Using virus-mediated VEGFC gene therapy, <a href="#16" class="mim-tip-reference" title="Karkkainen, M. J., Saaristo, A., Jussila, L., Karila, K. A., Lawrence, E. C., Pajusola, K., Bueler, H., Eichmann, A., Kauppinen, R., Kettunen, M. I., Yla-Herttuala, S., Finegold, D. N., Ferrell, R. E., Alitalo, K. <strong>A model for gene therapy of human hereditary lymphedema.</strong> Proc. Nat. Acad. Sci. 98: 12677-12682, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592985</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11592985[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.221449198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592985">Karkkainen et al. (2001)</a> generated functional lymphatic vessels in the lymphedema mice. The results suggested that growth factor gene therapy is applicable to human lymphedema as well and provided a paradigm for other diseases associated with mutant receptors, i.e., ligand therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11592985+10835628" 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">rs267606818 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606818;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=rs267606818" 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=rs267606818" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with lymphatic malformation-1 (LMPHM1; <a href="/entry/153100">153100</a>) in members of 3 generations, <a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al. (2000)</a> identified a heterozygous G-A transition in the FLT4 gene, resulting in a gly857-to-arg (G857R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835628" 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">rs121909650 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909650;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=rs121909650" 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=rs121909650" 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=RCV000017648 OR RCV004719652 OR RCV004751213" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017648, RCV004719652, RCV004751213" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017648...</a>
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<p>In a family with hereditary lymphedema (LMPHM1; <a href="/entry/153100">153100</a>) in at least 4 generations, <a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al. (2000)</a> identified a heterozygous mutation in the FLT4 gene, resulting in an arg1041-to-pro (R1041P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835628" 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 LYMPHATIC MALFORMATION 1</strong>
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FLT4, LEU1044PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909651 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909651;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=rs121909651" 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=rs121909651" 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=RCV000017649" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017649" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017649</a>
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<p>In a large family with autosomal dominant lymphedema (LMPHM1; <a href="/entry/153100">153100</a>) in 5 generations and many different sibships, <a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al. (2000)</a> identified heterozygosity for a transition in the FLT4 gene, resulting in a leu1044-to-pro (L1044P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835628" 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 LYMPHATIC MALFORMATION 1</strong>
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FLT4, PRO1114LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909652 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909652;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=rs121909652" 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=rs121909652" 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=RCV000017650 OR RCV005000985" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017650, RCV005000985" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017650...</a>
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<span class="mim-text-font">
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<p>In a mother and 2 daughters with primary lymphedema (LMPHM1; <a href="/entry/153100">153100</a>), <a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al. (2000)</a> identified a heterozygous pro1114-to-leu (P1114L) missense mutation of the FLT4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10835628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Ferrell, R. E., Levinson, K. L., Esman, J. H., Kimak, M. A., Lawrence, E. C., Barmada, M. M., Finegold, D. N. <strong>Hereditary lymphedema: evidence for linkage and genetic heterogeneity.</strong> Hum. Molec. Genet. 7: 2073-2078, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9817924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9817924</a>] [<a href="https://doi.org/10.1093/hmg/7.13.2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9817924">Ferrell et al. (1998)</a> had originally described the mutation in this family as a 3360G-A transition in the FLT4 gene, predicted to cause a nonconservative PRO1126LEU (P1126L) substitution in the mature receptor (<a href="#15" class="mim-tip-reference" title="Karkkainen, M. J., Ferrell, R. E., Lawrence, E. C., Kimak, M. A., Levinson, K. L., McTigue, M. A., Alitalo, K., Finegold, D. N. <strong>Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.</strong> Nature Genet. 25: 153-159, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10835628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10835628</a>] [<a href="https://doi.org/10.1038/75997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10835628">Karkkainen et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10835628+9817924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0006 LYMPHATIC MALFORMATION 1</strong>
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FLT4, HIS1035ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909653 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909653;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=rs121909653" 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=rs121909653" 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=RCV000017651" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017651" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017651</a>
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<p>In a family in which the father and 4 of 7 children had congenital lymphedema (LMPHM1; <a href="/entry/153100">153100</a>), <a href="#12" class="mim-tip-reference" title="Irrthum, A., Karkkainen, M. J., Devriendt, K., Alitalo, K., Vikkula, M. <strong>Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase.</strong> Am. J. Hum. Genet. 67: 295-301, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10856194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10856194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10856194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/303019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10856194">Irrthum et al. (2000)</a> demonstrated a heterozygous his1035-to-arg (H1035R) missense mutation in the FLT4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10856194" 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 HEMANGIOMA, CAPILLARY INFANTILE, SOMATIC</strong>
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FLT4, PRO954SER
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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> rs34255532 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34255532;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/rs34255532?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=rs34255532" 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=rs34255532" 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=RCV000017652 OR RCV000249222 OR RCV000860875 OR RCV003323277" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017652, RCV000249222, RCV000860875, RCV003323277" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017652...</a>
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<p>In 1 of 15 infantile hemangioma (<a href="/entry/602089">602089</a>) specimens, <a href="#30" class="mim-tip-reference" title="Walter, J. W., North, P. E., Waner, M., Mizeracki, A., Blei, F., Walker, J. W. T., Reinisch, J. F., Marchuk, D. A. <strong>Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma.</strong> Genes Chromosomes Cancer 33: 295-303, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807987/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807987</a>] [<a href="https://doi.org/10.1002/gcc.10028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807987">Walter et al. (2002)</a> found a pro954-to-ser (P954S) missense mutation in the kinase insert of the FLT4 gene. This result, and the finding of a somatic missense mutation in the VEGFR2 gene (<a href="/entry/191306#0001">191306.0001</a>) in another of the 15 specimens, suggested that alteration of the FLT4 signaling pathway in endothelial and/or pericytic cells may be a mechanism involved in hemangioma formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11807987" 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="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 LYMPHATIC MALFORMATION 1</strong>
