2898 lines
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- *607984 - SPROUTY RTK SIGNALING ANTAGONIST 4; SPRY4
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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">*607984</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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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="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607984">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<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 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=ENSG00000187678;t=ENST00000434127" 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=81848" 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=607984" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="small">
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<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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<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=ENSG00000187678;t=ENST00000434127" 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_001127496,NM_001293289,NM_001293290,NM_030964,XM_011537685,XM_017009910" 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_001127496" 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=607984" 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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<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=10466&isoform_id=10466_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/SPRY4" 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/12655913,13625182,14916719,21755969,23308574,42795685,133777952,133777954,188595697,648216319,648216322,767937853,1034646312,1767853346,2462604588,2462604590" 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/Q9C004" 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=81848" 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=ENSG00000187678;t=ENST00000434127" 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=SPRY4" 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=SPRY4" 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+81848" 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/SPRY4" 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:81848" 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/81848" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr5&hgg_gene=ENST00000434127.3&hgg_start=142310430&hgg_end=142325021&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607984[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 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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<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=607984[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://gnomad.broadinstitute.org/gene/ENSG00000187678" 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=SPRY4" 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=SPRY4" 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=SPRY4" 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=SPRY4&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/PA37975" 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:15533" 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/FBgn0014388.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:1345144" 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/SPRY4#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:1345144" 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/81848/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=81848" 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://zfin.org/ZDB-GENE-010803-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=SPRY4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607984
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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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SPROUTY RTK SIGNALING ANTAGONIST 4; SPRY4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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SPROUTY, DROSOPHILA, HOMOLOG OF, 4
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SPRY4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SPRY4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/5/616?start=-3&limit=10&highlight=616">5q31.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:142310430-142325021&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">5:142,310,430-142,325,021</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
|
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<a href="/geneMap/5/616?start=-3&limit=10&highlight=616">
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5q31.3
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</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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Hypogonadotropic hypogonadism 17 with or without anosmia
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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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<a href="/entry/615266"> 615266 </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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</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="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607984" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607984" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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</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="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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</span>
|
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</span>
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>SPRY4 is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It is positioned upstream of RAS (see HRAS; <a href="/entry/190020">190020</a>) activation and impairs the formation of active GTP-RAS (<a href="#3" class="mim-tip-reference" title="Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M. <strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong> Europ. J. Biochem. 269: 2546-2556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12027893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12027893</a>] [<a href="https://doi.org/10.1046/j.1432-1033.2002.02921.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12027893">Leeksma et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12027893" 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>By differential display RT-PCR of activated versus resting umbilical artery smooth muscle cells, <a href="#3" class="mim-tip-reference" title="Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M. <strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong> Europ. J. Biochem. 269: 2546-2556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12027893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12027893</a>] [<a href="https://doi.org/10.1046/j.1432-1033.2002.02921.