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Entry
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- *164760 - RAF1 PROTOONCOGENE, SERINE/THREONINE KINASE ; RAF1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*164760</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/164760">Table View</a>
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</li>
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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>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000132155;t=ENST00000251849" 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=5894" 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=164760" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000132155;t=ENST00000251849" 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_001354689,NM_001354690,NM_001354691,NM_001354692,NM_001354693,NM_001354694,NM_001354695,NM_002880,NR_148940,NR_148941,NR_148942,XM_011533974,XM_017006966,XM_047448649,XM_047448650,XM_047448651" 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_002880" 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=164760" 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=01265&isoform_id=01265_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/RAF1" 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/35842,125651,496091,4506401,17390263,29419512,30016945,119584538,119584539,166706819,189053374,194382828,194384150,311851678,440503027,576060879,767923931,957950095,957950098,957950101,1034634870,1233267483,1233267522,1237937656,1237937772,1237938104,1237938372,1241781456,2217345300,2217345302,2217345304,2462591661,2462591663,2462591665,2462591667,2462591669" 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/P04049" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5894" 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=ENSG00000132155;t=ENST00000251849" 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=RAF1" 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=RAF1" 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+5894" 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/RAF1" 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:5894" 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/5894" 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=chr3&hgg_gene=ENST00000251849.9&hgg_start=12583601&hgg_end=12664117&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9829" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9829" 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/raf1" 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=164760[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=164760[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/RAF1/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/ENSG00000132155" 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=RAF1" 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=RAF1" 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=RAF1" 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=RAF1&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/PA34183" 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:9829" 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/FBgn0003079.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:97847" 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/RAF1#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:97847" 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/5894/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://omia.org/OMIA001547/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5894" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003030;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-090826-2" 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:5894" 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=RAF1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
164760
|
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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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RAF1 PROTOONCOGENE, SERINE/THREONINE KINASE ; RAF1
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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>
|
|
<span class="mim-font">
|
|
V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1<br />
|
|
ONCOGENE RAF1<br />
|
|
TRANSFORMING REPLICATION-DEFECTIVE MURINE RETROVIRUS 3611-MSV<br />
|
|
ONCOGENE MIL<br />
|
|
CRAF
|
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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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<a id="includedTitles" class="mim-anchor"></a>
|
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<div>
|
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<p>
|
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
RAF1/SRGAP3 FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
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|
</div>
|
|
<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=RAF1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">RAF1</a></em></strong>
|
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</span>
|
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</p>
|
|
</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/70?start=-3&limit=10&highlight=70">3p25.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:12583601-12664117&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'})">3:12,583,601-12,664,117</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615916,611554,611553" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/70?start=-3&limit=10&highlight=70">
|
|
3p25.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1NN
|
|
|
|
</span>
|
|
</td>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p><a href="#23" class="mim-tip-reference" title="Rapp, U. R., Goldsborough, M. D., Mark, G. E., Bonner, T. I., Groffen, J., Reynolds, F. H., Jr., Stephenson, J. R. <strong>Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus.</strong> Proc. Nat. Acad. Sci. 80: 4218-4222, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6308607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6308607</a>] [<a href="https://doi.org/10.1073/pnas.80.14.4218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6308607">Rapp et al. (1983)</a> cloned a unique acutely transforming replication-defective mouse type C virus and characterized its acquired oncogene, called v-raf. The viral genome bears close similarities to the Moloney murine leukemia virus (see MOS, <a href="/entry/190060">190060</a>). The cellular homolog, c-raf, is present in 1 or 2 copies per haploid genome in mouse and human DNA. The MIL oncogene, a second oncogene in the avian retrovirus MH2, which contains the MYC oncogene, is the avian equivalent of the murine RAF oncogene, i.e., they are identical. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6308607" 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="#4" class="mim-tip-reference" title="Bonner, T., O'Brien, S. J., Nash, W. G., Rapp, U. R., Morton, C. C., Leder, P. <strong>The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4.</strong> Science 223: 71-74, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6691137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6691137</a>] [<a href="https://doi.org/10.1126/science.6691137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6691137">Bonner et al. (1984)</a> assigned the RAF1 gene to chromosome 3p25 by in situ hybridization. This suggested that RAF1 may be involved in mixed parotid gland tumors with the t(3;8)(p25;q21) translocation (Mark et al. (<a href="#16" class="mim-tip-reference" title="Mark, J., Dahlenfors, R., Ekedahl, C., Stenman, G. <strong>The mixed salivary gland tumor--a normally benign human neoplasm frequently showing specific chromosomal abnormalities.</strong> Cancer Genet. Cytogenet. 2: 231-234, 1980."None>1980</a>, <a href="#17" class="mim-tip-reference" title="Mark, J., Dahlenfors, R., Ekedahl, C., Stenman, G. <strong>Chromosomal patterns in a benign human neoplasm, the mixed salivary gland tumour.</strong> Hereditas 96: 141-148, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6282787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6282787</a>] [<a href="https://doi.org/10.1111/j.1601-5223.1982.tb00044.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6282787">1982</a>)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6691137+6282787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Tory, K., Latif, F., Modi, W., Schmidt, L., Wei, M. H., Li, H., Cobler, P., Orcutt, M. L., Delisio, J., Geil, L., Zbar, B., Lerman, M. I. <strong>A genetic linkage map of 96 loci on the short arm of human chromosome 3.</strong> Genomics 13: 275-286, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1612588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1612588</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90243-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1612588">Tory et al. (1992)</a> constructed a genetic linkage map of 96 loci on 3p, extending from the terminal band to the centromere. Multipoint linkage analysis indicated that the male, female, and sex-averaged maps extend for 102, 147, and 116 cM, respectively. RAF1 and 16 DNA markers were localized by fluorescence in situ hybridization. RAF1 was regionalized to 3p25. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1612588" 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>Pseudogenes</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Bonner, T., O'Brien, S. J., Nash, W. G., Rapp, U. R., Morton, C. C., Leder, P. <strong>The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4.</strong> Science 223: 71-74, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6691137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6691137</a>] [<a href="https://doi.org/10.1126/science.6691137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6691137">Bonner et al. (1984)</a> showed that RAF2, a processed pseudogene, is on chromosome 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6691137" 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="Hiroshige, S., Carlock, L., Smith, M. <strong>Regional assignment of the RAF2 gene to the region 4pter-4p15. (Abstract)</strong> Am. J. Hum. Genet. 39: A157, 1986."None>Hiroshige et al. (1986)</a> assigned the RAF2 pseudogene to region 4pter-p15 by the study of hybrid cells containing various chromosome 4 regions.</p>
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<p>The function of RAF1 was reviewed by <a href="#14" class="mim-tip-reference" title="Li, P., Wood, K., Mamon, H., Haser, W., Roberts, T. <strong>Raf-1: a kinase currently without a cause but not lacking in effects.</strong> Cell 64: 479-482, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1846778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1846778</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90228-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1846778">Li et al. (1991)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1846778" 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="Wang, H.-G., Rapp, U. R., Reed, J. C. <strong>Bcl-2 targets the protein kinase Raf-1 to mitochondria.</strong> Cell 87: 629-638, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929532</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81383-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929532">Wang et al. (1996)</a> showed that RAF1 can be targeted to the mitochondria by BCL2 (<a href="/entry/151430">151430</a>), a regulator of apoptotic cell death. Active RAF1 improved BCL2-mediated resistance to apoptosis. They also showed that RAF1 phosphorylates BAD (<a href="/entry/603167">603167</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929532" 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="#1" class="mim-tip-reference" title="Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., Cheresh, D. A. <strong>Role of Raf in vascular protection from distinct apoptotic stimuli.</strong> Science 301: 94-96, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843393</a>] [<a href="https://doi.org/10.1126/science.1082015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843393">Alavi et al. (2003)</a> showed that basic fibroblast growth factor (FGFB; <a href="/entry/134920">134920</a>) and vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>) differentially activate Raf1, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. BFGF activated Raf1 via p21-activated protein kinase-1 (PAK1; <a href="/entry/602590">602590</a>) phosphorylation of serines 338 and 339, resulting in Raf1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase-1 (MEK1; <a href="/entry/176872">176872</a>). In contrast, VEGF activated Raf1 via Src kinase (CSK; <a href="/entry/124095">124095</a>), leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. <a href="#1" class="mim-tip-reference" title="Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., Cheresh, D. A. <strong>Role of Raf in vascular protection from distinct apoptotic stimuli.