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Entry
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- *136350 - FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1
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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">*136350</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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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="#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/136350">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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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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<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=ENSG00000077782;t=ENST00000447712" 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=2260" 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=136350" 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=ENSG00000077782;t=ENST00000447712" 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_001174063,NM_001174064,NM_001174065,NM_001174066,NM_001174067,NM_001354367,NM_001354368,NM_001354369,NM_001354370,NM_001410922,NM_015850,NM_023105,NM_023106,NM_023110" 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_023110" 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=136350" 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=00634&isoform_id=00634_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/FGFR1" 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/31368,31378,31385,31387,31389,31391,31393,35110,120046,179415,182530,182532,182534,182536,182547,182561,183879,183881,183883,558584,1247529,4261930,13186234,13186236,13186251,21955340,22450878,33338046,45934432,60552859,62087418,62896995,62897813,105990522,119583707,119583708,119583709,119583710,119583711,119583712,119583713,119583714,119583715,119583716,119583717,119583718,119583719,119583720,158256940,158258377,194318488,194318490,226222426,226222428,291327489,291327491,291327493,291327495,291327497,906358681,957949396,957949399,957949402,957949405,957949408,1172923691,1172923693,1229732560,1229732571,1237937818,1237938292,2287780805" 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/P11362" 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=2260" 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=ENSG00000077782;t=ENST00000447712" 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=FGFR1" 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=FGFR1" 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+2260" 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/FGFR1" 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:2260" 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/2260" 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=chr8&hgg_gene=ENST00000447712.7&hgg_start=38411143&hgg_end=38468635&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:3688" 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:3688" 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/fgfr1" 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=136350[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=136350[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/FGFR1/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/ENSG00000077782" 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=FGFR1" 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=FGFR1" 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=FGFR1" 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=FGFR1&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/PA28127" 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:3688" 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/FBgn0010389.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:95522" 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/FGFR1#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:95522" 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/2260/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2260" 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=WBGene00001184;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-060503-14" 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:2260" 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=FGFR1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 109409003, 238905009, 254144002, 70410008, 709105005, 766032007<br />
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<strong>ICD10CM:</strong> Q75.03<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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136350
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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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FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
FMS-LIKE TYROSINE KINASE 2; FLT2<br />
|
|
FMS-LIKE GENE; FLG
|
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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:
|
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</span>
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</p>
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</div>
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<div>
|
|
<span class="h3 mim-font">
|
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FGFR1/BCR FUSION GENE, INCLUDED
|
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</span>
|
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</div>
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<div>
|
|
<span class="h4 mim-font">
|
|
|
|
FGFR1/FGFR1OP2 FUSION GENE, INCLUDED<br />
|
|
FGFR1/ZNF198 FUSION GENE, INCLUDED<br />
|
|
FGFR1/TACC1 FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
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</div>
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<div>
|
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<br />
|
|
</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=FGFR1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FGFR1</a></em></strong>
|
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</span>
|
|
</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/8/211?start=-3&limit=10&highlight=211">8p11.23</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr8:38411143-38468635&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'})">8:38,411,143-38,468,635</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
|
</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613001,615465,147950,123150,166250,101600,190440" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
|
<th>
|
|
Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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<a href="/geneMap/8/211?start=-3&limit=10&highlight=211">
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8p11.23
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</a>
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<span class="mim-font">
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Encephalocraniocutaneous lipomatosis, somatic mosaic
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<span class="mim-font">
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<a href="/entry/613001"> 613001 </a>
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<span class="mim-font">
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Hartsfield syndrome
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<span class="mim-font">
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<a href="/entry/615465"> 615465 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Hypogonadotropic hypogonadism 2 with or without anosmia
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<span class="mim-font">
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<a href="/entry/147950"> 147950 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Jackson-Weiss syndrome
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<span class="mim-font">
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<a href="/entry/123150"> 123150 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Osteoglophonic dysplasia
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<span class="mim-font">
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<a href="/entry/166250"> 166250 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Pfeiffer syndrome
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<span class="mim-font">
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<a href="/entry/101600"> 101600 </a>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Trigonocephaly 1
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<span class="mim-font">
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<a href="/entry/190440"> 190440 </a>
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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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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/136350" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/136350" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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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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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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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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<strong>TEXT</strong>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p><a href="#50" class="mim-tip-reference" title="Ruta, M., Howk, R., Ricca, G., Drohan, W., Zabelshansky, M., Laureys, G., Barton, D. E., Francke, U., Schlessinger, J., Givol, D. <strong>A novel protein tyrosine kinase gene whose expression is modulated during endothelial cell differentiation.</strong> Oncogene 3: 9-15, 1988."None>Ruta et al. (1988)</a> isolated a novel gene from a human endothelial cell cDNA library by hybridizing at relaxed stringency using the v-fms oncogene as a probe. DNA sequence analysis of a 2-kb cDNA insert showed an open reading frame encoding a putative protein tyrosine kinase.</p><p><a href="#49" class="mim-tip-reference" title="Ruta, M., Burgess, W., Givol, D., Epstein, J., Neiger, N., Kaplow, J., Crumley, G., Dionne, C., Jaye, M., Schlessinger, J. <strong>Receptor for acidic fibroblast growth factor is related to the tyrosine kinase encoded by the FMS-like gene (FLG).</strong> Proc. Nat. Acad. Sci. 86: 8722-8726, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2554327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2554327</a>] [<a href="https://doi.org/10.1073/pnas.86.22.8722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2554327">Ruta et al. (1989)</a> found that acidic fibroblast growth factor (FGFA; <a href="/entry/131220">131220</a>) stimulates tyrosine kinase activity of FLG in vitro and in living cells, suggesting that FLG encodes the membrane receptor for acidic FGF. The protein FLG is the human equivalent of a known chicken basic FGF receptor (<a href="#26" class="mim-tip-reference" title="Lee, P. L., Johnson, D. E., Cousens, L. S., Fried, V. A., Williams, L. T. <strong>Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor.</strong> Science 245: 57-60, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544996</a>] [<a href="https://doi.org/10.1126/science.2544996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544996">Lee et al., 1989</a>). <a href="#26" class="mim-tip-reference" title="Lee, P. L., Johnson, D. E., Cousens, L. S., Fried, V. A., Williams, L. T. <strong>Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor.</strong> Science 245: 57-60, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544996</a>] [<a href="https://doi.org/10.1126/science.2544996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544996">Lee et al. (1989)</a> isolated a 130-kD protein on the basis of its ability to bind specifically to basic fibroblast growth factor (FGF2; <a href="/entry/134920">134920</a>). They then isolated a cDNA using an oligonucleotide probe corresponding to the amino acid sequences of tryptic peptide fragments of the purified protein. The putative FGFB receptor encoded by this cDNA was found to be a transmembrane protein that contained 3 extracellular immunoglobulin-like domains, an unusual acidic region, and an intracellular tyrosine kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2554327+2544996" 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="#65" class="mim-tip-reference" title="Wang, L.-Y., Edenson, S. P., Yu, Y.-L., Senderowicz, L., Turck, C. W. <strong>A natural kinase-deficient variant of fibroblast growth factor receptor 1.</strong> Biochemistry 35: 10134-10142, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756477</a>] [<a href="https://doi.org/10.1021/bi952611n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8756477">Wang et al. (1996)</a> identified cDNAs encoding an FGFR1 splice variant that lacks a portion of the tyrosine kinase catalytic domain. This splice variant, termed FGFR1-prime, is expressed in human lung fibroblasts and several other human cell lines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8756477" 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>Biochemical Features</strong>
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<p><a href="#40" class="mim-tip-reference" title="Plotnikov, A. N., Schlessinger, J., Hubbard, S. R., Mohammadi, M. <strong>Structural basis for FGF receptor dimerization and activation.</strong> Cell 98: 641-650, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10490103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10490103</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80051-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10490103">Plotnikov et al. (1999)</a> determined the crystal structure of FGF2 (<a href="/entry/134920">134920</a>) bound to a naturally occurring variant of FGFR1 consisting of immunoglobulin-like domains 2 (D2) and 3 (D3) at 2.8-angstrom resolution. Two FGF2:FGFR1 complexes form a 2-fold symmetric dimer. Within each complex, FGF2 interacts extensively with D2 and D3 as well as with the linker between the 2 domains. The dimer is stabilized by interactions between FGF2 and D2 of the adjoining complex and by a direct interaction between D2 of each receptor. A positively charged canyon formed by a cluster of exposed basic residues likely represents the heparin-binding site. A general model for FGF- and heparin-induced FGFR dimerization was inferred from the crystal structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10490103" 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>To elucidate the structural determinants governing specificity in FGF signaling, <a href="#39" class="mim-tip-reference" title="Plotnikov, A. N., Hubbard, S. R., Schlessinger, J., Mohammadi, M. <strong>Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity.</strong> Cell 101: 413-424, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10830168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10830168</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80851-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10830168">Plotnikov et al. (2000)</a> determined the crystal structures of FGF1 (<a href="/entry/131220">131220</a>) and FGF2 complexed with the ligand-binding domains (D2 and D3) of FGFR1 and FGFR2, respectively. They found that highly conserved FGF-D2 and FGF-linker interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and 2 loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10830168" 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>Gene Structure</strong>
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<p>The 2 classes of sequences for recognition and splicing of pre-mRNA in eukaryotes, GT-AG and AT-AC, are characterized by the nearly invariant dinucleotides present at the extreme 5-prime (donor) and 3-prime (acceptor) ends of the intron. Among GT-AG introns, which comprise the vast majority, the more extended consensus sequence at the 5-prime splice site is A(C)AG/gta(g)agt (where the slash indicates the exon-intron boundary and the nucleotide in parentheses is an alternate). This sequence is complementary to part of the U1 snRNA and is important in intron recognition. <a href="#61" class="mim-tip-reference" title="Twigg, S. R. F., Burns, H. D., Oldridge, M., Heath, J. K., Wilkie, A. O. M. <strong>Conserved use of a non-canonical 5-prime splice site (/GA) in alternative splicing by fibroblast growth factor receptors 1, 2 and 3.</strong> Hum. Molec. Genet. 7: 685-691, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499422</a>] [<a href="https://doi.org/10.1093/hmg/7.4.685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499422">Twigg et al. (1998)</a> determined the genomic structure of the Fgfr2 gene of the mouse and identified a divergent 5-prime splice site (ACA/gaaagt), conserved in FGFR1, FGFR2 (<a href="/entry/176943">176943</a>), and FGFR3 (<a href="/entry/134934">134934</a>) from humans, mice, and Xenopus that is used for alternative splicing of a hexanucleotide sequence, encoding val-thr, at the end of exon 10. This is the only example known of the use of /ga in vertebrate splicing. Similarities to a splice site in the Antennapedia gene of Drosophila suggested that this variant motif is involved in alternative splicing of short sequences at the 5-prime splice site. Inclusion or exclusion of the val/thr dipeptide may play an important role in controlling FGFR signaling through the Ras/MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499422" 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="#50" class="mim-tip-reference" title="Ruta, M., Howk, R., Ricca, G., Drohan, W., Zabelshansky, M., Laureys, G., Barton, D. E., Francke, U., Schlessinger, J., Givol, D. <strong>A novel protein tyrosine kinase gene whose expression is modulated during endothelial cell differentiation.</strong> Oncogene 3: 9-15, 1988."None>Ruta et al. (1988)</a> localized the FGFR1 gene, which they designated FLG, to 8p12-p11.2 by in situ hybridization. Assignment to chromosome 8 was also indicated by Southern blot analysis of DNA from hamster-human hybrid cells. This region of mapping is involved in myeloproliferative disorders. <a href="#71" class="mim-tip-reference" title="Wood, S., Schertzer, M., Yaremko, M. L. <strong>Sequence identity locates CEBPD and FGFR1 to mapped human loci within proximal 8p.</strong> Cytogenet. Cell Genet. 70: 188-191, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789168</a>] [<a href="https://doi.org/10.1159/000134030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7789168">Wood et al. (1995)</a> mapped both FGFR1 and CEBPD (<a href="/entry/116898">116898</a>) to 8p11.2-p11.1 by analysis of somatic cell hybrids combined with fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7789168" 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="#65" class="mim-tip-reference" title="Wang, L.-Y., Edenson, S. P., Yu, Y.-L., Senderowicz, L., Turck, C. W. <strong>A natural kinase-deficient variant of fibroblast growth factor receptor 1.</strong> Biochemistry 35: 10134-10142, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8756477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8756477</a>] [<a href="https://doi.org/10.1021/bi952611n" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8756477">Wang et al. (1996)</a> reported that the FGFR1-prime variant bound specifically to acidic FGF but ligand binding caused neither receptor autophosphorylation nor activation of phospholipase C (PLC). The authors suggested that the kinase-deficient variant may have an important role in regulating cellular responses elicited by acidic FGF stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8756477" 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="Jung, J., Zheng, M., Goldfarb, M., Zaret, K. S. <strong>Initiation of mammalian liver development from endoderm by fibroblast growth factors.</strong> Science 284: 1998-2003, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10373120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10373120</a>] [<a href="https://doi.org/10.1126/science.284.5422.1998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10373120">Jung et al. (1999)</a> studied the initiation of mammalian liver development from endoderm by fibroblast growth factors. The hepatogenic response was restricted to endoderm tissue, which selectively coexpresses FGF receptors 1 and 4 (<a href="/entry/134935">134935</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10373120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using in situ hybridization, <a href="#36" class="mim-tip-reference" title="Pirvola, U., Ylikoski, J., Trokovic, R., Hebert, J. M., McConnell, S. K., Partanen, J. <strong>FGFR1 is required for the development of the auditory sensory epithelium.</strong> Neuron 35: 671-680, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12194867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12194867</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00824-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12194867">Pirvola et al. (2002)</a> detected Fgfr1 expression at several stages during inner ear development in mouse, especially in regions contributing to the formation of the organ of Corti. To further study the function of Fgfr1 in the developing inner ear, <a href="#36" class="mim-tip-reference" title="Pirvola, U., Ylikoski, J., Trokovic, R., Hebert, J. M., McConnell, S. K., Partanen, J. <strong>FGFR1 is required for the development of the auditory sensory epithelium.</strong> Neuron 35: 671-680, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12194867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12194867</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00824-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12194867">Pirvola et al. (2002)</a> analyzed mice carrying partial loss-of-function mutations (<a href="#34" class="mim-tip-reference" title="Partanen, J., Schwartz, L., Rossant, J. <strong>Opposite phenotypes of hypomorphic and Y766 phosphorylation site mutations reveal a function for Fgfr1 in anteroposterior patterning of mouse embryos.</strong> Genes Dev. 12: 2332-2344, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9694798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.12.15.2332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9694798">Partanen et al., 1998</a>) and otic epithelium-specific null mutations in Fgfr1. <a href="#36" class="mim-tip-reference" title="Pirvola, U., Ylikoski, J., Trokovic, R., Hebert, J. M., McConnell, S. K., Partanen, J. <strong>FGFR1 is required for the development of the auditory sensory epithelium.</strong> Neuron 35: 671-680, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12194867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12194867</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00824-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12194867">Pirvola et al. (2002)</a> observed a reduction in the number of auditory hair cells in Fgfr1 mutants and hypothesized that FGFR1 is required for proliferation of precursor cells that give rise to the auditory sensory epithelium. The authors concluded that FGFR1 is essential for the normal formation of the organ of Corti and that phenotype severity observed in Fgfr1 mutants is dependent on the dose of FGFR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12194867+9694798" 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="#52" class="mim-tip-reference" title="Schlessinger, J. <strong>Common distinct elements in cellular signaling via EGF and FGF receptors.</strong> Science 306: 1506-1507, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15567848/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15567848</a>] [<a href="https://doi.org/10.1126/science.1105396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15567848">Schlessinger (2004)</a> reviewed the signaling pathways that are activated by EGF and FGF receptors. Both receptors stimulate a similar complement of intracellular signaling pathways. However, whereas activated EGF receptors function as the main platform for recruitment of signaling proteins, signaling through the FGF receptors is mediated primarily by assembly of a multidocking protein complex. Furthermore, FGF receptor signaling is subject to additional intracellular and extracellular control mechanisms that do not affect EGF receptor signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15567848" 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="#54" class="mim-tip-reference" title="Siffroi-Fernandez, S., Cinaroglu, A., Fuhrmann-Panfalone, V., Normand, G., Bugra, K., Sahel, J., Hicks, D. <strong>Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma.</strong> Arch. Ophthal. 123: 368-376, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15767480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15767480</a>] [<a href="https://doi.org/10.1001/archopht.123.3.368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15767480">Siffroi-Fernandez et al. (2005)</a> examined FGF high and low affinity receptor (FGFR) expression, activation of FGFR1 by acidic FGF (FGF1), and proliferative effects on Y79 retinoblastoma (see <a href="/entry/180200">180200</a>) cells. They found that Y79 retinoblastoma expresses protein and mRNA of all 4 FGFRs. FGFR1 was differentially phosphorylated by FGF1. Proliferation of Y79 cells induced by FGF1 was entirely mediated by FGFR1. FGF1-induced proliferation was dependent on the presence and sulfation of heparan sulfate proteoglycan (HSPG; <a href="/entry/142460">142460</a>). <a href="#54" class="mim-tip-reference" title="Siffroi-Fernandez, S., Cinaroglu, A., Fuhrmann-Panfalone, V., Normand, G., Bugra, K., Sahel, J., Hicks, D. <strong>Acidic fibroblast growth factor (FGF-1) and FGF receptor 1 signaling in human Y79 retinoblastoma.</strong> Arch. Ophthal. 123: 368-376, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15767480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15767480</a>] [<a href="https://doi.org/10.1001/archopht.123.3.368" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15767480">Siffroi-Fernandez et al. (2005)</a> concluded that their study demonstrated a role for the FGF1/FGFR1 pathway in retinoblastoma proliferation and might contribute to developing therapeutic strategies to limit retinoblastoma growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15767480" 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="Furdui, C. M., Lew, E. D., Schlessinger, J., Anderson, K. S. <strong>Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction.</strong> Molec. Cell 21: 711-717, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16507368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16507368</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.01.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16507368">Furdui et al. (2006)</a> demonstrated that the 5 tyrosines autophosphorylated in the catalytic core of mammalian FGFR1 are phosphorylated by a precisely controlled and ordered reaction. They also showed that the rate of substrate phosphorylation by FGFR1 is enhanced at least 50- and 500-fold after autophosphorylation of FGFR1 on tyr653 and tyr654, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16507368" 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>FGF receptors are derived from FGFRs 1 through 4. The difference in the number of immunoglobulin-like loops (alpha-type and beta-type) and alternative splicing of mRNA corresponding to the third immunoglobulin-like loop (IIIa, IIIb, and IIIc) produce several subtypes of FGFRs. <a href="#62" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> demonstrated that a previously undescribed receptor conversion of FGFR1(IIIc) by Klotho (<a href="/entry/604824">604824</a>) generates the FGF23 (<a href="/entry/605380">605380</a>) receptor. Using a renal homogenate, <a href="#62" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> found that Klotho binds to FGF23. Forced expression of Klotho enabled the high affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wildtype mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signaling, <a href="#62" class="mim-tip-reference" title="Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., Yamashita, T. <strong>Klotho converts canonical FGF receptor into a specific receptor for FGF23.</strong> Nature 444: 770-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17086194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17086194</a>] [<a href="https://doi.org/10.1038/nature05315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17086194">Urakawa et al. (2006)</a> searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17086194" 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="#32" class="mim-tip-reference" title="Neugebauer, J. M., Amack, J. D., Peterson, A. G., Bisgrove, B. W., Yost, H. J. <strong>FGF signalling during embryo development regulates cilia length in diverse epithelia.</strong> Nature 458: 651-654, 2009. Note: Erratum: Nature 463: 384 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19242413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19242413</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19242413[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/nature07753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19242413">Neugebauer et al. (2009)</a> provided several lines of evidence showing that fibroblast growth factor signaling regulates cilia length and function in diverse epithelia during zebrafish and Xenopus development. Morpholino knockdown of Fgfr1 in zebrafish cell-autonomously reduced cilia length in Kupffer vesicle and perturbed directional fluid flow required for left-right patterning of the embryo. Expression of a dominant-negative Fgfr1, treatment with a pharmacologic inhibitor of FGF signaling, or genetic and morpholino reduction of redundant FGF ligands Fgf8 (<a href="/entry/600483">600483</a>) and Fgf24 reproduced this cilia length phenotype. Knockdown of Fgfr1 also resulted in shorter tethering of cilia in the otic vesicle and shorter motile cilia in the pronephric ducts. In Xenopus, expression of a dominant-negative fgfr1 resulted in shorter monocilia in the gastrocoel roof plate that control left-right patterning and in shorter multicilia in external mucociliary epithelium. <a href="#32" class="mim-tip-reference" title="Neugebauer, J. M., Amack, J. D., Peterson, A. G., Bisgrove, B. W., Yost, H. J. <strong>FGF signalling during embryo development regulates cilia length in diverse epithelia.</strong> Nature 458: 651-654, 2009. Note: Erratum: Nature 463: 384 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19242413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19242413</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19242413[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/nature07753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19242413">Neugebauer et al. (2009)</a> concluded that their results indicated a fundamental and highly conserved role for FGF signaling in the regulation of cilia length in multiple tissues. Abrogation of Fgfr1 signaling downregulates expression of 2 ciliogenic transcription factors, foxj1 (<a href="/entry/602291">602291</a>) and rfx2 (<a href="/entry/142765">142765</a>), and of the intraflagellar transport gene ift88 (<a href="/entry/600595">600595</a>), indicating that FGF signaling mediates cilia length through an Fgf8/Fgf24-Fgfr1-intraflagellar transport pathway. <a href="#32" class="mim-tip-reference" title="Neugebauer, J. M., Amack, J. D., Peterson, A. G., Bisgrove, B. W., Yost, H. J. <strong>FGF signalling during embryo development regulates cilia length in diverse epithelia.</strong> Nature 458: 651-654, 2009. Note: Erratum: Nature 463: 384 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19242413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19242413</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19242413[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/nature07753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19242413">Neugebauer et al. (2009)</a> proposed that a subset of developmental defects and diseases ascribed to FGF signaling are due in part to loss of cilia function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19242413" 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="Ding, B.-S., Cao, Z., Lis, R., Nolan, D. J., Guo, P., Simons, M., Penfold, M. E., Shido, K., Rabbany, S. Y., Rafii, S. <strong>Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.</strong> Nature 505: 97-102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24256728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24256728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24256728[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/nature12681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24256728">Ding et al. (2014)</a> combined an inducible endothelial cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury to show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The profibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors CXCR7 (<a href="/entry/610376">610376</a>) and CXCR4 (<a href="/entry/162643">162643</a>) in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor ID1 (<a href="/entry/600349">600349</a>), deploying proregenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive Fgfr1 signaling in liver sinusoidal endothelial cells counterbalanced Cxcr7-dependent proregenerative response and augmented Cxcr4 expression. This predominance of Cxcr4 over Cxcr7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin (<a href="/entry/125660">125660</a>)-positive hepatic stellate-like cells and enforcing a profibrotic vascular niche. Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice restored the proregenerative pathway and prevented Fgfr1-mediated maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. <a href="#9" class="mim-tip-reference" title="Ding, B.-S., Cao, Z., Lis, R., Nolan, D. J., Guo, P., Simons, M., Penfold, M. E., Shido, K., Rabbany, S. Y., Rafii, S. <strong>Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.</strong> Nature 505: 97-102, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24256728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24256728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24256728[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/nature12681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24256728">Ding et al. (2014)</a> demonstrated that in response to liver injury, differential recruitment of proregenerative CXCR7-ID1 versus profibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24256728" 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="Lievens, P. M.-J., Kuznetsova, T., Kochlasmazashvili, G., Cesca, F., Gorinski, N., Galil, D. A., Cherkas, V., Ronkina, N., Lafera, J., Gaestel, M., Ponimaskin, E. <strong>ZDHHC3 tyrosine phosphorylation regulates neural cell adhesion molecule palmitoylation.</strong> Molec. Cell. Biol. 36: 2208-2225, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27247265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27247265</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27247265[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/10.1128/MCB.00144-16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27247265">Lievens et al. (2016)</a> reported that mouse Zdhhc3 (<a href="/entry/617150">617150</a>) catalyzed S-palmitoylation of the transmembrane isoforms of Ncam1, Ncam140 and Ncam180. Using site-directed mutagenesis and inhibitor studies, they showed that Fgf2 induced phosphorylation of Zdhhc3 on tyr18 via the tyrosine kinase activity of its receptor, Fgfr1. Src (<a href="/entry/190090">190090</a>) directly phosphorylated Zdhhc3 on tyr295 and tyr297. The 2 kinases had opposite effects on Zdhhc3 activity, with Fgfr1-dependent phosphorylation enhancing Zdhhc3 activity, and Src-dependent phosphorylation inhibiting Zdhhc3 activity. Autopalmitoylation, an intermediate reaction state in palmitate transfer to target proteins, was enhanced by absence of all 5 tyrosines in Zdhhc3 and was abolished with the dominant-negative cys157-to-ser (C157S) mutation at the active site of Zdhhc3. Overexpression of tyrosine-mutant Zdhhc3 in cultured rat hippocampal neurons increased the number of neurites and tended to increase neurite length. <a href="#27" class="mim-tip-reference" title="Lievens, P. M.-J., Kuznetsova, T., Kochlasmazashvili, G., Cesca, F., Gorinski, N., Galil, D. A., Cherkas, V., Ronkina, N., Lafera, J., Gaestel, M., Ponimaskin, E. <strong>ZDHHC3 tyrosine phosphorylation regulates neural cell adhesion molecule palmitoylation.</strong> Molec. Cell. Biol. 36: 2208-2225, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27247265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27247265</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27247265[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/10.1128/MCB.00144-16" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27247265">Lievens et al. (2016)</a> concluded that FGF2-FGFR1 signaling facilitates ZDHHC3 tyrosine phosphorylation and triggers NCAM1 palmitoylation for neurite extension, whereas SRC-mediated ZDHHC3 phosphorylation inhibits NCAM1 palmitoylation and neurite extension. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27247265" 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="#47" class="mim-tip-reference" title="Robin, N. H., Feldman, G. J., Mitchell, H. F., Lorenz, P., Wilroy, R. S., Zackai, E. H., Allanson, J. E., Reich, E. W., Pfeiffer, R. A., Clarke, L. A., Warman, M. L., Mulliken, J. B., Brueton, L. A., Winter, R. M., Price, R. A., Gasser, D. L., Muenke, M. <strong>Linkage of Pfeiffer syndrome to chromosome 8 centromere and evidence for genetic heterogeneity.</strong> Hum. Molec. Genet. 3: 2153-2158, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7881412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7881412</a>] [<a href="https://doi.org/10.1093/hmg/3.12.2153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7881412">Robin et al. (1994)</a> found that in some families with Pfeiffer syndrome (<a href="/entry/101600">101600</a>), the disorder shows linkage to markers on chromosome 8. By performing fluorescence in situ hybridization using yeast artificial chromosomes (YACs) that contained the linked DNA markers, they localized one gene for Pfeiffer syndrome to the pericentromeric region of chromosome 8. Close linkage was excluded in other Pfeiffer syndrome families. Because the FGFR1 gene is located in that region and because mutations in other FGFR genes had been demonstrated in skeletal dysplasias (FGFR2 (<a href="/entry/176943">176943</a>) in Crouzon and Jackson-Weiss syndromes, and FGFR3 (<a href="/entry/134934">134934</a>) in achondroplasia), it became a prime candidate for the site of the mutation in chromosome 8-linked Pfeiffer syndrome. <a href="#31" class="mim-tip-reference" title="Muenke, M., Schell, U., Hehr, A., Robin, N. H., Losken, H. W., Schinzel, A., Pulleyn, L. J., Rutland, P., Reardon, W., Malcolm, S., Winter, R. M. <strong>A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome.</strong> Nature Genet. 8: 269-274, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874169</a>] [<a href="https://doi.org/10.1038/ng1194-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874169">Muenke et al. (1994)</a> found a C-to-G transversion in exon 5 of the FGFR1 gene, predicting a proline-to-arginine substitution in the putative extracellular domain, in all affected members of 5 unrelated Pfeiffer syndrome families but not in any unaffected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874169+7881412" 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="#35" class="mim-tip-reference" title="Passos-Bueno, M. R., Wilcox, W. R., Jabs, E. W., Sertie, A. L., Alonso, L. G., Kitoh, H. <strong>Clinical spectrum of fibroblast growth factor receptor mutations.</strong> Hum. Mutat. 14: 115-125, 1999. Note: Erratum: Hum. Mutat. 17: 431 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10425034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10425034</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)14:2<115::AID-HUMU3>3.0.CO;2-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10425034">Passos-Bueno et al. (1999)</a> provided an up-to-date listing of the mutations in FGFR1, FGFR2, and FGFR3 that are associated with distinct clinical entities, including achondroplasia (<a href="/entry/100800">100800</a>), hypochondroplasia (<a href="/entry/146000">146000</a>), thanatophoric dysplasia (see <a href="/entry/187600">187600</a> and <a href="/entry/187601">187601</a>), Antley-Bixler syndrome (<a href="/entry/207410">207410</a>), Apert syndrome (<a href="/entry/101200">101200</a>), Beare-Stevenson syndrome (<a href="/entry/123790">123790</a>), Crouzon syndrome (<a href="/entry/123500">123500</a>), Jackson-Weiss syndrome (<a href="/entry/123150">123150</a>), Pfeiffer syndrome (<a href="/entry/101600">101600</a>), and Saethre-Chotzen syndrome (<a href="/entry/101400">101400</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10425034" 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="#48" class="mim-tip-reference" title="Roscioli, T., Flanagan, S., Kumar, P., Masel, J., Gattas, M., Hyland, V. J., Glass, I. A. <strong>Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature.</strong> Am. J. Med. Genet. 93: 22-28, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861678</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<22::aid-ajmg5>3.0.co;2-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861678">Roscioli et al. (2000)</a> reported the case of a patient with the skeletal findings of Jackson-Weiss syndrome who manifested only mild craniofacial anomalies. They demonstrated heterozygosity for the P252R missense mutation (<a href="#0001">136350.0001</a>). The observations represented a further example of the phenomenon of an activated FGFR molecule resulting in overlapping manifestations in FGFR syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Kress, W., Petersen, B., Collmann, H., Grimm, T. <strong>An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly.</strong> Cytogenet. Cell Genet. 91: 138-140, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173846</a>] [<a href="https://doi.org/10.1159/000056834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173846">Kress et al. (2000)</a> screened 10 patients with nonsyndromic trigonocephaly (TRIGNO1; <a href="/entry/190440">190440</a>) for mutations in exon 5 of FGFR1 gene, exons 8 and 10 of the FGFR2 gene, exon 7 of the FGFR3 gene, and exon 1 of the TWIST1 (<a href="/entry/601622">601622</a>) gene (all regions known to be involved in autosomal dominant craniosynostosis syndromes). They identified 1 patient with a mutation in the FGFR1 gene (I300T; <a href="#0011">136350.0011</a>). <a href="#18" class="mim-tip-reference" title="Hurley, M. E., White, M. J., Green, A. J., Kelleher, J. <strong>Antley-Bixler syndrome with radioulnar synostosis.</strong> Pediat. Radiol. 34: 148-151, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14513299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14513299</a>] [<a href="https://doi.org/10.1007/s00247-003-1066-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14513299">Hurley et al. (2004)</a> reported a male infant with an Antley-Bixler syndrome-like skeletal phenotype (see <a href="/entry/207410">207410</a>) and abnormal genitalia (see POR deficiency, <a href="/entry/201750">201750</a>) in whom they identified the I300T mutation; the authors stated that the significance of the FGFR1 mutation was unclear. In the patient reported by <a href="#18" class="mim-tip-reference" title="Hurley, M. E., White, M. J., Green, A. J., Kelleher, J. <strong>Antley-Bixler syndrome with radioulnar synostosis.</strong> Pediat. Radiol. 34: 148-151, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14513299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14513299</a>] [<a href="https://doi.org/10.1007/s00247-003-1066-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14513299">Hurley et al. (2004)</a>, <a href="#17" class="mim-tip-reference" title="Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L. <strong>Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.</strong> Am. J. Hum. Genet. 76: 729-749, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15793702[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793702">Huang et al. (2005)</a> subsequently identified compound heterozygosity for a frameshift and a substitution mutation in the gene for cytochrome P450 oxidoreductase (POR; <a href="/entry/124015#0015">124015.0015</a> and <a href="/entry/124015#0016">124015.0016</a>, respectively) as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11173846+14513299+15793702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an extensive review of the genetics of craniofacial development and malformation, <a href="#69" class="mim-tip-reference" title="Wilkie, A. O. M., Morriss-Kay, G. M. <strong>Genetics of craniofacial development and malformation.</strong> Nature Rev. Genet. 2: 458-468, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11389462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11389462</a>] [<a href="https://doi.org/10.1038/35076601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11389462">Wilkie and Morriss-Kay (2001)</a> provided a useful diagram of the molecular pathways in cranial suture development with a listing of all craniofacial disorders caused by mutations in the corresponding genes. Four proteins were indicated as having strong evidence for existing in the pathway, with successive downstream targets as follows: TWIST1--FGFR2--FGFR1--CBFA1 (<a href="/entry/600211">600211</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11389462" 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="#70" class="mim-tip-reference" title="Wilkie, A. O. M., Patey, S. J., Kan, S., van den Ouweland, A. M. W., Hamel, B. C. J. <strong>FGFs, their receptors, and human limb malformations: clinical and molecular correlations.</strong> Am. J. Med. Genet. 112: 266-278, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12357470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12357470</a>] [<a href="https://doi.org/10.1002/ajmg.10775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12357470">Wilkie et al. (2002)</a> reviewed the association of mutations in FGFR1 and FGFR2 with disorders of limb patterning. They also stated that mutations of FGFR3 and FGF23 (<a href="/entry/605380">605380</a>) affect growth of the limb bones, e.g., in achondroplasia and autosomal dominant hypophosphatemic rickets (<a href="/entry/193100">193100</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12357470" 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 diverse group of skeletal disorders are caused by activating mutations in the genes encoding fibroblast growth factor receptors FGFR1, FGFR2, and FGFR3. In general, mutations in FGFR1 and FGFR2 cause most of the syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutations. Osteoglophonic dysplasia (<a href="/entry/166250">166250</a>) is a 'crossover' disorder that has skeletal phenotypes usually associated with FGFR1, FGFR2, and FGFR3 mutations. <a href="#68" class="mim-tip-reference" title="White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., Evans, W. E., Ichikawa, S., Fields, J., Yu, X., Shaw, N. J., McLellan, N. J., McKeown, C., FitzPatrick, D., Yu, K., Ornitz, D. M., Econs, M. J. <strong>Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.</strong> Am. J. Hum. Genet. 76: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/427956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625620">White et al. (2005)</a> demonstrated that osteoglophonic dysplasia is caused by missense mutations in highly conserved residues comprising the ligand-binding and transmembrane membranes of FGFR1, thus defining novel roles for this receptor as a negative regulator of long bone growth. <a href="#68" class="mim-tip-reference" title="White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., Evans, W. E., Ichikawa, S., Fields, J., Yu, X., Shaw, N. J., McLellan, N. J., McKeown, C., FitzPatrick, D., Yu, K., Ornitz, D. M., Econs, M. J. <strong>Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.</strong> Am. J. Hum. Genet. 76: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/427956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625620">White et al. (2005)</a> demonstrated that the Y372C mutation (<a href="#0008">136350.0008</a>) is an activating mutation, i.e., a gain-of-function mutation. In contrast, inactivating mutations in FGFR1 are responsible for autosomal dominant Kallmann syndrome; see, for example, <a href="#0002">136350.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15625620" 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>Role in Cancer</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Bruno, I. G., Jin, W., Cote, G. J. <strong>Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements.</strong> Hum. Molec. Genet. 13: 2409-2420, 2004. Note: Erratum: Hum. Molec. Genet. 13: 2725 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15333583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15333583</a>] [<a href="https://doi.org/10.1093/hmg/ddh272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15333583">Bruno et al. (2004)</a> noted that FGFR1-beta, the splice variant resulting from alternative splicing of exon 3 (also termed alpha-exon) of FGFR1, has been associated with cancer in humans. They targeted the intronic silencing sequence (ISS) elements flanking the alpha-exon with antisense morpholino oligonucleotides, resulting in increased alpha-exon inclusion of between 10% and 70% in vivo. The effect was dose-dependent, sequence-specific, and reproducible in several human cell lines, but did not necessarily correlate with blocking of protein association in vitro. Simultaneous targeting of the ISS elements had no additive effect, suggesting that splicing regulation occurred through a shared mechanism. The correction of FGFR1 gene splicing to more than 90% alpha-exon inclusion in glioblastoma cells had no discernible effect on cell growth in culture, but was associated with an increase in unstimulated CASP3 (<a href="/entry/600636">600636</a>) and CASP7 (<a href="/entry/601761">601761</a>) activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15333583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By sequencing the exons encoding the kinase domains of 20 receptor tyrosine kinases in 19 glioblastomas, <a href="#44" class="mim-tip-reference" title="Rand, V., Huang, J., Stockwell, T., Ferriera, S., Buzko, O., Levy, S., Busam, D., Li, K., Edwards, J. B., Eberhart, C., Murphy, K. M., Tsiamouri, A., Beeson, K., Simpson, A. J. G., Venter, J. C., Riggins, G. J., Strausberg, R. L. <strong>Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas.</strong> Proc. Nat. Acad. Sci. 102: 14344-14349, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16186508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16186508</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16186508[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0507200102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16186508">Rand et al. (2005)</a> identified 2 somatic mutations in the FGFR1 gene in separate tumors, as well as a somatic mutation in the PDGFRA (<a href="/entry/173490">173490</a>) gene in another tumor. Structural analysis suggested that the FGFR1 mutations, asn546 to lys (N546K) and arg576 to trp (R576W), could lead to upregulation of constitutive kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16186508" 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="#20" class="mim-tip-reference" title="Jones, D. T. W., Hutter, B., Jager, N., Korshunov, A., Kool, M., Warnatz, H.-J., Zichner, T., Lambert, S. R., Ryzhova, M., Quang, D. A. K., Fontebasso, A. M., Stutz, A. M., and 63 others. <strong>Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.</strong> Nature Genet. 45: 927-932, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23817572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23817572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23817572[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.2682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23817572">Jones et al. (2013)</a> described whole-genome sequencing of 96 pilocytic astrocytomas (see <a href="/entry/137800">137800</a>), with matched RNA sequencing for 73 samples, conducted by the International Cancer Genome Consortium PedBrain Tumor Project. <a href="#20" class="mim-tip-reference" title="Jones, D. T. W., Hutter, B., Jager, N., Korshunov, A., Kool, M., Warnatz, H.-J., Zichner, T., Lambert, S. R., Ryzhova, M., Quang, D. A. K., Fontebasso, A. M., Stutz, A. M., and 63 others. <strong>Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.</strong> Nature Genet. 45: 927-932, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23817572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23817572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23817572[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.2682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23817572">Jones et al. (2013)</a> identified recurrent activating mutations in FGFR1 and PTPN11 (<a href="/entry/176876">176876</a>) and novel NTRK2 (<a href="/entry/600456">600456</a>) fusion genes in noncerebellar tumors. Novel BRAF (<a href="/entry/164757">164757</a>)-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, <a href="#20" class="mim-tip-reference" title="Jones, D. T. W., Hutter, B., Jager, N., Korshunov, A., Kool, M., Warnatz, H.-J., Zichner, T., Lambert, S. R., Ryzhova, M., Quang, D. A. K., Fontebasso, A. M., Stutz, A. M., and 63 others. <strong>Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.</strong> Nature Genet. 45: 927-932, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23817572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23817572</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23817572[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.2682" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23817572">Jones et al. (2013)</a> identified the same FGFR1 mutations in a subset of H3F3A (<a href="/entry/601128">601128</a>)-mutated pediatric glioblastoma with additional alterations in the NF1 gene (<a href="/entry/613113">613113</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23817572" 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>Hypogonadotropic Hypogonadism 2 with or without Anosmia</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> took advantage of 2 overlapping interstitial deletions at 8p12-p11 in individuals with different contiguous gene syndromes that both included Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>). Mutation analysis of the FGFR1 gene identified loss-of-function mutations in FGFR1 as the basis of autosomal dominant Kallmann syndrome; a gain-of-function mutation in FGFR1 (see <a href="#0001">136350.0001</a>) causes a form of craniosynostosis. <a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> suggested that the X-chromosome-encoded KAL1 gene product, the extracellular matrix protein anosmin-1 (<a href="/entry/300836">300836</a>), is involved in fibroblast growth factor (FGF) signaling and proposed that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> examined the FGFR1 gene in 7 unrelated patients with normosmic idiopathic hypogonadotropic hypogonadism and identified heterozygous mutations in 3 individuals, 2 from mixed pedigrees in which some family members were anosmic (<a href="#0013">136350.0013</a> and <a href="#0014">136350.0014</a>, respectively) and 1 with associated midline defects (<a href="#0015">136350.0015</a>). One parent from each of the mixed pedigrees had isolated congenital anosmia (see <a href="/entry/107200">107200</a>). Structural and biochemical analysis of the mutations revealed that all resulted in receptor loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sisters with normosmic hypogonadotropic hypogonadism in whom <a href="#53" class="mim-tip-reference" title="Seminara, S. B., Beranova, M., Oliveira, L. M. B., Martin, K. A., Crowley, W. F., Jr., Hall, J. E. <strong>Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations.</strong> J. Clin. Endocr. Metab. 85: 556-562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690855</a>] [<a href="https://doi.org/10.1210/jcem.85.2.6357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690855">Seminara et al. (2000)</a> had previously identified compound heterozygosity for missense mutations in the GNRHR gene (Q106R, <a href="/entry/138850#0001">138850.0001</a> and R262Q, <a href="/entry/138850#0002">138850.0002</a>), <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> identified heterozygosity for an additional missense mutation in the FGFR1 gene (R470L; <a href="#0016">136350.0016</a>). The mutation was also found in the father, who had a history of delayed puberty and was heterozygous for the R262Q mutation in GNRHR; and in the unaffected daughter of the younger sister, who had undergone normal puberty and had no mutations in GNRHR. <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> also studied another family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone. The authors identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; <a href="#0017">136350.0017</a>) in the proband, his father, and his sister; and they identified heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (<a href="/entry/608137#0002">608137.0002</a>), in the proband, his mother, and his brother. <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with isolated hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17235395+10690855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 19-year-old man and an unrelated 10-year-old boy with normosmic hypogonadotropic hypogonadism, both of whom were known to carry mutations in the FGF8 gene (<a href="/entry/600483#0003">600483.0003</a> and <a href="/entry/600483#0004">600483.0004</a>, respectively), <a href="#11" class="mim-tip-reference" title="Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., Quinton, R., Na, S., and 9 others. <strong>Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.</strong> J. Clin. Invest. 118: 2822-2831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596921[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/JCI34538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596921">Falardeau et al. (2008)</a> identified additional mutations in the FGFR1 gene (see <a href="#0023">136350.0023</a>-<a href="#0025">136350.0025</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596921" 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="#43" class="mim-tip-reference" title="Raivio, T., Sidis, Y., Plummer, L., Chen, H., Ma, J., Mukherjee, A., Jacobson-Dickman, E., Quinton, R., Van Vliet, G., Lavoie, H., Hughes, V. A., Dwyer, A., Hayes, F. J., Xu, S., Sparks, S., Kaiser, U. B., Mohammadi, M., Pitteloud, N. <strong>Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 94: 4380-4390, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19820032/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19820032</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19820032[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/10.1210/jc.2009-0179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19820032">Raivio et al. (2009)</a> sequenced the FGFR1 gene in 134 patients with normosmic IHH and identified heterozygous loss-of-function mutations in 9 (7%). Screening of 5 more HH-associated genes in the 9 mutation-positive patients revealed additional mutations in 5 patients, including mutations in the GNRHR (<a href="/entry/138850">138850</a>), PROKR2 (<a href="/entry/607123">607123</a>), and FGF8 (<a href="/entry/600483">600483</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19820032" 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="#58" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> studied a large French Canadian pedigree with several consanguineous loops, in which the proband and 3 additional family members had anosmic HH associated with a missense mutation in the HS6ST1 gene (<a href="/entry/604846#0002">604846.0002</a>). Because of the phenotypic variability and reduced penetrance displayed in the family, the authors screened 8 additional known HH-associated genes and detected a missense mutation in FGFR1 that was also present in the 4 affected members as well as 1 unaffected individual (<a href="#0025">136350.0025</a>). In another family in which a man with anosmic HH and his unaffected brother both carried a missense mutation in HS6ST1 (<a href="/entry/604846#0001">604846.0001</a>), screening revealed an additional missense mutation in the NELF gene (<a href="/entry/608137#0001">608137.0001</a>) in the proband. <a href="#58" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate in which <a href="#58" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> had identified mutations in both the FGFR1 (<a href="#0025">136350.0025</a>) and HS6ST1 (<a href="/entry/604846#0002">604846.0002</a>) genes, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> analyzed 7 genes involved in the FGF8 (<a href="/entry/600483">600483</a>)-FGFR1 (<a href="/entry/136350">136350</a>) network and identified additional mutations in 2 more genes, FGF17 (<a href="/entry/603725#0001">603725.0001</a>) and FLRT3 (<a href="/entry/604808#0001">604808.0001</a> and <a href="/entry/604808#0002">604808.0002</a>). In addition, in 4 more unrelated probands with anosmic HH, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified heterozygosity for 4 different missense mutations in FGFR1 (<a href="#0026">136350.0026</a>-<a href="#0029">136350.0029</a>) as well as heterozygosity for 4 other genes in the FGF network: IL17RD (<a href="/entry/606807#0002">606807.0002</a>), SPRY4 (<a href="/entry/607984#0002">607984.0002</a>), DUSP6 (<a href="/entry/602748#0002">602748.0002</a>), and FLRT3 (<a href="/entry/604808#0003">604808.0003</a>), respectively. <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21700882+23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with anosmic hypogonadotropic hypogonadism (HH16; <a href="/entry/614897">614897</a>) who was heterozygous for a missense mutation in the SEMA3A gene (<a href="/entry/603961">603961</a>), <a href="#16" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[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/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> also identified heterozygosity for a missense mutation in FGFR1. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927827" 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="#64" class="mim-tip-reference" title="Villanueva, C., Jacobson-Dickman, E., Xu, C., Manouvrier, S., Dwyer, A. A., Sykiotis, G. P., Beenken, A., Liu, Y., Tommiska, J., Hu, Y., Tiosano, D., Gerard, M., and 15 others. <strong>Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.</strong> Genet. Med. 17: 651-659, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394172[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/gim.2014.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394172">Villanueva et al. (2015)</a> reported 7 probands with mutations in the FGFR1 gene (see, e.g., <a href="#0026">136350.0026</a>) who exhibited split hand/foot malformations (SHFM) as well as HH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25394172" 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>Hartsfield Syndrome</em></strong></p><p>
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In 1 female and 5 male patients with holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; <a href="/entry/615465">615465</a>), <a href="#55" class="mim-tip-reference" title="Simonis, N., Migeotte, I., Lambert, N., Perazzolo, C., de Silva, D. C., Dimitrov, B., Heinrichs, C., Janssens, S., Kerr, B., Mortier, G., Van Vliet, G., Lepage, P., Casimir, G., Abramowicz, M., Smits, G., Vilain, C. <strong>FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.</strong> J. Med. Genet. 50: 585-592, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23812909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23812909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23812909[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/10.1136/jmedgenet-2013-101603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23812909">Simonis et al. (2013)</a> identified missense mutations in the FGFR1 gene (see, e.g., <a href="#0030">136350.0030</a>-<a href="#0032">136350.0032</a>). Most patients were heterozygous, but 2 patients carried homozygous mutations (see, e.g., <a href="#0031">136350.0031</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23812909" 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>Encephalocraniocutaneous Lipomatosis</em></strong></p><p>