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FLT4, VAL878MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909654 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909654;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=rs121909654" 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=rs121909654" 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=RCV000017653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017653</a>
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<p>In 4 affected individuals of a family with autosomal dominant lymphedema (LMPHM1; <a href="/entry/153100">153100</a>), <a href="#10" class="mim-tip-reference" title="Ghalamkarpour, A., Morlot, S., Raas-Rothschild, A., Utkus, A., Mulliken, J. B., Boon, L. M., Vikkula, M. <strong>Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.</strong> Clin. Genet. 70: 330-335, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965327</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00687.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965327">Ghalamkarpour et al. (2006)</a> identified a heterozygous 2632G-A transition in the FLT4 gene, resulting in a val878-to-met (V878M) substitution in the tyrosine kinase domain I of the protein. One affected family member was a 22-week-old fetus who was found to have fetal hydrops with bilateral leg edema, pleural effusions, hydrothorax, and pulmonary hypoplasia on ultrasound. The pregnancy was terminated. Other affected family members had congenital lymphedema of the legs with variable severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965327" 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">rs121909655 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909655;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=rs121909655" 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=rs121909655" 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=RCV000017654 OR RCV003398529" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017654, RCV003398529" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017654...</a>
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<p>In affected members of a family with autosomal dominant lymphedema (LMPHM1; <a href="/entry/153100">153100</a>) spanning 5 generations, <a href="#10" class="mim-tip-reference" title="Ghalamkarpour, A., Morlot, S., Raas-Rothschild, A., Utkus, A., Mulliken, J. B., Boon, L. M., Vikkula, M. <strong>Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations.</strong> Clin. Genet. 70: 330-335, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965327</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00687.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965327">Ghalamkarpour et al. (2006)</a> identified a heterozygous 3257T-C transition in the FLT4 gene, resulting in an ile1086-to-thr (I1086T) substitution in the tyrosine kinase II domain of the protein. The proband had a severe phenotype with elephantiasis up to the inguinal ligament bilaterally, chronic venous ulcerations, cellulitis, and papillomatosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 LYMPHATIC MALFORMATION 1</strong>
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FLT4, GLU1106LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909656 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909656;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=rs121909656" 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=rs121909656" 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=RCV000017655" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017655" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017655</a>
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<p>In 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema (LMPHM1; <a href="/entry/153100">153100</a>), <a href="#28" class="mim-tip-reference" title="Spiegel, R., Ghalamkarpour, A., Daniel-Spiegel, E., Vikkula, M., Shalev, S. A. <strong>Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.</strong> J. Hum. Genet. 51: 846-850, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16924388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16924388</a>] [<a href="https://doi.org/10.1007/s10038-006-0031-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16924388">Spiegel et al. (2006)</a> identified heterozygosity for a 3316G-A transition in the FLT4 gene, resulting in a glu1106-to-lys (E1106K) substitution. The mutation was not found in 110 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16924388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 LYMPHATIC MALFORMATION 1</strong>
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FLT4, 3-BP DEL, 3323TCT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776833 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776833;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=rs587776833" 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=rs587776833" 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=RCV000017656 OR RCV002254267" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017656, RCV002254267" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017656...</a>
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<p>In affected members of a family with hereditary lymphedema (LMPHM1; <a href="/entry/153100">153100</a>), <a href="#6" class="mim-tip-reference" title="Evans, A. L., Bell, R., Brice, G., Comeglio, P., Lipede, C., Jeffery, S., Mortimer, P., Sarfarazi, M., Child, A. H. <strong>Identification of eight novel VEGFR-3 mutations in families with primary lymphoedema.</strong> J. Med. Genet. 40: 697-703, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960217</a>] [<a href="https://doi.org/10.1136/jmg.40.9.697" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960217">Evans et al. (2003)</a> identified a heterozygous 3-bp in-frame deletion (3323delTCT), resulting in the deletion of residue phe1108 in the tyrosine kinase II domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960217" 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>.0012 LYMPHATIC MALFORMATION 1</strong>
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FLT4, ALA855THR
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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> rs121909657 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909657;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/rs121909657?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=rs121909657" 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=rs121909657" 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=RCV000017657 OR RCV003387726 OR RCV004719653" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017657, RCV003387726, RCV004719653" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017657...</a>
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<p>In a Hispanic female with congenital lymphedema (LMPHM1; <a href="/entry/153100">153100</a>) who was born of first-cousin parents, <a href="#9" class="mim-tip-reference" title="Ghalamkarpour, A., Holnthoner, W., Saharinen, P., Boon, L. M., Mulliken, J. B., Alitalo, K., Vikkula, M. <strong>Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.</strong> J. Med. Genet. 46: 399-404, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19289394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19289394</a>] [<a href="https://doi.org/10.1136/jmg.2008.064469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19289394">Ghalamkarpour et al. (2009)</a> identified homozygosity for a 2563G-A transition in exon 18 of the FLT4 gene, resulting in an ala855-to-thr (A855T) substitution in the ATP-binding domain of the receptor. The unaffected parents were heterozygous for the mutation, which was not found in 110 controls. Assessment of receptor function showed reduced phosphorylation of the receptor, with impaired ligand-induced internalization and defective downstream signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19289394" 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 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 7</strong>
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FLT4, TYR361TER
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001003426" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001003426" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001003426</a>