</strong> Science 301: 94-96, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843393</a>] [<a href="https://doi.org/10.1126/science.1082015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843393">Alavi et al. (2003)</a> concluded that RAF1 may be a pivotal regulator of endothelial cell survival during angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843393" 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="Lorenz, K., Lohse, M. J., Quitterer, U. <strong>Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2.</strong> Nature 426: 574-579, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14654844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14654844</a>] [<a href="https://doi.org/10.1038/nature02158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14654844">Lorenz et al. (2003)</a> demonstrated that the RAF kinase inhibitor protein (RKIP; <a href="/entry/604591">604591</a>) is a physiologic inhibitor of GRK2 (<a href="/entry/109635">109635</a>). After stimulation of G protein-coupled receptors, RKIP dissociates from its known target, RAF1, to associate with GRK2 and block its activity. This switch is triggered by a protein kinase C (PKC; see <a href="/entry/176960">176960</a>)-dependent phosphorylation of RKIP on serine-153. <a href="#15" class="mim-tip-reference" title="Lorenz, K., Lohse, M. J., Quitterer, U. <strong>Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2.</strong> Nature 426: 574-579, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14654844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14654844</a>] [<a href="https://doi.org/10.1038/nature02158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14654844">Lorenz et al. (2003)</a> concluded that their data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from RAF1 and by blocking receptor internalization. A physiologic role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signaling and contractile activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14654844" 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="O'Neill, E., Rushworth, L., Baccarini, M., Kolch, W. <strong>Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1.</strong> Science 306: 2267-2270, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15618521/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15618521</a>] [<a href="https://doi.org/10.1126/science.1103233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15618521">O'Neill et al. (2004)</a> used proteomic analysis of RAF1 signaling complexes to show that RAF1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2; <a href="/entry/605030">605030</a>). RAF1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity. Depletion of MST2 from Raf1-null mouse or human cells abrogated sensitivity to apoptosis, whereas overexpression of MST2 induced apoptosis. Conversely, depletion of Raf1 from Raf1 +/+ mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both RAF1 and MST2 prevented apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15618521" 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 creating a kinase-defective version of Raf1 in mice or by using a Raf1 inhibitor, <a href="#18" class="mim-tip-reference" title="Noble, C., Mercer, K., Hussain, J., Carragher, L., Giblett, S., Hayward, R., Patterson, C., Marais, R., Pritchard, C. A. <strong>CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation.</strong> Molec. Cell 31: 862-872, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18922468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18922468</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18922468[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.08.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18922468">Noble et al. (2008)</a> showed that Raf1 autophosphorylation on ser621 prevented its degradation by the proteasome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18922468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Drosophila Schneider S2 cells, <a href="#22" class="mim-tip-reference" title="Rajakulendran, T., Sahmi, M., Lefrancois, M., Sicheri, F., Therrien, M. <strong>A dimerization-dependent mechanism drives RAF catalytic activation.</strong> Nature 461: 542-545, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19727074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19727074</a>] [<a href="https://doi.org/10.1038/nature08314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19727074">Rajakulendran et al. (2009)</a> demonstrated that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which they termed the side-to-side dimer. Moreover, they found that the RAF-related pseudokinase KSR (<a href="/entry/601132">601132</a>) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19727074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Hollander, J. A., Im, H.-I., Amelio, A. L., Kocerha, J., Bali, P., Lu, Q., Willoughby, D., Wahlestedt, C., Conkright, M. D., Kenny, P. J. <strong>Striatal microRNA controls cocaine intake through CREB signalling.</strong> Nature 466: 197-202, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20613834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20613834</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20613834[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20613834">Hollander et al. (2010)</a> found that microRNA-212 (MIR212; <a href="/entry/613487">613487</a>) was upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR212 decreased responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on Creb (<a href="/entry/123810">123810</a>) signaling. Studies in rats and HEK cells showed that amplification of CREB signaling occurred through miR212-enhanced RAF1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential Creb coactivator TORC (see CRTC1; <a href="/entry/607536">607536</a>). miR212 activated RAF1, at least in part, through repression of SPRED1 (<a href="/entry/609291">609291</a>). <a href="#11" class="mim-tip-reference" title="Hollander, J. A., Im, H.-I., Amelio, A. L., Kocerha, J., Bali, P., Lu, Q., Willoughby, D., Wahlestedt, C., Conkright, M. D., Kenny, P. J. <strong>Striatal microRNA controls cocaine intake through CREB signalling.</strong> Nature 466: 197-202, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20613834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20613834</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20613834[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20613834">Hollander et al. (2010)</a> concluded that striatal miR212 signaling has a key role in determining vulnerability to cocaine addiction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20613834" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoprecipitation of endogenous LZTR1 (<a href="/entry/600574">600574</a>) followed by Western blotting, <a href="#28" class="mim-tip-reference" title="Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y. <strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong> Hum. Genet. 138: 21-35, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>] [<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30368668">Umeki et al. (2019)</a> showed that LZTR1 bound to the RAF1-SHOC2 (<a href="/entry/602775">602775</a>)-PPP1CB (<a href="/entry/600590">600590</a>) complex. Mutations in all these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" 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>Oncogenic Function</em></strong></p><p>
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<a href="#25" class="mim-tip-reference" title="Shimizu, K., Nakatsu, Y., Sekiguchi, M., Hokamura, K., Tanaka, K., Terada, M., Sugimura, T. <strong>Molecular cloning of an activated human oncogene, homologous to v-raf, from primary stomach cancer.</strong> Proc. Nat. Acad. Sci. 82: 5641-5645, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3862088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3862088</a>] [<a href="https://doi.org/10.1073/pnas.82.17.5641" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3862088">Shimizu et al. (1985)</a> identified the activated RAF gene in the stomach cancer of a Japanese patient. Stomach cancer is the most common cancer in Japan. <a href="#8" class="mim-tip-reference" title="Fukui, M., Yamamoto, T., Kawai, S., Maruo, K., Toyoshima, K. <strong>Detection of a raf-related and two other transforming DNA sequences in human tumors maintained in nude mice.</strong> Proc. Nat. Acad. Sci. 82: 5954-5958, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2994056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2994056</a>] [<a href="https://doi.org/10.1073/pnas.82.17.5954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2994056">Fukui et al. (1985)</a> found that transforming DNA in a human glioblastoma line was apparently the RAF gene. <a href="#26" class="mim-tip-reference" title="Teyssier, J. R., Henry, I., Dozier, C., Ferre, D., Adnet, J. J., Pluot, M. <strong>Recurrent deletion of the short arm of chromosome 3 in human renal cell carcinoma: shift of the c-raf 1 locus.</strong> J. Nat. Cancer Inst. 77: 1187-1191, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3467112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3467112</a>]" pmid="3467112">Teyssier et al. (1986)</a> presented evidence for a relationship of RAF1 to renal cell carcinoma (<a href="/entry/144700">144700</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3862088+3467112+2994056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Kasid, U., Pfeifer, A., Weichselbaum, R. R., Dritschilo, A., Mark, G. E. <strong>The raf oncogene is associated with a radiation-resistant human laryngeal cancer.</strong> Science 237: 1039-1041, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3616625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3616625</a>] [<a href="https://doi.org/10.1126/science.3616625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3616625">Kasid et al. (1987)</a> transfected tumor cell DNA into NIH/3T3 cells to demonstrate that a radiation-resistant laryngeal carcinoma cell line contained altered RAF1 sequences. The karyotype of the tumor cells showed absence of chromosome 3, and transformed cells had double-minute chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3616625" 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="#21" class="mim-tip-reference" title="Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., Rosen, N. <strong>RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.</strong> Nature 464: 427-430, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20179705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20179705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20179705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20179705">Poulikakos et al. (2010)</a> used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for the paradoxical activation of the enzyme by inhibitors. Induction of ERK signaling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one promoter, but results in transactivation of the drug-free protomer. In BRAF(V600E) (<a href="/entry/164757#0001">164757.0001</a>) tumors, RAS is not activated, thus transactivation is minimal and ERK signaling is inhibited in cells exposed to RAF inhibitors. These results indicated that RAF inhibitors will be effective in tumors in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicted that they would have a higher therapeutic index and greater antitumor activity than mitogen-activated protein kinase kinase (MEK) inhibitors, but could also cause toxicity due to the MEK/ERK activation. <a href="#21" class="mim-tip-reference" title="Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., Rosen, N. <strong>RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.</strong> Nature 464: 427-430, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20179705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20179705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20179705[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20179705">Poulikakos et al. (2010)</a> noted that these predictions were borne out in a clinical trial of the RAF inhibitor PLX4032, as reported by <a href="#5" class="mim-tip-reference" title="Chapman, P., Puzanov, I., sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R., Grippo, J., Nolop, K., Flaherty, K. <strong>Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032. (Abstract)</strong> Europ. J. Cancer Suppl. 7: 5 only, 2009."None>Chapman et al. (2009)</a> and <a href="#7" class="mim-tip-reference" title="Flaherty, K., Puzanov, I., Sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P. <strong>Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. (Abstract-9000)</strong> J. Clin. Oncol. 27 (suppl.): 15s, 2009."None>Flaherty et al. (2009)</a>. The model indicated that promotion of RAF dimerization by elevation of wildtype RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumors. In agreement with this prediction, RAF inhibitors do not inhibit ERK signaling in cells that coexpress BRAF(V600E) and mutant RAS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20179705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., and 9 others. <strong>RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.