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In 5 unrelated patients with encephalocraniocutaneous lipomatosis (ECCL; <a href="/entry/613001">613001</a>), <a href="#2" class="mim-tip-reference" title="Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others. <strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong> Am. J. Hum. Genet. 98: 579-587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942290">Bennett et al. (2016)</a> identified mosaicism for 2 missense variants in the FGFR1 gene: 3 patients carried an N546K substitution (<a href="#0033">136350.0033</a>), and 2 carried a K656E substitution (<a href="#0034">136350.0034</a>). The alternate allele fraction ranged from 23 to 55% in fibroblasts from affected tissues, but the mutations were not detected in saliva or blood samples. Neither variant was found in the Exome Variant Server, ExAC, or dbSNP databases. <a href="#2" class="mim-tip-reference" title="Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others. <strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong> Am. J. Hum. Genet. 98: 579-587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942290">Bennett et al. (2016)</a> noted that these 2 residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with central nervous system tumors. Functional studies of ECCL fibroblast cell lines showed increased levels of phosphorylated FGFRs and phosphorylated FRS2 (<a href="/entry/607743">607743</a>), as well as constitutive activation of RAS (see <a href="/entry/190020">190020</a>)/MAPK (see <a href="/entry/176872">176872</a>) signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26942290" 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>Nonsyndromic Cleft Lip/Palate</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C. <strong>Impaired FGF signaling contributes to cleft lip and palate.</strong> Proc. Nat. Acad. Sci. 104: 4512-4517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0607956104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360555">Riley et al. (2007)</a> analyzed 12 genes involved in the fibroblast growth factor signaling pathway in nonsyndromic cleft lip or palate families and identified 7 likely disease-causing mutations in which structural analysis predicted functional impairment in the FGFR1, FGFR2, FGFR3, and FGF8 (<a href="/entry/600483">600483</a>) genes. <a href="#45" class="mim-tip-reference" title="Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C. <strong>Impaired FGF signaling contributes to cleft lip and palate.</strong> Proc. Nat. Acad. Sci. 104: 4512-4517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0607956104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360555">Riley et al. (2007)</a> suggested that the FGF signaling pathway may contribute to as much as 3 to 5% of nonsyndromic cleft lip or palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360555" 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="#72" class="mim-tip-reference" title="Xiao, S., Nalabolu, S. R., Aster, J. C., Ma, J., Abruzzo, L., Jaffe, E. S., Stone, R., Weissman, S. M., Hudson, T. J., Fletcher, J. A. <strong>FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.</strong> Nature Genet. 18: 84-87, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425908</a>] [<a href="https://doi.org/10.1038/ng0198-84" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425908">Xiao et al. (1998)</a> noted that a specific chromosome translocation, t(8;13)(p11;q11-12), had been found in both lymphoma and myeloid leukemia cells from patients with stem cell leukemia/lymphoma (SCLL; <a href="/entry/613523">613523</a>), supporting bi-lineage differentiation from a transformed stem cell. <a href="#72" class="mim-tip-reference" title="Xiao, S., Nalabolu, S. R., Aster, J. C., Ma, J., Abruzzo, L., Jaffe, E. S., Stone, R., Weissman, S. M., Hudson, T. J., Fletcher, J. A. <strong>FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.</strong> Nature Genet. 18: 84-87, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425908</a>] [<a href="https://doi.org/10.1038/ng0198-84" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425908">Xiao et al. (1998)</a> found that the 8p11 translocation breakpoints in each of 4 patients interrupted intron 8 of the FGFR1 gene. These translocations were associated with aberrant transcripts in which 4 predicted zinc finger domains, contributed by a novel and widely expressed chromosome 13 gene, ZNF198 (<a href="/entry/602221">602221</a>), were fused to the FGFR1 tyrosine-kinase domain. Transient expression studies showed that the ZNF198-FGFR1 fusion transcript directs the synthesis of an approximately 87-kD polypeptide, localizing predominantly to the cytoplasm. The studies demonstrated an FGFR1 oncogenic role and suggested a tumorigenic mechanism in which ZNF198-FGFR1 activation results from ZNF198 zinc finger-mediated homodimerization. Some of the FGFR-associated hereditary skeletal disorders result from mutations that effect constitutive FGFR activation. In vitro evidence for mutational FGFR activation in these syndromes includes ligand-independent receptor tyrosine phosphorylation and increased cell proliferation. Nevertheless, individuals with FGFR-associated skeletal syndromes are not known to be at increased risk for SCLL or other types of cancer. The level of FGFR1 tyrosine-kinase activation in hereditary skeletal syndromes may be insufficient to effect neoplastic transformation of hematopoietic stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9425908" 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="#28" class="mim-tip-reference" title="Lorenzi, M. V., Horii, Y., Yamanaka, R., Sakaguchi, K., Miki, T. <strong>FRAG1, a gene that potently activates fibroblast growth factor receptor by C-terminal fusion through chromosomal rearrangement.</strong> Proc. Nat. Acad. Sci. 93: 8956-8961, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8799135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8799135</a>] [<a href="https://doi.org/10.1073/pnas.93.17.8956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8799135">Lorenzi et al. (1996)</a> described FGFR2 activation by a C-terminal alteration through a chromosomal rearrangement in a rat osteosarcoma. Alterations of FGFR3 (<a href="/entry/134934">134934</a>), whose germline activating mutations are responsible for major forms of dwarfism including achondroplasia, were found by <a href="#6" class="mim-tip-reference" title="Chesi, M., Nardini, E., Brents, L. A., Schrock, E., Ried, T., Kuehl, W. M., Bergsagel, P. L. <strong>Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.</strong> Nature Genet. 16: 260-264, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9207791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9207791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9207791[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/ng0797-260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9207791">Chesi et al. (1997)</a> in t(4;14) translocations associated with multiple myeloma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8799135+9207791" 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="#41" class="mim-tip-reference" title="Popovici, C., Adelaide, J., Ollendorff, V., Chaffanet, M., Guasch, G., Jacrot, M., Leroux, D., Birnbaum, D., Pebusque, M.-J. <strong>Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13)(p12;q12).</strong> Proc. Nat. Acad. Sci. 95: 5712-5717, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9576949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9576949</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9576949[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.10.5712" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9576949">Popovici et al. (1998)</a> described the molecular characterization of the t(8;13) translocation that involves the FGFR1 and ZNF198 genes. The 2 reciprocal fusion transcripts, ZNF198/FGFR1 and FGFR1/ZNF198, were expressed in malignant cells. The ZNF198/FGFR1 fusion protein contained the ZNF198 putative zinc finger motifs and the catalytic domain of FGFR1, and the authors showed that the protein has a constitutive tyrosine kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9576949" 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="Kulkarni, S., Reiter, A., Smedley, D., Goldman, J. M., Cross, N. C. P. <strong>The genomic structure of ZNF198 and location of breakpoints in the t(8;13) myeloproliferative syndrome.</strong> Genomics 55: 118-121, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9889006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9889006</a>] [<a href="https://doi.org/10.1006/geno.1998.5634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9889006">Kulkarni et al. (1999)</a> determined that the common t(8;13)(p11;q12) translocation results in a consistent fusion between ZNF198 exon 17 and FGFR1 exon 9. However, amplification of genomic DNA from 6 patients with t(8;13) revealed patient-specific products, suggesting clustering of several breakpoints. An additional patient showed a breakpoint within ZNF198 exon 18. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9889006" 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="#42" class="mim-tip-reference" title="Popovici, C., Zhang, B., Gregoire, M.-J., Jonveaux, P., Lafage-Pochitaloff, M., Birnbaum, D., Pebusque, M.-J. <strong>The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1.</strong> Blood 93: 1381-1389, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949182</a>]" pmid="9949182">Popovici et al. (1999)</a> identified the FOP gene (<a href="/entry/605392">605392</a>) as the fusion partner of FGFR1 in the 8p11 myeloproliferative disorder involving the t(6;8)(q27;p11) translocation. Using RT-PCR, they detected both FGFR1-FOP and FOP-FGFR1 fusion transcripts, with the break occurring in intron 8 of FGFR1 or intron 6 of FOP, in 2 patients with the 8p11 myeloproliferative disorder but not in normal subjects or those with other tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949182" 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="Guasch, G., Mack, G. J., Popovici, C., Dastugue, N., Birnbaum, D., Rattner, J. B., Pebusque, M.-J. <strong>FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33).</strong> Blood 95: 1788-1796, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10688839/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10688839</a>]" pmid="10688839">Guasch et al. (2000)</a> identified the CEP1 gene (<a href="/entry/605496">605496</a>) as the fusion partner of the FGFR1 gene in the 8p11 myeloproliferative disorder involving the t(8;9)(p11;q33) translocation. By RT-PCR and genomic sequence analysis, they detected reciprocal fusion transcripts with the breakpoint localized in exon 8 of FGFR1 and in an intron of CEP1. Immunoblot analysis showed that the CEP1-FGFR1 fusion protein is expressed as a constitutively tyrosine-phosphorylated, 150-kD tyrosine kinase. Immunofluorescence microscopy demonstrated that the CEP1-FGFR1 fusion protein, like other FGFR1 fusion proteins, is detected mainly in the cytoplasm, contrasting with the centrosome and plasma membrane localizations of the respective wildtype proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10688839" 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="#57" class="mim-tip-reference" title="Sohal, J., Chase, A., Mould, S., Corcoran, M., Oscier, D., Iqbal, S., Parker, S., Welborn, J., Harris, R. I., Martinelli, G., Montefusco, V., Sinclair, P., Wilkins, B. S., van den Berg, H., Vanstraelen, D., Goldman, J. M., Cross, N. C. P. <strong>Identification of four new translocations involving FGFR1 in myeloid disorders.</strong> Genes Chromosomes Cancer 32: 155-163, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11550283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11550283</a>] [<a href="https://doi.org/10.1002/gcc.1177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11550283">Sohal et al. (2001)</a> identified 4 translocations that most likely involve FGFR1 in myeloid disorders. <a href="#8" class="mim-tip-reference" title="Demiroglu, A., Steer, E. J., Heath, C., Taylor, K., Bentley, M., Allen, S. L., Koduru, P., Brody, J. P., Hawson, G., Rodwell, R., Doody, M.-L., Carnicero, F., Reiter, A., Goldman, J. M., Melo, J. V., Cross, N. C. P. <strong>The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins.</strong> Blood 98: 3778-3783, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739186</a>] [<a href="https://doi.org/10.1182/blood.v98.13.3778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739186">Demiroglu et al. (2001)</a> described 2 patients with a clinical and hematologic diagnosis of chronic myeloid leukemia (CML; <a href="/entry/608232">608232</a>) in chronic phase who had an acquired t(8;22)(p11;q11). They confirmed that both patients were negative for a BCR (<a href="/entry/151410">151410</a>)-ABL fusion gene and that both had an in-frame mRNA fusion between BCR exon 4 and FGFR1 exon 9. Thus, a BCR-FGFR1 fusion may occur in patients with apparently typical CML. The possibility of successful treatment with specific FGFR1 inhibitors was suggested. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11550283+11739186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Grand, E. K., Grand, F. H., Chase, A. J., Ross, F. M., Corcoran, M. M., Oscier, D. G., Cross, N. C. P. <strong>Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome.</strong> Genes Chromosomes Cancer 40: 78-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034873</a>] [<a href="https://doi.org/10.1002/gcc.20023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034873">Grand et al. (2004)</a> identified a (12;8)(p11;p11p22) insertion in a 75-year-old male who presented with a T-cell lymphoblastic lymphoma that progressed rapidly to AML. An obvious chronic myeloproliferative disease was not apparent during the course of his disease, but the clinical picture fit the overall pattern seen in patients with 8p11 myeloproliferative syndrome. In addition to the insertion, bone marrow cytogenetics following development of AML revealed loss of 1 copy of chromosome 7 in all cells analyzed. The patient also showed mild eosinophilia with infiltration of the affected lymph node and bone marrow by atypical eosinophils. <a href="#14" class="mim-tip-reference" title="Grand, E. K., Grand, F. H., Chase, A. J., Ross, F. M., Corcoran, M. M., Oscier, D. G., Cross, N. C. P. <strong>Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome.</strong> Genes Chromosomes Cancer 40: 78-83, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15034873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15034873</a>] [<a href="https://doi.org/10.1002/gcc.20023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15034873">Grand et al. (2004)</a> determined that the ins(12;8)(p11;p11p22) resulted in an in-frame fusion of exon 4 of the FGFR1OP2 gene (<a href="/entry/608858">608858</a>) to exon 9 of the FGFR1 gene. The chimeric protein contains 526 amino acids and has a calculated molecular mass of 60 kD. FGFR1OP2-FGFR1 has the first 2 coiled-coil domains of FGFR1OP2 fused to the entire tyrosine kinase domain and part of the juxtamembrane region of FGFR1. Reciprocal FGFR1-FGFR1OP2 transcripts were not detected. Since the direction of FGFR1OP2 transcription is in the opposite orientation to the direction of FGFR1 transcription, an inversion must have taken place in the formation of the chimeric gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15034873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male patient with hypogonadotropic hypogonadism and cleft lip and palate without 'frank' anosmia (see <a href="/entry/147950">147950</a>), <a href="#22" class="mim-tip-reference" title="Kim, H. G., Herrick, S. R., Lemyre, E., Kishikawa, S., Salisz, J. A., Seminara, S., MacDonald, M. E., Bruns, G. A. P., Morton, C. C., Quade, B. J., Gusella, J. F. <strong>Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. (Letter)</strong> J. Med. Genet. 42: 666-672, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061567</a>] [<a href="https://doi.org/10.1136/jmg.2004.026989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061567">Kim et al. (2005)</a> identified a balanced reciprocal translocation, t(7;8)(p12.3;p11.2). Positional cloning of the breakpoints revealed that the translocation disrupts the FGFR1 gene between exons 2 and 3 and predicts a novel fusion gene product. <a href="#22" class="mim-tip-reference" title="Kim, H. G., Herrick, S. R., Lemyre, E., Kishikawa, S., Salisz, J. A., Seminara, S., MacDonald, M. E., Bruns, G. A. P., Morton, C. C., Quade, B. J., Gusella, J. F. <strong>Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. (Letter)</strong> J. Med. Genet. 42: 666-672, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061567</a>] [<a href="https://doi.org/10.1136/jmg.2004.026989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061567">Kim et al. (2005)</a> stated that this was the first case in which a constitutional FGFR1 translocation was associated with a developmental disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061567" 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="#56" class="mim-tip-reference" title="Singh, D., Chan, J. M., Zoppoli, P., Niola, F., Sullivan, R., Castano, A., Liu, E. M., Reichel, J., Porrati, P., Pellegatta, S., Qiu, K., Gao, Z., and 12 others. <strong>Transforming fusions of FGFR and TACC genes in human glioblastoma.</strong> Science 337: 1231-1235, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22837387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22837387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22837387[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1220834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22837387">Singh et al. (2012)</a> reported that a small subset of glioblastoma multiforme tumors (GBMs; <a href="/entry/137800">137800</a>) (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes FGFR1 or FGFR3 to the transforming acidic coiled-coil (TACC) coding domains of TACC1 (<a href="/entry/605301">605301</a>) or TACC3 (<a href="/entry/605303">605303</a>), respectively. The FGFR-TACC fusion protein displayed oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrected the aneuploidy, and oral administration of an FGFR inhibitor prolonged survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. <a href="#56" class="mim-tip-reference" title="Singh, D., Chan, J. M., Zoppoli, P., Niola, F., Sullivan, R., Castano, A., Liu, E. M., Reichel, J., Porrati, P., Pellegatta, S., Qiu, K., Gao, Z., and 12 others. <strong>Transforming fusions of FGFR and TACC genes in human glioblastoma.</strong> Science 337: 1231-1235, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22837387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22837387</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22837387[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1220834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22837387">Singh et al. (2012)</a> concluded that FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22837387" 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="#74" class="mim-tip-reference" title="Zhou, Y.-X., Xu, X., Chen, L., Li, C., Brodie, S. G., Deng, C.-X. <strong>A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures.</strong> Hum. Molec. Genet. 9: 2001-2008, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942429/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942429</a>] [<a href="https://doi.org/10.1093/hmg/9.13.2001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10942429">Zhou et al. (2000)</a> showed that mice carrying a pro250-to-arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation pro252 to arg (<a href="#0001">136350.0001</a>) in humans, exhibit anterio-posteriorly shortened, laterally widened, and vertically heightened neurocrania. Cranial sutures of early postnatal mutant mice exhibited multiple premature fusions, accelerated osteoblast proliferation, and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Markedly increased expression of Cbfa1 (RUNX2; <a href="/entry/600211">600211</a>) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro by demonstrating that transfection with wildtype or mutant Fgfr1 induced Cbfa1 expression. The induced expression was also observed using the Fgf ligands Fgf2 and Fgf8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942429" 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>To study the role of Fgfr1 in mammary gland tumorigenesis, <a href="#66" class="mim-tip-reference" title="Welm, B. E., Freeman, K. W., Chen, M., Contreras, A., Spencer, D. M., Rosen, J. M. <strong>Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland.</strong> J. Cell Biol. 157: 703-714, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12011115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12011115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12011115[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/10.1083/jcb.200107119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12011115">Welm et al. (2002)</a> developed a transgenic mouse carrying an Fgfr1 gene that could be pharmacologically induced to dimerize with the drug AP20187 independent of Fgf levels. Treatment of transgenic mice with AP20187 resulted in tyrosine phosphorylation, increased cell proliferation, activation of Mapk and Akt (<a href="/entry/164730">164730</a>), and lateral budding of the mammary glands. Change in ductal morphology was seen in ovariectomized animals, suggesting that ovarian hormones were not required. Chronic activation of the transgene resulted in progressively invasive lesions characterized by multicell-layered lateral buds, decreased myoepithelium, increased vascular branching, and loss of cell polarity. <a href="#66" class="mim-tip-reference" title="Welm, B. E., Freeman, K. W., Chen, M., Contreras, A., Spencer, D. M., Rosen, J. M. <strong>Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland.</strong> J. Cell Biol. 157: 703-714, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12011115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12011115</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12011115[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/10.1083/jcb.200107119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12011115">Welm et al. (2002)</a> concluded that acute Fgfr1 signaling results in increased lateral budding of the mammary ductal epithelium and that sustained activation induces alveolar hyperplasia and invasive lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12011115" 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="#60" class="mim-tip-reference" title="Trokovic, N., Trokovic, R., Mai, P., Partanen, J. <strong>Fgfr1 regulates patterning of the pharyngeal region.</strong> Genes Dev. 17: 141-153, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12514106[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.250703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514106">Trokovic et al. (2003)</a> found that mice homozygous for a hypomorphic allele of Fgfr1 had craniofacial defects, some of which appeared to result from a failure in the early development of the second branchial arch. A stream of neural crest cells originating from the rhombomere-4 region migrated toward the second branchial arch in the mutant mice, but most cells failed to enter the second arch and accumulated in a region proximal to it. Both rescue of the hypomorphic Fgfr1 allele and inactivation of a conditional Fgfr1 allele specifically in neural crest cells indicated that the Fgfr1-regulated entry of neural crest cells into the second branchial arch was not cell autonomous, but appeared to depend upon prior gene expression in the overlying pharyngeal ectoderm. Abnormal gene expression in the hypomorphic Fgfr1 mutants led to mispatterning in the pharyngeal region at a stage prior to neural crest entry. <a href="#60" class="mim-tip-reference" title="Trokovic, N., Trokovic, R., Mai, P., Partanen, J. <strong>Fgfr1 regulates patterning of the pharyngeal region.</strong> Genes Dev. 17: 141-153, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12514106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12514106</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12514106[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.250703" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12514106">Trokovic et al. (2003)</a> concluded that Fgfr1 patterns the pharyngeal region to create a permissive environment for neural crest cell migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12514106" 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>To establish the contribution of FGFR1 to cardiac development, <a href="#7" class="mim-tip-reference" title="Dell'Era, P., Ronca, R., Coco, L., Nicoli, S., Metra, M., Presta, M. <strong>Fibroblast growth factor receptor-1 is essential for in vitro cardiomyocyte development.</strong> Circ. Res. 93: 414-420, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12893744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12893744</a>] [<a href="https://doi.org/10.1161/01.RES.0000089460.12061.E1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12893744">Dell'Era et al. (2003)</a> investigated the capacity of murine Fgfr1 +/- and Fgfr1 -/- embryonic stem (ES) cells to differentiate to cardiomyocytes in vitro. Clusters of pulsating cardiomyocytes were observed in more than 90% of 3-dimensional embryoid bodies (EBs) from Fgfr1 +/- ES cells at day 9 to 10 of differentiation, but only 10% or fewer of Fgfr1 -/- EBs showed beating foci at day 16. Fgfr1 -/- EBs were further characterized by impaired expression of early cardiac transcription factors and late structural cardiac genes, as well as alterations in the expression of mesoderm-related early genes. However, Fgfr1 +/- and Fgfr1 -/- EBs similarly expressed cardiogenic precursor, endothelial, hematopoietic, and skeletal muscle markers, indicating that the Fgfr1 null mutation exerts a selective effect on cardiomyocyte development in differentiating ES cells. Inhibitors of FGFR signaling prevented cardiomyocyte differentiation in Fgfr1 +/- EBs without affecting the expression of the hematopoietic/endothelial marker Flk1 (see <a href="/entry/191306">191306</a>). <a href="#7" class="mim-tip-reference" title="Dell'Era, P., Ronca, R., Coco, L., Nicoli, S., Metra, M., Presta, M. <strong>Fibroblast growth factor receptor-1 is essential for in vitro cardiomyocyte development.</strong> Circ. Res. 93: 414-420, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12893744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12893744</a>] [<a href="https://doi.org/10.1161/01.RES.0000089460.12061.E1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12893744">Dell'Era et al. (2003)</a> concluded that FGFR1-mediated signaling has a nonredundant role in cardiomyocyte development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12893744" 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="Magnusson, P. U., Dimberg, A., Mellberg, S., Lukinius, A., Claesson-Welsh, L. <strong>FGFR-1 regulates angiogenesis through cytokines interleukin-4 and pleiotrophin.</strong> Blood 110: 4214-4222, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875810</a>] [<a href="https://doi.org/10.1182/blood-2007-01-067314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17875810">Magnusson et al. (2007)</a> found that differentiating stem cell cultures, or embryoid bodies, from Fgfr1 -/- mice displayed increased vascularization and distinct, elongated vessel morphology. Teratomas derived from Fgfr1 -/- stem cells also showed abnormal vessel morphology and were characterized by increased growth rate. The increased vascularization and altered endothelial cell morphology were dependent on secreted factors based on the transfer of the Fgfr1 -/- vascular phenotype by conditioned medium to Fgfr1 +/- embryoid bodies. Il4 (<a href="/entry/147780">147780</a>) was downregulated and pleiotrophin (PTN; <a href="/entry/162095">162095</a>) was upregulated in Fgfr1 -/- embryoid bodies compared with Fgfr1 +/- cultures, and <a href="#29" class="mim-tip-reference" title="Magnusson, P. U., Dimberg, A., Mellberg, S., Lukinius, A., Claesson-Welsh, L. <strong>FGFR-1 regulates angiogenesis through cytokines interleukin-4 and pleiotrophin.</strong> Blood 110: 4214-4222, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17875810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17875810</a>] [<a href="https://doi.org/10.1182/blood-2007-01-067314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17875810">Magnusson et al. (2007)</a> showed that these cytokines acted as negative and positive angiogenic regulators, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17875810" 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>The hush puppy (hspy) mutation in mice leads to dominant inheritance of pinna and ossicle malformations, skull abnormalities, reduced rows of cochlear hair cells, and raised threshold for auditory responses. <a href="#5" class="mim-tip-reference" title="Calvert, J. A., Dedos, S. G. Hawker, K., Fleming, M., Lewis, M. A., Steel, K. P. <strong>A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice.</strong> Mammalian Genome 22: 290-305, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21479780/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21479780</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21479780[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/10.1007/s00335-011-9324-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21479780">Calvert et al. (2011)</a> identified hspy as a point mutation in the Fgfr1 gene leading to substitution of a conserved trp residue with arg (W691R) in the Fgfr1 kinase domain. Transfection of HEK293 cells with hspy mutant Fgfr1 resulted in normal protein expression and membrane trafficking. However, the mutant Fgfr1 was unresponsive to Fgf in calcium mobilization and downstream signaling through MAP kinase or PLC-gamma (see <a href="/entry/172420">172420</a>). Homozygous hspy mutant embryos were lost early in gastrulation and were developmentally retarded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21479780" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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By SSCP analysis of FGFR1 in patients with Pfeiffer syndrome (<a href="/entry/101600">101600</a>), <a href="#31" class="mim-tip-reference" title="Muenke, M., Schell, U., Hehr, A., Robin, N. H., Losken, H. W., Schinzel, A., Pulleyn, L. J., Rutland, P., Reardon, W., Malcolm, S., Winter, R. M. <strong>A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome.</strong> Nature Genet. 8: 269-274, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874169</a>] [<a href="https://doi.org/10.1038/ng1194-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874169">Muenke et al. (1994)</a> found a C-to-G transversion at position 755 of exon 5, predicting a pro252-to-arg substitution located between the second and third putative Ig domain of the FGFR1 protein. Proline residue is highly conserved in evolution, being present in chicken, mouse, rat, and all 4 human FGFR genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874169" 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>Jackson-Weiss Syndrome</em></strong></p><p>
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<a href="#48" class="mim-tip-reference" title="Roscioli, T., Flanagan, S., Kumar, P., Masel, J., Gattas, M., Hyland, V. J., Glass, I. A. <strong>Clinical findings in a patient with FGFR1 P252R mutation and comparison with the literature.</strong> Am. J. Med. Genet. 93: 22-28, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861678</a>] [<a href="https://doi.org/10.1002/1096-8628(20000703)93:1<22::aid-ajmg5>3.0.co;2-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861678">Roscioli et al. (2000)</a> reported the case of a patient with the skeletal findings of Jackson-Weiss syndrome (JWS; <a href="/entry/123150">123150</a>) who manifested only mild craniofacial anomalies. They demonstrated heterozygosity for the P252R missense mutation in the FGFR1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861678" 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>Variant Function</em></strong></p><p>
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By surface plasmon resonance analysis and X-ray crystallography, <a href="#19" class="mim-tip-reference" title="Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Linhardt, R. J., Mohammadi, M. <strong>Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.</strong> Hum. Molec. Genet. 13: 69-78, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14613973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14613973</a>] [<a href="https://doi.org/10.1093/hmg/ddh011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14613973">Ibrahimi et al. (2004)</a> characterized the effects of proline-to-arginine mutations in FGFR1c and FGFR3c on ligand binding. Both the FGFR1c P252R mutation and the FGFR3c P250R (<a href="/entry/134934#0014">134934.0014</a>) mutation exhibited an enhancement in ligand binding in comparison to their respective wildtype receptors. Binding of both mutant receptors to FGF9 (<a href="/entry/600921">600921</a>) was notably enhanced and implicated FGF9 as a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure of the P252R mutant in complex with FGF2 showed that enhanced ligand binding was due to an additional set of receptor-ligand hydrogen bonds, similar to the gain-of-function interactions that occur in the crystal structure of the FGFR2c P253R (<a href="/entry/176943#0011">176943.0011</a>) mutant in complex with FGF2. However, unlike the P253R mutant, neither the FGFR1c P252R mutant nor the FRGR3c P250R mutant bound appreciably to FGF7 (<a href="/entry/148180">148180</a>) or FGF10 (<a href="/entry/602115">602115</a>). <a href="#19" class="mim-tip-reference" title="Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Linhardt, R. J., Mohammadi, M. <strong>Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.</strong> Hum. Molec. Genet. 13: 69-78, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14613973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14613973</a>] [<a href="https://doi.org/10.1093/hmg/ddh011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14613973">Ibrahimi et al. (2004)</a> suggested that this might explain why limb phenotypes observed in type I Pfeiffer syndrome (<a href="/entry/101600">101600</a>) and Muenke syndrome (<a href="/entry/602849">602849</a>) are less severe than limb abnormalities observed in Apert syndrome (<a href="/entry/101200">101200</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14613973" 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">rs1586111679 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586111679;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=rs1586111679" 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=rs1586111679" 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=RCV000030924" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030924" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030924</a>