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<p>In a mother and son (family 1-04970), both with tetralogy of Fallot (CHTD7; <a href="/entry/618780">618780</a>), <a href="#13" class="mim-tip-reference" title="Jin, S. C., Homsy, J., Zaidi, S., Lu, Q., Morton, S., DePalma, S. R., Zeng, X., Qi, H., Chang, W., Sierant, M. C., Hung, W.-C., Haider, S., and 33 others. <strong>Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.</strong> Nature Genet. 49: 1593-1601, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28991257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28991257</a>] [<a href="https://doi.org/10.1038/ng.3970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28991257">Jin et al. (2017)</a> identified a tyrosine-to-stop substitution at codon 361 of the FLT4 protein (Y361X). The son additionally had right-sided aortic arch. <a href="#11" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 02/17/2020."None>Hamosh (2020)</a> noted that this variant was absent from the gnomAD database on February 17, 2020. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28991257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs755445139 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs755445139;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/rs755445139?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=rs755445139" 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=rs755445139" 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=RCV001003427 OR RCV001585912" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001003427, RCV001585912" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001003427...</a>
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<p>In 2 unrelated probands (1-03410 and 1-05967) with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries (CHTD7; <a href="/entry/618780">618780</a>), <a href="#13" class="mim-tip-reference" title="Jin, S. C., Homsy, J., Zaidi, S., Lu, Q., Morton, S., DePalma, S. R., Zeng, X., Qi, H., Chang, W., Sierant, M. C., Hung, W.-C., Haider, S., and 33 others. <strong>Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.</strong> Nature Genet. 49: 1593-1601, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28991257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28991257</a>] [<a href="https://doi.org/10.1038/ng.3970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28991257">Jin et al. (2017)</a> identified deletion of a C nucleotide in the FLT4 gene resulting in a proline-to-arginine substitution at codon 30, followed by a premature termination codon 3 amino acids downstream (Pro30ArgfsTer3). In family 1-03410, the mutation occurred as a de novo event. The proband also had right-sided aortic arch. In family 1-05967, the proband had inherited the mutation from her unaffected mother. She additionally had double aortic arch. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28991257" 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="#26" class="mim-tip-reference" title="Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. <strong>Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.</strong> Genet. Med. 21: 1001-1007, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232381</a>] [<a href="https://doi.org/10.1038/s41436-018-0260-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232381">Reuter et al. (2019)</a> identified this mutation in a patient (CGC-034) with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries, as well as congenital lymphedema. She had inherited the mutation from her mother, who had normal echocardiography results. The mother's father had bradycardia. <a href="#26" class="mim-tip-reference" title="Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. <strong>Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.</strong> Genet. Med. 21: 1001-1007, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232381</a>] [<a href="https://doi.org/10.1038/s41436-018-0260-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232381">Reuter et al. (2019)</a> recorded the mutation as c.89delC (c.89delC, NM_182925.4). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 23-year-old female (TOF293) with tetralogy of Fallot, right-sided aortic arch, and absent pulmonary valve (CHTD7; <a href="/entry/618780">618780</a>), <a href="#26" class="mim-tip-reference" title="Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. <strong>Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.</strong> Genet. Med. 21: 1001-1007, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232381</a>] [<a href="https://doi.org/10.1038/s41436-018-0260-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232381">Reuter et al. (2019)</a> identified heterozygous deletion of exons 25 through 29 of the FLT4 gene (chr5:180,031,767-180,040,470del). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232381" 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">rs1581616817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1581616817;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=rs1581616817" 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=rs1581616817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 79-year-old man (TOF158) with tetralogy of Fallot, right-sided aortic arch, and atrial flutter requiring ablation (CHTD7; <a href="/entry/618780">618780</a>), and in his daughter with tetralogy of Fallot, <a href="#26" class="mim-tip-reference" title="Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. <strong>Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.</strong> Genet. Med. 21: 1001-1007, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232381</a>] [<a href="https://doi.org/10.1038/s41436-018-0260-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232381">Reuter et al. (2019)</a> identified a C-to-T transition at nucleotide 3574 (c.3574C-T, NM_182925.4) of the FLT4 gene, resulting in a glutamine-to-termination substitution at codon 1192 (Q1192X). The variant was absent from gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232381" 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">rs1581655293 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1581655293;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=rs1581655293" 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=rs1581655293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 29-year-old man (TOF284) with tetralogy of Fallot, major aortopulmonary collateral arteries, and aortic valve replacement (CHTD7; <a href="/entry/618780">618780</a>), <a href="#26" class="mim-tip-reference" title="Reuter, M. S., Jobling, R., Chaturvedi, R. R., Manshaei, R., Costain, G., Heung, T., Curtis, M., Hosseini, S. M., Liston, E., Lowther, C., Oechslin, E., Sticht, H., and 9 others. <strong>Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.</strong> Genet. Med. 21: 1001-1007, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30232381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30232381</a>] [<a href="https://doi.org/10.1038/s41436-018-0260-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30232381">Reuter et al. (2019)</a> identified duplication of a G at nucleotide 1622 (c.1622dupG, NM_182925.4) of the FLT4 gene, resulting in a frameshift and premature termination (Gln542ProfsTer3). The variant was absent from gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30232381" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Milroy1892" class="mim-tip-reference" title="Milroy, W. F. <strong>An undescribed variety of hereditary oedema.</strong> New York Med. J. 56: 505-508, 1892.">Milroy (1892)</a>; <a href="#Offori1993" class="mim-tip-reference" title="Offori, T. W., Platt, C. C., Stephens, M., Hopkinson, G. B. <strong>Angiosarcoma in congenital hereditary lymphoedema (Milroy's disease): diagnostic beacons and a review of the literature.</strong> Clin. Exp. Derm. 18: 174-177, 1993.">Offori et al. (1993)</a>
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Aprelikova, O., Pajusola, K., Partanen, J., Armstrong, E., Alitalo, R., Bailey, S. K., McMahon, J., Wasmuth, J., Huebner, K., Alitalo, K.
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<strong>FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter.</strong>
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Cancer Res. 52: 746-748, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1310071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1310071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1310071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Benedito, R., Rocha, S. F., Woeste, M., Zamykal, M., Radtke, F., Casanovas, O., Duarte, A., Pytowski, B., Adams, R. H.
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<strong>Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling.</strong>
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Nature 484: 110-114, 2012.
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[<a href="https://doi.org/10.1002/gcc.10028" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature09002" target="_blank">Full Text</a>]
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Zhang, Y., Lu, Y., Ma, L., Cao, X., Xiao, J., Chen, J., Jiao, S., Gao, Y., Liu, C., Duan, Z., Li, D., He, Y., Wei, B., Wang, H.