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12027893">Leeksma et al. (2002)</a> isolated cDNAs encoding SPRY4. A 4.9-kb cDNA represents the major transcript and encodes a deduced 322-amino acid protein. SPRY4 contains a prototypic cysteine-rich region, 3 potential Src homology-3 (SH3)-binding proline-rich regions, and a PEST sequence. It shares 88% amino acid identity with mouse Spry4. Northern blot analysis detected expression of a 4.9-kb transcript in all tissues examined. In vitro transcription-translation yielded a protein with an apparent molecular mass of about 35 kD. Alternative splicing and use of an alternate polyadenylation site results in a 7.0-kb cDNA representing a transcript with a premature stop codon, due to a single-nucleotide shift. The deduced truncated protein contains 106 amino acids, and the transcript contains 5 polyadenylation sites, 9 ATTTA sequences, 2 Alu repeats, and 3 CAGAC motifs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12027893" 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="#1" class="mim-tip-reference" title="Khaitan, D., Dinger, M. E., Mazar, J., Crawford, J., Smith, M. A., Mattick, J. S., Perera, R. J. <strong>The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.</strong> Cancer Res. 71: 3852-3862, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21558391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21558391</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-10-4460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21558391">Khaitan et al. (2011)</a> reported that a long noncoding RNA, SPRY4IT1 (<a href="/entry/617617">617617</a>), is transcribed from the second intron of the SPRY4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21558391" 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>By FISH, <a href="#3" class="mim-tip-reference" title="Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M. <strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong> Europ. J. Biochem. 269: 2546-2556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12027893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12027893</a>] [<a href="https://doi.org/10.1046/j.1432-1033.2002.02921.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12027893">Leeksma et al. (2002)</a> mapped the SPRY4 gene to chromosome 5q31.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12027893" 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="#3" class="mim-tip-reference" title="Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M. <strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong> Europ. J. Biochem. 269: 2546-2556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12027893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12027893</a>] [<a href="https://doi.org/10.1046/j.1432-1033.2002.02921.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12027893">Leeksma et al. (2002)</a> found that SPRY4 suppressed the insulin receptor (<a href="/entry/147670">147670</a>)- and epidermal growth factor receptor (EGFR; <a href="/entry/131550">131550</a>)-transduced MAPK signaling pathway, but it did not inhibit MAPK activation by a constitutively active mutant RAS. They concluded that SPRY4 impairs the formation of GTP-RAS. By yeast 2-hybrid screening and coimmunoprecipitation of transfected COS cells, <a href="#3" class="mim-tip-reference" title="Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M. <strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong> Europ. J. Biochem. 269: 2546-2556, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12027893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12027893</a>] [<a href="https://doi.org/10.1046/j.1432-1033.2002.02921.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12027893">Leeksma et al. (2002)</a> determined that SPRY4 interacts with the C terminus of testis-specific protein kinase-1 (TESK1; <a href="/entry/601782">601782</a>). This interaction increased following EGF (<a href="/entry/131530">131530</a>) stimulation. TESK1 and SPRY4 colocalized in peri- and paranuclear cytoplasmic puncta, but there was no substantial translocation to the plasma membrane upon receptor tyrosine kinase stimulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12027893" 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="#5" class="mim-tip-reference" title="Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., Yoshimura, A. <strong>Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1.</strong> Nature Cell Biol. 5: 427-432, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717443</a>] [<a href="https://doi.org/10.1038/ncb978" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717443">Sasaki et al. (2003)</a> characterized mouse Spry4. They found that Spry4 suppressed vascular epithelial growth factor (VEGF; <a href="/entry/192240">192240</a>)-induced, Ras-independent activation of Raf1 (<a href="/entry/164760">164760</a>), but it did not affect EGF-induced, Ras-dependent activation of Raf1. Spry4 bound Raf1 through its C-terminal cysteine-rich domain, and this binding was necessary for inhibition of Raf1 activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717443" 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>Unlike humans, who have a continuous row of teeth, mice have only molars and incisors separated by a toothless region called a diastema. <a href="#2" class="mim-tip-reference" title="Klein, O. D., Minowada, G., Peterkova, R., Kangas, A., Yu, B. D., Lesot, H., Peterka, M., Jernvall, J., Martin, G. R. <strong>Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling.</strong> Dev. Cell 11: 181-190, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16890158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16890158</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16890158[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.devcel.2006.05.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16890158">Klein et al. (2006)</a> showed that Spry2 (<a href="/entry/602466">602466</a>) in epithelium and Spry4 in mesenchyme prevent diastema tooth formation by preventing diastema tooth buds from engaging in the Fgf-mediated bidirectional signaling that normally sustains tooth development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16890158" 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 14 unrelated individuals with congenital hypogonadotropic hypogonadism (HH17; <a href="/entry/615266">615266</a>), <a href="#4" 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 missense mutations in the SPRY4 gene (see, e.g., <a href="#0001">607984.0001</a>-<a href="#0004">607984.0004</a>). In 3 of the patients, their SPRY4 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene, including FGFR1 (<a href="/entry/136350#0027">136350.0027</a>) and DUSP6 (<a href="/entry/602748#0001">602748.0001</a> and <a href="/entry/602748#0003">602748.0003</a>). <a href="#4" 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 congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. <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><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between variation in the SPRY4 gene and craniosynostosis, see <a href="/entry/123100">123100</a>.</p>