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<p><a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> found a 2-bp deletion in the FGFR1 gene, 1970-1971delCA, in 2 brothers with autosomal dominant Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>) and in their unaffected mother. They proposed that the product of the X-linked KAL1 gene (<a href="/entry/300836">300836</a>), the extracellular matrix protein anosmin-1, is involved in FGF signaling and that the lack of penetrance in females may be due to gender difference in anosmin-1 dosage because KAL1 partially escapes X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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FGFR1, TRP666ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1563433902 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1563433902;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=rs1563433902" 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=rs1563433902" 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=RCV000030925" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030925" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030925</a>
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<p><a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> demonstrated a trp666-to-arg (W666R) mutation in exon 15 of the FGFR1 gene in a sporadic female case of Kallmann syndrome and cleft palate (HH2; <a href="/entry/147950">147950</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</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">rs121909628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909628;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=rs121909628" 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=rs121909628" 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=RCV000030926 OR RCV000156953 OR RCV000156954 OR RCV000760399 OR RCV002513084 OR RCV004584329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030926, RCV000156953, RCV000156954, RCV000760399, RCV002513084, RCV004584329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030926...</a>
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<p><a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> observed heterozygosity for an arg622-to-stop (R622X) mutation in the FGFR1 gene in 3 members of a family affected with Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>), 2 of whom also had cleft palate or cleft lip. The mutation was also found in a family member with isolated anosmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" 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="#73" class="mim-tip-reference" title="Xu, N., Qin, Y., Reindollar, R. H., Tho, S. P. T., McDonough, P. G., Layman, L. C. <strong>A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism.</strong> J. Clin. Endocr. Metab. 92: 1155-1158, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200176</a>] [<a href="https://doi.org/10.1210/jc.2006-1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200176">Xu et al. (2007)</a> identified heterozygosity for the R622X mutation, resulting from a 1864C-T transition in the FGFR1 gene, in 4 affected members of a family segregating normosmic complete hypogonadotropic hypogonadism with full penetrance and no other FGFR1-associated anomalies typically found in Kallmann syndrome. The mutation, which is predicted to encode a truncated protein or result in nonsense-mediated decay, was not found in 3 unaffected family members or 100 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200176" 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>.0005 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</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> rs121909629 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909629;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/rs121909629?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=rs121909629" 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=rs121909629" 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=RCV000030927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030927</a>
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<p><a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> found an FGFR1 amino acid substitution, val607-to-met (V607M), in 2 sibs (male and female) with Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>) and in their unaffected father; both affected individuals had mirror movements of the hands (bimanual synkinesia). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" 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">rs1586287678 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1586287678;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=rs1586287678" 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=rs1586287678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>), <a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> found a mutation at the exon 7 donor splice site of the FGFR1 gene, 936G-A, in 2 affected sibs (male and female) and in their unaffected mother; all 3 had 7 or 8 missing teeth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" 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 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA</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">rs121909630 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909630;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=rs121909630" 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=rs121909630" 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=RCV000030929" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030929" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030929</a>
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<p>Whereas other familial and sporadic cases of Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>) have heterozygous mutations in the FGFR1 gene, <a href="#10" class="mim-tip-reference" title="Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others. <strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong> Nature Genet. 33: 463-465, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12627230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12627230</a>] [<a href="https://doi.org/10.1038/ng1122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12627230">Dode et al. (2003)</a> found homozygosity for an FGFR1 mutation, ala167 to ser (A167S), in exon 5. In addition to Kallmann syndrome, the patient had cleft palate, corpus callosum agenesis, unilateral hearing loss, and fusion of the fourth and fifth metacarpal bones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12627230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 OSTEOGLOPHONIC DYSPLASIA</strong>
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FGFR1, TYR372CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909631 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909631;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=rs121909631" 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=rs121909631" 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=RCV000017679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017679</a>
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<p>In a kindred with osteoglophonic dysplasia (OGD; <a href="/entry/166250">166250</a>) with a father and 2 sons affected, <a href="#68" class="mim-tip-reference" title="White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., Evans, W. E., Ichikawa, S., Fields, J., Yu, X., Shaw, N. J., McLellan, N. J., McKeown, C., FitzPatrick, D., Yu, K., Ornitz, D. M., Econs, M. J. <strong>Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.</strong> Am. J. Hum. Genet. 76: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/427956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625620">White et al. (2005)</a> found heterozygosity for a 1115G-A transition in exon 10 of FGFR1, replacing a tyrosine with a cysteine residue at amino acid position 372 (Y372C). The family was identified because of skeletal anomalies and progressive weakness in the family members. One of the sons possessed a distinct osteoglophonic dysplasia facial phenotype characterized by craniosynostosis, severe nasal-maxillary hypoplasia, telecanthus, and prominent supraorbital ridge. He had growth retardation, with a peak stature of 40 inches and a weight of 100 pounds. The proband's father and brother had the same skeletal syndrome; the father's peak stature was 48 inches. They also had shortened necks, broad and shortened thumbs, brachydactyly, and generalized osteopenia. In addition, the father and proband never had tooth eruption, as documented by radiographs. The proband and his father were hypophosphatemic secondary to renal phosphate wasting. This family also had 1,25-dihydroxy-vitamin D concentrations that were inappropriately low, given the degree of hypophosphatemia. The proband in this family died at age 28, presumably from a pulmonary embolism due to extended immobilization; the father died at age 59 years, from respiratory distress under similar immobilizing conditions; and the second brother died at age 24 years, from pneumonia. The analogous mutations that result in unpaired cysteine residues in FGFR2 (Y375C; <a href="/entry/176943#0015">176943.0015</a>) and FGFR3 (Y373C; <a href="/entry/134934#0016">134934.0016</a>) cause Beare-Stevenson cutis gyrata syndrome (<a href="/entry/123790">123790</a>) and thanatophoric dysplasia type I (<a href="/entry/187600">187600</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15625620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<strong>.0009 OSTEOGLOPHONIC DYSPLASIA</strong>
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FGFR1, ASN330ILE
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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> rs121909632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909632;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/rs121909632?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=rs121909632" 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=rs121909632" 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=RCV000017678" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017678" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017678</a>
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<p>In a patient with osteoglophonic dysplasia (OGD; <a href="/entry/166250">166250</a>), <a href="#68" class="mim-tip-reference" title="White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., Evans, W. E., Ichikawa, S., Fields, J., Yu, X., Shaw, N. J., McLellan, N. J., McKeown, C., FitzPatrick, D., Yu, K., Ornitz, D. M., Econs, M. J. <strong>Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.</strong> Am. J. Hum. Genet. 76: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/427956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625620">White et al. (2005)</a> found a heterozygous 929T-A transversion in exon 9 of the FGFR1 gene, resulting in an asn330-to-ile (N330I) change. The parents were negative for the mutation, indicating that it had occurred de novo. It is noteworthy that exon 9 is present only in the 'c' isoform of FGFR1, indicating that specific changes in FGFR1c will lead to osteoglophonic dysplasia. <a href="#68" class="mim-tip-reference" title="White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., Evans, W. E., Ichikawa, S., Fields, J., Yu, X., Shaw, N. J., McLellan, N. J., McKeown, C., FitzPatrick, D., Yu, K., Ornitz, D. M., Econs, M. J. <strong>Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.</strong> Am. J. Hum. Genet. 76: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/427956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625620">White et al. (2005)</a> demonstrated hypophosphatemia secondary to renal phosphate wasting in patients with this disorder, and found elevated circulating levels of fibroblast growth factor-23 (FGF23; <a href="/entry/605380">605380</a>), a known phosphaturic factor, in this patient. FGF23 had been shown to be produced by the nonossifying lesions in some patients with fibrous dysplasia of bone (<a href="#46" class="mim-tip-reference" title="Riminucci, M., Collins, M. T., Fedarko, N. S., Cherman, N., Corsi, A., White, K. E., Waguespack, S., Gupta, A., Hannon, T., Econs, M. J., Bianco, P., Robey, P. G. <strong>FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting.</strong> J. Clin. Invest. 112: 683-692, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12952917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12952917</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12952917[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/JCI18399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12952917">Riminucci et al., 2003</a>). The nonossifying lesions of dysplasia presumably produce FGF23, accounting for the hypophosphatemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15625620+12952917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Farrow, E. G., Davis, S. I., Mooney, S. D., Beighton, P., Mascarenhas, L., Gutierrez, Y. R., Pitukcheewanont, P., White, K. E. <strong>Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. (Letter)</strong> Am. J. Med. Genet. 140A: 537-539, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470795</a>] [<a href="https://doi.org/10.1002/ajmg.a.31106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470795">Farrow et al. (2006)</a> reported another patient with osteoglophonic dysplasia caused by the N330I mutation. Structural analysis indicated that asn330 is a surface-exposed residue, and the mutation is predicted to remove an N-linked glycosylation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16470795" 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">rs121909634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909634;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=rs121909634" 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=rs121909634" 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=RCV000017682 OR RCV002254904 OR RCV002514106" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017682, RCV002254904, RCV002514106" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017682...</a>
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<p>In a patient with osteoglophonic dysplasia (OGD; <a href="/entry/166250">166250</a>), <a href="#68" class="mim-tip-reference" title="White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., Evans, W. E., Ichikawa, S., Fields, J., Yu, X., Shaw, N. J., McLellan, N. J., McKeown, C., FitzPatrick, D., Yu, K., Ornitz, D. M., Econs, M. J. <strong>Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.</strong> Am. J. Hum. Genet. 76: 361-367, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15625620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15625620</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15625620[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/427956" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15625620">White et al. (2005)</a> found a heterozygous 1135T-C transition in exon 10 of the FGFR1 gene, resulting in a cys379-to-arg (C379R) amino acid change. The parents were negative for the mutation. This patient had normal plasma phosphate concentrations and a normal serum FGF23 (<a href="/entry/605380">605380</a>) concentration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15625620" 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> rs121909633 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909633;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/rs121909633?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=rs121909633" 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=rs121909633" 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=RCV000017681 OR RCV000502492 OR RCV000514891 OR RCV000766015 OR RCV001407682 OR RCV004532374" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017681, RCV000502492, RCV000514891, RCV000766015, RCV001407682, RCV004532374" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017681...</a>
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<p>In a 7-month-old girl with isolated trigonocephaly (TRIGNO1; <a href="/entry/190440">190440</a>), <a href="#23" class="mim-tip-reference" title="Kress, W., Petersen, B., Collmann, H., Grimm, T. <strong>An unusual FGFR1 mutation (fibroblast growth factor receptor 1 mutation) in a girl with non-syndromic trigonocephaly.</strong> Cytogenet. Cell Genet. 91: 138-140, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11173846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11173846</a>] [<a href="https://doi.org/10.1159/000056834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11173846">Kress et al. (2000)</a> identified an ile300-to-thr (I300T) mutation in exon 5 of the FGFR1 gene. The mutation was not found in more than 300 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11173846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a male infant with an Antley-Bixler syndrome-like skeletal phenotype (see <a href="/entry/207410">207410</a>) and abnormal genitalia (see POR deficiency, <a href="/entry/201750">201750</a>), <a href="#18" class="mim-tip-reference" title="Hurley, M. E., White, M. J., Green, A. J., Kelleher, J. <strong>Antley-Bixler syndrome with radioulnar synostosis.</strong> Pediat. Radiol. 34: 148-151, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14513299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14513299</a>] [<a href="https://doi.org/10.1007/s00247-003-1066-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14513299">Hurley et al. (2004)</a> identified the I300T mutation; the authors stated that the significance of the FGFR1 mutation was unclear. <a href="#17" class="mim-tip-reference" title="Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L. <strong>Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.</strong> Am. J. Hum. Genet. 76: 729-749, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15793702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15793702</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15793702[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/429417" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15793702">Huang et al. (2005)</a> subsequently identified compound heterozygosity for a frameshift and a missense mutation in the gene for cytochrome P450 oxidoreductase (POR; see <a href="/entry/124015#0015">124015.0015</a> and <a href="/entry/124015#0016">124015.0016</a>, respectively) in this patient as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14513299+15793702" 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">rs121909634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909634;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=rs121909634" 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=rs121909634" 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=RCV000017682 OR RCV002254904 OR RCV002514106" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017682, RCV002254904, RCV002514106" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017682...</a>
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<p>In a patient with osteoglophonic dysplasia (OGD; <a href="/entry/166250">166250</a>) originally reported by <a href="#1" class="mim-tip-reference" title="Beighton, P., Cremin, B. J., Kozlowski, K. <strong>Osteoglophonic dwarfism.</strong> Pediat. Radiol. 10: 46-50, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7422392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7422392</a>] [<a href="https://doi.org/10.1007/BF01644343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7422392">Beighton et al. (1980)</a>, <a href="#12" class="mim-tip-reference" title="Farrow, E. G., Davis, S. I., Mooney, S. D., Beighton, P., Mascarenhas, L., Gutierrez, Y. R., Pitukcheewanont, P., White, K. E. <strong>Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. (Letter)</strong> Am. J. Med. Genet. 140A: 537-539, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16470795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16470795</a>] [<a href="https://doi.org/10.1002/ajmg.a.31106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16470795">Farrow et al. (2006)</a> identified a heterozygous 1141T-C transition in exon 10 of the FGFR1 gene, resulting in a cys381-to-arg (C381R) substitution predicted to disrupt the transmembrane domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7422392+16470795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</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">rs121909635 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909635;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=rs121909635" 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=rs121909635" 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=RCV000017684 OR RCV004528116" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017684, RCV004528116" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017684...</a>
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<p>In an 18-year-old female with normosmic idiopathic hypogonadotropic hypogonadism and her brother, who had Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>), <a href="#37" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> identified heterozygosity for a 709G-A transition in exon 6 of the FGFR1 gene, predicted to result in a gly237-to-ser (G237S) substitution in the Ig-like domain D2 within the extracellular region of the protein. The sibs' father, who also carried the mutation, had congenital anosmia with normal puberty. Structural analysis of the mutant protein revealed inhibition of proper folding of D2, likely leading to loss of cell surface expression of FGFR1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606836" 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">rs267606805 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606805;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=rs267606805" 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=rs267606805" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs267606806 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606806;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/rs267606806?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=rs267606806" 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=rs267606806" 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=RCV000030930 OR RCV001857786 OR RCV003234553 OR RCV003234554" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030930, RCV001857786, RCV003234553, RCV003234554" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030930...</a>
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<p>In a 25-year-old Hispanic male with normosmic idiopathic hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>) and unilateral cryptorchidism, who had 2 congenitally missing teeth, <a href="#37" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> identified complex heterozygosity for 2 mutations in exon 16 of the FGFR1 gene on the same allele: one was a 2165C-A transversion resulting in a pro722-to-his (P722H) substitution and the other was a 2172C-G transversion resulting in an asn724-to-lys (N724K) substitution. The patient's mother, who was also heterozygous for the mutations, had congenital anosmia and normal puberty. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 brothers with normosmic idiopathic hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>), 1 of whom also had cleft lip and palate and 3 missing teeth, <a href="#37" class="mim-tip-reference" title="Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., Yialamas, M., Hall, J. E., Grant, E., Mohammadi, M., Crowley, W. F., Jr. <strong>Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.</strong> Proc. Nat. Acad. Sci. 103: 6281-6286, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16606836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16606836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16606836[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600962103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16606836">Pitteloud et al. (2006)</a> identified heterozygosity for a 2038C-T transition in exon 15 of the FGFR1 gene, resulting in a gln680-to-ter (Q680X) substitution in the tyrosine kinase domain. The sibs' father, who was also heterozygous for the mutation, reported having delayed puberty. The mutation is predicted to cause the deletion of a catalytically essential portion of the tyrosine kinase domain and lead to a 'kinase dead' receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16606836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sisters with hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>) in whom <a href="#53" class="mim-tip-reference" title="Seminara, S. B., Beranova, M., Oliveira, L. M. B., Martin, K. A., Crowley, W. F., Jr., Hall, J. E. <strong>Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations.</strong> J. Clin. Endocr. Metab. 85: 556-562, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10690855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10690855</a>] [<a href="https://doi.org/10.1210/jcem.85.2.6357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10690855">Seminara et al. (2000)</a> had previously identified compound heterozygosity for missense mutations in the GNRHR gene (Q106R, <a href="/entry/138850#0001">138850.0001</a>, and R262Q, <a href="/entry/138850#0002">138850.0002</a>), <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> identified heterozygosity for an additional 1409G-T transversion in exon 10 of the FGFR1 gene, resulting in an arg470-to-leu (R470L) substitution. The mutation was also found in the father, who had a history of delayed puberty and was heterozygous for the R262Q mutation in GNRHR, and in the unaffected daughter of the younger sister, who had undergone normal puberty and had no mutations in GNRHR. The R470L mutation was not found in 200 controls. <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with idiopathic hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17235395+10690855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a family in which the proband had severe Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>), his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> identified heterozygosity for a 1025T-C transition in exon 7 of the FGFR1 gene, resulting in a leu342-to-ser (L342S) substitution in the proband, his father, and his sister. The mutation was not found in 200 controls. Heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (<a href="/entry/608137#0002">608137.0002</a>), was identified in the proband, his mother, and his brother. <a href="#38" class="mim-tip-reference" title="Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. <strong>Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism.</strong> J. Clin. Invest. 117: 457-463, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17235395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17235395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17235395[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/JCI29884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17235395">Pitteloud et al. (2007)</a> concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with idiopathic hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17235395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 16-year-old female with cleft lip and palate who presented with anosmia, irregular menstrual periods, and agenesis of 2 teeth (HH2; <a href="/entry/147950">147950</a>), <a href="#45" class="mim-tip-reference" title="Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C. <strong>Impaired FGF signaling contributes to cleft lip and palate.</strong> Proc. Nat. Acad. Sci. 104: 4512-4517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0607956104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360555">Riley et al. (2007)</a> identified an arg609-to-ter (R609X) substitution in the tyrosine kinase domain of the FGFR1 gene, resulting in a loss of function. Her father, who also carried the R609X mutation, had isolated cleft lip and palate and a normal sense of smell and was fertile. The mutation was not found in the unaffected mother or brother; a deceased paternal great aunt was also reported to have cleft lip. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</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">rs587776835 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776835;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=rs587776835" 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=rs587776835" 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=RCV000030935" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030935" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030935</a>
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<p>In a 14-year-old Japanese boy with Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>), <a href="#51" class="mim-tip-reference" title="Sato, N., Ohyama, K., Fukami, M., Okada, M., Ogata, T. <strong>Kallmann syndrome: somatic and germline mutations of the fibroblast growth factor receptor 1 gene in a mother and the son.</strong> J. Clin. Endocr. Metab. 91: 1415-1418, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16418210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16418210</a>] [<a href="https://doi.org/10.1210/jc.2005-2266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16418210">Sato et al. (2006)</a> found a heterozygous 2-bp deletion in exon 10 of the FGFR1 gene, 1317_1318delTG, that was predicted to cause a frameshift at serine-439 and premature termination (Ser439fsTer461). The boy presented with hypogonadotropic hypogonadism, olfactory dysfunction, and dental agenesis and his fertile mother with olfactory dysfunction and dental agenesis. After selective amplification of the mutant allele, the deletion was detected in nail DNA, but not in leukocyte DNA, from the mother. The authors concluded that the 2-bp deletion took place as a somatic mutation in the mother and was transmitted to the proband through germline mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16418210" 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>.0020 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA</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">rs121909640 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909640;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=rs121909640" 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=rs121909640" 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=RCV000017691 OR RCV003311661 OR RCV004724747" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017691, RCV003311661, RCV004724747" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017691...</a>
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<p>In a 17-year-old male with hypogonadotropic hypogonadism with normal olfaction (HH2; <a href="/entry/147950">147950</a>), <a href="#59" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., deCastro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> detected a G-to-A transition in exon 3 of the FGFR1 gene that resulted in a gly48-to-ser (G48S) substitution. The conserved gly48 is located in the IgI domain involved in the autoinhibitory function. The patient showed no midline defect and had normal sulci and olfactory bulbs at MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" 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>.0021 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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FGFR1, PRO366LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909641;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=rs121909641" 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=rs121909641" 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=RCV000030936 OR RCV000156970 OR RCV000763182 OR RCV001824283 OR RCV003234537" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030936, RCV000156970, RCV000763182, RCV001824283, RCV003234537" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030936...</a>
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<p>In a 17-year-old patient with familial Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>) <a href="#59" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., deCastro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> detected a C-to-T transition at nucleotide 1097 in exon 9 of the FGFR1 gene that resulted in a pro366-to-leu (P366L) substitution. The mutation was also identified in his 2 paternal aunts with Kallmann syndrome as well as in his asymptomatic father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" 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>.0022 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA</strong>