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[<a href="https://doi.org/10.1016/j.immuni.2014.01.013" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/17/2020
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/13/2019<br>Marla J. F. O'Neill - updated : 04/17/2018<br>Paul J. Converse - updated : 9/19/2014<br>Ada Hamosh - updated : 4/24/2012<br>Ada Hamosh - updated : 6/30/2010<br>Cassandra L. Kniffin - updated : 6/10/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>Ada Hamosh - updated : 10/20/2008<br>Cassandra L. Kniffin - updated : 4/18/2008<br>Ada Hamosh - updated : 6/26/2007<br>Marla J. F. O'Neill - updated : 12/29/2006<br>Cassandra L. Kniffin - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 9/29/2006<br>Cassandra L. Kniffin - reorganized : 11/19/2003<br>Victor A. McKusick - updated : 11/4/2003<br>Victor A. McKusick - updated : 3/14/2002<br>Victor A. McKusick - updated : 1/14/2002<br>Victor A. McKusick - updated : 10/3/2000<br>Victor A. McKusick - updated : 5/25/2000<br>Victor A. McKusick - updated : 2/10/1999<br>Victor A. McKusick - updated : 1/6/1999<br>Victor A. McKusick - updated : 11/10/1998<br>Victor A. McKusick - updated : 10/27/1998
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Victor A. McKusick : 6/1/1992
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alopez : 06/25/2020
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alopez : 02/18/2020<br>carol : 02/18/2020<br>alopez : 02/17/2020<br>alopez : 02/17/2020<br>alopez : 09/13/2019<br>carol : 12/18/2018<br>alopez : 11/07/2018<br>carol : 04/18/2018<br>carol : 04/17/2018<br>mgross : 09/29/2014<br>carol : 9/22/2014<br>mcolton : 9/19/2014<br>carol : 1/30/2013<br>carol : 1/29/2013<br>carol : 1/2/2013<br>alopez : 4/25/2012<br>terry : 4/24/2012<br>alopez : 6/30/2010<br>terry : 6/30/2010<br>wwang : 9/28/2009<br>wwang : 7/1/2009<br>ckniffin : 6/10/2009<br>wwang : 6/1/2009<br>ckniffin : 5/20/2009<br>wwang : 3/5/2009<br>ckniffin : 2/25/2009<br>alopez : 10/22/2008<br>terry : 10/20/2008<br>wwang : 4/18/2008<br>alopez : 7/2/2007<br>terry : 6/26/2007<br>wwang : 12/29/2006<br>ckniffin : 11/6/2006<br>carol : 11/6/2006<br>ckniffin : 11/1/2006<br>wwang : 9/29/2006<br>wwang : 9/29/2006<br>carol : 11/19/2003<br>ckniffin : 11/12/2003<br>tkritzer : 11/6/2003<br>terry : 11/4/2003<br>cwells : 3/20/2002<br>cwells : 3/18/2002<br>terry : 3/14/2002<br>terry : 3/8/2002<br>carol : 1/20/2002<br>mcapotos : 1/14/2002<br>mcapotos : 1/14/2002<br>carol : 10/5/2000<br>terry : 10/3/2000<br>alopez : 5/25/2000<br>alopez : 11/18/1999<br>terry : 3/9/1999<br>carol : 3/3/1999<br>carol : 2/10/1999<br>terry : 2/10/1999<br>carol : 1/18/1999<br>terry : 1/7/1999<br>terry : 1/6/1999<br>carol : 11/18/1998<br>carol : 11/17/1998<br>terry : 11/16/1998<br>terry : 11/10/1998<br>dkim : 11/6/1998<br>alopez : 10/29/1998<br>terry : 10/27/1998<br>dkim : 7/2/1998<br>carol : 7/20/1992<br>carol : 6/1/1992
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<span class="mim-font">
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<strong>*</strong> 136352
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<h3>
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FMS-LIKE TYROSINE KINASE 4; FLT4
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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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VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3; VEGFR3
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FLT4</em></strong>
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<strong>SNOMEDCT:</strong> 399889006;
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<em>
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Cytogenetic location: 5q35.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:180,601,506-180,650,298 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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5q35.3
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Congenital heart defects, multiple types, 7
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<span class="mim-font">
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618780
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Autosomal dominant
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<span class="mim-font">
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3
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Hemangioma, capillary infantile, somatic
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<span class="mim-font">
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602089
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<span class="mim-font">
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3
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Lymphatic malformation 1
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<span class="mim-font">
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153100
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Autosomal dominant
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<span class="mim-font">
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3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>By screening a placenta cDNA library with a mouse Flt3 probe, Galland et al. (1992) isolated a human gene encoding a putative receptor-type tyrosine kinase. The deduced amino acid sequence of the intracellular portion of the molecule showed that it was strongly related to FLT1 (165070) and KDR (191306) and to a lesser degree to members of the class III receptor-type tyrosine kinases: FMS (164770), PDGFR (173490, 173410), KIT (164920), and FLT3 (136351). </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>Galland et al. (1992) mapped FLT4 to chromosome 5q34-q35, telomeric to the FMS and PDGFRB genes, by in situ hybridization. They assigned the mouse homolog to chromosome 11 by the same method. In the process of creating a radiation hybrid map of 18 genes, Warrington et al. (1992) demonstrated that the FLT4 gene is located on distal 5q between GABRA1 (137160) at 5q34-q35 and DRD1 (126449) at 5q35.1. Aprelikova et al. (1992) also mapped the FLT4 gene to chromosome 5q33-qter. </p>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<p>Among the factors stimulating angiogenesis, the acidic and basic fibroblast growth factors FGF1 (131220) and FGF2 (134920) and the vascular endothelial growth factor VEGF (192240) exert their effects via specific cell surface receptor tyrosine kinases: for FGF1 and FGF2, FGF receptor-1 (FGFR1; 136350), also known as FLT2, and the endothelial-specific FMS-like tyrosine kinase-1; and for VEGF, the KDR/FLK1 receptor. The protein product of the FLT4 receptor tyrosine kinase cDNA is structurally similar to the FLT1 and KDR/FLK1 receptors (Pajusola et al., 1992), but FLT4 does not bind VEGF (Pajusola et al., 1994). Lee et al. (1996) identified and characterized a vascular endothelial growth factor-related protein (VEGFC; 601528) that specifically binds to the extracellular domain of Flt4 and stimulates tyrosine phosphorylation and mitogenesis of endothelial cells. </p><p>Kaipainen et al. (1995) analyzed the expression