</strong> Nature 464: 431-435, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130576</a>] [<a href="https://doi.org/10.1038/nature08833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130576">Hatzivassiliou et al. (2010)</a> demonstrated that ATP-competitive RAF inhibitors have 2 opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumors, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signaling pathway and decrease tumor growth. Notably, in KRAS mutant and RAS/RAF wildtype tumors, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumor growth in some xenograft models. Inhibitor binding activates wildtype RAF isoforms by inducing dimerization, membrane localization, and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, <a href="#9" class="mim-tip-reference" title="Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., and 9 others. <strong>RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.</strong> Nature 464: 431-435, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20130576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20130576</a>] [<a href="https://doi.org/10.1038/nature08833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20130576">Hatzivassiliou et al. (2010)</a> demonstrated that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signaling pathways, depending on the cellular context. The authors stated that their work provided new insights into the therapeutic use of ATP-competitive RAF inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20130576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#12" class="mim-tip-reference" title="Jones, D. T. W., Kocialkowski, S., Liu, L., Pearson, D. M., Ichimura, K., Collins, V. P. <strong>Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma.</strong> Oncogene 28: 2119-2123, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19363522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19363522</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19363522[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2009.73" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19363522">Jones et al. (2009)</a> found a tandem duplication at chromosome 3p25 in a pilocytic astrocytoma (see <a href="/entry/137800">137800</a>) that resulted in fusion of exons 1 through 12 of the SRGAP3 gene (<a href="/entry/606525">606525</a>) to exons 10 through 17 of the RAF1 gene. The fusion transcript encodes a deduced protein containing the first 513 N-terminal amino acids of SRGAP3, including the FES (<a href="/entry/190030">190030</a>)/CIP4 (TRIP10; <a href="/entry/604504">604504</a>) homology domain, fused to 318 C-terminal amino acids of RAF1, including the entire RAF1 kinase domain. The fusion protein showed higher activity than wildtype RAF1 in phosphorylation of endogenous Mek1 in mouse fibroblasts, and it conferred anchorage-independent cell growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19363522" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Noonan Syndrome 5 or LEOPARD syndrome 2</em></strong>
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<p><a href="#20" class="mim-tip-reference" title="Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. <strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong> Nature Genet. 39: 1007-1012, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603483</a>] [<a href="https://doi.org/10.1038/ng2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603483">Pandit et al. (2007)</a> analyzed the RAF1 gene in 231 individuals with Noonan syndrome who did not have mutations in the PTPN11 (<a href="/entry/176876">176876</a>), KRAS (<a href="/entry/190070">190070</a>), or SOS1 (<a href="/entry/182530">182530</a>) genes, and in 6 persons with LEOPARD syndrome who did not have mutations in PTPN11. They identified 13 different missense mutations (see, e.g., <a href="#0001">164760.0001</a>-<a href="#0003">164760.0003</a>) in 18 unrelated patients with NS (NS5; <a href="/entry/611553">611553</a>) and 2 missense mutations (<a href="#0001">164760.0001</a> and <a href="#0004">164760.0004</a>) in 2 patients with LEOPARD syndrome (LPRD2; <a href="/entry/611554">611554</a>), respectively. Most mutations altered a motif flanking ser259 located in the CR2 domain, critical for autoinhibition of RAF1 through 14-3-3 (see <a href="/entry/113508">113508</a>) binding. Of 17 NS patients with a RAF1 mutation in either of 2 hotspots (clustering around ser259 or ser612), 16 (94%) had hypertrophic cardiomyopathy (CMH; see <a href="/entry/192600">192600</a>), compared with an 18% prevalence of CMH among NS patients in general. <a href="#20" class="mim-tip-reference" title="Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. <strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong> Nature Genet. 39: 1007-1012, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603483</a>] [<a href="https://doi.org/10.1038/ng2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603483">Pandit et al. (2007)</a> also scanned RAF1 exons mutated in NS and LEOPARD patients in 241 unrelated individuals with nonsyndromic CMH who did not have mutations in 8 myofilament genes known to cause CMH, and the authors identified a thr260-to-ile mutation in the RAF1 gene in 1 patient. Ectopically expressed RAF1 mutants from the 2 CMH hotspots had increased kinase activity and enhanced ERK (see <a href="/entry/176948">176948</a>) activation, whereas non-CMH-associated mutants were kinase impaired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603483" 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="#24" class="mim-tip-reference" title="Razzaque, M. A., Nishizawa, T., Komoike, Y., Yagi, H., Furutani, M., Amo, R., Kamisago, M., Momma, K., Katayama, H., Nakagawa, M., Fujiwara, Y., Matsushima, M., Mizuno, K., Tokuyama, M., Hirota, H., Muneuchi, J., Higashinakagawa, T., Matsuoka, R. <strong>Germline gain-of-function mutations in RAF1 cause Noonan syndrome.</strong> Nature Genet. 39: 1013-1017, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603482</a>] [<a href="https://doi.org/10.1038/ng2078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603482">Razzaque et al. (2007)</a> analyzed the RAF1 gene in 30 individuals clinically diagnosed with Noonan syndrome who were negative for mutations in the PTPN11, KRAS, HRAS (<a href="/entry/190020">190020</a>), or SOS1 genes, and identified 5 different missense mutations in RAF1 in 10 (33%) individuals. The authors noted that 8 of the 10 mutation-positive patients with 1 of 4 mutations causing changes in the CR2 domain of RAF1 (see, e.g., <a href="#0001">164760.0001</a> and <a href="#0003">164760.0003</a>) had hypertrophic cardiomyopathy, whereas the 2 affected individuals with a mutation leading to changes in the CR3 domain did not (<a href="#0004">164760.0004</a>). Transfection studies in HEK293 cells demonstrated that all 5 mutations in RAF1 behaved as gain-of-function mutants with increased kinase and ERK activation compared with wildtype RAF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Dilated Cardiomyopathy 1NN</em></strong>
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<p>In 8 patients from South and North India and 2 patients from Japan with nonsyndromic dilated cardiomyopathy (CMD1NN; <a href="/entry/615916">615916</a>), <a href="#6" class="mim-tip-reference" title="Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D. S., Rani, B., Govindaraj, P., and 17 others. <strong>RAF1 mutations in childhood-onset dilated cardiomyopathy.</strong> Nature Genet. 46: 635-639, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24777450[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24777450">Dhandapany et al. (2014)</a> identified heterozygous mutations in the RAF1 gene (see, e.g., <a href="#0005">164760.0005</a>-<a href="#0007">164760.0007</a>) that segregated with disease in the families and were not found in ancestry-matched controls. Biochemical studies showed that the CMD-associated RAF1 mutants had altered kinase activity, resulting in largely unchanged ERK (see <a href="/entry/601795">601795</a>) activation but in AKT (<a href="/entry/164730">164730</a>) that was hyperactivated in a BRAF (<a href="/entry/164757">164757</a>)-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24777450" 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="mim-changed mim-change"><p><strong><em>Associations Pending Confirmation</em></strong>
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<div class="mim-changed mim-change"><p>For discussion of a possible association between cleft palate, cardiac defects, genital anomalies, and ectrodactyly (CCGE; <a href="/entry/600460">600460</a>) and mutation in the RAF1 gene, see <a href="#0008">164760.0008</a>.</p></div>
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<p>To examine the in vivo role of RAF1 in the heart, <a href="#31" class="mim-tip-reference" title="Yamaguchi, O., Watanabe, T., Nishida, K., Kashiwase, K., Higuchi, Y., Takeda, T., Hikoso, S., Hirotani, S., Asahi, M., Taniike, M., Nakai, A., Tsujimoto, I., and 9 others. <strong>Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.</strong> J. Clin. Invest. 114: 937-943, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI20317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467832">Yamaguchi et al. (2004)</a> generated cardiac muscle-specific Raf1 conditionally deleted mice. The mice demonstrated left ventricular systolic dysfunction and heart dilation without cardiac hypertrophy or lethality, and showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 (see <a href="/entry/176872">176872</a> and <a href="/entry/601263">601263</a>, respectively) and ERK (see <a href="/entry/601795">601795</a>) showed no difference, but the kinase activity of apoptosis signal-regulating kinase-1 (ASK1; <a href="/entry/602448">602448</a>), JNK (see <a href="/entry/601158">601158</a>), and p38 (<a href="/entry/600289">600289</a>) increased significantly compared to that of controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. <a href="#31" class="mim-tip-reference" title="Yamaguchi, O., Watanabe, T., Nishida, K., Kashiwase, K., Higuchi, Y., Takeda, T., Hikoso, S., Hirotani, S., Asahi, M., Taniike, M., Nakai, A., Tsujimoto, I., and 9 others. <strong>Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.</strong> J. Clin. Invest. 114: 937-943, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI20317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467832">Yamaguchi et al. (2004)</a> concluded that RAF1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15467832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=164760[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<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> rs80338796 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338796;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/rs80338796?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=rs80338796" 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=rs80338796" 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=RCV000014985 OR RCV000014986 OR RCV000020509 OR RCV000149826 OR RCV000157426 OR RCV000157685 OR RCV000515222 OR RCV000824754 OR RCV000856803 OR RCV001731288 OR RCV001813205 OR RCV002399323 OR RCV003231105" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014985, RCV000014986, RCV000020509, RCV000149826, RCV000157426, RCV000157685, RCV000515222, RCV000824754, RCV000856803, RCV001731288, RCV001813205, RCV002399323, RCV003231105" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014985...</a>
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<p>In 7 unrelated patients with Noonan syndrome (NS5; <a href="/entry/611553">611553</a>) and 1 patient with LEOPARD syndrome-2 (LPRD2; <a href="/entry/611554">611554</a>), <a href="#20" class="mim-tip-reference" title="Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. <strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong> Nature Genet. 39: 1007-1012, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603483</a>] [<a href="https://doi.org/10.1038/ng2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603483">Pandit et al. (2007)</a> identified heterozygosity for a 770C-T transition in exon 7 of the RAF1 gene, resulting in a ser257-to-leu (S257L) substitution at a conserved residue in the CR2 domain. All patients had hypertrophic cardiomyopathy (CMH), including a 3.6-year-old girl with CMH at birth and a 35-year-old woman with LEOPARD syndrome. Ectopically expressed S257L mutants demonstrated increased kinase activity and enhanced ERK (see <a href="/entry/176948">176948</a>) activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603483" 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="#24" class="mim-tip-reference" title="Razzaque, M. A., Nishizawa, T., Komoike, Y., Yagi, H., Furutani, M., Amo, R., Kamisago, M., Momma, K., Katayama, H., Nakagawa, M., Fujiwara, Y., Matsushima, M., Mizuno, K., Tokuyama, M., Hirota, H., Muneuchi, J., Higashinakagawa, T., Matsuoka, R. <strong>Germline gain-of-function mutations in RAF1 cause Noonan syndrome.</strong> Nature Genet. 39: 1013-1017, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603482</a>] [<a href="https://doi.org/10.1038/ng2078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603482">Razzaque et al. (2007)</a> identified the S257L mutation of the RAF1 gene in 4 unrelated patients with Noonan syndrome, 3 with obstructive and 1 with nonobstructive CMH. The mutation was not found in 100 control individuals or in 100 patients with CMH without Noonan syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603482" 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">rs121434594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434594;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=rs121434594" 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=rs121434594" 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=RCV000014987 OR RCV000159076 OR RCV000208421 OR RCV000211849 OR RCV000468714 OR RCV000618568 OR RCV000622893 OR RCV001813206 OR RCV003450640" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014987, RCV000159076, RCV000208421, RCV000211849, RCV000468714, RCV000618568, RCV000622893, RCV001813206, RCV003450640" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014987...</a>