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FGFR1, PRO722SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121909642 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909642;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=rs121909642" 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=rs121909642" 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=RCV000030937" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030937" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030937</a>
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<p>In a 22-year-old patient with familial Kallmann syndrome (HH2; <a href="/entry/147950">147950</a>), <a href="#59" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., deCastro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> identified a 2164C-to-T transition in exon 16 of the FGFR1 gene that resulted in a pro722-to-ser (P722S) substitution. Cleft lip and bimanual synkinesia were observed. The mutation was also reported in his maternal first cousin, who had Kallmann syndrome without bimanual synkinesia. <a href="#59" class="mim-tip-reference" title="Trarbach, E. B., Costa, E. M. F., Versiani, B., deCastro, M., Baptista, M. T. M., Garmes, H. M., de Mendonca, B. B., Latronico, A. C. <strong>Novel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmia.</strong> J. Clin. Endocr. Metab. 91: 4006-4012, 2006. Note: Erratum: J. Clin. Endocr. Metab. 93: 2013 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16882753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16882753</a>] [<a href="https://doi.org/10.1210/jc.2005-2793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16882753">Trarbach et al. (2006)</a> noted that a different mutation of pro722 had been reported with another mutation on the same allele (<a href="#0014">136350.0014</a>); this patient had Kallmann syndrome with dental agenesis but not bimanual synkinesia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16882753" 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>.0023 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA</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">rs121909643 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909643;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=rs121909643" 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=rs121909643" 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=RCV000030938" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030938" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030938</a>
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<p>In a 19-year-old man who was evaluated at age 15.5 years for delayed puberty and found to have a hypogonadal serum testosterone level with undetectable serum gonadotropins (HH2; <a href="/entry/147950">147950</a>), <a href="#11" class="mim-tip-reference" title="Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., Quinton, R., Na, S., and 9 others. <strong>Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.</strong> J. Clin. Invest. 118: 2822-2831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596921[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/JCI34538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596921">Falardeau et al. (2008)</a> identified homozygosity for an F40L mutation in the FGF8 gene (<a href="/entry/600483#0003">600483.0003</a>) and also identified compound heterozygosity for a gln764-to-his (Q764H) mutation and an asp768-to-tyr (D768Y; <a href="#0024">136350.0024</a>) mutation in the FGFR1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596921" 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">rs121909644 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909644;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=rs121909644" 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=rs121909644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the asp768-to-tyr (D768Y) mutation in the FGFR1 gene that was found in compound heterozygous state in a patient with hypogonadotropic hypogonadism-2 without anosmia (HH2; <a href="/entry/147950">147950</a>) by <a href="#11" class="mim-tip-reference" title="Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., Quinton, R., Na, S., and 9 others. <strong>Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.</strong> J. Clin. Invest. 118: 2822-2831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596921[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/JCI34538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596921">Falardeau et al. (2008)</a>, see <a href="#0023">136350.0023</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596921" 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">rs121909645 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909645;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=rs121909645" 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=rs121909645" 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 10-year-old boy of mixed European descent who was born with microphallus and found to have undetectable serum testosterone and gonadotropins and normal olfaction (HH2; <a href="/entry/147950">147950</a>), and his father, who had normal olfaction, bilateral hearing loss, and a history of delayed puberty, <a href="#11" class="mim-tip-reference" title="Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., Quinton, R., Na, S., and 9 others. <strong>Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.</strong> J. Clin. Invest. 118: 2822-2831, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596921/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596921</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596921[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/JCI34538" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596921">Falardeau et al. (2008)</a> identified heterozygosity for a 794G-A transition in the FGFR1 gene, resulting in an arg250-to-gln (R250Q) substitution. The boy was also heterozygous for a de novo missense mutation in the FGF8 gene (<a href="/entry/600483#0004">600483.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596921" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 55-year-old woman with hypogonadotropic hypogonadism with anosmia from a large French Canadian pedigree with several consanguineous loops, previously reported by <a href="#67" class="mim-tip-reference" title="White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. <strong>The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review.</strong> Am. J. Med. Genet. 15: 417-435, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881209</a>] [<a href="https://doi.org/10.1002/ajmg.1320150307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881209">White et al. (1983)</a> and in which affected individuals displayed variable phenotypes, <a href="#58" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> identified homozygosity for a missense mutation in the HS6ST1 gene (R296W; <a href="/entry/604846#0002">604846.0002</a>). The proband's brother, who also had anosmic HH, was heterozygous for the HS6ST1 mutation, as was their unaffected father and 3 other family members, including 1 with anosmic HH, 1 with anosmic HH and cleft palate, and 1 unaffected individual. Analysis of 8 known HH-associated genes revealed that the proband, her brother, and their unaffected father were all also heterozygous for the R250Q mutation in FGFR1, as were 2 other family members, 1 with anosmic HH and 1 with anosmic HH and cleft palate. The R250Q FGFR1 mutation was also found in heterozygosity in an unaffected family member who did not carry the HS6ST1 mutation. No mutations were identified in the other HH-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6881209+21700882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the French Canadian pedigree in which <a href="#58" class="mim-tip-reference" title="Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. <strong>Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.</strong> Proc. Nat. Acad. Sci. 108: 11524-11529, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21700882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21700882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21700882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1102284108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21700882">Tornberg et al. (2011)</a> had identified mutations in both the FGFR1 and HS6ST1 genes, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified additional mutations in 2 FGF-network genes, FGF17 (I108T; <a href="/entry/603725#0001">603725.0001</a>) and FLRT3 (E97G, <a href="/entry/604808#0001">604808.0001</a> and S144I, <a href="/entry/604808#0002">604808.0002</a>). Analysis of physical interactions between the ligand-binding region of FGFR1 and FGF17 by surface-plasmon-resonance spectroscopy demonstrated that the FGF17 I108T mutant was defective in FGFR1 activation compared to wildtype; in addition, the I108T mutant completely failed to activate the FGFR1 R250Q mutant, indicating that these 2 loss-of-function substitutions act in an additive manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21700882+23643382" 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">rs886037634 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037634;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=rs886037634" 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=rs886037634" 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 female patient with congenital hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>), who was anosmic and also displayed hearing loss, abnormal dentition, and low bone mass, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified heterozygosity for a c.1042G-A transition in exon 8b of the FGFR1 gene, resulting in a gly348-to-arg (G348R) substitution in the D3 domain. The patient was also heterozygous for a missense mutation in the IL17RD gene (Y379C; <a href="/entry/606807#0002">606807.0002</a>). Her mother, who carried only a heterozygous Y379C mutation in IL17RD, was anosmic but did not display other features of hypogonadotropic hypogonadism. Neither mutation was found in the unaffected father or in 155 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a white European male patient born with micropenis, bilateral cryptorchidism, split feet, and cleft lip, who also exhibited dental anomalies including partial double teeth involving the canines, <a href="#64" class="mim-tip-reference" title="Villanueva, C., Jacobson-Dickman, E., Xu, C., Manouvrier, S., Dwyer, A. A., Sykiotis, G. P., Beenken, A., Liu, Y., Tommiska, J., Hu, Y., Tiosano, D., Gerard, M., and 15 others. <strong>Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.</strong> Genet. Med. 17: 651-659, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25394172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25394172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25394172[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/gim.2014.166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25394172">Villanueva et al. (2015)</a> identified heterozygosity for the G348R mutation in the FGFR1 gene. The proband failed to undergo puberty, and at age 15 years, his serum hormone values were consistent with hypogonadotropic hypogonadism. MRI revealed normal olfactory structures, consistent with his self-reported normal sense of smell. There was no family history of reproductive or skeletal disorders; mutation status of his parents was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25394172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a sporadic male patient with congenital hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>), who was anosmic and had absent puberty, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified heterozygosity for a c.1447C-A transversion in exon 11 of the FGFR1 gene, resulting in a pro483-to-thr (P483T) substitution in the tyrosine kinase domain. The patient was also heterozygous for a missense mutation in the SPRY4 gene (S241Y; <a href="/entry/607984#0002">607984.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a male patient with congenital hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>), who was anosmic and also had abnormal dentition, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified heterozygosity for a c.2075A-G transition in exon 16 of the FGFR1 gene, resulting in a glu692-to-gly (E692G) substitution in the tyrosine kinase domain. The patient was also heterozygous for a missense mutation in the DUSP6 gene (S182F; <a href="/entry/602748#0002">602748.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a female proband with congenital hypogonadotropic hypogonadism (HH2; <a href="/entry/147950">147950</a>), who was anosmic and also had hearing loss and low bone mass, <a href="#30" class="mim-tip-reference" title="Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. <strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong> Am. J. Hum. Genet. 92: 725-743, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23643382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23643382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23643382[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23643382">Miraoui et al. (2013)</a> identified heterozygosity for a c.2008G-A transition in exon 15 of the FGFR1 gene, resulting in a glu670-to-lys (E670K) substitution in the tyrosine kinase domain.i The patient was also heterozygous for a missense mutation in the FLRT3 gene (Q69K; <a href="/entry/604808#0003">604808.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23643382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a man with holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; <a href="/entry/615465">615465</a>), who was previously reported as patient 4 by <a href="#63" class="mim-tip-reference" title="Vilain, C., Mortier, G., Van Vliet, G., Dubourg, C., Heinrichs, C., de Silva, D., Verloes, A., Baumann, C. <strong>Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: further delineation and review.</strong> Am. J. Med. Genet. 149A: 1476-1481, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19504604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19504604</a>] [<a href="https://doi.org/10.1002/ajmg.a.32678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19504604">Vilain et al. (2009)</a>, <a href="#55" class="mim-tip-reference" title="Simonis, N., Migeotte, I., Lambert, N., Perazzolo, C., de Silva, D. C., Dimitrov, B., Heinrichs, C., Janssens, S., Kerr, B., Mortier, G., Van Vliet, G., Lepage, P., Casimir, G., Abramowicz, M., Smits, G., Vilain, C. <strong>FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.</strong> J. Med. Genet. 50: 585-592, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23812909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23812909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23812909[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/10.1136/jmedgenet-2013-101603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23812909">Simonis et al. (2013)</a> identified heterozygosity for a de novo c.2174G-A transition in the FGFR1 gene, resulting in a cys725-to-tyr (C725Y) substitution at a highly conserved residue in the intracellular C-terminal loop of the tyrosine kinase domain. The mutation was not present in his unaffected parents. The patient, whose IQ was measured at 63 at age 6.75 years, worked in a sheltered workshop. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23812909+19504604" 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">rs397515481 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515481;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=rs397515481" 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=rs397515481" 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 male infant with severe holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; <a href="/entry/615465">615465</a>), who was previously reported as patient 3 by <a href="#63" class="mim-tip-reference" title="Vilain, C., Mortier, G., Van Vliet, G., Dubourg, C., Heinrichs, C., de Silva, D., Verloes, A., Baumann, C. <strong>Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: further delineation and review.</strong> Am. J. Med. Genet. 149A: 1476-1481, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19504604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19504604</a>] [<a href="https://doi.org/10.1002/ajmg.a.32678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19504604">Vilain et al. (2009)</a>, <a href="#55" class="mim-tip-reference" title="Simonis, N., Migeotte, I., Lambert, N., Perazzolo, C., de Silva, D. C., Dimitrov, B., Heinrichs, C., Janssens, S., Kerr, B., Mortier, G., Van Vliet, G., Lepage, P., Casimir, G., Abramowicz, M., Smits, G., Vilain, C. <strong>FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.</strong> J. Med. Genet. 50: 585-592, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23812909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23812909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23812909[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/10.1136/jmedgenet-2013-101603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23812909">Simonis et al. (2013)</a> identified homozygosity for a c.494T-C transition in the FGFR1 gene, resulting in a leu165-to-ser (L165S) substitution at a highly conserved residue in the extracellular ligand-binding domain D2. The first-cousin Sri Lankan parents were heterozygous for the mutation and were reported to be asymptomatic and spontaneously fertile. The patient died at 5 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23812909+19504604" 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">rs398122946 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122946;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=rs398122946" 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=rs398122946" 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=RCV000056315" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056315" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056315</a>
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<p>In a female patient with mild holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; <a href="/entry/615465">615465</a>), <a href="#55" class="mim-tip-reference" title="Simonis, N., Migeotte, I., Lambert, N., Perazzolo, C., de Silva, D. C., Dimitrov, B., Heinrichs, C., Janssens, S., Kerr, B., Mortier, G., Van Vliet, G., Lepage, P., Casimir, G., Abramowicz, M., Smits, G., Vilain, C. <strong>FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.</strong> J. Med. Genet. 50: 585-592, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23812909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23812909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23812909[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/10.1136/jmedgenet-2013-101603" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23812909">Simonis et al. (2013)</a> identified heterozygosity for a de novo c.1867G-T transversion in the FGFR1 gene, resulting in an asp623-to-tyr (D623Y) substitution in the ATP binding pocket of the intracellular tyrosine kinase domain. The mutation was not present in her unaffected parents. The patient attended mainstream school with support. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23812909" 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> rs779707422 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs779707422;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/rs779707422?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=rs779707422" 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=rs779707422" 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=RCV000210485 OR RCV000487433 OR RCV004668850" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210485, RCV000487433, RCV004668850" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210485...</a>
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<p>In 3 patients with encephalocraniocutaneous lipomatosis (ECCL; <a href="/entry/613001">613001</a>), including a 15-year-old boy originally described by <a href="#33" class="mim-tip-reference" title="Nowaczyk, M. J. M., Mernagh, J. R., Bourgeois, J. M., Thompson, P. J., Jurriaans, E. <strong>Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis.</strong> Am. J. Med. Genet. 91: 261-266, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10766980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10766980</a>]" pmid="10766980">Nowaczyk et al. (2000)</a> and a 5-year-old girl previously reported by <a href="#25" class="mim-tip-reference" title="Kupsik, M., Brandling-Bennett, H. <strong>An infant with an alopecic plaque on the scalp and ocular choristomas: case presentation.</strong> Pediat. Derm. 30: 491-492, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23819449/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23819449</a>] [<a href="https://doi.org/10.1111/j.1525-1470.2012.01837.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23819449">Kupsik and Brandling-Bennett (2013)</a>, <a href="#2" class="mim-tip-reference" title="Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others. <strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong> Am. J. Hum. Genet. 98: 579-587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942290">Bennett et al. (2016)</a> identified mosaicism for a c.1638C-A transversion (c.1638C-A, NM_023110.2) in the FGFR1 gene, resulting in an asn546-to-lys (N546K) substitution in the first tyrosine kinase domain of the cytoplasmic kinase core. In the 15-year-old boy (LR13-278), the N546K substitution was identified in cultured fibroblasts from unaffected skin at an alternate allele fraction (AAF) of 35%, from a scalp nevus (42% AAF), and an eyelid dermoid (54% AAF). In the 5-year-old girl (LR14-261), the N546K mutation was present in cultured fibroblasts from a scalp nevus (55% AAF) but was not detected in saliva. In the third patient (IN_0039), a 17-month-old boy who had an unaffected monozygotic twin sib, N546K was identified in cultured fibroblasts from unaffected skin (23% AAF) and from a scalp lesion (33% AAF), but was not detected in the unaffected twin's blood. The N546K variant was not found in the Exome Variant Server, ExAC, or dbSNP databases. <a href="#2" class="mim-tip-reference" title="Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others. <strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong> Am. J. Hum. Genet. 98: 579-587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942290">Bennett et al. (2016)</a> stated that N546 is 1 of the 2 residues most commonly mutated among FGFR1 mutation-containing tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. The 15-year-old boy with the N546K mutation had been diagnosed with a tectal tumor. Functional analysis in patient fibroblasts demonstrated elevated autophosphorylation of FGFRs, the FGFR-dependent substrate FRS2 (<a href="/entry/607743">607743</a>), and the RAS (see <a href="/entry/190020">190020</a>)-pathway components CRAF (<a href="/entry/164760">164760</a>) and ERK1 (<a href="/entry/601795">601795</a>)/ERK2 (<a href="/entry/176948">176948</a>), compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10766980+23819449+26942290" 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">rs869320694 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320694;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=rs869320694" 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=rs869320694" 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=RCV000210479 OR RCV001849345" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000210479, RCV001849345" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000210479...</a>
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<p>In a 7-year-old boy (LR12-068) with encephalocraniocutaneous lipomatosis (ECCL; <a href="/entry/613001">613001</a>) and an unrelated 2.75-year-old boy (NIH-183) with ECCL who was previously reported by <a href="#3" class="mim-tip-reference" title="Bieser, S., Reis, M., Guzman, M., Gauvain, K., Elbabaa, S., Braddock, S. R., Abdel-Baki, M. S. <strong>Grade II pilocytic astrocytoma in a 3-month-old patient with encephalocraniocutaneous lipomatosis (ECCL): case report and literature review of low grade gliomas in ECCL.</strong> Am. J. Med. Genet. 167A: 878-881, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25705862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25705862</a>] [<a href="https://doi.org/10.1002/ajmg.a.37017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25705862">Bieser et al. (2015)</a>, <a href="#2" class="mim-tip-reference" title="Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others. <strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong> Am. J. Hum. Genet. 98: 579-587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942290">Bennett et al. (2016)</a> identified mosaicism for a c.1966A-G transition (c.1966A-G, NM_023110.2) in the FGFR1 gene, resulting in a lys656-to-glu (K656E) substitution within the second tyrosine kinase domain of the cytoplasmic kinase core. In the younger boy, the K656E substitution was present in cultured fibroblasts from affected scalp at an alternate allele fraction (AAF) of 45%, but was not detected in blood. In the older boy, K565E was identified in cultured fibroblasts from a scalp nevus (47% AAF) and in fibroblasts from a pilocytic astrocytoma (32% AAF). The K565E variant was not found in the Exome Variant Server, ExAC, or dbSNP databases. <a href="#2" class="mim-tip-reference" title="Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others. <strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong> Am. J. Hum. Genet. 98: 579-587, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.02.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26942290">Bennett et al. (2016)</a> stated that K656 is 1 of the 2 residues most commonly mutated among FGFR1 mutation-containing tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and noted that most of the tumors associated with substitutions in these 2 residues are central nervous system gliomas, including pilocytic astrocytomas, the same type of tumor seen at increased frequency in patients with ECCL. Both boys with the K656E mutation were diagnosed with pilocytic astrocytoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25705862+26942290" 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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Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others.
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<strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong>
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Am. J. Hum. Genet. 98: 579-587, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26942290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26942290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26942290[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=26942290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bieser, S., Reis, M., Guzman, M., Gauvain, K., Elbabaa, S., Braddock, S. R., Abdel-Baki, M. S.
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<strong>Grade II pilocytic astrocytoma in a 3-month-old patient with encephalocraniocutaneous lipomatosis (ECCL): case report and literature review of low grade gliomas in ECCL.</strong>
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Am. J. Med. Genet. 167A: 878-881, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25705862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25705862</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25705862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37017" target="_blank">Full Text</a>]
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<span class="mim-text-font">
|
|
Patricia A. Hartz - updated : 10/07/2016
|
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Marla J. F. O'Neill - updated : 4/4/2016<br>Marla J. F. O'Neill - updated : 9/10/2015<br>Marla J. F. O'Neill - updated : 10/23/2014<br>Ada Hamosh - updated : 2/3/2014<br>Ada Hamosh - updated : 1/28/2014<br>Marla J. F. O'Neill - updated : 10/28/2013<br>Marla J. F. O'Neill - updated : 10/9/2013<br>Marla J. F. O'Neill - updated : 6/5/2013<br>Ada Hamosh - updated : 11/19/2012<br>Patricia A. Hartz - updated : 10/23/2012<br>Marla J. F. O'Neill - updated : 10/17/2012<br>Marla J. F. O'Neill - updated : 9/25/2012<br>Patricia A. Hartz - updated : 10/6/2010<br>Ada Hamosh - updated : 2/18/2010<br>Ada Hamosh - updated : 4/16/2009<br>Marla J. F. O'Neill - updated : 3/23/2009<br>Marla J. F. O'Neill - updated : 1/26/2009<br>Patricia A. Hartz - updated : 10/23/2008<br>John A. Phillips, III - updated : 10/29/2007<br>John A. Phillips, III - updated : 9/28/2007<br>George E. Tiller - updated : 6/21/2007<br>John A. Phillips, III - updated : 5/17/2007<br>Paul J. Converse - updated : 5/17/2007<br>Paul J. Converse - updated : 5/3/2007<br>Marla J. F. O'Neill - updated : 4/30/2007<br>Marla J. F. O'Neill - updated : 3/13/2007<br>Ada Hamosh - updated : 1/23/2007<br>Marla J. F. O'Neill - updated : 6/2/2006<br>Patricia A. Hartz - updated : 3/31/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>George E. Tiller - updated : 2/17/2006<br>Jane Kelly - updated : 12/9/2005<br>Marla J. F. O'Neill - updated : 9/13/2005<br>Marla J. F. O'Neill - updated : 8/30/2005<br>Victor A. McKusick - updated : 2/14/2005<br>Ada Hamosh - updated : 12/10/2004<br>Victor A. McKusick - updated : 11/15/2004<br>Patricia A. Hartz - updated : 8/19/2004<br>Marla J. F. O'Neill - updated : 3/9/2004<br>Patricia A. Hartz - updated : 10/27/2003<br>Dawn Watkins-Chow - updated : 3/28/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 10/16/2002<br>Patricia A. Hartz - updated : 10/8/2002<br>Victor A. McKusick - updated : 2/15/2002<br>Victor A. McKusick - updated : 11/7/2001<br>Victor A. McKusick - updated : 9/19/2001<br>Paul J. Converse - updated : 12/27/2000<br>Paul J. Converse - updated : 11/7/2000<br>George E. Tiller - updated : 10/26/2000<br>Victor A. McKusick - updated : 7/10/2000<br>Stylianos E. Antonarakis - updated : 6/7/2000<br>Ada Hamosh - updated : 9/21/1999<br>Stylianos E. Antonarakis - updated : 9/15/1999<br>Ada Hamosh - updated : 6/18/1999<br>Victor A. McKusick - updated : 6/11/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Victor A. McKusick - updated : 12/29/1997<br>Jennifer P. Macke - updated : 6/3/1997
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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">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/31/1989
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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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<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>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/01/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 06/11/2019<br>carol : 09/13/2017<br>mgross : 10/07/2016<br>carol : 08/11/2016<br>carol : 04/21/2016<br>alopez : 4/4/2016<br>carol : 9/10/2015<br>alopez : 8/12/2015<br>mcolton : 7/30/2015<br>carol : 3/10/2015<br>carol : 10/24/2014<br>mcolton : 10/23/2014<br>alopez : 2/3/2014<br>alopez : 1/28/2014<br>carol : 10/28/2013<br>carol : 10/9/2013<br>alopez : 6/5/2013<br>terry : 4/1/2013<br>alopez : 11/19/2012<br>mgross : 11/8/2012<br>terry : 10/23/2012<br>carol : 10/17/2012<br>carol : 10/17/2012<br>carol : 10/17/2012<br>carol : 10/16/2012<br>carol : 9/25/2012<br>carol : 9/25/2012<br>terry : 9/7/2012<br>terry : 8/8/2012<br>carol : 2/17/2012<br>alopez : 3/10/2011<br>mgross : 10/6/2010<br>carol : 9/2/2010<br>terry : 2/18/2010<br>alopez : 4/21/2009<br>alopez : 4/21/2009<br>terry : 4/16/2009<br>wwang : 3/30/2009<br>terry : 3/23/2009<br>joanna : 3/9/2009<br>joanna : 2/2/2009<br>carol : 1/26/2009<br>mgross : 10/23/2008<br>mgross : 10/23/2008<br>carol : 9/4/2008<br>carol : 10/29/2007<br>alopez : 9/28/2007<br>wwang : 6/25/2007<br>terry : 6/21/2007<br>wwang : 6/13/2007<br>alopez : 5/17/2007<br>mgross : 5/17/2007<br>mgross : 5/17/2007<br>terry : 5/3/2007<br>wwang : 4/30/2007<br>carol : 3/14/2007<br>carol : 3/13/2007<br>alopez : 1/24/2007<br>terry : 1/23/2007<br>carol : 12/5/2006<br>carol : 6/2/2006<br>terry : 6/2/2006<br>mgross : 6/2/2006<br>mgross : 3/31/2006<br>wwang : 3/23/2006<br>ckniffin : 3/21/2006<br>wwang : 3/7/2006<br>terry : 2/17/2006<br>alopez : 12/9/2005<br>carol : 9/13/2005<br>terry : 9/13/2005<br>terry : 9/13/2005<br>carol : 8/30/2005<br>carol : 8/30/2005<br>terry : 7/11/2005<br>alopez : 2/15/2005<br>terry : 2/14/2005<br>alopez : 12/14/2004<br>terry : 12/10/2004<br>alopez : 11/15/2004<br>mgross : 8/19/2004<br>tkritzer : 3/11/2004<br>tkritzer : 3/9/2004<br>alopez : 11/17/2003<br>cwells : 10/31/2003<br>terry : 10/27/2003<br>alopez : 4/1/2003<br>cwells : 3/28/2003<br>alopez : 3/20/2003<br>terry : 3/19/2003<br>carol : 10/24/2002<br>tkritzer : 10/22/2002<br>terry : 10/16/2002<br>mgross : 10/8/2002<br>cwells : 3/6/2002<br>cwells : 2/22/2002<br>terry : 2/15/2002<br>carol : 11/12/2001<br>terry : 11/7/2001<br>mcapotos : 9/19/2001<br>mgross : 12/27/2000<br>mgross : 12/27/2000<br>mgross : 11/7/2000<br>carol : 11/2/2000<br>mcapotos : 10/26/2000<br>mcapotos : 10/26/2000<br>carol : 7/18/2000<br>terry : 7/10/2000<br>mgross : 6/7/2000<br>carol : 10/6/1999<br>carol : 9/21/1999<br>mgross : 9/15/1999<br>alopez : 6/18/1999<br>alopez : 6/18/1999<br>dholmes : 7/22/1998<br>carol : 6/15/1998<br>terry : 6/15/1998<br>terry : 6/11/1998<br>terry : 6/11/1998<br>carol : 5/6/1998<br>terry : 4/20/1998<br>psherman : 4/15/1998<br>terry : 1/7/1998<br>terry : 12/30/1997<br>terry : 12/29/1997<br>alopez : 9/10/1997<br>alopez : 9/9/1997<br>terry : 7/28/1997<br>terry : 11/20/1996<br>mark : 1/8/1996<br>terry : 11/17/1995<br>mark : 10/20/1995<br>carol : 12/6/1994<br>carol : 6/24/1993<br>supermim : 3/16/1992<br>carol : 2/24/1992