of FLT4 by in situ hybridization during mouse embryogenesis and in adult human tissues. The FLT4 mRNA signals first became detectable in the angioblasts of head mesenchyme, the cardinal vein, and extraembryonally in the allantois of 8.5-day postcoitus (p.c.) embryos. In 12.5-day p.c. embryos, the FLT4 signal decorated developing venous and presumptive lymphatic endothelia, but arterial endothelia were negative. During later stages of development, FLT4 mRNA became restricted to vascular plexuses devoid of red cells, representing developing lymphatic vessels. In adult human tissues, only the lymphatic endothelia and some high endothelial venules expressed FLT4 mRNA. Increased expression occurred in lymphatic sinuses in metastatic lymph nodes and in lymphangioma. The results suggested that FLT4 is a marker for lymphatic vessels and some high endothelial venules in human adult tissues. They also supported the theory of the venous origin of lymphatic vessels. </p><p>Vascular endothelial growth factor is a key regulator of blood vessel development in embryos and angiogenesis in adult tissues. Unlike VEGF, the related VEGFC stimulates the growth of lymphatic vessels through its specific lymphatic endothelial receptor VEGFR3. Dumont et al. (1998) showed that targeted inactivation of the VEGFR3 gene in mice resulted in defective blood vessel development in early embryos. Vasculogenesis and angiogenesis occurred, but large vessels became abnormally organized with defective lumens, leading to fluid accumulation in the pericardial cavity and cardiovascular failure at embryonic day 9.5. Thus, VEGFR3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels. </p><p>In studies of the mouse cornea in vivo, Cursiefen et al. (2006) demonstrated that the presence of Vegfr3 in the corneal epithelium is critical for suppressing inflammatory corneal angiogenesis, by acting as a decoy receptor and binding the angiogenic growth factors VEGFC and VEGFD (FIGF; 300091). Cursiefen et al. (2006) concluded that VEGFR3, which provides proangiogenic signaling when expressed on endothelium, may also have antiangiogenic properties when expressed at an avascular site by nonendothelial cells. </p><p>In studies in zebrafish to investigate the role of Notch (see 190198) signaling in angiogenesis, Siekmann and Lawson (2007) found that Flt4 is expressed in segmental artery tip cells and becomes ectopically expressed throughout the sprout in the absence of Notch. Loss of Flt4 could partially restore normal endothelial cell number in Rbpsuh (147183)-deficient segmental arteries. Finally, loss of the Notch ligand Dll4 (605185) also led to an increased number of endothelial cells within segmental arteries. Siekmann and Lawson (2007) concluded that their studies taken together indicated that proper specification of cell identity, position, and behavior in a developing blood vessel sprout is required for normal angiogenesis, and implicated the Notch signaling pathway in this process. </p><p>Tammela et al. (2008) demonstrated that VEGFR3 is highly expressed in angiogenic sprouts, and that genetic targeting of VEGFR3 or blocking of VEGFR3 signaling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching, and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR2 (191306) inhibitors, whereas antibodies against VEGFR3 and VEGFR2 in combination resulted in additive inhibition of angiogenesis and tumor growth. Furthermore, genetic or pharmacologic disruption of the Notch signaling pathway led to widespread endothelial VEGFR3 expression and excessive sprouting, which was inhibited by blocking VEGFR3 signals. Tammela et al. (2008) concluded that their results implicated VEGFR3 as a regulator of vascular network formation. The authors suggested that targeting VEGFR3 may provide additional efficacy for antiangiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR2 inhibitors. </p><p>Wang et al. (2010) demonstrated with genetic experiments in mouse and zebrafish that ephrin-B2 (EFNB2; 600527), a transmembrane ligand for Ephrin receptor tyrosine kinases, promotes sprouting behavior and motility in the angiogenic endothelium. Wang et al. (2010) linked this proangiogenic function to a crucial role of ephrin-B2 in the VEGF signaling pathway, which they studied in detail for VEGFR3, the receptor for VEGF-C. In the absence of ephrin-B2, the internalization of VEGFR3 in cultured cells and mutant mice is defective, which compromises downstream signal transduction by the small GTPase Rac1 (602048), Akt (164730), and the mitogen-activated protein kinase Erk (601795). Wang et al. (2010) concluded that VEGFR3 signaling is coupled to receptor internalization. Ephrin-B2 is a key regulator of this process and thereby controls angiogenic and lymphangiogenic growth. </p><p>Benedito et al. (2012) used inducible loss-of-function genetics in combination with inhibitors in vivo to demonstrate that DLL4 (605185) protein expression in retinal tip cells is only weakly modulated by VEGFR2 (191306) signaling. Surprisingly, Notch (190198) inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGFA (192240) receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGFC (601528), was strongly modulated by Notch. VEGFR3 kinase activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signaling activity. Benedito et al. (2012) concluded that their results established that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. They proposed that successful antiangiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signaling. </p><p>By screening immunity-related proteins and their receptors for bacteria- or LPS-induced expression, Zhang et al. (2014) detected upregulation of VEGFR3 and VEGFC in macrophages. Serum VEGFC was also increased in patient and mouse models of septic shock. Ligation of VEGFR3 by VEGFC attenuated proinflammatory cytokine production. In the absence of either the ligand-binding domain or tyrosine kinase activity of Vegfr3, mice became more sensitive to septic shock. Vegfr3 restrained Tlr4 (603030)-NFKB (see 164011) activation by regulating the PI3K (see 601232)-Akt signaling pathway and Socs1 (603597) expression. Zhang et al. (2014) proposed that in addition to targeting lymphatic vessels, VEGFR3 signaling via VEGFC prevents microphagic overreaction to infections complicated by lymphedema. </p><p>Lorenz et al. (2018) used the developing liver as a model organ to study angiocrine signals and showed that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, Lorenz et al. (2018) demonstrated that vessel perfusion activates beta-1 integrin (135630) and VEGFR3. Notably, both beta-1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes, and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrated that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Lorenz et al. (2018) concluded that their findings uncovered a signaling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><strong><em>Lymphatic Malformation 1</em></strong></p><p>