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<p>In 5 affected individuals of 2 unrelated families with Noonan syndrome (NS5; <a href="/entry/611553">611553</a>), <a href="#20" class="mim-tip-reference" title="Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. <strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong> Nature Genet. 39: 1007-1012, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603483</a>] [<a href="https://doi.org/10.1038/ng2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603483">Pandit et al. (2007)</a> identified heterozygosity for a 781C-T transition in exon 7 of the RAF1 gene, resulting in a pro261-to-ser (P261S) substitution at a conserved residue in the CR2 domain. Four of the 5 patients had hypertrophic cardiomyopathy (CMH); the 1 individual with a P261S change but without CMH was a 6-year-old girl whose 38-year-old mother had the same mutation and had been diagnosed with CMH at 23 years of age. The mutation was not found in 210 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603483" 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="#24" class="mim-tip-reference" title="Razzaque, M. A., Nishizawa, T., Komoike, Y., Yagi, H., Furutani, M., Amo, R., Kamisago, M., Momma, K., Katayama, H., Nakagawa, M., Fujiwara, Y., Matsushima, M., Mizuno, K., Tokuyama, M., Hirota, H., Muneuchi, J., Higashinakagawa, T., Matsuoka, R. <strong>Germline gain-of-function mutations in RAF1 cause Noonan syndrome.</strong> Nature Genet. 39: 1013-1017, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603482</a>] [<a href="https://doi.org/10.1038/ng2078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603482">Razzaque et al. (2007)</a> identified the P261S mutation in 3 Noonan syndrome patients, a 1-year-old boy and his 33-year-old father and an unrelated 16-year-old boy. All 3 displayed CMH. The mutation was not found in 100 control individuals or in 100 individuals with CMH without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that P261S behaved as a gain-of-function mutant with increased kinase and ERK (see <a href="/entry/176948">176948</a>) activation compared with wildtype RAF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603482" 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">rs80338799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338799;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=rs80338799" 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=rs80338799" 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 sister and brother with Noonan syndrome (NS5; <a href="/entry/611553">611553</a>), <a href="#20" class="mim-tip-reference" title="Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. <strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong> Nature Genet. 39: 1007-1012, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603483</a>] [<a href="https://doi.org/10.1038/ng2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603483">Pandit et al. (2007)</a> identified heterozygosity for a 1472C-G transversion in exon 14 of the RAF1 gene, resulting in a thr491-to-arg (T491R) substitution in the CR3 domain. Neither sib had hypertrophic cardiomyopathy. The mutation was not found in 210 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603483" 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">rs80338797 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338797;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=rs80338797" 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=rs80338797" 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=RCV000014989 OR RCV000014990 OR RCV000020508 OR RCV000159089 OR RCV000254689 OR RCV000440827 OR RCV000824753 OR RCV001256891 OR RCV004532353" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014989, RCV000014990, RCV000020508, RCV000159089, RCV000254689, RCV000440827, RCV000824753, RCV001256891, RCV004532353" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014989...</a>
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<p>In a 43-year-old woman with LEOPARD syndrome-2 (LPRD2; <a href="/entry/611554">611554</a>), <a href="#20" class="mim-tip-reference" title="Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others. <strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong> Nature Genet. 39: 1007-1012, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603483</a>] [<a href="https://doi.org/10.1038/ng2073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603483">Pandit et al. (2007)</a> identified an 1837C-G transversion in exon 17 of the RAF1 gene, resulting in a leu613-to-val (L613V) substitution at a conserved residue in the C terminus. The patient had hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603483" 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="#24" class="mim-tip-reference" title="Razzaque, M. A., Nishizawa, T., Komoike, Y., Yagi, H., Furutani, M., Amo, R., Kamisago, M., Momma, K., Katayama, H., Nakagawa, M., Fujiwara, Y., Matsushima, M., Mizuno, K., Tokuyama, M., Hirota, H., Muneuchi, J., Higashinakagawa, T., Matsuoka, R. <strong>Germline gain-of-function mutations in RAF1 cause Noonan syndrome.</strong> Nature Genet. 39: 1013-1017, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17603482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17603482</a>] [<a href="https://doi.org/10.1038/ng2078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17603482">Razzaque et al. (2007)</a> identified the L613V mutation, which they designated as being located in the CR3 domain of RAF1, in 2 unrelated boys with Noonan syndrome (NS5; <a href="/entry/611553">611553</a>), neither of whom had hypertrophic cardiomyopathy. The mutation was not found in 100 control individuals or in 100 patients with hypertrophic cardiomyopathy without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that L613V behaved as a gain-of-function mutant with increased kinase and ERK (see <a href="/entry/176948">176948</a>) activation compared with wildtype RAF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17603482" 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">rs587777586 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777586;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=rs587777586" 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=rs587777586" 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=RCV000131334" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000131334" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000131334</a>
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<p>In 3 patients with nonsyndromic dilated cardiomyopathy (CMD1NN; <a href="/entry/615916">615916</a>), a 40-year-old South Indian mother and her 4-year-old son and an unrelated 21-year-old South Indian woman, <a href="#6" class="mim-tip-reference" title="Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D. S., Rani, B., Govindaraj, P., and 17 others. <strong>RAF1 mutations in childhood-onset dilated cardiomyopathy.</strong> Nature Genet. 46: 635-639, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24777450[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24777450">Dhandapany et al. (2014)</a> identified heterozygosity for a c.1808T-C transition in the RAF1 gene, resulting in a leu603-to-pro (L603P) substitution at a highly conserved residue in the CR3 domain. Age at onset of disease in the 3 patients was 24 years, 3 years, and 10 years, respectively. The mutation was not found in the 4-year-old boy's unaffected father, in 500 ancestry-matched South Indian controls, or in 13,600 European and African American alleles in the Exome Sequencing Project database. Functional analysis in HEK293 cells showed impaired kinase activity and reduced ERK (see <a href="/entry/601795">601795</a>) activation with the L603P mutant. Constitutive expression of the L603P mutant in zebrafish embryos resulted in a heart failure phenotype, including elongated ventricular and atrial chambers, profound pericardial edema, blood congestion at the cardiac inflow tract, and impaired cardiac contractions. Immunoblotting showed AKT hyperactivation, and the heart defects were partially rescued by treatment with rapamycin, an AKT-mTOR (<a href="/entry/601231">601231</a>) inhibitor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24777450" 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> rs587777587 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777587;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/rs587777587?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=rs587777587" 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=rs587777587" 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=RCV000131336 OR RCV000852545 OR RCV001657807 OR RCV001849941 OR RCV004984679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000131336, RCV000852545, RCV001657807, RCV001849941, RCV004984679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000131336...</a>
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<p>In a 15-year-old South Indian girl and an unrelated 21-year-old North Indian man with nonsyndromic dilated cardiomyopathy (CMD1NN; <a href="/entry/615916">615916</a>), <a href="#6" class="mim-tip-reference" title="Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D. S., Rani, B., Govindaraj, P., and 17 others. <strong>RAF1 mutations in childhood-onset dilated cardiomyopathy.</strong> Nature Genet. 46: 635-639, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24777450[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24777450">Dhandapany et al. (2014)</a> identified heterozygosity for a c.1922T-C transition in the RAF1 gene, resulting in a thr641-to-met (T641M) substitution at a highly conserved residue. Age at onset of disease in the 2 patients was 7 years and 16 years, respectively. The mutation, which segregated with disease in the available family, was not found in 500 ancestry-matched South Indian controls or in 350 ancestry-matched North Indian controls. Functional analysis in HEK293 cells showed a mild increase in kinase activity with the T641M mutant that was less augmented than that of the CMH-associated RAF1 mutants tested, L613V (<a href="#0004">164760.0004</a>) and S257L (<a href="#0001">164760.0001</a>). ERK (see <a href="/entry/601795">601795</a>) activation with the T641M mutant was similar to that observed with wildtype RAF1 and was significantly less than with the CMH-associated mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24777450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 CARDIOMYOPATHY, DILATED, 1NN</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777588 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777588;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/rs587777588?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=rs587777588" 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=rs587777588" 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=RCV000131337 OR RCV001588987 OR RCV001775085 OR RCV001857459" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000131337, RCV001588987, RCV001775085, RCV001857459" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000131337...</a>