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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>
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<h3>
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<span class="mim-font">
|
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<strong>*</strong> 136350
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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|
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FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1
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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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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
FMS-LIKE TYROSINE KINASE 2; FLT2<br />
|
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FMS-LIKE GENE; FLG
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</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
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</span>
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</p>
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</div>
|
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<div>
|
|
<span class="h3 mim-font">
|
|
FGFR1/BCR FUSION GENE, INCLUDED
|
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</span>
|
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</div>
|
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|
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<div>
|
|
<span class="h4 mim-font">
|
|
|
|
FGFR1/FGFR1OP2 FUSION GENE, INCLUDED<br />
|
|
FGFR1/ZNF198 FUSION GENE, INCLUDED<br />
|
|
FGFR1/TACC1 FUSION GENE, INCLUDED
|
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</span>
|
|
</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: FGFR1</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 109409003, 238905009, 254144002, 70410008, 709105005, 766032007;
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<strong>ICD10CM:</strong> Q75.03;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: 8p11.23
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 8:38,411,143-38,468,635 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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|
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<div>
|
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<br />
|
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</div>
|
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<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="7">
|
|
<span class="mim-font">
|
|
8p11.23
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Encephalocraniocutaneous lipomatosis, somatic mosaic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613001
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hartsfield syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
615465
|
|
</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">
|
|
Hypogonadotropic hypogonadism 2 with or without anosmia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
147950
|
|
</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">
|
|
Jackson-Weiss syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
123150
|
|
</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">
|
|
Osteoglophonic dysplasia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
166250
|
|
</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">
|
|
Pfeiffer syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
101600
|
|
</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">
|
|
Trigonocephaly 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
190440
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
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<p>Ruta et al. (1988) isolated a novel gene from a human endothelial cell cDNA library by hybridizing at relaxed stringency using the v-fms oncogene as a probe. DNA sequence analysis of a 2-kb cDNA insert showed an open reading frame encoding a putative protein tyrosine kinase.</p><p>Ruta et al. (1989) found that acidic fibroblast growth factor (FGFA; 131220) stimulates tyrosine kinase activity of FLG in vitro and in living cells, suggesting that FLG encodes the membrane receptor for acidic FGF. The protein FLG is the human equivalent of a known chicken basic FGF receptor (Lee et al., 1989). Lee et al. (1989) isolated a 130-kD protein on the basis of its ability to bind specifically to basic fibroblast growth factor (FGF2; 134920). They then isolated a cDNA using an oligonucleotide probe corresponding to the amino acid sequences of tryptic peptide fragments of the purified protein. The putative FGFB receptor encoded by this cDNA was found to be a transmembrane protein that contained 3 extracellular immunoglobulin-like domains, an unusual acidic region, and an intracellular tyrosine kinase domain. </p><p>Wang et al. (1996) identified cDNAs encoding an FGFR1 splice variant that lacks a portion of the tyrosine kinase catalytic domain. This splice variant, termed FGFR1-prime, is expressed in human lung fibroblasts and several other human cell lines. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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<p>Plotnikov et al. (1999) determined the crystal structure of FGF2 (134920) bound to a naturally occurring variant of FGFR1 consisting of immunoglobulin-like domains 2 (D2) and 3 (D3) at 2.8-angstrom resolution. Two FGF2:FGFR1 complexes form a 2-fold symmetric dimer. Within each complex, FGF2 interacts extensively with D2 and D3 as well as with the linker between the 2 domains. The dimer is stabilized by interactions between FGF2 and D2 of the adjoining complex and by a direct interaction between D2 of each receptor. A positively charged canyon formed by a cluster of exposed basic residues likely represents the heparin-binding site. A general model for FGF- and heparin-induced FGFR dimerization was inferred from the crystal structure. </p><p>To elucidate the structural determinants governing specificity in FGF signaling, Plotnikov et al. (2000) determined the crystal structures of FGF1 (131220) and FGF2 complexed with the ligand-binding domains (D2 and D3) of FGFR1 and FGFR2, respectively. They found that highly conserved FGF-D2 and FGF-linker interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and 2 loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing. </p>
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<h4>
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<strong>Gene Structure</strong>
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</h4>
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<p>The 2 classes of sequences for recognition and splicing of pre-mRNA in eukaryotes, GT-AG and AT-AC, are characterized by the nearly invariant dinucleotides present at the extreme 5-prime (donor) and 3-prime (acceptor) ends of the intron. Among GT-AG introns, which comprise the vast majority, the more extended consensus sequence at the 5-prime splice site is A(C)AG/gta(g)agt (where the slash indicates the exon-intron boundary and the nucleotide in parentheses is an alternate). This sequence is complementary to part of the U1 snRNA and is important in intron recognition. Twigg et al. (1998) determined the genomic structure of the Fgfr2 gene of the mouse and identified a divergent 5-prime splice site (ACA/gaaagt), conserved in FGFR1, FGFR2 (176943), and FGFR3 (134934) from humans, mice, and Xenopus that is used for alternative splicing of a hexanucleotide sequence, encoding val-thr, at the end of exon 10. This is the only example known of the use of /ga in vertebrate splicing. Similarities to a splice site in the Antennapedia gene of Drosophila suggested that this variant motif is involved in alternative splicing of short sequences at the 5-prime splice site. Inclusion or exclusion of the val/thr dipeptide may play an important role in controlling FGFR signaling through the Ras/MAPK pathway. </p>
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<strong>Mapping</strong>
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<p>Ruta et al. (1988) localized the FGFR1 gene, which they designated FLG, to 8p12-p11.2 by in situ hybridization. Assignment to chromosome 8 was also indicated by Southern blot analysis of DNA from hamster-human hybrid cells. This region of mapping is involved in myeloproliferative disorders. Wood et al. (1995) mapped both FGFR1 and CEBPD (116898) to 8p11.2-p11.1 by analysis of somatic cell hybrids combined with fluorescence in situ hybridization. </p>
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<h4>
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<strong>Gene Function</strong>
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<p>Wang et al. (1996) reported that the FGFR1-prime variant bound specifically to acidic FGF but ligand binding caused neither receptor autophosphorylation nor activation of phospholipase C (PLC). The authors suggested that the kinase-deficient variant may have an important role in regulating cellular responses elicited by acidic FGF stimulation. </p><p>Jung et al. (1999) studied the initiation of mammalian liver development from endoderm by fibroblast growth factors. The hepatogenic response was restricted to endoderm tissue, which selectively coexpresses FGF receptors 1 and 4 (134935). </p><p>Using in situ hybridization, Pirvola et al. (2002) detected Fgfr1 expression at several stages during inner ear development in mouse, especially in regions contributing to the formation of the organ of Corti. To further study the function of Fgfr1 in the developing inner ear, Pirvola et al. (2002) analyzed mice carrying partial loss-of-function mutations (Partanen et al., 1998) and otic epithelium-specific null mutations in Fgfr1. Pirvola et al. (2002) observed a reduction in the number of auditory hair cells in Fgfr1 mutants and hypothesized that FGFR1 is required for proliferation of precursor cells that give rise to the auditory sensory epithelium. The authors concluded that FGFR1 is essential for the normal formation of the organ of Corti and that phenotype severity observed in Fgfr1 mutants is dependent on the dose of FGFR1. </p><p>Schlessinger (2004) reviewed the signaling pathways that are activated by EGF and FGF receptors. Both receptors stimulate a similar complement of intracellular signaling pathways. However, whereas activated EGF receptors function as the main platform for recruitment of signaling proteins, signaling through the FGF receptors is mediated primarily by assembly of a multidocking protein complex. Furthermore, FGF receptor signaling is subject to additional intracellular and extracellular control mechanisms that do not affect EGF receptor signaling. </p><p>Siffroi-Fernandez et al. (2005) examined FGF high and low affinity receptor (FGFR) expression, activation of FGFR1 by acidic FGF (FGF1), and proliferative effects on Y79 retinoblastoma (see 180200) cells. They found that Y79 retinoblastoma expresses protein and mRNA of all 4 FGFRs. FGFR1 was differentially phosphorylated by FGF1. Proliferation of Y79 cells induced by FGF1 was entirely mediated by FGFR1. FGF1-induced proliferation was dependent on the presence and sulfation of heparan sulfate proteoglycan (HSPG; 142460). Siffroi-Fernandez et al. (2005) concluded that their study demonstrated a role for the FGF1/FGFR1 pathway in retinoblastoma proliferation and might contribute to developing therapeutic strategies to limit retinoblastoma growth. </p><p>Furdui et al. (2006) demonstrated that the 5 tyrosines autophosphorylated in the catalytic core of mammalian FGFR1 are phosphorylated by a precisely controlled and ordered reaction. They also showed that the rate of substrate phosphorylation by FGFR1 is enhanced at least 50- and 500-fold after autophosphorylation of FGFR1 on tyr653 and tyr654, respectively. </p><p>FGF receptors are derived from FGFRs 1 through 4. The difference in the number of immunoglobulin-like loops (alpha-type and beta-type) and alternative splicing of mRNA corresponding to the third immunoglobulin-like loop (IIIa, IIIb, and IIIc) produce several subtypes of FGFRs. Urakawa et al. (2006) demonstrated that a previously undescribed receptor conversion of FGFR1(IIIc) by Klotho (604824) generates the FGF23 (605380) receptor. Using a renal homogenate, Urakawa et al. (2006) found that Klotho binds to FGF23. Forced expression of Klotho enabled the high affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wildtype mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signaling, Urakawa et al. (2006) searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. </p><p>Neugebauer et al. (2009) provided several lines of evidence showing that fibroblast growth factor signaling regulates cilia length and function in diverse epithelia during zebrafish and Xenopus development. Morpholino knockdown of Fgfr1 in zebrafish cell-autonomously reduced cilia length in Kupffer vesicle and perturbed directional fluid flow required for left-right patterning of the embryo. Expression of a dominant-negative Fgfr1, treatment with a pharmacologic inhibitor of FGF signaling, or genetic and morpholino reduction of redundant FGF ligands Fgf8 (600483) and Fgf24 reproduced this cilia length phenotype. Knockdown of Fgfr1 also resulted in shorter tethering of cilia in the otic vesicle and shorter motile cilia in the pronephric ducts. In Xenopus, expression of a dominant-negative fgfr1 resulted in shorter monocilia in the gastrocoel roof plate that control left-right patterning and in shorter multicilia in external mucociliary epithelium. Neugebauer et al. (2009) concluded that their results indicated a fundamental and highly conserved role for FGF signaling in the regulation of cilia length in multiple tissues. Abrogation of Fgfr1 signaling downregulates expression of 2 ciliogenic transcription factors, foxj1 (602291) and rfx2 (142765), and of the intraflagellar transport gene ift88 (600595), indicating that FGF signaling mediates cilia length through an Fgf8/Fgf24-Fgfr1-intraflagellar transport pathway. Neugebauer et al. (2009) proposed that a subset of developmental defects and diseases ascribed to FGF signaling are due in part to loss of cilia function. </p><p>Ding et al. (2014) combined an inducible endothelial cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury to show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The profibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors CXCR7 (610376) and CXCR4 (162643) in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor ID1 (600349), deploying proregenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive Fgfr1 signaling in liver sinusoidal endothelial cells counterbalanced Cxcr7-dependent proregenerative response and augmented Cxcr4 expression. This predominance of Cxcr4 over Cxcr7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin (125660)-positive hepatic stellate-like cells and enforcing a profibrotic vascular niche. Endothelial cell-specific ablation of either Fgfr1 or Cxcr4 in mice restored the proregenerative pathway and prevented Fgfr1-mediated maladaptive subversion of angiocrine factors. Similarly, selective Cxcr7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Ding et al. (2014) demonstrated that in response to liver injury, differential recruitment of proregenerative CXCR7-ID1 versus profibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. </p><p>Lievens et al. (2016) reported that mouse Zdhhc3 (617150) catalyzed S-palmitoylation of the transmembrane isoforms of Ncam1, Ncam140 and Ncam180. Using site-directed mutagenesis and inhibitor studies, they showed that Fgf2 induced phosphorylation of Zdhhc3 on tyr18 via the tyrosine kinase activity of its receptor, Fgfr1. Src (190090) directly phosphorylated Zdhhc3 on tyr295 and tyr297. The 2 kinases had opposite effects on Zdhhc3 activity, with Fgfr1-dependent phosphorylation enhancing Zdhhc3 activity, and Src-dependent phosphorylation inhibiting Zdhhc3 activity. Autopalmitoylation, an intermediate reaction state in palmitate transfer to target proteins, was enhanced by absence of all 5 tyrosines in Zdhhc3 and was abolished with the dominant-negative cys157-to-ser (C157S) mutation at the active site of Zdhhc3. Overexpression of tyrosine-mutant Zdhhc3 in cultured rat hippocampal neurons increased the number of neurites and tended to increase neurite length. Lievens et al. (2016) concluded that FGF2-FGFR1 signaling facilitates ZDHHC3 tyrosine phosphorylation and triggers NCAM1 palmitoylation for neurite extension, whereas SRC-mediated ZDHHC3 phosphorylation inhibits NCAM1 palmitoylation and neurite extension. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Skeletal Disorders</em></strong></p><p>
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Robin et al. (1994) found that in some families with Pfeiffer syndrome (101600), the disorder shows linkage to markers on chromosome 8. By performing fluorescence in situ hybridization using yeast artificial chromosomes (YACs) that contained the linked DNA markers, they localized one gene for Pfeiffer syndrome to the pericentromeric region of chromosome 8. Close linkage was excluded in other Pfeiffer syndrome families. Because the FGFR1 gene is located in that region and because mutations in other FGFR genes had been demonstrated in skeletal dysplasias (FGFR2 (176943) in Crouzon and Jackson-Weiss syndromes, and FGFR3 (134934) in achondroplasia), it became a prime candidate for the site of the mutation in chromosome 8-linked Pfeiffer syndrome. Muenke et al. (1994) found a C-to-G transversion in exon 5 of the FGFR1 gene, predicting a proline-to-arginine substitution in the putative extracellular domain, in all affected members of 5 unrelated Pfeiffer syndrome families but not in any unaffected individuals. </p><p>Passos-Bueno et al. (1999) provided an up-to-date listing of the mutations in FGFR1, FGFR2, and FGFR3 that are associated with distinct clinical entities, including achondroplasia (100800), hypochondroplasia (146000), thanatophoric dysplasia (see 187600 and 187601), Antley-Bixler syndrome (207410), Apert syndrome (101200), Beare-Stevenson syndrome (123790), Crouzon syndrome (123500), Jackson-Weiss syndrome (123150), Pfeiffer syndrome (101600), and Saethre-Chotzen syndrome (101400). </p><p>Roscioli et al. (2000) reported the case of a patient with the skeletal findings of Jackson-Weiss syndrome who manifested only mild craniofacial anomalies. They demonstrated heterozygosity for the P252R missense mutation (136350.0001). The observations represented a further example of the phenomenon of an activated FGFR molecule resulting in overlapping manifestations in FGFR syndromes. </p><p>Kress et al. (2000) screened 10 patients with nonsyndromic trigonocephaly (TRIGNO1; 190440) for mutations in exon 5 of FGFR1 gene, exons 8 and 10 of the FGFR2 gene, exon 7 of the FGFR3 gene, and exon 1 of the TWIST1 (601622) gene (all regions known to be involved in autosomal dominant craniosynostosis syndromes). They identified 1 patient with a mutation in the FGFR1 gene (I300T; 136350.0011). Hurley et al. (2004) reported a male infant with an Antley-Bixler syndrome-like skeletal phenotype (see 207410) and abnormal genitalia (see POR deficiency, 201750) in whom they identified the I300T mutation; the authors stated that the significance of the FGFR1 mutation was unclear. In the patient reported by Hurley et al. (2004), Huang et al. (2005) subsequently identified compound heterozygosity for a frameshift and a substitution mutation in the gene for cytochrome P450 oxidoreductase (POR; 124015.0015 and 124015.0016, respectively) as well. </p><p>In an extensive review of the genetics of craniofacial development and malformation, Wilkie and Morriss-Kay (2001) provided a useful diagram of the molecular pathways in cranial suture development with a listing of all craniofacial disorders caused by mutations in the corresponding genes. Four proteins were indicated as having strong evidence for existing in the pathway, with successive downstream targets as follows: TWIST1--FGFR2--FGFR1--CBFA1 (600211). </p><p>Wilkie et al. (2002) reviewed the association of mutations in FGFR1 and FGFR2 with disorders of limb patterning. They also stated that mutations of FGFR3 and FGF23 (605380) affect growth of the limb bones, e.g., in achondroplasia and autosomal dominant hypophosphatemic rickets (193100), respectively. </p><p>A diverse group of skeletal disorders are caused by activating mutations in the genes encoding fibroblast growth factor receptors FGFR1, FGFR2, and FGFR3. In general, mutations in FGFR1 and FGFR2 cause most of the syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutations. Osteoglophonic dysplasia (166250) is a 'crossover' disorder that has skeletal phenotypes usually associated with FGFR1, FGFR2, and FGFR3 mutations. White et al. (2005) demonstrated that osteoglophonic dysplasia is caused by missense mutations in highly conserved residues comprising the ligand-binding and transmembrane membranes of FGFR1, thus defining novel roles for this receptor as a negative regulator of long bone growth. White et al. (2005) demonstrated that the Y372C mutation (136350.0008) is an activating mutation, i.e., a gain-of-function mutation. In contrast, inactivating mutations in FGFR1 are responsible for autosomal dominant Kallmann syndrome; see, for example, 136350.0002. </p><p><strong><em>Role in Cancer</em></strong></p><p>
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Bruno et al. (2004) noted that FGFR1-beta, the splice variant resulting from alternative splicing of exon 3 (also termed alpha-exon) of FGFR1, has been associated with cancer in humans. They targeted the intronic silencing sequence (ISS) elements flanking the alpha-exon with antisense morpholino oligonucleotides, resulting in increased alpha-exon inclusion of between 10% and 70% in vivo. The effect was dose-dependent, sequence-specific, and reproducible in several human cell lines, but did not necessarily correlate with blocking of protein association in vitro. Simultaneous targeting of the ISS elements had no additive effect, suggesting that splicing regulation occurred through a shared mechanism. The correction of FGFR1 gene splicing to more than 90% alpha-exon inclusion in glioblastoma cells had no discernible effect on cell growth in culture, but was associated with an increase in unstimulated CASP3 (600636) and CASP7 (601761) activity. </p><p>By sequencing the exons encoding the kinase domains of 20 receptor tyrosine kinases in 19 glioblastomas, Rand et al. (2005) identified 2 somatic mutations in the FGFR1 gene in separate tumors, as well as a somatic mutation in the PDGFRA (173490) gene in another tumor. Structural analysis suggested that the FGFR1 mutations, asn546 to lys (N546K) and arg576 to trp (R576W), could lead to upregulation of constitutive kinase activity. </p><p>Jones et al. (2013) described whole-genome sequencing of 96 pilocytic astrocytomas (see 137800), with matched RNA sequencing for 73 samples, conducted by the International Cancer Genome Consortium PedBrain Tumor Project. Jones et al. (2013) identified recurrent activating mutations in FGFR1 and PTPN11 (176876) and novel NTRK2 (600456) fusion genes in noncerebellar tumors. Novel BRAF (164757)-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, Jones et al. (2013) identified the same FGFR1 mutations in a subset of H3F3A (601128)-mutated pediatric glioblastoma with additional alterations in the NF1 gene (613113). </p><p><strong><em>Hypogonadotropic Hypogonadism 2 with or without Anosmia</em></strong></p><p>
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Dode et al. (2003) took advantage of 2 overlapping interstitial deletions at 8p12-p11 in individuals with different contiguous gene syndromes that both included Kallmann syndrome (HH2; 147950). Mutation analysis of the FGFR1 gene identified loss-of-function mutations in FGFR1 as the basis of autosomal dominant Kallmann syndrome; a gain-of-function mutation in FGFR1 (see 136350.0001) causes a form of craniosynostosis. Dode et al. (2003) suggested that the X-chromosome-encoded KAL1 gene product, the extracellular matrix protein anosmin-1 (300836), is involved in fibroblast growth factor (FGF) signaling and proposed that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males. </p><p>Pitteloud et al. (2006) examined the FGFR1 gene in 7 unrelated patients with normosmic idiopathic hypogonadotropic hypogonadism and identified heterozygous mutations in 3 individuals, 2 from mixed pedigrees in which some family members were anosmic (136350.0013 and 136350.0014, respectively) and 1 with associated midline defects (136350.0015). One parent from each of the mixed pedigrees had isolated congenital anosmia (see 107200). Structural and biochemical analysis of the mutations revealed that all resulted in receptor loss of function. </p><p>In 2 sisters with normosmic hypogonadotropic hypogonadism in whom Seminara et al. (2000) had previously identified compound heterozygosity for missense mutations in the GNRHR gene (Q106R, 138850.0001 and R262Q, 138850.0002), Pitteloud et al. (2007) identified heterozygosity for an additional missense mutation in the FGFR1 gene (R470L; 136350.0016). The mutation was also found in the father, who had a history of delayed puberty and was heterozygous for the R262Q mutation in GNRHR; and in the unaffected daughter of the younger sister, who had undergone normal puberty and had no mutations in GNRHR. Pitteloud et al. (2007) also studied another family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone. The authors identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his sister; and they identified heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (608137.0002), in the proband, his mother, and his brother. Pitteloud et al. (2007) concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with isolated hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. </p><p>In a 19-year-old man and an unrelated 10-year-old boy with normosmic hypogonadotropic hypogonadism, both of whom were known to carry mutations in the FGF8 gene (600483.0003 and 600483.0004, respectively), Falardeau et al. (2008) identified additional mutations in the FGFR1 gene (see 136350.0023-136350.0025, respectively). </p><p>Raivio et al. (2009) sequenced the FGFR1 gene in 134 patients with normosmic IHH and identified heterozygous loss-of-function mutations in 9 (7%). Screening of 5 more HH-associated genes in the 9 mutation-positive patients revealed additional mutations in 5 patients, including mutations in the GNRHR (138850), PROKR2 (607123), and FGF8 (600483) genes. </p><p>Tornberg et al. (2011) studied a large French Canadian pedigree with several consanguineous loops, in which the proband and 3 additional family members had anosmic HH associated with a missense mutation in the HS6ST1 gene (604846.0002). Because of the phenotypic variability and reduced penetrance displayed in the family, the authors screened 8 additional known HH-associated genes and detected a missense mutation in FGFR1 that was also present in the 4 affected members as well as 1 unaffected individual (136350.0025). In another family in which a man with anosmic HH and his unaffected brother both carried a missense mutation in HS6ST1 (604846.0001), screening revealed an additional missense mutation in the NELF gene (608137.0001) in the proband. Tornberg et al. (2011) concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction. </p><p>In the large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate in which Tornberg et al. (2011) had identified mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified additional mutations in 2 more genes, FGF17 (603725.0001) and FLRT3 (604808.0001 and 604808.0002). In addition, in 4 more unrelated probands with anosmic HH, Miraoui et al. (2013) identified heterozygosity for 4 different missense mutations in FGFR1 (136350.0026-136350.0029) as well as heterozygosity for 4 other genes in the FGF network: IL17RD (606807.0002), SPRY4 (607984.0002), DUSP6 (602748.0002), and FLRT3 (604808.0003), respectively. Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. </p><p>In a patient with anosmic hypogonadotropic hypogonadism (HH16; 614897) who was heterozygous for a missense mutation in the SEMA3A gene (603961), Hanchate et al. (2012) also identified heterozygosity for a missense mutation in FGFR1. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder. </p><p>Villanueva et al. (2015) reported 7 probands with mutations in the FGFR1 gene (see, e.g., 136350.0026) who exhibited split hand/foot malformations (SHFM) as well as HH. </p><p><strong><em>Hartsfield Syndrome</em></strong></p><p>
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In 1 female and 5 male patients with holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; 615465), Simonis et al. (2013) identified missense mutations in the FGFR1 gene (see, e.g., 136350.0030-136350.0032). Most patients were heterozygous, but 2 patients carried homozygous mutations (see, e.g., 136350.0031). </p><p><strong><em>Encephalocraniocutaneous Lipomatosis</em></strong></p><p>
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In 5 unrelated patients with encephalocraniocutaneous lipomatosis (ECCL; 613001), Bennett et al. (2016) identified mosaicism for 2 missense variants in the FGFR1 gene: 3 patients carried an N546K substitution (136350.0033), and 2 carried a K656E substitution (136350.0034). The alternate allele fraction ranged from 23 to 55% in fibroblasts from affected tissues, but the mutations were not detected in saliva or blood samples. Neither variant was found in the Exome Variant Server, ExAC, or dbSNP databases. Bennett et al. (2016) noted that these 2 residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with central nervous system tumors. Functional studies of ECCL fibroblast cell lines showed increased levels of phosphorylated FGFRs and phosphorylated FRS2 (607743), as well as constitutive activation of RAS (see 190020)/MAPK (see 176872) signaling. </p><p><strong><em>Nonsyndromic Cleft Lip/Palate</em></strong></p><p>