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In affected members of a family with lymphatic malformation-1 (LMPHM1; 153100), Ferrell et al. (1998) identified a mutation in the FLT4 gene (136352.0005). </p><p>Karkkainen et al. (2000) identified mutations at the FLT4 locus in several families with hereditary lymphedema. They found that all disease-associated alleles analyzed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. These studies established that vascular endothelial growth factor receptor-3 is important for normal lymphatic vascular function. </p><p>In a family with hereditary lymphedema, Irrthum et al. (2000) identified a mutation in the FLT4 gene (136352.0006) that cosegregated with the disease. In vitro expression showed that this mutation inhibited the autophosphorylation of the receptor. </p><p>Evans et al. (2003) identified 8 different heterozygous mutations in the FLT4 gene (see, e.g., 136352.0011) in affected members of 12 different Caucasian families with hereditary lymphedema. All the mutations occurred in the tyrosine kinase domains. Several families showed incomplete penetrance of the phenotype. </p><p>Kim and Dumont (2003) reviewed molecular mechanisms in lymphangiogenesis and their implications for human disease. In addition to VEGFR3 and FOXC2 (602402), 6 'lymphangiogenic markers' were reviewed. The role of some of these lymphangiogenetic mechanisms in cancer and metastasis was also reviewed. </p><p>Ghalamkarpour et al. (2006) identified mutations in the FLT4 gene (see, e.g., 136352.0008-136352.0009) in affected members from 3 unrelated families with autosomal dominant lymphedema and in a sporadic case. </p><p>In 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema, Spiegel et al. (2006) identified heterozygosity for a missense mutation in the VEGFR3 gene (136352.0010). </p><p>Connell et al. (2009) identified mutations in the FLT4 gene, including 14 novel mutations, in 22 (42%) of 52 patients with primary lymphedema. Mutation prevalence was 75% in patients with a typical Milroy phenotype and a positive family history, and 68% if positive family history was not a diagnostic criterion. No mutations were found outside the kinase domains, showing that analysis of nonkinase domains of FLT4 is not useful for Milroy disease patients. No mutations were identified in the VEGFC gene (601528), which encodes the FLT4 ligand. </p><p>In a Hispanic female with congenital lymphedema who was born of first-cousin parents, Ghalamkarpour et al. (2009) identified homozygosity for a missense mutation in the ATP-binding domain of the FLT4 gene (136352.0012). Her unaffected parents were heterozygous for the hypomorphic mutation, which was not found in 110 controls. </p><p><strong><em>Congenital Heart Defects, Multiple Types, 7</em></strong></p><p>
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In a cohort of 2,871 probands with congenital heart disease, comprising 2,645 parent-offspring trios and 226 singletons, Jin et al. (2017) performed whole-exome sequencing and identified 10 probands who were heterozygous for frameshift or nonsense mutations in the FLT4 gene. In 2 probands the mutations appeared to have arisen de novo and in 2 probands the mutations were inherited from an affected parent; however, in 6 probands, the mutation was inherited from an unaffected parent. Cardiac diagnoses in affected individuals included tetralogy of Fallot, pulmonary stenosis or atresia, absent pulmonary valve, right aortic arch, double aortic arch, and major aortopulmonary collateral arteries. The authors stated that FLT4 mutation carriers had no extracardiac malformations (unspecified), but elsewhere in the text stated that 1 proband had an extracardiac congenital anomaly. </p><p>Reuter et al. (2019) sequenced 175 adult patients with tetralogy of Fallot and 56 with other congenital cardiac anomalies for loss-of-function and deleterious mutations in FLT4 and other VEGF pathway genes. They identified 9 (5.1%) probands with novel FLT4 variants, all of whom came from the group of individuals with tetralogy of Fallot. Seven of the variants were predicted to have a loss-of-function effect, implicating haploinsufficiency, and comprised 2 stopgain, 3 frameshift, 1 splice site, and 1 multiexon deletion mutation; the other 2 mutations, a missense and an in-frame deletion, were predicted to be deleterious. In addition to variants in FLT4, multiple variants were also identified in the KDR (191306) gene. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<p>The Chy mouse mutant, characterized by accumulation of chylous ascites and swelling of the limbs, was obtained by ethylnitrosourea-induced mutagenesis (Lyon and Glenister (1984, 1986)). The phenotype is linked to mouse chromosome 11. Karkkainen et al. (2001) sequenced the Vegfr3 candidate gene on chromosome 11 in Chy mice and found a heterozygous 3157A-T mutation resulting in an ile1053-to-phe (I1053F) substitution in the tyrosine kinase domain. This mutation was located in a highly conserved catalytic domain of the receptor, in close proximity to the VEGFR3 mutations in human primary lymphedema. The I1053F mutant receptor was tyrosine kinase inactive. Although lymphedema patients with heterozygous missense mutations of VEGFR3 retain some receptor activity because of the presence of the wildtype allele (Karkkainen et al., 2000), the mutant VEGFR3 can be classified as a dominant-negative receptor similar to certain mutant KIT receptors in piebaldism (172800) and RET receptors (164761) in Hirschsprung disease (142623). Karkkainen et al. (2001) found that neuropilin-2 (NRP2; 602070) bound VEGFC and was expressed in the visceral, but not in the cutaneous, lymphatic endothelia. This may explain why hypoplastic cutaneous, but not visceral, lymphatic vessels were found in the Chy mice. Using virus-mediated VEGFC gene therapy, Karkkainen et al. (2001) generated functional lymphatic vessels in the lymphedema mice. The results suggested that growth factor gene therapy is applicable to human lymphedema as well and provided a paradigm for other diseases associated with mutant receptors, i.e., ligand therapy. </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>17 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-text-font">
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<strong>.0001 MOVED TO 136352.0005</strong>
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LYMPHATIC MALFORMATION 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLT4, GLY857ARG
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<br />
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SNP: rs267606818,
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ClinVar: RCV000017647, RCV003441720
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with lymphatic malformation-1 (LMPHM1; 153100) in members of 3 generations, Karkkainen et al. (2000) identified a heterozygous G-A transition in the FLT4 gene, resulting in a gly857-to-arg (G857R) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LYMPHATIC MALFORMATION 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLT4, ARG1041PRO
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<br />
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SNP: rs121909650,