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<p>In a 44-year-old Japanese man who had onset of nonsyndromic dilated cardiomyopathy (CMD1NN; <a href="/entry/615916">615916</a>) at 40 years of age, <a href="#6" class="mim-tip-reference" title="Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D. S., Rani, B., Govindaraj, P., and 17 others. <strong>RAF1 mutations in childhood-onset dilated cardiomyopathy.</strong> Nature Genet. 46: 635-639, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24777450[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24777450">Dhandapany et al. (2014)</a> identified heterozygosity for a c.709G-A transition in the RAF1 gene, resulting in an ala237-to-thr (A237T) substitution at a highly conserved residue. The mutation was not found in 300 Japanese controls. Functional analysis in HEK293 cells showed a mild increase in kinase activity with the A237T mutant that was less augmented than that of the CMH-associated RAF1 mutants tested, L613V (<a href="#0004">164760.0004</a>) and S257L (<a href="#0001">164760.0001</a>). ERK (see <a href="/entry/601795">601795</a>) activation with the A237T mutant was similar to that observed with wildtype RAF1 and was significantly less than with the CMH-associated mutants, whereas activation of AKT and tuberin (TSC2; <a href="/entry/191092">191092</a>) was excessive compared to CMH-associated mutants or wildtype RAF1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24777450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV005055410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV005055410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV005055410</a>
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<div class="mim-changed mim-change"><p>This variant is classified as a variant of unknown significance because its contribution to cleft palate, cardiac defects, genital anomalies, and ectrodactyly (CCGE; <a href="/entry/600460">600460</a>) has not been confirmed.</p><p>In a consanguineous Turkish family in which 2 deceased sibs exhibited features of CCGE, <a href="#30" class="mim-tip-reference" title="Wong, S., Tan, Y. X., Loh, A. Y. T., Tan, K. Y., Lee, H., Aziz, Z., Nelson, S. F., Ozkan, E., Kayserili, H., Escande-Beillard, N., Reversade, B. <strong>RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis.</strong> EMBO Molec. Med. 15: e17078, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37066513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37066513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37066513[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/10.15252/emmm.202217078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37066513">Wong et al. (2023)</a> performed homozygosity mapping and exome sequencing and identified a c.1628C-T transition in the RAF1 gene, resulting in a thr543-to-met (T543M) substitution at a highly conserved residue within the CR3 kinase domain. Sanger sequencing confirmed the variant and its presence in homozygosity in the affected brother and in heterozygosity in the unaffected first-cousin parents and an unaffected sib; it was not found in in-house or public variant databases. Functional analysis in HEK293T cells showed that the T542M mutant was globally hypophosphorylated compared to wildtype, and Western blot analysis after EGF (<a href="/entry/131530">131530</a>) stimulation revealed that unlike wildtype RAF1, the mutant failed to to induce downstream MEK1 (MAP2K1; <a href="/entry/176872">176872</a>)/MEK2 (MAP2K2; <a href="/entry/601263">601263</a>) or ERK1 (MAPK3; <a href="/entry/601795">601795</a>)/ERK2 (MAPK1; <a href="/entry/176948">176948</a>) phosphorylation. The authors concluded that T543M is a loss-of-function mutation that dampens RAF1-mediated MEK/ERK signaling. In vivo studies in Xenopus laevis embryos confirmed these results, showing significantly reduced downstream ERK1/2 phosphorylation with the T543M mutant relative to wildtype RAF1, and the mutant induced minimal ectopic mesoderm, comparable to uninjected controls. In addition, overexpression of T543M did not induce ectopic neuronal differentiation, a hallmark of FGF (<a href="/entry/131220">131220</a>)-mediated posteriorization of the central nervous system, indicating that the T543M mutant cannot sustain FGF signaling. HEK293T cells homozygous for T543M showed only 10 to 20% of wildtype RAF1 levels, and mutant protein levels could be partially rescued by treatment with a proteasome inhibitor, suggesting that T543M RAF1 is unstable and targeted for proteasome-mediated degradation. In addition, the mutant cells undergoing apoptotic stimuli showed a dose-dependent and statistically significant difference in cell death compared to wildtype cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37066513" 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></div>
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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<strong>See Also:</strong>
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<a href="#Bonner1985" class="mim-tip-reference" title="Bonner, T. I., Kerby, S. B., Sutrave, P., Gunnell, M. A., Mark, G., Rapp, U. R. <strong>Structure and biological activity of human homologs of the raf/mil oncogene.</strong> Molec. Cell. Biol. 5: 1400-1407, 1985.">Bonner et al. (1985)</a>; <a href="#Bonner1986" class="mim-tip-reference" title="Bonner, T. I., Oppermann, H., Seeburg, P., Kerby, S. B., Gunnell, M. A., Young, A. C., Rapp, U. R. <strong>The complete coding sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene.</strong> Nucleic Acids Res. 14: 1009-1015, 1986.">Bonner et al. (1986)</a>
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<strong>REFERENCES</strong>
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Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., Cheresh, D. A.
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<strong>Role of Raf in vascular protection from distinct apoptotic stimuli.</strong>
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Science 301: 94-96, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1082015" target="_blank">Full Text</a>]
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Bonner, T. I., Kerby, S. B., Sutrave, P., Gunnell, M. A., Mark, G., Rapp, U. R.
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<strong>Structure and biological activity of human homologs of the raf/mil oncogene.</strong>
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Molec. Cell. Biol. 5: 1400-1407, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2993863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2993863</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2993863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/mcb.5.6.1400-1407.1985" target="_blank">Full Text</a>]
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Bonner, T. I., Oppermann, H., Seeburg, P., Kerby, S. B., Gunnell, M. A., Young, A. C., Rapp, U. R.
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<strong>The complete coding sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene.</strong>
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Nucleic Acids Res. 14: 1009-1015, 1986.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3003687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3003687</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3003687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/nar/14.2.1009" target="_blank">Full Text</a>]
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Bonner, T., O'Brien, S. J., Nash, W. G., Rapp, U. R., Morton, C. C., Leder, P.
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<strong>The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4.</strong>
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Science 223: 71-74, 1984.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6691137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6691137</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6691137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.6691137" target="_blank">Full Text</a>]
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Chapman, P., Puzanov, I., sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R., Grippo, J., Nolop, K., Flaherty, K.
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<strong>Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032. (Abstract)</strong>
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Europ. J. Cancer Suppl. 7: 5 only, 2009.
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Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D. S., Rani, B., Govindaraj, P., and 17 others.
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<strong>RAF1 mutations in childhood-onset dilated cardiomyopathy.</strong>
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Nature Genet. 46: 635-639, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24777450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24777450</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24777450[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24777450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2963" target="_blank">Full Text</a>]
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Flaherty, K., Puzanov, I., Sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P.
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<a id="Shimizu1985" class="mim-anchor"></a>
|
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<div class="">
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<p class="mim-text-font">
|
|
Shimizu, K., Nakatsu, Y., Sekiguchi, M., Hokamura, K., Tanaka, K., Terada, M., Sugimura, T.
|
|
<strong>Molecular cloning of an activated human oncogene, homologous to v-raf, from primary stomach cancer.</strong>
|
|
Proc. Nat. Acad. Sci. 82: 5641-5645, 1985.
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|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3862088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3862088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3862088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.82.17.5641" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Teyssier1986" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Teyssier, J. R., Henry, I., Dozier, C., Ferre, D., Adnet, J. J., Pluot, M.
|
|
<strong>Recurrent deletion of the short arm of chromosome 3 in human renal cell carcinoma: shift of the c-raf 1 locus.</strong>
|
|
J. Nat. Cancer Inst. 77: 1187-1191, 1986.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3467112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3467112</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3467112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Tory1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tory, K., Latif, F., Modi, W., Schmidt, L., Wei, M. H., Li, H., Cobler, P., Orcutt, M. L., Delisio, J., Geil, L., Zbar, B., Lerman, M. I.
|
|
<strong>A genetic linkage map of 96 loci on the short arm of human chromosome 3.</strong>
|
|
Genomics 13: 275-286, 1992.
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1612588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1612588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1612588" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(92)90243-l" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Umeki2019" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Umeki, I., Niihori, T., Abe, T., Kanno, S., Okamoto, N., Mizuno, S., Kurosawa, K., Nagasaki, K., Yoshida, M., Ohashi, H., Inoue, S., Matsubara, Y., Fujiwara, I., Kure, S., Aoki, Y.
|
|
<strong>Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.</strong>
|
|
Hum. Genet. 138: 21-35, 2019.
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30368668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30368668</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30368668" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-018-1951-7" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="29" class="mim-anchor"></a>
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<a id="Wang1996" class="mim-anchor"></a>
|
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<div class="">
|
|
<p class="mim-text-font">
|
|
Wang, H.-G., Rapp, U. R., Reed, J. C.
|
|
<strong>Bcl-2 targets the protein kinase Raf-1 to mitochondria.</strong>
|
|
Cell 87: 629-638, 1996.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929532</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81383-5" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="30" class="mim-anchor"></a>
|
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<a id="Wong2023" class="mim-anchor"></a>
|
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<div class="mim-changed mim-change">
|
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<p class="mim-text-font">
|
|
Wong, S., Tan, Y. X., Loh, A. Y. T., Tan, K. Y., Lee, H., Aziz, Z., Nelson, S. F., Ozkan, E., Kayserili, H., Escande-Beillard, N., Reversade, B.
|
|
<strong>RAF1 deficiency causes a lethal syndrome that underscores RTK signaling during embryogenesis.</strong>
|
|
EMBO Molec. Med. 15: e17078, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37066513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37066513</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37066513[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37066513" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.15252/emmm.202217078" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Yamaguchi2004" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Yamaguchi, O., Watanabe, T., Nishida, K., Kashiwase, K., Higuchi, Y., Takeda, T., Hikoso, S., Hirotani, S., Asahi, M., Taniike, M., Nakai, A., Tsujimoto, I., and 9 others.