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Riley et al. (2007) analyzed 12 genes involved in the fibroblast growth factor signaling pathway in nonsyndromic cleft lip or palate families and identified 7 likely disease-causing mutations in which structural analysis predicted functional impairment in the FGFR1, FGFR2, FGFR3, and FGF8 (600483) genes. Riley et al. (2007) suggested that the FGF signaling pathway may contribute to as much as 3 to 5% of nonsyndromic cleft lip or palate. </p>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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<p>Xiao et al. (1998) noted that a specific chromosome translocation, t(8;13)(p11;q11-12), had been found in both lymphoma and myeloid leukemia cells from patients with stem cell leukemia/lymphoma (SCLL; 613523), supporting bi-lineage differentiation from a transformed stem cell. Xiao et al. (1998) found that the 8p11 translocation breakpoints in each of 4 patients interrupted intron 8 of the FGFR1 gene. These translocations were associated with aberrant transcripts in which 4 predicted zinc finger domains, contributed by a novel and widely expressed chromosome 13 gene, ZNF198 (602221), were fused to the FGFR1 tyrosine-kinase domain. Transient expression studies showed that the ZNF198-FGFR1 fusion transcript directs the synthesis of an approximately 87-kD polypeptide, localizing predominantly to the cytoplasm. The studies demonstrated an FGFR1 oncogenic role and suggested a tumorigenic mechanism in which ZNF198-FGFR1 activation results from ZNF198 zinc finger-mediated homodimerization. Some of the FGFR-associated hereditary skeletal disorders result from mutations that effect constitutive FGFR activation. In vitro evidence for mutational FGFR activation in these syndromes includes ligand-independent receptor tyrosine phosphorylation and increased cell proliferation. Nevertheless, individuals with FGFR-associated skeletal syndromes are not known to be at increased risk for SCLL or other types of cancer. The level of FGFR1 tyrosine-kinase activation in hereditary skeletal syndromes may be insufficient to effect neoplastic transformation of hematopoietic stem cells. </p><p>Lorenzi et al. (1996) described FGFR2 activation by a C-terminal alteration through a chromosomal rearrangement in a rat osteosarcoma. Alterations of FGFR3 (134934), whose germline activating mutations are responsible for major forms of dwarfism including achondroplasia, were found by Chesi et al. (1997) in t(4;14) translocations associated with multiple myeloma. </p><p>Popovici et al. (1998) described the molecular characterization of the t(8;13) translocation that involves the FGFR1 and ZNF198 genes. The 2 reciprocal fusion transcripts, ZNF198/FGFR1 and FGFR1/ZNF198, were expressed in malignant cells. The ZNF198/FGFR1 fusion protein contained the ZNF198 putative zinc finger motifs and the catalytic domain of FGFR1, and the authors showed that the protein has a constitutive tyrosine kinase activity. </p><p>Kulkarni et al. (1999) determined that the common t(8;13)(p11;q12) translocation results in a consistent fusion between ZNF198 exon 17 and FGFR1 exon 9. However, amplification of genomic DNA from 6 patients with t(8;13) revealed patient-specific products, suggesting clustering of several breakpoints. An additional patient showed a breakpoint within ZNF198 exon 18. </p><p>Popovici et al. (1999) identified the FOP gene (605392) as the fusion partner of FGFR1 in the 8p11 myeloproliferative disorder involving the t(6;8)(q27;p11) translocation. Using RT-PCR, they detected both FGFR1-FOP and FOP-FGFR1 fusion transcripts, with the break occurring in intron 8 of FGFR1 or intron 6 of FOP, in 2 patients with the 8p11 myeloproliferative disorder but not in normal subjects or those with other tumors. </p><p>Guasch et al. (2000) identified the CEP1 gene (605496) as the fusion partner of the FGFR1 gene in the 8p11 myeloproliferative disorder involving the t(8;9)(p11;q33) translocation. By RT-PCR and genomic sequence analysis, they detected reciprocal fusion transcripts with the breakpoint localized in exon 8 of FGFR1 and in an intron of CEP1. Immunoblot analysis showed that the CEP1-FGFR1 fusion protein is expressed as a constitutively tyrosine-phosphorylated, 150-kD tyrosine kinase. Immunofluorescence microscopy demonstrated that the CEP1-FGFR1 fusion protein, like other FGFR1 fusion proteins, is detected mainly in the cytoplasm, contrasting with the centrosome and plasma membrane localizations of the respective wildtype proteins. </p><p>Sohal et al. (2001) identified 4 translocations that most likely involve FGFR1 in myeloid disorders. Demiroglu et al. (2001) described 2 patients with a clinical and hematologic diagnosis of chronic myeloid leukemia (CML; 608232) in chronic phase who had an acquired t(8;22)(p11;q11). They confirmed that both patients were negative for a BCR (151410)-ABL fusion gene and that both had an in-frame mRNA fusion between BCR exon 4 and FGFR1 exon 9. Thus, a BCR-FGFR1 fusion may occur in patients with apparently typical CML. The possibility of successful treatment with specific FGFR1 inhibitors was suggested. </p><p>Grand et al. (2004) identified a (12;8)(p11;p11p22) insertion in a 75-year-old male who presented with a T-cell lymphoblastic lymphoma that progressed rapidly to AML. An obvious chronic myeloproliferative disease was not apparent during the course of his disease, but the clinical picture fit the overall pattern seen in patients with 8p11 myeloproliferative syndrome. In addition to the insertion, bone marrow cytogenetics following development of AML revealed loss of 1 copy of chromosome 7 in all cells analyzed. The patient also showed mild eosinophilia with infiltration of the affected lymph node and bone marrow by atypical eosinophils. Grand et al. (2004) determined that the ins(12;8)(p11;p11p22) resulted in an in-frame fusion of exon 4 of the FGFR1OP2 gene (608858) to exon 9 of the FGFR1 gene. The chimeric protein contains 526 amino acids and has a calculated molecular mass of 60 kD. FGFR1OP2-FGFR1 has the first 2 coiled-coil domains of FGFR1OP2 fused to the entire tyrosine kinase domain and part of the juxtamembrane region of FGFR1. Reciprocal FGFR1-FGFR1OP2 transcripts were not detected. Since the direction of FGFR1OP2 transcription is in the opposite orientation to the direction of FGFR1 transcription, an inversion must have taken place in the formation of the chimeric gene. </p><p>In a male patient with hypogonadotropic hypogonadism and cleft lip and palate without 'frank' anosmia (see 147950), Kim et al. (2005) identified a balanced reciprocal translocation, t(7;8)(p12.3;p11.2). Positional cloning of the breakpoints revealed that the translocation disrupts the FGFR1 gene between exons 2 and 3 and predicts a novel fusion gene product. Kim et al. (2005) stated that this was the first case in which a constitutional FGFR1 translocation was associated with a developmental disorder. </p><p>Singh et al. (2012) reported that a small subset of glioblastoma multiforme tumors (GBMs; 137800) (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes FGFR1 or FGFR3 to the transforming acidic coiled-coil (TACC) coding domains of TACC1 (605301) or TACC3 (605303), respectively. The FGFR-TACC fusion protein displayed oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrected the aneuploidy, and oral administration of an FGFR inhibitor prolonged survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. Singh et al. (2012) concluded that FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition. </p>
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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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<span class="mim-text-font">
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<p>Zhou et al. (2000) showed that mice carrying a pro250-to-arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation pro252 to arg (136350.0001) in humans, exhibit anterio-posteriorly shortened, laterally widened, and vertically heightened neurocrania. Cranial sutures of early postnatal mutant mice exhibited multiple premature fusions, accelerated osteoblast proliferation, and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Markedly increased expression of Cbfa1 (RUNX2; 600211) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro by demonstrating that transfection with wildtype or mutant Fgfr1 induced Cbfa1 expression. The induced expression was also observed using the Fgf ligands Fgf2 and Fgf8. </p><p>To study the role of Fgfr1 in mammary gland tumorigenesis, Welm et al. (2002) developed a transgenic mouse carrying an Fgfr1 gene that could be pharmacologically induced to dimerize with the drug AP20187 independent of Fgf levels. Treatment of transgenic mice with AP20187 resulted in tyrosine phosphorylation, increased cell proliferation, activation of Mapk and Akt (164730), and lateral budding of the mammary glands. Change in ductal morphology was seen in ovariectomized animals, suggesting that ovarian hormones were not required. Chronic activation of the transgene resulted in progressively invasive lesions characterized by multicell-layered lateral buds, decreased myoepithelium, increased vascular branching, and loss of cell polarity. Welm et al. (2002) concluded that acute Fgfr1 signaling results in increased lateral budding of the mammary ductal epithelium and that sustained activation induces alveolar hyperplasia and invasive lesions. </p><p>Trokovic et al. (2003) found that mice homozygous for a hypomorphic allele of Fgfr1 had craniofacial defects, some of which appeared to result from a failure in the early development of the second branchial arch. A stream of neural crest cells originating from the rhombomere-4 region migrated toward the second branchial arch in the mutant mice, but most cells failed to enter the second arch and accumulated in a region proximal to it. Both rescue of the hypomorphic Fgfr1 allele and inactivation of a conditional Fgfr1 allele specifically in neural crest cells indicated that the Fgfr1-regulated entry of neural crest cells into the second branchial arch was not cell autonomous, but appeared to depend upon prior gene expression in the overlying pharyngeal ectoderm. Abnormal gene expression in the hypomorphic Fgfr1 mutants led to mispatterning in the pharyngeal region at a stage prior to neural crest entry. Trokovic et al. (2003) concluded that Fgfr1 patterns the pharyngeal region to create a permissive environment for neural crest cell migration. </p><p>To establish the contribution of FGFR1 to cardiac development, Dell'Era et al. (2003) investigated the capacity of murine Fgfr1 +/- and Fgfr1 -/- embryonic stem (ES) cells to differentiate to cardiomyocytes in vitro. Clusters of pulsating cardiomyocytes were observed in more than 90% of 3-dimensional embryoid bodies (EBs) from Fgfr1 +/- ES cells at day 9 to 10 of differentiation, but only 10% or fewer of Fgfr1 -/- EBs showed beating foci at day 16. Fgfr1 -/- EBs were further characterized by impaired expression of early cardiac transcription factors and late structural cardiac genes, as well as alterations in the expression of mesoderm-related early genes. However, Fgfr1 +/- and Fgfr1 -/- EBs similarly expressed cardiogenic precursor, endothelial, hematopoietic, and skeletal muscle markers, indicating that the Fgfr1 null mutation exerts a selective effect on cardiomyocyte development in differentiating ES cells. Inhibitors of FGFR signaling prevented cardiomyocyte differentiation in Fgfr1 +/- EBs without affecting the expression of the hematopoietic/endothelial marker Flk1 (see 191306). Dell'Era et al. (2003) concluded that FGFR1-mediated signaling has a nonredundant role in cardiomyocyte development. </p><p>Magnusson et al. (2007) found that differentiating stem cell cultures, or embryoid bodies, from Fgfr1 -/- mice displayed increased vascularization and distinct, elongated vessel morphology. Teratomas derived from Fgfr1 -/- stem cells also showed abnormal vessel morphology and were characterized by increased growth rate. The increased vascularization and altered endothelial cell morphology were dependent on secreted factors based on the transfer of the Fgfr1 -/- vascular phenotype by conditioned medium to Fgfr1 +/- embryoid bodies. Il4 (147780) was downregulated and pleiotrophin (PTN; 162095) was upregulated in Fgfr1 -/- embryoid bodies compared with Fgfr1 +/- cultures, and Magnusson et al. (2007) showed that these cytokines acted as negative and positive angiogenic regulators, respectively. </p><p>The hush puppy (hspy) mutation in mice leads to dominant inheritance of pinna and ossicle malformations, skull abnormalities, reduced rows of cochlear hair cells, and raised threshold for auditory responses. Calvert et al. (2011) identified hspy as a point mutation in the Fgfr1 gene leading to substitution of a conserved trp residue with arg (W691R) in the Fgfr1 kinase domain. Transfection of HEK293 cells with hspy mutant Fgfr1 resulted in normal protein expression and membrane trafficking. However, the mutant Fgfr1 was unresponsive to Fgf in calcium mobilization and downstream signaling through MAP kinase or PLC-gamma (see 172420). Homozygous hspy mutant embryos were lost early in gastrulation and were developmentally retarded. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>34 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PFEIFFER SYNDROME</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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JACKSON-WEISS SYNDROME, 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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FGFR1, PRO252ARG
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<br />
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SNP: rs121909627,
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gnomAD: rs121909627,
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ClinVar: RCV000017669, RCV000017670, RCV000644520, RCV001200303, RCV002496391, RCV004798731
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</span>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Pfeiffer Syndrome</em></strong></p><p>
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By SSCP analysis of FGFR1 in patients with Pfeiffer syndrome (101600), Muenke et al. (1994) found a C-to-G transversion at position 755 of exon 5, predicting a pro252-to-arg substitution located between the second and third putative Ig domain of the FGFR1 protein. Proline residue is highly conserved in evolution, being present in chicken, mouse, rat, and all 4 human FGFR genes. </p><p><strong><em>Jackson-Weiss Syndrome</em></strong></p><p>
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Roscioli et al. (2000) reported the case of a patient with the skeletal findings of Jackson-Weiss syndrome (JWS; 123150) who manifested only mild craniofacial anomalies. They demonstrated heterozygosity for the P252R missense mutation in the FGFR1 gene. </p><p><strong><em>Variant Function</em></strong></p><p>
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By surface plasmon resonance analysis and X-ray crystallography, Ibrahimi et al. (2004) characterized the effects of proline-to-arginine mutations in FGFR1c and FGFR3c on ligand binding. Both the FGFR1c P252R mutation and the FGFR3c P250R (134934.0014) mutation exhibited an enhancement in ligand binding in comparison to their respective wildtype receptors. Binding of both mutant receptors to FGF9 (600921) was notably enhanced and implicated FGF9 as a potential pathophysiologic ligand for mutant FGFRs in mediating craniosynostosis. The crystal structure of the P252R mutant in complex with FGF2 showed that enhanced ligand binding was due to an additional set of receptor-ligand hydrogen bonds, similar to the gain-of-function interactions that occur in the crystal structure of the FGFR2c P253R (176943.0011) mutant in complex with FGF2. However, unlike the P253R mutant, neither the FGFR1c P252R mutant nor the FRGR3c P250R mutant bound appreciably to FGF7 (148180) or FGF10 (602115). Ibrahimi et al. (2004) suggested that this might explain why limb phenotypes observed in type I Pfeiffer syndrome (101600) and Muenke syndrome (602849) are less severe than limb abnormalities observed in Apert syndrome (101200). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</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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FGFR1, 2-BP DEL, 1970CA
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<br />
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SNP: rs1586111679,
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ClinVar: RCV000030924
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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>Dode et al. (2003) found a 2-bp deletion in the FGFR1 gene, 1970-1971delCA, in 2 brothers with autosomal dominant Kallmann syndrome (HH2; 147950) and in their unaffected mother. They proposed that the product of the X-linked KAL1 gene (300836), the extracellular matrix protein anosmin-1, is involved in FGF signaling and that the lack of penetrance in females may be due to gender difference in anosmin-1 dosage because KAL1 partially escapes X inactivation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</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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FGFR1, TRP666ARG
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<br />
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SNP: rs1563433902,
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ClinVar: RCV000030925
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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>Dode et al. (2003) demonstrated a trp666-to-arg (W666R) mutation in exon 15 of the FGFR1 gene in a sporadic female case of Kallmann syndrome and cleft palate (HH2; 147950). </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 HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</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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FGFR1, ARG622TER
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<br />
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SNP: rs121909628,
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ClinVar: RCV000030926, RCV000156953, RCV000156954, RCV000760399, RCV002513084, RCV004584329
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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>Dode et al. (2003) observed heterozygosity for an arg622-to-stop (R622X) mutation in the FGFR1 gene in 3 members of a family affected with Kallmann syndrome (HH2; 147950), 2 of whom also had cleft palate or cleft lip. The mutation was also found in a family member with isolated anosmia. </p><p>Xu et al. (2007) identified heterozygosity for the R622X mutation, resulting from a 1864C-T transition in the FGFR1 gene, in 4 affected members of a family segregating normosmic complete hypogonadotropic hypogonadism with full penetrance and no other FGFR1-associated anomalies typically found in Kallmann syndrome. The mutation, which is predicted to encode a truncated protein or result in nonsense-mediated decay, was not found in 3 unaffected family members or 100 controls. </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 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</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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FGFR1, VAL607MET
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<br />
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SNP: rs121909629,
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gnomAD: rs121909629,
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ClinVar: RCV000030927
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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>Dode et al. (2003) found an FGFR1 amino acid substitution, val607-to-met (V607M), in 2 sibs (male and female) with Kallmann syndrome (HH2; 147950) and in their unaffected father; both affected individuals had mirror movements of the hands (bimanual synkinesia). </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 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</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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FGFR1, 936G-A
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<br />
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SNP: rs1586287678,
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ClinVar: RCV000030928
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with Kallmann syndrome (HH2; 147950), Dode et al. (2003) found a mutation at the exon 7 donor splice site of the FGFR1 gene, 936G-A, in 2 affected sibs (male and female) and in their unaffected mother; all 3 had 7 or 8 missing teeth. </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>.0007 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA</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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FGFR1, ALA167SER
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<br />
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SNP: rs121909630,
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ClinVar: RCV000030929
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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>Whereas other familial and sporadic cases of Kallmann syndrome (HH2; 147950) have heterozygous mutations in the FGFR1 gene, Dode et al. (2003) found homozygosity for an FGFR1 mutation, ala167 to ser (A167S), in exon 5. In addition to Kallmann syndrome, the patient had cleft palate, corpus callosum agenesis, unilateral hearing loss, and fusion of the fourth and fifth metacarpal bones. </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>.0008 OSTEOGLOPHONIC DYSPLASIA</strong>
|
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</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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FGFR1, TYR372CYS
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<br />
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SNP: rs121909631,
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ClinVar: RCV000017679
|
|
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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 kindred with osteoglophonic dysplasia (OGD; 166250) with a father and 2 sons affected, White et al. (2005) found heterozygosity for a 1115G-A transition in exon 10 of FGFR1, replacing a tyrosine with a cysteine residue at amino acid position 372 (Y372C). The family was identified because of skeletal anomalies and progressive weakness in the family members. One of the sons possessed a distinct osteoglophonic dysplasia facial phenotype characterized by craniosynostosis, severe nasal-maxillary hypoplasia, telecanthus, and prominent supraorbital ridge. He had growth retardation, with a peak stature of 40 inches and a weight of 100 pounds. The proband's father and brother had the same skeletal syndrome; the father's peak stature was 48 inches. They also had shortened necks, broad and shortened thumbs, brachydactyly, and generalized osteopenia. In addition, the father and proband never had tooth eruption, as documented by radiographs. The proband and his father were hypophosphatemic secondary to renal phosphate wasting. This family also had 1,25-dihydroxy-vitamin D concentrations that were inappropriately low, given the degree of hypophosphatemia. The proband in this family died at age 28, presumably from a pulmonary embolism due to extended immobilization; the father died at age 59 years, from respiratory distress under similar immobilizing conditions; and the second brother died at age 24 years, from pneumonia. The analogous mutations that result in unpaired cysteine residues in FGFR2 (Y375C; 176943.0015) and FGFR3 (Y373C; 134934.0016) cause Beare-Stevenson cutis gyrata syndrome (123790) and thanatophoric dysplasia type I (187600), respectively. </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>.0009 OSTEOGLOPHONIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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FGFR1, ASN330ILE
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<br />
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SNP: rs121909632,
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gnomAD: rs121909632,
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ClinVar: RCV000017678
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|
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|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with osteoglophonic dysplasia (OGD; 166250), White et al. (2005) found a heterozygous 929T-A transversion in exon 9 of the FGFR1 gene, resulting in an asn330-to-ile (N330I) change. The parents were negative for the mutation, indicating that it had occurred de novo. It is noteworthy that exon 9 is present only in the 'c' isoform of FGFR1, indicating that specific changes in FGFR1c will lead to osteoglophonic dysplasia. White et al. (2005) demonstrated hypophosphatemia secondary to renal phosphate wasting in patients with this disorder, and found elevated circulating levels of fibroblast growth factor-23 (FGF23; 605380), a known phosphaturic factor, in this patient. FGF23 had been shown to be produced by the nonossifying lesions in some patients with fibrous dysplasia of bone (Riminucci et al., 2003). The nonossifying lesions of dysplasia presumably produce FGF23, accounting for the hypophosphatemia. </p><p>Farrow et al. (2006) reported another patient with osteoglophonic dysplasia caused by the N330I mutation. Structural analysis indicated that asn330 is a surface-exposed residue, and the mutation is predicted to remove an N-linked glycosylation site. </p>
|
|
</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>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 OSTEOGLOPHONIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
FGFR1, CYS379ARG
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|
<br />
|
|
|
|
SNP: rs121909634,
|
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|
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|
|
ClinVar: RCV000017682, RCV002254904, RCV002514106
|
|
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|
|
|
</span>
|
|
</div>
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|
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<div>
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|
<span class="mim-text-font">
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|
<p>In a patient with osteoglophonic dysplasia (OGD; 166250), White et al. (2005) found a heterozygous 1135T-C transition in exon 10 of the FGFR1 gene, resulting in a cys379-to-arg (C379R) amino acid change. The parents were negative for the mutation. This patient had normal plasma phosphate concentrations and a normal serum FGF23 (605380) concentration. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0011 TRIGONOCEPHALY 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
FGFR1, ILE300THR
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<br />
|
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|
|
SNP: rs121909633,
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|
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|
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gnomAD: rs121909633,
|
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|
|
|
ClinVar: RCV000017681, RCV000502492, RCV000514891, RCV000766015, RCV001407682, RCV004532374
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-month-old girl with isolated trigonocephaly (TRIGNO1; 190440), Kress et al. (2000) identified an ile300-to-thr (I300T) mutation in exon 5 of the FGFR1 gene. The mutation was not found in more than 300 control chromosomes. </p><p>In a male infant with an Antley-Bixler syndrome-like skeletal phenotype (see 207410) and abnormal genitalia (see POR deficiency, 201750), Hurley et al. (2004) identified the I300T mutation; the authors stated that the significance of the FGFR1 mutation was unclear. Huang et al. (2005) subsequently identified compound heterozygosity for a frameshift and a missense mutation in the gene for cytochrome P450 oxidoreductase (POR; see 124015.0015 and 124015.0016, respectively) in this patient as well. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 OSTEOGLOPHONIC DYSPLASIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, CYS381ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909634,
|
|
|
|
|
|
|
|
ClinVar: RCV000017682, RCV002254904, RCV002514106
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with osteoglophonic dysplasia (OGD; 166250) originally reported by Beighton et al. (1980), Farrow et al. (2006) identified a heterozygous 1141T-C transition in exon 10 of the FGFR1 gene, resulting in a cys381-to-arg (C381R) substitution predicted to disrupt the transmembrane domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, GLY237SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909635,
|
|
|
|
|
|
|
|
ClinVar: RCV000017684, RCV004528116
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-year-old female with normosmic idiopathic hypogonadotropic hypogonadism and her brother, who had Kallmann syndrome (HH2; 147950), Pitteloud et al. (2006) identified heterozygosity for a 709G-A transition in exon 6 of the FGFR1 gene, predicted to result in a gly237-to-ser (G237S) substitution in the Ig-like domain D2 within the extracellular region of the protein. The sibs' father, who also carried the mutation, had congenital anosmia with normal puberty. Structural analysis of the mutant protein revealed inhibition of proper folding of D2, likely leading to loss of cell surface expression of FGFR1. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, PRO722HIS AND ASN724LYS
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs267606805, rs267606806,
|
|
|
|
|
|
gnomAD: rs267606806,
|
|
|
|
|
|
ClinVar: RCV000030930, RCV001857786, RCV003234553, RCV003234554
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 25-year-old Hispanic male with normosmic idiopathic hypogonadotropic hypogonadism (HH2; 147950) and unilateral cryptorchidism, who had 2 congenitally missing teeth, Pitteloud et al. (2006) identified complex heterozygosity for 2 mutations in exon 16 of the FGFR1 gene on the same allele: one was a 2165C-A transversion resulting in a pro722-to-his (P722H) substitution and the other was a 2172C-G transversion resulting in an asn724-to-lys (N724K) substitution. The patient's mother, who was also heterozygous for the mutations, had congenital anosmia and normal puberty. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, GLN680TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909636,
|
|
|
|
|
|
|
|
ClinVar: RCV000030931, RCV000156950
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with normosmic idiopathic hypogonadotropic hypogonadism (HH2; 147950), 1 of whom also had cleft lip and palate and 3 missing teeth, Pitteloud et al. (2006) identified heterozygosity for a 2038C-T transition in exon 15 of the FGFR1 gene, resulting in a gln680-to-ter (Q680X) substitution in the tyrosine kinase domain. The sibs' father, who was also heterozygous for the mutation, reported having delayed puberty. The mutation is predicted to cause the deletion of a catalytically essential portion of the tyrosine kinase domain and lead to a 'kinase dead' receptor. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, ARG470LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909637,
|
|
|
|
|
|
gnomAD: rs121909637,
|
|
|
|
|
|
ClinVar: RCV000030932, RCV001851897
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with hypogonadotropic hypogonadism (HH2; 147950) in whom Seminara et al. (2000) had previously identified compound heterozygosity for missense mutations in the GNRHR gene (Q106R, 138850.0001, and R262Q, 138850.0002), Pitteloud et al. (2007) identified heterozygosity for an additional 1409G-T transversion in exon 10 of the FGFR1 gene, resulting in an arg470-to-leu (R470L) substitution. The mutation was also found in the father, who had a history of delayed puberty and was heterozygous for the R262Q mutation in GNRHR, and in the unaffected daughter of the younger sister, who had undergone normal puberty and had no mutations in GNRHR. The R470L mutation was not found in 200 controls. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with idiopathic hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, LEU342SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909638,
|
|
|
|
|
|
|
|
ClinVar: RCV000030933, RCV003234536
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family in which the proband had severe Kallmann syndrome (HH2; 147950), his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, Pitteloud et al. (2007) identified heterozygosity for a 1025T-C transition in exon 7 of the FGFR1 gene, resulting in a leu342-to-ser (L342S) substitution in the proband, his father, and his sister. The mutation was not found in 200 controls. Heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (608137.0002), was identified in the proband, his mother, and his brother. Pitteloud et al. (2007) concluded that defects in 2 different genes can synergize to produce a more severe phenotype in families with idiopathic hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, ARG609TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909639,
|
|
|
|
|
|
|
|
ClinVar: RCV000030934, RCV000478244, RCV000500417, RCV003764580
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old female with cleft lip and palate who presented with anosmia, irregular menstrual periods, and agenesis of 2 teeth (HH2; 147950), Riley et al. (2007) identified an arg609-to-ter (R609X) substitution in the tyrosine kinase domain of the FGFR1 gene, resulting in a loss of function. Her father, who also carried the R609X mutation, had isolated cleft lip and palate and a normal sense of smell and was fertile. The mutation was not found in the unaffected mother or brother; a deceased paternal great aunt was also reported to have cleft lip. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, 2-BP DEL, 1317TG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776835,
|
|
|
|
|
|
|
|
ClinVar: RCV000030935
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 14-year-old Japanese boy with Kallmann syndrome (HH2; 147950), Sato et al. (2006) found a heterozygous 2-bp deletion in exon 10 of the FGFR1 gene, 1317_1318delTG, that was predicted to cause a frameshift at serine-439 and premature termination (Ser439fsTer461). The boy presented with hypogonadotropic hypogonadism, olfactory dysfunction, and dental agenesis and his fertile mother with olfactory dysfunction and dental agenesis. After selective amplification of the mutant allele, the deletion was detected in nail DNA, but not in leukocyte DNA, from the mother. The authors concluded that the 2-bp deletion took place as a somatic mutation in the mother and was transmitted to the proband through germline mosaicism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
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</div>
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</div>
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|
|
<div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
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|
FGFR1, GLY48SER
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909640,
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|
|
|
|
|
|
|