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SPRY4, LYS177ARG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78310959;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs78310959</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs78310959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs78310959;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/rs78310959?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=rs78310959" 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=rs78310959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 male patients, 3 sporadic and 1 familial, with congenital hypogonadotropic hypogonadism (HH17; <a href="/entry/615266">615266</a>), <a href="#4" 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.530A-G transition in exon 3 of the SPRY4 gene, resulting in a lys177-to-arg (K177R) substitution at a highly conserved residue in the link between the phosphotyrosine-binding and SPRY translocation domains. The mutation was not found in 155 controls, but was present in the 1000 Genomes Project at a minor allele frequency of 0.3%. All 4 patients were anosmic, and 1 also had hearing loss and 1 had abnormal dentition. <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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<strong>.0002 HYPOGONADOTROPIC HYPOGONADISM 17 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
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SPRY4, SER241TYR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs139512218;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs139512218</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs139512218 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs139512218;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/rs139512218?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=rs139512218" 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=rs139512218" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 patients with congenital hypogonadotropic hypogonadism (HH17; <a href="/entry/615266">615266</a>), 3 female and 1 male, <a href="#4" 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.722C-A transversion in exon 3 of the SPRY4 gene, resulting in a ser241-to-tyr (S241Y) substitution at a highly conserved residue in the SPRY translocation domain. The mutation was found in 1 of 155 controls (minor allele frequency, 0.6%) and was reported in the 1000 Genomes Project at an MAF of 0.8%. Three of the patients were anosmic; those 3 patients also carried a heterozygous missense mutation in another HH-associated gene: 2 in DUSP6 (<a href="/entry/602748#0001">602748.0001</a> and <a href="/entry/602748#0003">602748.0003</a>) and 1 in FGFR1 (<a href="/entry/136350#0027">136350.0027</a>). Additional features in the 3 anosmic patients included 2 with low bone mass and 1 with hearing loss. The remaining female patient was normosmic; she also had low bone mass as well as abnormal dentition. <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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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 17 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">rs587776981 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776981;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=rs587776981" 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=rs587776981" 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 normosmic male patient with congenital hypogonadotropic hypogonadism (HH17; <a href="/entry/615266">615266</a>), <a href="#4" 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.46G-A transition in exon 3 of the SPRY4 gene, resulting in a val16-to-ile (V16I) substitution in the N terminus. The mutation was not found in 155 controls or the 1000 Genomes Project. <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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<strong>.0004 HYPOGONADOTROPIC HYPOGONADISM 17 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"><span class="text-primary">●</span> rs142439525 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs142439525;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/rs142439525?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=rs142439525" 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=rs142439525" 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=RCV000043615 OR RCV000969209" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043615, RCV000969209" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043615...</a>
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<p>In a female patient with congenital hypogonadotropic hypogonadism (HH17; <a href="/entry/615266">615266</a>), <a href="#4" 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.910G-A transition in exon 3 of the SPRY4 gene, resulting in a val304-to-ile (V304I) substitution at a highly conserved residue in the C terminus. The mutation was not found in 155 controls or the 1000 Genomes Project. This normosmic patient underwent partial puberty. <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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Khaitan, D., Dinger, M. E., Mazar, J., Crawford, J., Smith, M. A., Mattick, J. S., Perera, R. J.
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<strong>The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.</strong>
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Cancer Res. 71: 3852-3862, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21558391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21558391</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21558391" 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/10.1158/0008-5472.CAN-10-4460" target="_blank">Full Text</a>]
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Klein, O. D., Minowada, G., Peterkova, R., Kangas, A., Yu, B. D., Lesot, H., Peterka, M., Jernvall, J., Martin, G. R.
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<strong>Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling.</strong>
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Dev. Cell 11: 181-190, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16890158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16890158</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16890158[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=16890158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2006.05.014" target="_blank">Full Text</a>]
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<a id="Leeksma2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M.
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<strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong>
|
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Europ. J. Biochem. 269: 2546-2556, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12027893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12027893</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12027893" 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/10.1046/j.1432-1033.2002.02921.x" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Miraoui2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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.
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<strong>Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.</strong>
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Am. J. Hum. Genet. 92: 725-743, 2013.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.04.008" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Sasaki2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., Yoshimura, A.