|
|
<strong>Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.</strong>
|
|
J. Clin. Invest. 114: 937-943, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467832[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15467832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI20317" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 02/06/2025
|
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</span>
|
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</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Ada Hamosh - updated : 01/10/2019<br>Marla J. F. O'Neill - updated : 7/30/2014<br>Ada Hamosh - updated : 8/24/2010<br>Patricia A. Hartz - updated : 5/19/2010<br>Ada Hamosh - updated : 4/15/2010<br>Ada Hamosh - updated : 10/19/2009<br>Patricia A. Hartz - updated : 5/29/2009<br>Marla J. F. O'Neill - updated : 10/24/2007<br>Ada Hamosh - updated : 1/14/2005<br>Marla J. F. O'Neill - updated : 12/2/2004<br>Ada Hamosh - updated : 12/30/2003<br>Ada Hamosh - updated : 7/24/2003<br>Jennifer P. Macke - updated : 10/20/1998
|
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</span>
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</div>
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</div>
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</div>
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<div>
|
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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
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</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Victor A. McKusick : 6/2/1986
|
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</span>
|
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</div>
|
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</div>
|
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</div>
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<div>
|
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<a id="editHistory" class="mim-anchor"></a>
|
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|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
carol : 02/06/2025
|
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</span>
|
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</div>
|
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</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
carol : 12/30/2019<br>alopez : 05/28/2019<br>alopez : 01/10/2019<br>carol : 10/20/2016<br>carol : 08/23/2016<br>carol : 11/14/2014<br>carol : 8/1/2014<br>mcolton : 7/30/2014<br>mgross : 8/25/2010<br>terry : 8/24/2010<br>carol : 7/16/2010<br>mgross : 5/20/2010<br>mgross : 5/20/2010<br>terry : 5/19/2010<br>alopez : 4/20/2010<br>terry : 4/15/2010<br>alopez : 10/26/2009<br>alopez : 10/26/2009<br>terry : 10/19/2009<br>mgross : 6/2/2009<br>terry : 5/29/2009<br>wwang : 10/25/2007<br>wwang : 10/25/2007<br>terry : 10/24/2007<br>alopez : 1/20/2005<br>alopez : 1/20/2005<br>terry : 1/14/2005<br>carol : 12/2/2004<br>mgross : 4/13/2004<br>mgross : 3/17/2004<br>alopez : 12/31/2003<br>terry : 12/30/2003<br>carol : 7/24/2003<br>terry : 7/24/2003<br>alopez : 10/20/1998<br>mark : 6/4/1996<br>carol : 4/7/1993<br>carol : 6/1/1992<br>supermim : 3/16/1992<br>carol : 3/2/1992<br>carol : 2/20/1991<br>supermim : 3/20/1990
|
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</span>
|
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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|
<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 164760
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
RAF1 PROTOONCOGENE, SERINE/THREONINE KINASE ; RAF1
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
|
|
|
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|
|
<div>
|
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<div >
|
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1<br />
|
|
ONCOGENE RAF1<br />
|
|
TRANSFORMING REPLICATION-DEFECTIVE MURINE RETROVIRUS 3611-MSV<br />
|
|
ONCOGENE MIL<br />
|
|
CRAF
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
RAF1/SRGAP3 FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
|
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|
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|
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<div>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: RAF1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 3p25.2
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 3:12,583,601-12,664,117 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
3p25.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiomyopathy, dilated, 1NN
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615916
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
LEOPARD syndrome 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
611554
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Noonan syndrome 5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
611553
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Rapp et al. (1983) cloned a unique acutely transforming replication-defective mouse type C virus and characterized its acquired oncogene, called v-raf. The viral genome bears close similarities to the Moloney murine leukemia virus (see MOS, 190060). The cellular homolog, c-raf, is present in 1 or 2 copies per haploid genome in mouse and human DNA. The MIL oncogene, a second oncogene in the avian retrovirus MH2, which contains the MYC oncogene, is the avian equivalent of the murine RAF oncogene, i.e., they are identical. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bonner et al. (1984) assigned the RAF1 gene to chromosome 3p25 by in situ hybridization. This suggested that RAF1 may be involved in mixed parotid gland tumors with the t(3;8)(p25;q21) translocation (Mark et al. (1980, 1982)). </p><p>Tory et al. (1992) constructed a genetic linkage map of 96 loci on 3p, extending from the terminal band to the centromere. Multipoint linkage analysis indicated that the male, female, and sex-averaged maps extend for 102, 147, and 116 cM, respectively. RAF1 and 16 DNA markers were localized by fluorescence in situ hybridization. RAF1 was regionalized to 3p25. </p><p><strong><em>Pseudogenes</em></strong></p><p>
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Bonner et al. (1984) showed that RAF2, a processed pseudogene, is on chromosome 4. </p><p>Hiroshige et al. (1986) assigned the RAF2 pseudogene to region 4pter-p15 by the study of hybrid cells containing various chromosome 4 regions.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The function of RAF1 was reviewed by Li et al. (1991). </p><p>Wang et al. (1996) showed that RAF1 can be targeted to the mitochondria by BCL2 (151430), a regulator of apoptotic cell death. Active RAF1 improved BCL2-mediated resistance to apoptosis. They also showed that RAF1 phosphorylates BAD (603167). </p><p>Alavi et al. (2003) showed that basic fibroblast growth factor (FGFB; 134920) and vascular endothelial growth factor (VEGF; 192240) differentially activate Raf1, resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. BFGF activated Raf1 via p21-activated protein kinase-1 (PAK1; 602590) phosphorylation of serines 338 and 339, resulting in Raf1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase-1 (MEK1; 176872). In contrast, VEGF activated Raf1 via Src kinase (CSK; 124095), leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. Alavi et al. (2003) concluded that RAF1 may be a pivotal regulator of endothelial cell survival during angiogenesis. </p><p>Lorenz et al. (2003) demonstrated that the RAF kinase inhibitor protein (RKIP; 604591) is a physiologic inhibitor of GRK2 (109635). After stimulation of G protein-coupled receptors, RKIP dissociates from its known target, RAF1, to associate with GRK2 and block its activity. This switch is triggered by a protein kinase C (PKC; see 176960)-dependent phosphorylation of RKIP on serine-153. Lorenz et al. (2003) concluded that their data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from RAF1 and by blocking receptor internalization. A physiologic role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signaling and contractile activity. </p><p>O'Neill et al. (2004) used proteomic analysis of RAF1 signaling complexes to show that RAF1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2; 605030). RAF1 prevents dimerization and phosphorylation of the activation loop of MST2 independently of its protein kinase activity. Depletion of MST2 from Raf1-null mouse or human cells abrogated sensitivity to apoptosis, whereas overexpression of MST2 induced apoptosis. Conversely, depletion of Raf1 from Raf1 +/+ mouse or human cells led to MST2 activation and apoptosis. The concomitant depletion of both RAF1 and MST2 prevented apoptosis. </p><p>By creating a kinase-defective version of Raf1 in mice or by using a Raf1 inhibitor, Noble et al. (2008) showed that Raf1 autophosphorylation on ser621 prevented its degradation by the proteasome. </p><p>Using Drosophila Schneider S2 cells, Rajakulendran et al. (2009) demonstrated that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which they termed the side-to-side dimer. Moreover, they found that the RAF-related pseudokinase KSR (601132) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. </p><p>Hollander et al. (2010) found that microRNA-212 (MIR212; 613487) was upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR212 decreased responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on Creb (123810) signaling. Studies in rats and HEK cells showed that amplification of CREB signaling occurred through miR212-enhanced RAF1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential Creb coactivator TORC (see CRTC1; 607536). miR212 activated RAF1, at least in part, through repression of SPRED1 (609291). Hollander et al. (2010) concluded that striatal miR212 signaling has a key role in determining vulnerability to cocaine addiction. </p><p>Using immunoprecipitation of endogenous LZTR1 (600574) followed by Western blotting, Umeki et al. (2019) showed that LZTR1 bound to the RAF1-SHOC2 (602775)-PPP1CB (600590) complex. Mutations in all these genes cause Noonan syndrome or Noonan-like phenotypes. Cells transfected with siRNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at ser259. </p><p><strong><em>Oncogenic Function</em></strong></p><p>
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|
Shimizu et al. (1985) identified the activated RAF gene in the stomach cancer of a Japanese patient. Stomach cancer is the most common cancer in Japan. Fukui et al. (1985) found that transforming DNA in a human glioblastoma line was apparently the RAF gene. Teyssier et al. (1986) presented evidence for a relationship of RAF1 to renal cell carcinoma (144700). </p><p>Kasid et al. (1987) transfected tumor cell DNA into NIH/3T3 cells to demonstrate that a radiation-resistant laryngeal carcinoma cell line contained altered RAF1 sequences. The karyotype of the tumor cells showed absence of chromosome 3, and transformed cells had double-minute chromosomes. </p><p>Poulikakos et al. (2010) used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for the paradoxical activation of the enzyme by inhibitors. Induction of ERK signaling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one promoter, but results in transactivation of the drug-free protomer. In BRAF(V600E) (164757.0001) tumors, RAS is not activated, thus transactivation is minimal and ERK signaling is inhibited in cells exposed to RAF inhibitors. These results indicated that RAF inhibitors will be effective in tumors in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicted that they would have a higher therapeutic index and greater antitumor activity than mitogen-activated protein kinase kinase (MEK) inhibitors, but could also cause toxicity due to the MEK/ERK activation. Poulikakos et al. (2010) noted that these predictions were borne out in a clinical trial of the RAF inhibitor PLX4032, as reported by Chapman et al. (2009) and Flaherty et al. (2009). The model indicated that promotion of RAF dimerization by elevation of wildtype RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumors. In agreement with this prediction, RAF inhibitors do not inhibit ERK signaling in cells that coexpress BRAF(V600E) and mutant RAS. </p><p>Hatzivassiliou et al. (2010) demonstrated that ATP-competitive RAF inhibitors have 2 opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumors, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signaling pathway and decrease tumor growth. Notably, in KRAS mutant and RAS/RAF wildtype tumors, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumor growth in some xenograft models. Inhibitor binding activates wildtype RAF isoforms by inducing dimerization, membrane localization, and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, Hatzivassiliou et al. (2010) demonstrated that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signaling pathways, depending on the cellular context. The authors stated that their work provided new insights into the therapeutic use of ATP-competitive RAF inhibitors. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Jones et al. (2009) found a tandem duplication at chromosome 3p25 in a pilocytic astrocytoma (see 137800) that resulted in fusion of exons 1 through 12 of the SRGAP3 gene (606525) to exons 10 through 17 of the RAF1 gene. The fusion transcript encodes a deduced protein containing the first 513 N-terminal amino acids of SRGAP3, including the FES (190030)/CIP4 (TRIP10; 604504) homology domain, fused to 318 C-terminal amino acids of RAF1, including the entire RAF1 kinase domain. The fusion protein showed higher activity than wildtype RAF1 in phosphorylation of endogenous Mek1 in mouse fibroblasts, and it conferred anchorage-independent cell growth. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Noonan Syndrome 5 or LEOPARD syndrome 2</em></strong></p><p>