ClinVar: RCV000017691, RCV003311661, RCV004724747
|
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|
|
|
|
</span>
|
|
</div>
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|
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|
|
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<div>
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<span class="mim-text-font">
|
|
<p>In a 17-year-old male with hypogonadotropic hypogonadism with normal olfaction (HH2; 147950), Trarbach et al. (2006) detected a G-to-A transition in exon 3 of the FGFR1 gene that resulted in a gly48-to-ser (G48S) substitution. The conserved gly48 is located in the IgI domain involved in the autoinhibitory function. The patient showed no midline defect and had normal sulci and olfactory bulbs at MRI. </p>
|
|
</span>
|
|
</div>
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
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<span class="mim-text-font">
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|
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|
FGFR1, PRO366LEU
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|
|
|
<br />
|
|
|
|
SNP: rs121909641,
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|
|
|
|
|
|
|
ClinVar: RCV000030936, RCV000156970, RCV000763182, RCV001824283, RCV003234537
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 17-year-old patient with familial Kallmann syndrome (HH2; 147950) Trarbach et al. (2006) detected a C-to-T transition at nucleotide 1097 in exon 9 of the FGFR1 gene that resulted in a pro366-to-leu (P366L) substitution. The mutation was also identified in his 2 paternal aunts with Kallmann syndrome as well as in his asymptomatic father. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, PRO722SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909642,
|
|
|
|
|
|
|
|
ClinVar: RCV000030937
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 22-year-old patient with familial Kallmann syndrome (HH2; 147950), Trarbach et al. (2006) identified a 2164C-to-T transition in exon 16 of the FGFR1 gene that resulted in a pro722-to-ser (P722S) substitution. Cleft lip and bimanual synkinesia were observed. The mutation was also reported in his maternal first cousin, who had Kallmann syndrome without bimanual synkinesia. Trarbach et al. (2006) noted that a different mutation of pro722 had been reported with another mutation on the same allele (136350.0014); this patient had Kallmann syndrome with dental agenesis but not bimanual synkinesia. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, GLN764HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909643,
|
|
|
|
|
|
|
|
ClinVar: RCV000030938
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 19-year-old man who was evaluated at age 15.5 years for delayed puberty and found to have a hypogonadal serum testosterone level with undetectable serum gonadotropins (HH2; 147950), Falardeau et al. (2008) identified homozygosity for an F40L mutation in the FGF8 gene (600483.0003) and also identified compound heterozygosity for a gln764-to-his (Q764H) mutation and an asp768-to-tyr (D768Y; 136350.0024) mutation in the FGFR1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, ASP768TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909644,
|
|
|
|
|
|
|
|
ClinVar: RCV000030939
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the asp768-to-tyr (D768Y) mutation in the FGFR1 gene that was found in compound heterozygous state in a patient with hypogonadotropic hypogonadism-2 without anosmia (HH2; 147950) by Falardeau et al. (2008), see 136350.0023. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, ARG250GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121909645,
|
|
|
|
|
|
|
|
ClinVar: RCV000030940, RCV002514107
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 10-year-old boy of mixed European descent who was born with microphallus and found to have undetectable serum testosterone and gonadotropins and normal olfaction (HH2; 147950), and his father, who had normal olfaction, bilateral hearing loss, and a history of delayed puberty, Falardeau et al. (2008) identified heterozygosity for a 794G-A transition in the FGFR1 gene, resulting in an arg250-to-gln (R250Q) substitution. The boy was also heterozygous for a de novo missense mutation in the FGF8 gene (600483.0004). </p><p>In a 55-year-old woman with hypogonadotropic hypogonadism with anosmia from a large French Canadian pedigree with several consanguineous loops, previously reported by White et al. (1983) and in which affected individuals displayed variable phenotypes, Tornberg et al. (2011) identified homozygosity for a missense mutation in the HS6ST1 gene (R296W; 604846.0002). The proband's brother, who also had anosmic HH, was heterozygous for the HS6ST1 mutation, as was their unaffected father and 3 other family members, including 1 with anosmic HH, 1 with anosmic HH and cleft palate, and 1 unaffected individual. Analysis of 8 known HH-associated genes revealed that the proband, her brother, and their unaffected father were all also heterozygous for the R250Q mutation in FGFR1, as were 2 other family members, 1 with anosmic HH and 1 with anosmic HH and cleft palate. The R250Q FGFR1 mutation was also found in heterozygosity in an unaffected family member who did not carry the HS6ST1 mutation. No mutations were identified in the other HH-associated genes. </p><p>In the French Canadian pedigree in which Tornberg et al. (2011) had identified mutations in both the FGFR1 and HS6ST1 genes, Miraoui et al. (2013) identified additional mutations in 2 FGF-network genes, FGF17 (I108T; 603725.0001) and FLRT3 (E97G, 604808.0001 and S144I, 604808.0002). Analysis of physical interactions between the ligand-binding region of FGFR1 and FGF17 by surface-plasmon-resonance spectroscopy demonstrated that the FGF17 I108T mutant was defective in FGFR1 activation compared to wildtype; in addition, the I108T mutant completely failed to activate the FGFR1 R250Q mutant, indicating that these 2 loss-of-function substitutions act in an additive manner. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, GLY348ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037634,
|
|
|
|
|
|
|
|
ClinVar: RCV000043588, RCV000319353, RCV001542473, RCV004537181
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female patient with congenital hypogonadotropic hypogonadism (HH2; 147950), who was anosmic and also displayed hearing loss, abnormal dentition, and low bone mass, Miraoui et al. (2013) identified heterozygosity for a c.1042G-A transition in exon 8b of the FGFR1 gene, resulting in a gly348-to-arg (G348R) substitution in the D3 domain. The patient was also heterozygous for a missense mutation in the IL17RD gene (Y379C; 606807.0002). Her mother, who carried only a heterozygous Y379C mutation in IL17RD, was anosmic but did not display other features of hypogonadotropic hypogonadism. Neither mutation was found in the unaffected father or in 155 controls. </p><p>In a white European male patient born with micropenis, bilateral cryptorchidism, split feet, and cleft lip, who also exhibited dental anomalies including partial double teeth involving the canines, Villanueva et al. (2015) identified heterozygosity for the G348R mutation in the FGFR1 gene. The proband failed to undergo puberty, and at age 15 years, his serum hormone values were consistent with hypogonadotropic hypogonadism. MRI revealed normal olfactory structures, consistent with his self-reported normal sense of smell. There was no family history of reproductive or skeletal disorders; mutation status of his parents was not reported. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, PRO483THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515444,
|
|
|
|
|
|
gnomAD: rs397515444,
|
|
|
|
|
|
ClinVar: RCV000043589, RCV003234543
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic male patient with congenital hypogonadotropic hypogonadism (HH2; 147950), who was anosmic and had absent puberty, Miraoui et al. (2013) identified heterozygosity for a c.1447C-A transversion in exon 11 of the FGFR1 gene, resulting in a pro483-to-thr (P483T) substitution in the tyrosine kinase domain. The patient was also heterozygous for a missense mutation in the SPRY4 gene (S241Y; 607984.0002). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, GLU692GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515445,
|
|
|
|
|
|
|
|
ClinVar: RCV000043590, RCV003234544, RCV003764717
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient with congenital hypogonadotropic hypogonadism (HH2; 147950), who was anosmic and also had abnormal dentition, Miraoui et al. (2013) identified heterozygosity for a c.2075A-G transition in exon 16 of the FGFR1 gene, resulting in a glu692-to-gly (E692G) substitution in the tyrosine kinase domain. The patient was also heterozygous for a missense mutation in the DUSP6 gene (S182F; 602748.0002). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 HYPOGONADOTROPIC HYPOGONADISM 2 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, GLU670LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515446,
|
|
|
|
|
|
|
|
ClinVar: RCV000043591, RCV003234545, RCV004739327
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female proband with congenital hypogonadotropic hypogonadism (HH2; 147950), who was anosmic and also had hearing loss and low bone mass, Miraoui et al. (2013) identified heterozygosity for a c.2008G-A transition in exon 15 of the FGFR1 gene, resulting in a glu670-to-lys (E670K) substitution in the tyrosine kinase domain.i The patient was also heterozygous for a missense mutation in the FLRT3 gene (Q69K; 604808.0003). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 HARTSFIELD SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, CYS725TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122945,
|
|
|
|
|
|
|
|
ClinVar: RCV000056313
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a man with holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; 615465), who was previously reported as patient 4 by Vilain et al. (2009), Simonis et al. (2013) identified heterozygosity for a de novo c.2174G-A transition in the FGFR1 gene, resulting in a cys725-to-tyr (C725Y) substitution at a highly conserved residue in the intracellular C-terminal loop of the tyrosine kinase domain. The mutation was not present in his unaffected parents. The patient, whose IQ was measured at 63 at age 6.75 years, worked in a sheltered workshop. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 HARTSFIELD SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, LEU165SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397515481,
|
|
|
|
|
|
|
|
ClinVar: RCV000056314
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male infant with severe holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; 615465), who was previously reported as patient 3 by Vilain et al. (2009), Simonis et al. (2013) identified homozygosity for a c.494T-C transition in the FGFR1 gene, resulting in a leu165-to-ser (L165S) substitution at a highly conserved residue in the extracellular ligand-binding domain D2. The first-cousin Sri Lankan parents were heterozygous for the mutation and were reported to be asymptomatic and spontaneously fertile. The patient died at 5 years of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 HARTSFIELD SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR1, ASP623TYR
|
|
|
|
|
|
<br />
|
|
|
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SNP: rs398122946,
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ClinVar: RCV000056315
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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 female patient with mild holoprosencephaly, ectrodactyly, and cleft/lip palate (HRTFDS; 615465), Simonis et al. (2013) identified heterozygosity for a de novo c.1867G-T transversion in the FGFR1 gene, resulting in an asp623-to-tyr (D623Y) substitution in the ATP binding pocket of the intracellular tyrosine kinase domain. The mutation was not present in her unaffected parents. The patient attended mainstream school with support. </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>.0033 ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS</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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FGFR1, ASN546LYS
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<br />
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SNP: rs779707422,
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gnomAD: rs779707422,
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ClinVar: RCV000210485, RCV000487433, RCV004668850
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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 encephalocraniocutaneous lipomatosis (ECCL; 613001), including a 15-year-old boy originally described by Nowaczyk et al. (2000) and a 5-year-old girl previously reported by Kupsik and Brandling-Bennett (2013), Bennett et al. (2016) identified mosaicism for a c.1638C-A transversion (c.1638C-A, NM_023110.2) in the FGFR1 gene, resulting in an asn546-to-lys (N546K) substitution in the first tyrosine kinase domain of the cytoplasmic kinase core. In the 15-year-old boy (LR13-278), the N546K substitution was identified in cultured fibroblasts from unaffected skin at an alternate allele fraction (AAF) of 35%, from a scalp nevus (42% AAF), and an eyelid dermoid (54% AAF). In the 5-year-old girl (LR14-261), the N546K mutation was present in cultured fibroblasts from a scalp nevus (55% AAF) but was not detected in saliva. In the third patient (IN_0039), a 17-month-old boy who had an unaffected monozygotic twin sib, N546K was identified in cultured fibroblasts from unaffected skin (23% AAF) and from a scalp lesion (33% AAF), but was not detected in the unaffected twin's blood. The N546K variant was not found in the Exome Variant Server, ExAC, or dbSNP databases. Bennett et al. (2016) stated that N546 is 1 of the 2 residues most commonly mutated among FGFR1 mutation-containing tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. The 15-year-old boy with the N546K mutation had been diagnosed with a tectal tumor. Functional analysis in patient fibroblasts demonstrated elevated autophosphorylation of FGFRs, the FGFR-dependent substrate FRS2 (607743), and the RAS (see 190020)-pathway components CRAF (164760) and ERK1 (601795)/ERK2 (176948), compared to wildtype. </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>.0034 ENCEPHALOCRANIOCUTANEOUS LIPOMATOSIS</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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FGFR1, LYS656GLU
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<br />
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SNP: rs869320694,
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ClinVar: RCV000210479, RCV001849345
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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 7-year-old boy (LR12-068) with encephalocraniocutaneous lipomatosis (ECCL; 613001) and an unrelated 2.75-year-old boy (NIH-183) with ECCL who was previously reported by Bieser et al. (2015), Bennett et al. (2016) identified mosaicism for a c.1966A-G transition (c.1966A-G, NM_023110.2) in the FGFR1 gene, resulting in a lys656-to-glu (K656E) substitution within the second tyrosine kinase domain of the cytoplasmic kinase core. In the younger boy, the K656E substitution was present in cultured fibroblasts from affected scalp at an alternate allele fraction (AAF) of 45%, but was not detected in blood. In the older boy, K565E was identified in cultured fibroblasts from a scalp nevus (47% AAF) and in fibroblasts from a pilocytic astrocytoma (32% AAF). The K565E variant was not found in the Exome Variant Server, ExAC, or dbSNP databases. Bennett et al. (2016) stated that K656 is 1 of the 2 residues most commonly mutated among FGFR1 mutation-containing tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC) database, and noted that most of the tumors associated with substitutions in these 2 residues are central nervous system gliomas, including pilocytic astrocytomas, the same type of tumor seen at increased frequency in patients with ECCL. Both boys with the K656E mutation were diagnosed with pilocytic astrocytoma. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Beighton, P., Cremin, B. J., Kozlowski, K.
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<strong>Osteoglophonic dwarfism.</strong>
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Pediat. Radiol. 10: 46-50, 1980.
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[PubMed: 7422392]
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[Full Text: https://doi.org/10.1007/BF01644343]
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</p>
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<p class="mim-text-font">
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Bennett, J. T., Tan, T. Y., Alcantara, D., Tetrault, M., Timms, A. E., Jensen, D., Collins, S., Nowaczyk, M. J. M., Lindhurst, M. J., Christensen, K. M., Braddock, S. R., Brandling-Bennett, H., and 15 others.
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<strong>Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis.</strong>
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Am. J. Hum. Genet. 98: 579-587, 2016.
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<p class="mim-text-font">
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Bieser, S., Reis, M., Guzman, M., Gauvain, K., Elbabaa, S., Braddock, S. R., Abdel-Baki, M. S.
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<strong>Grade II pilocytic astrocytoma in a 3-month-old patient with encephalocraniocutaneous lipomatosis (ECCL): case report and literature review of low grade gliomas in ECCL.</strong>
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Bruno, I. G., Jin, W., Cote, G. J.
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<strong>Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements.</strong>
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Calvert, J. A., Dedos, S. G. Hawker, K., Fleming, M., Lewis, M. A., Steel, K. P.
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<strong>A missense mutation in Fgfr1 causes ear and skull defects in hush puppy mice.</strong>
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Chesi, M., Nardini, E., Brents, L. A., Schrock, E., Ried, T., Kuehl, W. M., Bergsagel, P. L.
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<strong>Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.</strong>
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Nature Genet. 16: 260-264, 1997.
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[PubMed: 9207791]
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Dell'Era, P., Ronca, R., Coco, L., Nicoli, S., Metra, M., Presta, M.
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<strong>Fibroblast growth factor receptor-1 is essential for in vitro cardiomyocyte development.</strong>
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Circ. Res. 93: 414-420, 2003.
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Demiroglu, A., Steer, E. J., Heath, C., Taylor, K., Bentley, M., Allen, S. L., Koduru, P., Brody, J. P., Hawson, G., Rodwell, R., Doody, M.-L., Carnicero, F., Reiter, A., Goldman, J. M., Melo, J. V., Cross, N. C. P.
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<strong>The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins.</strong>
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Blood 98: 3778-3783, 2001.
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[PubMed: 11739186]
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[Full Text: https://doi.org/10.1182/blood.v98.13.3778]
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<p class="mim-text-font">
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Ding, B.-S., Cao, Z., Lis, R., Nolan, D. J., Guo, P., Simons, M., Penfold, M. E., Shido, K., Rabbany, S. Y., Rafii, S.
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<strong>Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.</strong>
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Nature 505: 97-102, 2014.
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[PubMed: 24256728]
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[Full Text: https://doi.org/10.1038/nature12681]
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Dode, C., Levilliers, J., Dupont, J.-M., De Paepe, A., Le Du, N., Soussi-Yanicostas, N., Coimbra, R. S., Delmaghani, S., Compain-Nouaille, S., Baverel, F., Pecheux, C., Le Tessier, D., and 18 others.
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<strong>Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.</strong>
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Nature Genet. 33: 463-465, 2003.
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Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., Quinton, R., Na, S., and 9 others.
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<strong>Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice.</strong>
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<p class="mim-text-font">
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Farrow, E. G., Davis, S. I., Mooney, S. D., Beighton, P., Mascarenhas, L., Gutierrez, Y. R., Pitukcheewanont, P., White, K. E.
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<strong>Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. (Letter)</strong>
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<p class="mim-text-font">
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Furdui, C. M., Lew, E. D., Schlessinger, J., Anderson, K. S.
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<strong>Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction.</strong>
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Molec. Cell 21: 711-717, 2006.
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[PubMed: 16507368]
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<p class="mim-text-font">
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Grand, E. K., Grand, F. H., Chase, A. J., Ross, F. M., Corcoran, M. M., Oscier, D. G., Cross, N. C. P.
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<strong>Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome.</strong>
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<p class="mim-text-font">
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Guasch, G., Mack, G. J., Popovici, C., Dastugue, N., Birnbaum, D., Rattner, J. B., Pebusque, M.-J.
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<strong>FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33).</strong>
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Blood 95: 1788-1796, 2000.
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[PubMed: 10688839]
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<p class="mim-text-font">
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Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others.
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<strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong>
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PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.
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[PubMed: 22927827]
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[Full Text: https://doi.org/10.1371/journal.pgen.1002896]
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<li>
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<p class="mim-text-font">
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Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Van Vliet, G., Sack, J., Fluck, C. E., Miller, W. L.
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<strong>Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.</strong>
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[PubMed: 15793702]
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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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Hurley, M. E., White, M. J., Green, A. J., Kelleher, J.
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<strong>Antley-Bixler syndrome with radioulnar synostosis.</strong>
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Pediat. Radiol. 34: 148-151, 2004.
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[PubMed: 14513299]
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[Full Text: https://doi.org/10.1007/s00247-003-1066-7]
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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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Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Linhardt, R. J., Mohammadi, M.
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<strong>Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.</strong>
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Hum. Molec. Genet. 13: 69-78, 2004.
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[PubMed: 14613973]
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[Full Text: https://doi.org/10.1093/hmg/ddh011]
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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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Jones, D. T. W., Hutter, B., Jager, N., Korshunov, A., Kool, M., Warnatz, H.-J., Zichner, T., Lambert, S. R., Ryzhova, M., Quang, D. A. K., Fontebasso, A. M., Stutz, A. M., and 63 others.
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<strong>Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.</strong>
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Nature Genet. 45: 927-932, 2013.
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[PubMed: 23817572]
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[Full Text: https://doi.org/10.1038/ng.2682]
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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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Jung, J., Zheng, M., Goldfarb, M., Zaret, K. S.
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<strong>Initiation of mammalian liver development from endoderm by fibroblast growth factors.</strong>
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|
Science 284: 1998-2003, 1999.
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[PubMed: 10373120]
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[Full Text: https://doi.org/10.1126/science.284.5422.1998]
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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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Kim, H. G., Herrick, S. R., Lemyre, E., Kishikawa, S., Salisz, J. A., Seminara, S., MacDonald, M. E., Bruns, G. A. P., Morton, C. C., Quade, B. J., Gusella, J. F.
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|
<strong>Hypogonadotropic hypogonadism and cleft lip and palate caused by a balanced translocation producing haploinsufficiency for FGFR1. (Letter)</strong>
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|
J. Med. Genet. 42: 666-672, 2005.
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[PubMed: 16061567]
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[Full Text: https://doi.org/10.1136/jmg.2004.026989]
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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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Kress, W., Petersen, B., Collmann, H., Grimm, T.
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Patricia A. Hartz - updated : 10/07/2016<br>Marla J. F. O'Neill - updated : 4/4/2016<br>Marla J. F. O'Neill - updated : 9/10/2015<br>Marla J. F. O'Neill - updated : 10/23/2014<br>Ada Hamosh - updated : 2/3/2014<br>Ada Hamosh - updated : 1/28/2014<br>Marla J. F. O'Neill - updated : 10/28/2013<br>Marla J. F. O'Neill - updated : 10/9/2013<br>Marla J. F. O'Neill - updated : 6/5/2013<br>Ada Hamosh - updated : 11/19/2012<br>Patricia A. Hartz - updated : 10/23/2012<br>Marla J. F. O'Neill - updated : 10/17/2012<br>Marla J. F. O'Neill - updated : 9/25/2012<br>Patricia A. Hartz - updated : 10/6/2010<br>Ada Hamosh - updated : 2/18/2010<br>Ada Hamosh - updated : 4/16/2009<br>Marla J. F. O'Neill - updated : 3/23/2009<br>Marla J. F. O'Neill - updated : 1/26/2009<br>Patricia A. Hartz - updated : 10/23/2008<br>John A. Phillips, III - updated : 10/29/2007<br>John A. Phillips, III - updated : 9/28/2007<br>George E. Tiller - updated : 6/21/2007<br>John A. Phillips, III - updated : 5/17/2007<br>Paul J. Converse - updated : 5/17/2007<br>Paul J. Converse - updated : 5/3/2007<br>Marla J. F. O'Neill - updated : 4/30/2007<br>Marla J. F. O'Neill - updated : 3/13/2007<br>Ada Hamosh - updated : 1/23/2007<br>Marla J. F. O'Neill - updated : 6/2/2006<br>Patricia A. Hartz - updated : 3/31/2006<br>Cassandra L. Kniffin - updated : 3/21/2006<br>George E. Tiller - updated : 2/17/2006<br>Jane Kelly - updated : 12/9/2005<br>Marla J. F. O'Neill - updated : 9/13/2005<br>Marla J. F. O'Neill - updated : 8/30/2005<br>Victor A. McKusick - updated : 2/14/2005<br>Ada Hamosh - updated : 12/10/2004<br>Victor A. McKusick - updated : 11/15/2004<br>Patricia A. Hartz - updated : 8/19/2004<br>Marla J. F. O'Neill - updated : 3/9/2004<br>Patricia A. Hartz - updated : 10/27/2003<br>Dawn Watkins-Chow - updated : 3/28/2003<br>Victor A. McKusick - updated : 3/19/2003<br>Victor A. McKusick - updated : 10/16/2002<br>Patricia A. Hartz - updated : 10/8/2002<br>Victor A. McKusick - updated : 2/15/2002<br>Victor A. McKusick - updated : 11/7/2001<br>Victor A. McKusick - updated : 9/19/2001<br>Paul J. Converse - updated : 12/27/2000<br>Paul J. Converse - updated : 11/7/2000<br>George E. Tiller - updated : 10/26/2000<br>Victor A. McKusick - updated : 7/10/2000<br>Stylianos E. Antonarakis - updated : 6/7/2000<br>Ada Hamosh - updated : 9/21/1999<br>Stylianos E. Antonarakis - updated : 9/15/1999<br>Ada Hamosh - updated : 6/18/1999<br>Victor A. McKusick - updated : 6/11/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Victor A. McKusick - updated : 12/29/1997<br>Jennifer P. Macke - updated : 6/3/1997
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Victor A. McKusick : 3/31/1989
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carol : 06/01/2022<br>carol : 06/11/2019<br>carol : 09/13/2017<br>mgross : 10/07/2016<br>carol : 08/11/2016<br>carol : 04/21/2016<br>alopez : 4/4/2016<br>carol : 9/10/2015<br>alopez : 8/12/2015<br>mcolton : 7/30/2015<br>carol : 3/10/2015<br>carol : 10/24/2014<br>mcolton : 10/23/2014<br>alopez : 2/3/2014<br>alopez : 1/28/2014<br>carol : 10/28/2013<br>carol : 10/9/2013<br>alopez : 6/5/2013<br>terry : 4/1/2013<br>alopez : 11/19/2012<br>mgross : 11/8/2012<br>terry : 10/23/2012<br>carol : 10/17/2012<br>carol : 10/17/2012<br>carol : 10/17/2012<br>carol : 10/16/2012<br>carol : 9/25/2012<br>carol : 9/25/2012<br>terry : 9/7/2012<br>terry : 8/8/2012<br>carol : 2/17/2012<br>alopez : 3/10/2011<br>mgross : 10/6/2010<br>carol : 9/2/2010<br>terry : 2/18/2010<br>alopez : 4/21/2009<br>alopez : 4/21/2009<br>terry : 4/16/2009<br>wwang : 3/30/2009<br>terry : 3/23/2009<br>joanna : 3/9/2009<br>joanna : 2/2/2009<br>carol : 1/26/2009<br>mgross : 10/23/2008<br>mgross : 10/23/2008<br>carol : 9/4/2008<br>carol : 10/29/2007<br>alopez : 9/28/2007<br>wwang : 6/25/2007<br>terry : 6/21/2007<br>wwang : 6/13/2007<br>alopez : 5/17/2007<br>mgross : 5/17/2007<br>mgross : 5/17/2007<br>terry : 5/3/2007<br>wwang : 4/30/2007<br>carol : 3/14/2007<br>carol : 3/13/2007<br>alopez : 1/24/2007<br>terry : 1/23/2007<br>carol : 12/5/2006<br>carol : 6/2/2006<br>terry : 6/2/2006<br>mgross : 6/2/2006<br>mgross : 3/31/2006<br>wwang : 3/23/2006<br>ckniffin : 3/21/2006<br>wwang : 3/7/2006<br>terry : 2/17/2006<br>alopez : 12/9/2005<br>carol : 9/13/2005<br>terry : 9/13/2005<br>terry : 9/13/2005<br>carol : 8/30/2005<br>carol : 8/30/2005<br>terry : 7/11/2005<br>alopez : 2/15/2005<br>terry : 2/14/2005<br>alopez : 12/14/2004<br>terry : 12/10/2004<br>alopez : 11/15/2004<br>mgross : 8/19/2004<br>tkritzer : 3/11/2004<br>tkritzer : 3/9/2004<br>alopez : 11/17/2003<br>cwells : 10/31/2003<br>terry : 10/27/2003<br>alopez : 4/1/2003<br>cwells : 3/28/2003<br>alopez : 3/20/2003<br>terry : 3/19/2003<br>carol : 10/24/2002<br>tkritzer : 10/22/2002<br>terry : 10/16/2002<br>mgross : 10/8/2002<br>cwells : 3/6/2002<br>cwells : 2/22/2002<br>terry : 2/15/2002<br>carol : 11/12/2001<br>terry : 11/7/2001<br>mcapotos : 9/19/2001<br>mgross : 12/27/2000<br>mgross : 12/27/2000<br>mgross : 11/7/2000<br>carol : 11/2/2000<br>mcapotos : 10/26/2000<br>mcapotos : 10/26/2000<br>carol : 7/18/2000<br>terry : 7/10/2000<br>mgross : 6/7/2000<br>carol : 10/6/1999<br>carol : 9/21/1999<br>mgross : 9/15/1999<br>alopez : 6/18/1999<br>alopez : 6/18/1999<br>dholmes : 7/22/1998<br>carol : 6/15/1998<br>terry : 6/15/1998<br>terry : 6/11/1998<br>terry : 6/11/1998<br>carol : 5/6/1998<br>terry : 4/20/1998<br>psherman : 4/15/1998<br>terry : 1/7/1998<br>terry : 12/30/1997<br>terry : 12/29/1997<br>alopez : 9/10/1997<br>alopez : 9/9/1997<br>terry : 7/28/1997<br>terry : 11/20/1996<br>mark : 1/8/1996<br>terry : 11/17/1995<br>mark : 10/20/1995<br>carol : 12/6/1994<br>carol : 6/24/1993<br>supermim : 3/16/1992<br>carol : 2/24/1992
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