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ClinVar: RCV000017648, RCV004719652, RCV004751213
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with hereditary lymphedema (LMPHM1; 153100) in at least 4 generations, Karkkainen et al. (2000) identified a heterozygous mutation in the FLT4 gene, resulting in an arg1041-to-pro (R1041P) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLT4, LEU1044PRO
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<br />
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SNP: rs121909651,
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ClinVar: RCV000017649
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</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large family with autosomal dominant lymphedema (LMPHM1; 153100) in 5 generations and many different sibships, Karkkainen et al. (2000) identified heterozygosity for a transition in the FLT4 gene, resulting in a leu1044-to-pro (L1044P) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
FLT4, PRO1114LEU
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|
<br />
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|
|
SNP: rs121909652,
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|
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ClinVar: RCV000017650, RCV005000985
|
|
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|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and 2 daughters with primary lymphedema (LMPHM1; 153100), Karkkainen et al. (2000) identified a heterozygous pro1114-to-leu (P1114L) missense mutation of the FLT4 gene. </p><p>Ferrell et al. (1998) had originally described the mutation in this family as a 3360G-A transition in the FLT4 gene, predicted to cause a nonconservative PRO1126LEU (P1126L) substitution in the mature receptor (Karkkainen et al., 2000). </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, HIS1035ARG
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|
|
<br />
|
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|
|
SNP: rs121909653,
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|
|
ClinVar: RCV000017651
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family in which the father and 4 of 7 children had congenital lymphedema (LMPHM1; 153100), Irrthum et al. (2000) demonstrated a heterozygous his1035-to-arg (H1035R) missense mutation in the FLT4 gene. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HEMANGIOMA, CAPILLARY INFANTILE, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, PRO954SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs34255532,
|
|
|
|
|
|
gnomAD: rs34255532,
|
|
|
|
|
|
ClinVar: RCV000017652, RCV000249222, RCV000860875, RCV003323277
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 of 15 infantile hemangioma (602089) specimens, Walter et al. (2002) found a pro954-to-ser (P954S) missense mutation in the kinase insert of the FLT4 gene. This result, and the finding of a somatic missense mutation in the VEGFR2 gene (191306.0001) in another of the 15 specimens, suggested that alteration of the FLT4 signaling pathway in endothelial and/or pericytic cells may be a mechanism involved in hemangioma formation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, VAL878MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909654,
|
|
|
|
|
|
|
|
ClinVar: RCV000017653
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected individuals of a family with autosomal dominant lymphedema (LMPHM1; 153100), Ghalamkarpour et al. (2006) identified a heterozygous 2632G-A transition in the FLT4 gene, resulting in a val878-to-met (V878M) substitution in the tyrosine kinase domain I of the protein. One affected family member was a 22-week-old fetus who was found to have fetal hydrops with bilateral leg edema, pleural effusions, hydrothorax, and pulmonary hypoplasia on ultrasound. The pregnancy was terminated. Other affected family members had congenital lymphedema of the legs with variable severity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, ILE1086THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909655,
|
|
|
|
|
|
|
|
ClinVar: RCV000017654, RCV003398529
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with autosomal dominant lymphedema (LMPHM1; 153100) spanning 5 generations, Ghalamkarpour et al. (2006) identified a heterozygous 3257T-C transition in the FLT4 gene, resulting in an ile1086-to-thr (I1086T) substitution in the tyrosine kinase II domain of the protein. The proband had a severe phenotype with elephantiasis up to the inguinal ligament bilaterally, chronic venous ulcerations, cellulitis, and papillomatosis. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, GLU1106LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909656,
|
|
|
|
|
|
|
|
ClinVar: RCV000017655
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 14 affected and 2 unaffected members of a 3-generation consanguineous Israeli family of Muslim Arab origin with hereditary lymphedema (LMPHM1; 153100), Spiegel et al. (2006) identified heterozygosity for a 3316G-A transition in the FLT4 gene, resulting in a glu1106-to-lys (E1106K) substitution. The mutation was not found in 110 control individuals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, 3-BP DEL, 3323TCT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776833,
|
|
|
|
|
|
|
|
ClinVar: RCV000017656, RCV002254267
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with hereditary lymphedema (LMPHM1; 153100), Evans et al. (2003) identified a heterozygous 3-bp in-frame deletion (3323delTCT), resulting in the deletion of residue phe1108 in the tyrosine kinase II domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LYMPHATIC MALFORMATION 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, ALA855THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909657,
|
|
|
|
|
|
gnomAD: rs121909657,
|
|
|
|
|
|
ClinVar: RCV000017657, RCV003387726, RCV004719653
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Hispanic female with congenital lymphedema (LMPHM1; 153100) who was born of first-cousin parents, Ghalamkarpour et al. (2009) identified homozygosity for a 2563G-A transition in exon 18 of the FLT4 gene, resulting in an ala855-to-thr (A855T) substitution in the ATP-binding domain of the receptor. The unaffected parents were heterozygous for the mutation, which was not found in 110 controls. Assessment of receptor function showed reduced phosphorylation of the receptor, with impaired ligand-induced internalization and defective downstream signaling. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, TYR361TER
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV001003426
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son (family 1-04970), both with tetralogy of Fallot (CHTD7; 618780), Jin et al. (2017) identified a tyrosine-to-stop substitution at codon 361 of the FLT4 protein (Y361X). The son additionally had right-sided aortic arch. Hamosh (2020) noted that this variant was absent from the gnomAD database on February 17, 2020. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 7</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLT4, 2-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs755445139,