|
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Pandit et al. (2007) analyzed the RAF1 gene in 231 individuals with Noonan syndrome who did not have mutations in the PTPN11 (176876), KRAS (190070), or SOS1 (182530) genes, and in 6 persons with LEOPARD syndrome who did not have mutations in PTPN11. They identified 13 different missense mutations (see, e.g., 164760.0001-164760.0003) in 18 unrelated patients with NS (NS5; 611553) and 2 missense mutations (164760.0001 and 164760.0004) in 2 patients with LEOPARD syndrome (LPRD2; 611554), respectively. Most mutations altered a motif flanking ser259 located in the CR2 domain, critical for autoinhibition of RAF1 through 14-3-3 (see 113508) binding. Of 17 NS patients with a RAF1 mutation in either of 2 hotspots (clustering around ser259 or ser612), 16 (94%) had hypertrophic cardiomyopathy (CMH; see 192600), compared with an 18% prevalence of CMH among NS patients in general. Pandit et al. (2007) also scanned RAF1 exons mutated in NS and LEOPARD patients in 241 unrelated individuals with nonsyndromic CMH who did not have mutations in 8 myofilament genes known to cause CMH, and the authors identified a thr260-to-ile mutation in the RAF1 gene in 1 patient. Ectopically expressed RAF1 mutants from the 2 CMH hotspots had increased kinase activity and enhanced ERK (see 176948) activation, whereas non-CMH-associated mutants were kinase impaired. </p><p>Razzaque et al. (2007) analyzed the RAF1 gene in 30 individuals clinically diagnosed with Noonan syndrome who were negative for mutations in the PTPN11, KRAS, HRAS (190020), or SOS1 genes, and identified 5 different missense mutations in RAF1 in 10 (33%) individuals. The authors noted that 8 of the 10 mutation-positive patients with 1 of 4 mutations causing changes in the CR2 domain of RAF1 (see, e.g., 164760.0001 and 164760.0003) had hypertrophic cardiomyopathy, whereas the 2 affected individuals with a mutation leading to changes in the CR3 domain did not (164760.0004). Transfection studies in HEK293 cells demonstrated that all 5 mutations in RAF1 behaved as gain-of-function mutants with increased kinase and ERK activation compared with wildtype RAF1. </p><p><strong><em>Dilated Cardiomyopathy 1NN</em></strong></p><p>
|
|
In 8 patients from South and North India and 2 patients from Japan with nonsyndromic dilated cardiomyopathy (CMD1NN; 615916), Dhandapany et al. (2014) identified heterozygous mutations in the RAF1 gene (see, e.g., 164760.0005-164760.0007) that segregated with disease in the families and were not found in ancestry-matched controls. Biochemical studies showed that the CMD-associated RAF1 mutants had altered kinase activity, resulting in largely unchanged ERK (see 601795) activation but in AKT (164730) that was hyperactivated in a BRAF (164757)-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
For discussion of a possible association between cleft palate, cardiac defects, genital anomalies, and ectrodactyly (CCGE; 600460) and mutation in the RAF1 gene, see 164760.0008.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To examine the in vivo role of RAF1 in the heart, Yamaguchi et al. (2004) generated cardiac muscle-specific Raf1 conditionally deleted mice. The mice demonstrated left ventricular systolic dysfunction and heart dilation without cardiac hypertrophy or lethality, and showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 (see 176872 and 601263, respectively) and ERK (see 601795) showed no difference, but the kinase activity of apoptosis signal-regulating kinase-1 (ASK1; 602448), JNK (see 601158), and p38 (600289) increased significantly compared to that of controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. Yamaguchi et al. (2004) concluded that RAF1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism. </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">
|
|
<strong>ALLELIC VARIANTS</strong>
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</span>
|
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0001 NOONAN SYNDROME 5</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">
|
|
LEOPARD SYNDROME 2, INCLUDED
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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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RAF1, SER257LEU
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<br />
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SNP: rs80338796,
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gnomAD: rs80338796,
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ClinVar: RCV000014985, RCV000014986, RCV000020509, RCV000149826, RCV000157426, RCV000157685, RCV000515222, RCV000824754, RCV000856803, RCV001731288, RCV001813205, RCV002399323, RCV003231105
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 7 unrelated patients with Noonan syndrome (NS5; 611553) and 1 patient with LEOPARD syndrome-2 (LPRD2; 611554), Pandit et al. (2007) identified heterozygosity for a 770C-T transition in exon 7 of the RAF1 gene, resulting in a ser257-to-leu (S257L) substitution at a conserved residue in the CR2 domain. All patients had hypertrophic cardiomyopathy (CMH), including a 3.6-year-old girl with CMH at birth and a 35-year-old woman with LEOPARD syndrome. Ectopically expressed S257L mutants demonstrated increased kinase activity and enhanced ERK (see 176948) activation. </p><p>Razzaque et al. (2007) identified the S257L mutation of the RAF1 gene in 4 unrelated patients with Noonan syndrome, 3 with obstructive and 1 with nonobstructive CMH. The mutation was not found in 100 control individuals or in 100 patients with CMH without Noonan syndrome. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 NOONAN SYNDROME 5</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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RAF1, PRO261SER
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<br />
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|
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SNP: rs121434594,
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|
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ClinVar: RCV000014987, RCV000159076, RCV000208421, RCV000211849, RCV000468714, RCV000618568, RCV000622893, RCV001813206, RCV003450640
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected individuals of 2 unrelated families with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 781C-T transition in exon 7 of the RAF1 gene, resulting in a pro261-to-ser (P261S) substitution at a conserved residue in the CR2 domain. Four of the 5 patients had hypertrophic cardiomyopathy (CMH); the 1 individual with a P261S change but without CMH was a 6-year-old girl whose 38-year-old mother had the same mutation and had been diagnosed with CMH at 23 years of age. The mutation was not found in 210 control individuals. </p><p>Razzaque et al. (2007) identified the P261S mutation in 3 Noonan syndrome patients, a 1-year-old boy and his 33-year-old father and an unrelated 16-year-old boy. All 3 displayed CMH. The mutation was not found in 100 control individuals or in 100 individuals with CMH without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that P261S behaved as a gain-of-function mutant with increased kinase and ERK (see 176948) activation compared with wildtype RAF1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 NOONAN SYNDROME 5</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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RAF1, THR491ARG
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<br />
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|
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SNP: rs80338799,
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ClinVar: RCV000014988, RCV000680803, RCV001229313
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a sister and brother with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 1472C-G transversion in exon 14 of the RAF1 gene, resulting in a thr491-to-arg (T491R) substitution in the CR3 domain. Neither sib had hypertrophic cardiomyopathy. The mutation was not found in 210 control individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 LEOPARD SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
|
NOONAN SYNDROME 5, INCLUDED
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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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RAF1, LEU613VAL
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<br />
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|
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SNP: rs80338797,
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ClinVar: RCV000014989, RCV000014990, RCV000020508, RCV000159089, RCV000254689, RCV000440827, RCV000824753, RCV001256891, RCV004532353
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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 43-year-old woman with LEOPARD syndrome-2 (LPRD2; 611554), Pandit et al. (2007) identified an 1837C-G transversion in exon 17 of the RAF1 gene, resulting in a leu613-to-val (L613V) substitution at a conserved residue in the C terminus. The patient had hypertrophic cardiomyopathy. </p><p>Razzaque et al. (2007) identified the L613V mutation, which they designated as being located in the CR3 domain of RAF1, in 2 unrelated boys with Noonan syndrome (NS5; 611553), neither of whom had hypertrophic cardiomyopathy. The mutation was not found in 100 control individuals or in 100 patients with hypertrophic cardiomyopathy without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that L613V behaved as a gain-of-function mutant with increased kinase and ERK (see 176948) activation compared with wildtype RAF1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 CARDIOMYOPATHY, DILATED, 1NN</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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RAF1, LEU603PRO
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<br />
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SNP: rs587777586,
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ClinVar: RCV000131334
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 patients with nonsyndromic dilated cardiomyopathy (CMD1NN; 615916), a 40-year-old South Indian mother and her 4-year-old son and an unrelated 21-year-old South Indian woman, Dhandapany et al. (2014) identified heterozygosity for a c.1808T-C transition in the RAF1 gene, resulting in a leu603-to-pro (L603P) substitution at a highly conserved residue in the CR3 domain. Age at onset of disease in the 3 patients was 24 years, 3 years, and 10 years, respectively. The mutation was not found in the 4-year-old boy's unaffected father, in 500 ancestry-matched South Indian controls, or in 13,600 European and African American alleles in the Exome Sequencing Project database. Functional analysis in HEK293 cells showed impaired kinase activity and reduced ERK (see 601795) activation with the L603P mutant. Constitutive expression of the L603P mutant in zebrafish embryos resulted in a heart failure phenotype, including elongated ventricular and atrial chambers, profound pericardial edema, blood congestion at the cardiac inflow tract, and impaired cardiac contractions. Immunoblotting showed AKT hyperactivation, and the heart defects were partially rescued by treatment with rapamycin, an AKT-mTOR (601231) inhibitor. </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>.0006 CARDIOMYOPATHY, DILATED, 1NN</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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RAF1, THR641MET
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<br />
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SNP: rs587777587,
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gnomAD: rs587777587,
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ClinVar: RCV000131336, RCV000852545, RCV001657807, RCV001849941, RCV004984679
|
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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 15-year-old South Indian girl and an unrelated 21-year-old North Indian man with nonsyndromic dilated cardiomyopathy (CMD1NN; 615916), Dhandapany et al. (2014) identified heterozygosity for a c.1922T-C transition in the RAF1 gene, resulting in a thr641-to-met (T641M) substitution at a highly conserved residue. Age at onset of disease in the 2 patients was 7 years and 16 years, respectively. The mutation, which segregated with disease in the available family, was not found in 500 ancestry-matched South Indian controls or in 350 ancestry-matched North Indian controls. Functional analysis in HEK293 cells showed a mild increase in kinase activity with the T641M mutant that was less augmented than that of the CMH-associated RAF1 mutants tested, L613V (164760.0004) and S257L (164760.0001). ERK (see 601795) activation with the T641M mutant was similar to that observed with wildtype RAF1 and was significantly less than with the CMH-associated mutants. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 CARDIOMYOPATHY, DILATED, 1NN</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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RAF1, ALA237THR