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<strong>Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1.</strong>
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Nature Cell Biol. 5: 427-432, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717443</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncb978" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</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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Matthew B. Gross - updated : 08/10/2017
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 04/19/2017<br>Marla J. F. O'Neill - updated : 6/5/2013<br>Patricia A. Hartz - updated : 10/19/2006
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 7/25/2003
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<a id="editHistory" class="mim-anchor"></a>
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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 : 09/12/2019
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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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mgross : 08/10/2017<br>carol : 04/19/2017<br>alopez : 06/11/2013<br>alopez : 6/5/2013<br>mgross : 10/19/2006<br>mgross : 10/19/2006<br>mgross : 7/25/2003
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607984
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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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SPROUTY RTK SIGNALING ANTAGONIST 4; SPRY4
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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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<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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<h4>
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<span class="mim-font">
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SPROUTY, DROSOPHILA, HOMOLOG OF, 4
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</h4>
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</div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SPRY4</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 5q31.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:142,310,430-142,325,021 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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5q31.3
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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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Hypogonadotropic hypogonadism 17 with or without anosmia
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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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615266
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>SPRY4 is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It is positioned upstream of RAS (see HRAS; 190020) activation and impairs the formation of active GTP-RAS (Leeksma et al., 2002). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By differential display RT-PCR of activated versus resting umbilical artery smooth muscle cells, Leeksma et al. (2002) isolated cDNAs encoding SPRY4. A 4.9-kb cDNA represents the major transcript and encodes a deduced 322-amino acid protein. SPRY4 contains a prototypic cysteine-rich region, 3 potential Src homology-3 (SH3)-binding proline-rich regions, and a PEST sequence. It shares 88% amino acid identity with mouse Spry4. Northern blot analysis detected expression of a 4.9-kb transcript in all tissues examined. In vitro transcription-translation yielded a protein with an apparent molecular mass of about 35 kD. Alternative splicing and use of an alternate polyadenylation site results in a 7.0-kb cDNA representing a transcript with a premature stop codon, due to a single-nucleotide shift. The deduced truncated protein contains 106 amino acids, and the transcript contains 5 polyadenylation sites, 9 ATTTA sequences, 2 Alu repeats, and 3 CAGAC motifs. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Khaitan et al. (2011) reported that a long noncoding RNA, SPRY4IT1 (617617), is transcribed from the second intron of the SPRY4 gene. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By FISH, Leeksma et al. (2002) mapped the SPRY4 gene to chromosome 5q31.3. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Leeksma et al. (2002) found that SPRY4 suppressed the insulin receptor (147670)- and epidermal growth factor receptor (EGFR; 131550)-transduced MAPK signaling pathway, but it did not inhibit MAPK activation by a constitutively active mutant RAS. They concluded that SPRY4 impairs the formation of GTP-RAS. By yeast 2-hybrid screening and coimmunoprecipitation of transfected COS cells, Leeksma et al. (2002) determined that SPRY4 interacts with the C terminus of testis-specific protein kinase-1 (TESK1; 601782). This interaction increased following EGF (131530) stimulation. TESK1 and SPRY4 colocalized in peri- and paranuclear cytoplasmic puncta, but there was no substantial translocation to the plasma membrane upon receptor tyrosine kinase stimulation. </p><p>Sasaki et al. (2003) characterized mouse Spry4. They found that Spry4 suppressed vascular epithelial growth factor (VEGF; 192240)-induced, Ras-independent activation of Raf1 (164760), but it did not affect EGF-induced, Ras-dependent activation of Raf1. Spry4 bound Raf1 through its C-terminal cysteine-rich domain, and this binding was necessary for inhibition of Raf1 activation. </p><p>Unlike humans, who have a continuous row of teeth, mice have only molars and incisors separated by a toothless region called a diastema. Klein et al. (2006) showed that Spry2 (602466) in epithelium and Spry4 in mesenchyme prevent diastema tooth formation by preventing diastema tooth buds from engaging in the Fgf-mediated bidirectional signaling that normally sustains tooth development. </p>
|
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</span>
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 14 unrelated individuals with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for missense mutations in the SPRY4 gene (see, e.g., 607984.0001-607984.0004). In 3 of the patients, their SPRY4 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene, including FGFR1 (136350.0027) and DUSP6 (602748.0001 and 602748.0003). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
For discussion of a possible association between variation in the SPRY4 gene and craniosynostosis, see 123100.</p>
|
|
</span>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>4 Selected Examples):</strong>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 17 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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|
SPRY4, LYS177ARG ({dbSNP rs78310959})
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<br />
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|
|
SNP: rs78310959,
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|
|
gnomAD: rs78310959,
|
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|
|
ClinVar: RCV000043614, RCV000356060, RCV003934980
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 4 male patients, 3 sporadic and 1 familial, with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for a c.530A-G transition in exon 3 of the SPRY4 gene, resulting in a lys177-to-arg (K177R) substitution at a highly conserved residue in the link between the phosphotyrosine-binding and SPRY translocation domains. The mutation was not found in 155 controls, but was present in the 1000 Genomes Project at a minor allele frequency of 0.3%. All 4 patients were anosmic, and 1 also had hearing loss and 1 had abnormal dentition. </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 17 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