|
|
|
|
|
|
gnomAD: rs755445139,
|
|
|
|
|
|
ClinVar: RCV001003427, RCV001585912
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated probands (1-03410 and 1-05967) with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries (CHTD7; 618780), Jin et al. (2017) identified deletion of a C nucleotide in the FLT4 gene resulting in a proline-to-arginine substitution at codon 30, followed by a premature termination codon 3 amino acids downstream (Pro30ArgfsTer3). In family 1-03410, the mutation occurred as a de novo event. The proband also had right-sided aortic arch. In family 1-05967, the proband had inherited the mutation from her unaffected mother. She additionally had double aortic arch. </p><p>Reuter et al. (2019) identified this mutation in a patient (CGC-034) with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries, as well as congenital lymphedema. She had inherited the mutation from her mother, who had normal echocardiography results. The mother's father had bradycardia. Reuter et al. (2019) recorded the mutation as c.89delC (c.89delC, NM_182925.4). </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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 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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FLT4, EX25-29DEL
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<br />
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ClinVar: RCV001003428
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 23-year-old female (TOF293) with tetralogy of Fallot, right-sided aortic arch, and absent pulmonary valve (CHTD7; 618780), Reuter et al. (2019) identified heterozygous deletion of exons 25 through 29 of the FLT4 gene (chr5:180,031,767-180,040,470del). </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>.0016 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 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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FLT4, GLN1192TER
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<br />
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SNP: rs1581616817,
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ClinVar: RCV001003429
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 79-year-old man (TOF158) with tetralogy of Fallot, right-sided aortic arch, and atrial flutter requiring ablation (CHTD7; 618780), and in his daughter with tetralogy of Fallot, Reuter et al. (2019) identified a C-to-T transition at nucleotide 3574 (c.3574C-T, NM_182925.4) of the FLT4 gene, resulting in a glutamine-to-termination substitution at codon 1192 (Q1192X). The variant was absent from gnomAD. </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>.0017 CONGENITAL HEART DEFECTS, MULTIPLE TYPES, 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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FLT4, 1-BP DUP, 1622G
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<br />
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SNP: rs1581655293,
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ClinVar: RCV001003430
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 29-year-old man (TOF284) with tetralogy of Fallot, major aortopulmonary collateral arteries, and aortic valve replacement (CHTD7; 618780), Reuter et al. (2019) identified duplication of a G at nucleotide 1622 (c.1622dupG, NM_182925.4) of the FLT4 gene, resulting in a frameshift and premature termination (Gln542ProfsTer3). The variant was absent from gnomAD. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Milroy (1892); Offori et al. (1993)
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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>REFERENCES</strong>
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</h4>
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<strong>FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter.</strong>
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Lorenz, L., Axnick, J., Buschmann, T., Henning, C., Urner, S., Fang, S., Nurmi, H., Eichhorst, N., Holtmeier, R., Bodis, K., Hwang, J.-H., Mussig, K., Eberhard, D., Stypmann, J., Kuss, O., Roden, M., Alitalo, K., Haussinger, D., Lammert, E.
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<strong>New Mutants.</strong>
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Mouse Newsletter 71: 26 only, 1984.
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<strong>Gene order of Chy-vt-Re on chromosome 11.</strong>
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Mouse Newsletter 74: 96 only, 1986.
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Milroy, W. F.
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<strong>An undescribed variety of hereditary oedema.</strong>
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New York Med. J. 56: 505-508, 1892.
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Offori, T. W., Platt, C. C., Stephens, M., Hopkinson, G. B.
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<strong>Angiosarcoma in congenital hereditary lymphoedema (Milroy's disease): diagnostic beacons and a review of the literature.</strong>
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Clin. Exp. Derm. 18: 174-177, 1993.
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[PubMed: 8482001]
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|
Pajusola, K., Aprelikova, O., Korhonen, J., Kaipainen, A., Pertovaara, L., Alitalo, R., Alitalo, K.
|
|
<strong>FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines.</strong>
|
|
Cancer Res. 52: 5738-5743, 1992. Note: Erratum: Cancer Res. 53: 3845 only, 1993.
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|
[PubMed: 1327515]
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</p>
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<p class="mim-text-font">
|
|
Pajusola, K., Aprelikova, O., Pelicci, G., Weich, H., Claesson-Welsh, L., Alitalo, K.
|
|
<strong>Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors.</strong>
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Ada Hamosh - updated : 02/17/2020<br>Ada Hamosh - updated : 09/13/2019<br>Marla J. F. O'Neill - updated : 04/17/2018<br>Paul J. Converse - updated : 9/19/2014<br>Ada Hamosh - updated : 4/24/2012<br>Ada Hamosh - updated : 6/30/2010<br>Cassandra L. Kniffin - updated : 6/10/2009<br>Cassandra L. Kniffin - updated : 2/25/2009<br>Ada Hamosh - updated : 10/20/2008<br>Cassandra L. Kniffin - updated : 4/18/2008<br>Ada Hamosh - updated : 6/26/2007<br>Marla J. F. O'Neill - updated : 12/29/2006<br>Cassandra L. Kniffin - updated : 11/1/2006<br>Marla J. F. O'Neill - updated : 9/29/2006<br>Cassandra L. Kniffin - reorganized : 11/19/2003<br>Victor A. McKusick - updated : 11/4/2003<br>Victor A. McKusick - updated : 3/14/2002<br>Victor A. McKusick - updated : 1/14/2002<br>Victor A. McKusick - updated : 10/3/2000<br>Victor A. McKusick - updated : 5/25/2000<br>Victor A. McKusick - updated : 2/10/1999<br>Victor A. McKusick - updated : 1/6/1999<br>Victor A. McKusick - updated : 11/10/1998<br>Victor A. McKusick - updated : 10/27/1998
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