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<br />
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SNP: rs587777588,
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|
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gnomAD: rs587777588,
|
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|
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|
|
ClinVar: RCV000131337, RCV001588987, RCV001775085, RCV001857459
|
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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 44-year-old Japanese man who had onset of nonsyndromic dilated cardiomyopathy (CMD1NN; 615916) at 40 years of age, Dhandapany et al. (2014) identified heterozygosity for a c.709G-A transition in the RAF1 gene, resulting in an ala237-to-thr (A237T) substitution at a highly conserved residue. The mutation was not found in 300 Japanese controls. Functional analysis in HEK293 cells showed a mild increase in kinase activity with the A237T mutant that was less augmented than that of the CMH-associated RAF1 mutants tested, L613V (164760.0004) and S257L (164760.0001). ERK (see 601795) activation with the A237T mutant was similar to that observed with wildtype RAF1 and was significantly less than with the CMH-associated mutants, whereas activation of AKT and tuberin (TSC2; 191092) was excessive compared to CMH-associated mutants or wildtype RAF1. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
RAF1, THR543MET
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<br />
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|
|
ClinVar: RCV005055410
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>This variant is classified as a variant of unknown significance because its contribution to cleft palate, cardiac defects, genital anomalies, and ectrodactyly (CCGE; 600460) has not been confirmed.</p><p>In a consanguineous Turkish family in which 2 deceased sibs exhibited features of CCGE, Wong et al. (2023) performed homozygosity mapping and exome sequencing and identified a c.1628C-T transition in the RAF1 gene, resulting in a thr543-to-met (T543M) substitution at a highly conserved residue within the CR3 kinase domain. Sanger sequencing confirmed the variant and its presence in homozygosity in the affected brother and in heterozygosity in the unaffected first-cousin parents and an unaffected sib; it was not found in in-house or public variant databases. Functional analysis in HEK293T cells showed that the T542M mutant was globally hypophosphorylated compared to wildtype, and Western blot analysis after EGF (131530) stimulation revealed that unlike wildtype RAF1, the mutant failed to to induce downstream MEK1 (MAP2K1; 176872)/MEK2 (MAP2K2; 601263) or ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) phosphorylation. The authors concluded that T543M is a loss-of-function mutation that dampens RAF1-mediated MEK/ERK signaling. In vivo studies in Xenopus laevis embryos confirmed these results, showing significantly reduced downstream ERK1/2 phosphorylation with the T543M mutant relative to wildtype RAF1, and the mutant induced minimal ectopic mesoderm, comparable to uninjected controls. In addition, overexpression of T543M did not induce ectopic neuronal differentiation, a hallmark of FGF (131220)-mediated posteriorization of the central nervous system, indicating that the T543M mutant cannot sustain FGF signaling. HEK293T cells homozygous for T543M showed only 10 to 20% of wildtype RAF1 levels, and mutant protein levels could be partially rescued by treatment with a proteasome inhibitor, suggesting that T543M RAF1 is unstable and targeted for proteasome-mediated degradation. In addition, the mutant cells undergoing apoptotic stimuli showed a dose-dependent and statistically significant difference in cell death compared to wildtype cells. </p></div>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Bonner et al. (1985); Bonner et al. (1986)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Alavi, A., Hood, J. D., Frausto, R., Stupack, D. G., Cheresh, D. A.
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<strong>Role of Raf in vascular protection from distinct apoptotic stimuli.</strong>
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Science 301: 94-96, 2003.
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[PubMed: 12843393]
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[Full Text: https://doi.org/10.1126/science.1082015]
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<li>
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<p class="mim-text-font">
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|
Bonner, T. I., Kerby, S. B., Sutrave, P., Gunnell, M. A., Mark, G., Rapp, U. R.
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<strong>Structure and biological activity of human homologs of the raf/mil oncogene.</strong>
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Molec. Cell. Biol. 5: 1400-1407, 1985.
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Bonner, T. I., Oppermann, H., Seeburg, P., Kerby, S. B., Gunnell, M. A., Young, A. C., Rapp, U. R.
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<strong>The complete coding sequence of the human raf oncogene and the corresponding structure of the c-raf-1 gene.</strong>
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<p class="mim-text-font">
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Bonner, T., O'Brien, S. J., Nash, W. G., Rapp, U. R., Morton, C. C., Leder, P.
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<strong>The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4.</strong>
|
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Science 223: 71-74, 1984.
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[PubMed: 6691137]
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<p class="mim-text-font">
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Chapman, P., Puzanov, I., sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R., Grippo, J., Nolop, K., Flaherty, K.
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<strong>Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032. (Abstract)</strong>
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Europ. J. Cancer Suppl. 7: 5 only, 2009.
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Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D. S., Rani, B., Govindaraj, P., and 17 others.
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<strong>RAF1 mutations in childhood-onset dilated cardiomyopathy.</strong>
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[PubMed: 24777450]
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Flaherty, K., Puzanov, I., Sosman, J., Kim, K., Ribas, A., McArthur, G., Lee, R. J., Grippo, J. F., Nolop, K., Chapman, P.
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<strong>Phase I study of PLX4032: proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. (Abstract-9000)</strong>
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J. Clin. Oncol. 27 (suppl.): 15s, 2009.
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Fukui, M., Yamamoto, T., Kawai, S., Maruo, K., Toyoshima, K.
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<strong>Detection of a raf-related and two other transforming DNA sequences in human tumors maintained in nude mice.</strong>
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Proc. Nat. Acad. Sci. 82: 5954-5958, 1985.
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[PubMed: 2994056]
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[Full Text: https://doi.org/10.1073/pnas.82.17.5954]
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<p class="mim-text-font">
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Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G., Morales, T., Aliagas, I., and 9 others.
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<strong>RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.</strong>
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Nature 464: 431-435, 2010.
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<p class="mim-text-font">
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Hiroshige, S., Carlock, L., Smith, M.
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<strong>Regional assignment of the RAF2 gene to the region 4pter-4p15. (Abstract)</strong>
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Am. J. Hum. Genet. 39: A157, 1986.
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Hollander, J. A., Im, H.-I., Amelio, A. L., Kocerha, J., Bali, P., Lu, Q., Willoughby, D., Wahlestedt, C., Conkright, M. D., Kenny, P. J.
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<strong>Striatal microRNA controls cocaine intake through CREB signalling.</strong>
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Jones, D. T. W., Kocialkowski, S., Liu, L., Pearson, D. M., Ichimura, K., Collins, V. P.
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<strong>Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma.</strong>
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Kasid, U., Pfeifer, A., Weichselbaum, R. R., Dritschilo, A., Mark, G. E.
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<strong>The raf oncogene is associated with a radiation-resistant human laryngeal cancer.</strong>
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Science 237: 1039-1041, 1987.
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Li, P., Wood, K., Mamon, H., Haser, W., Roberts, T.
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<strong>Raf-1: a kinase currently without a cause but not lacking in effects.</strong>
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Cell 64: 479-482, 1991.
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[PubMed: 1846778]
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Lorenz, K., Lohse, M. J., Quitterer, U.
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Nature 426: 574-579, 2003.
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[PubMed: 14654844]
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Mark, J., Dahlenfors, R., Ekedahl, C., Stenman, G.
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<strong>The mixed salivary gland tumor--a normally benign human neoplasm frequently showing specific chromosomal abnormalities.</strong>
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Cancer Genet. Cytogenet. 2: 231-234, 1980.
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Mark, J., Dahlenfors, R., Ekedahl, C., Stenman, G.
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<strong>Chromosomal patterns in a benign human neoplasm, the mixed salivary gland tumour.</strong>
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Hereditas 96: 141-148, 1982.
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[PubMed: 6282787]
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[Full Text: https://doi.org/10.1111/j.1601-5223.1982.tb00044.x]
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<p class="mim-text-font">
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Noble, C., Mercer, K., Hussain, J., Carragher, L., Giblett, S., Hayward, R., Patterson, C., Marais, R., Pritchard, C. A.
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<strong>CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation.</strong>
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[PubMed: 18922468]
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<p class="mim-text-font">
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O'Neill, E., Rushworth, L., Baccarini, M., Kolch, W.
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<strong>Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1.</strong>
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Science 306: 2267-2270, 2004.
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[PubMed: 15618521]
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[Full Text: https://doi.org/10.1126/science.1103233]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Pandit, B., Sarkozy, A., Pennacchio, L. A., Carta, C., Oishi, K., Martinelli, S., Pogna, E. A., Schackwitz, W., Ustaszewska, A., Landstrom, A., Bos, J. M., Ommen, S. R., and 17 others.
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<strong>Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.</strong>
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Nature Genet. 39: 1007-1012, 2007.
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[PubMed: 17603483]
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[Full Text: https://doi.org/10.1038/ng2073]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M., Rosen, N.
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