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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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SPRY4, SER241TYR ({dbSNP rs139512218})
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<br />
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SNP: rs139512218,
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gnomAD: rs139512218,
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ClinVar: RCV000043616, RCV000454560, RCV000954651, RCV001849295
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</span>
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</div>
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<span class="mim-text-font">
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<p>In 4 patients with congenital hypogonadotropic hypogonadism (HH17; 615266), 3 female and 1 male, Miraoui et al. (2013) identified heterozygosity for a c.722C-A transversion in exon 3 of the SPRY4 gene, resulting in a ser241-to-tyr (S241Y) substitution at a highly conserved residue in the SPRY translocation domain. The mutation was found in 1 of 155 controls (minor allele frequency, 0.6%) and was reported in the 1000 Genomes Project at an MAF of 0.8%. Three of the patients were anosmic; those 3 patients also carried a heterozygous missense mutation in another HH-associated gene: 2 in DUSP6 (602748.0001 and 602748.0003) and 1 in FGFR1 (136350.0027). Additional features in the 3 anosmic patients included 2 with low bone mass and 1 with hearing loss. The remaining female patient was normosmic; she also had low bone mass as well as abnormal dentition. </p>
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</span>
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</div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 17 WITHOUT 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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SPRY4, VAL16ILE
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<br />
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SNP: rs587776981,
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ClinVar: RCV000043617
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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 normosmic male patient with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for a c.46G-A transition in exon 3 of the SPRY4 gene, resulting in a val16-to-ile (V16I) substitution in the N terminus. The mutation was not found in 155 controls or the 1000 Genomes Project. </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 17 WITHOUT 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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SPRY4, VAL304ILE
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<br />
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SNP: rs142439525,
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gnomAD: rs142439525,
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ClinVar: RCV000043615, RCV000969209
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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 congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for a c.910G-A transition in exon 3 of the SPRY4 gene, resulting in a val304-to-ile (V304I) substitution at a highly conserved residue in the C terminus. The mutation was not found in 155 controls or the 1000 Genomes Project. This normosmic patient underwent partial puberty. </p>
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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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<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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Khaitan, D., Dinger, M. E., Mazar, J., Crawford, J., Smith, M. A., Mattick, J. S., Perera, R. J.
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<strong>The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion.</strong>
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Cancer Res. 71: 3852-3862, 2011.
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[PubMed: 21558391]
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[Full Text: https://doi.org/10.1158/0008-5472.CAN-10-4460]
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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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Klein, O. D., Minowada, G., Peterkova, R., Kangas, A., Yu, B. D., Lesot, H., Peterka, M., Jernvall, J., Martin, G. R.
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<strong>Sprouty genes control diastema tooth development via bidirectional antagonism of epithelial-mesenchymal FGF signaling.</strong>
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Dev. Cell 11: 181-190, 2006.
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[PubMed: 16890158]
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[Full Text: https://doi.org/10.1016/j.devcel.2006.05.014]
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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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Leeksma, O. C., van Achterberg, T. A. E., Tsumura, Y., Toshima, J., Eldering, E., Kroes, W. G. M., Mellink, C., Spaargaren, M., Mizuno, K., Pannekoek, H., de Vries, C. J. M.
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<strong>Human sprouty 4, a new ras antagonist on 5q31, interacts with the dual specificity kinase TESK1.</strong>
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Europ. J. Biochem. 269: 2546-2556, 2002.
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[PubMed: 12027893]
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[Full Text: https://doi.org/10.1046/j.1432-1033.2002.02921.x]
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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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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>
|
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Am. J. Hum. Genet. 92: 725-743, 2013.
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[PubMed: 23643382]
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]
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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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Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., Yoshimura, A.
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<strong>Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1.</strong>
|
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Nature Cell Biol. 5: 427-432, 2003.
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[PubMed: 12717443]
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[Full Text: https://doi.org/10.1038/ncb978]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Matthew B. Gross - updated : 08/10/2017<br>Marla J. F. O'Neill - updated : 04/19/2017<br>Marla J. F. O'Neill - updated : 6/5/2013<br>Patricia A. Hartz - updated : 10/19/2006
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</span>
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Creation Date:
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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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Patricia A. Hartz : 7/25/2003
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</span>
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</div>
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<span class="mim-text-font">
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carol : 09/12/2019<br>mgross : 08/10/2017<br>carol : 04/19/2017<br>alopez : 06/11/2013<br>alopez : 6/5/2013<br>mgross : 10/19/2006<br>mgross : 10/19/2006<br>mgross : 7/25/2003
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