3584 lines
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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">*603961</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603961">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<div 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=ENSG00000075213;t=ENST00000265362" 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=10371" 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=603961" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<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=ENSG00000075213;t=ENST00000265362" 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_006080,XM_005250110,XM_047419751" 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_006080" 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=603961" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04908&isoform_id=04908_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/SEMA3A" 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/436560,3900859,5174673,8134674,30172710,30577057,41350048,41393505,51094940,62820025,111494030,119597388,158260931,374254654,530385415,2217365256,2462611934,2462611936,2462611939,2462611941,2462611943,2462611945,2462611947,2462611949" 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/Q14563" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=10371" 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=ENSG00000075213;t=ENST00000265362" 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=SEMA3A" 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=SEMA3A" 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+10371" 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/SEMA3A" 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:10371" 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/10371" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000265362.9&hgg_start=83955777&hgg_end=84492725&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:10723" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603961[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603961[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/SEMA3A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000075213" 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=SEMA3A" 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=SEMA3A" 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=SEMA3A" 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=SEMA3A&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/PA35645" 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:10723" 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/FBgn0011260.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:107558" 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/SEMA3A#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:107558" 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/10371/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=10371" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004889;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-991209-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10371" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=SEMA3A&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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603961
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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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SEMAPHORIN 3A; SEMA3A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
SEMAPHORIN III<br />
|
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SEMAPHORIN D; SEMAD<br />
|
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COLLAPSIN 1; COLL1
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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=SEMA3A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SEMA3A</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/7/380?start=-3&limit=10&highlight=380">7q21.11</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:83955777-84492725&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:83,955,777-84,492,725</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">
|
|
<a href="/geneMap/7/380?start=-3&limit=10&highlight=380">
|
|
7q21.11
|
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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">
|
|
{Hypogonadotropic hypogonadism 16 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">
|
|
|
|
<a href="/entry/614897"> 614897 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="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">
|
|
<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>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603961" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603961" 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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|
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<span class="mim-font">
|
|
<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="mapping" class="mim-anchor"></a>
|
|
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<p><a href="#4" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 1/14/2020."None>Gross (2020)</a> mapped the SEMA3A gene to chromosome 7q21.11 based on an alignment of the SEMA3A sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK289954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK289954</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#16" class="mim-tip-reference" title="Takahashi, T., Fournier, A., Nakamura, F., Wang, L.-H., Murakami, Y., Kalb, R. G., Fujisawa, H., Strittmatter, S. M. <strong>Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors.</strong> Cell 99: 59-69, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10520994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10520994</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80062-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10520994">Takahashi et al. (1999)</a> found that the 2 semaphorin-binding proteins, plexin-1 (PLXN1; <a href="/entry/601055">601055</a>) and neuropilin-1 (NP1, or NRP1; <a href="/entry/602069">602069</a>), form a stable complex. PLXN1 alone did not bind semaphorin-3A (SEMA3A), but the NRP1/PLXN1 complex had a higher affinity for SEMA3A than did NRP1 alone. While SEMA3A binding to NRP1 did not alter nonneuronal cell morphology, SEMA3A interaction with NRP1/PLXN1 complexes induced adherent cells to round up. Expression of a dominant-negative PLXN1 in sensory neurons blocked SEMA3A-induced growth cone collapse. SEMA3A treatment led to the redistribution of growth cone NRP1 and PLXN1 into clusters. Thus, the authors concluded that physiologic SEMA3A receptors consist of NRP1/PLXN1 complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10520994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Polleux, F., Morrow, T., Ghosh, A. <strong>Semaphorin 3A is a chemoattractant for cortical apical dendrites.</strong> Nature 404: 567-573, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10766232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10766232</a>] [<a href="https://doi.org/10.1038/35007001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10766232">Polleux et al. (2000)</a> demonstrated that the growth of apical dendrites toward the pial surface is regulated by a diffusible chemoattractant present at high levels near the marginal zone. A major component of the signal is SEMA3A, which was previously characterized as a chemorepellent for cortical axons. Soluble guanylate cyclase is asymmetrically localized to the developing apical dendrite, and is required for the chemoattractive effect of SEMA3A. Thus, the asymmetric localization of soluble guanylate cyclase confers distinct SEMA3A responses to axons and dendrites. <a href="#14" class="mim-tip-reference" title="Polleux, F., Morrow, T., Ghosh, A. <strong>Semaphorin 3A is a chemoattractant for cortical apical dendrites.</strong> Nature 404: 567-573, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10766232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10766232</a>] [<a href="https://doi.org/10.1038/35007001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10766232">Polleux et al. (2000)</a> concluded that these observations reveal a mechanism by which a single chemotropic signal can pattern both axons and dendrites during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10766232" 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>Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. <a href="#12" class="mim-tip-reference" title="Marin, O., Yaron, A., Bagri, A., Tessier-Lavigne, M., Rubenstein, J. L. R. <strong>Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions.</strong> Science 293: 872-875, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486090</a>] [<a href="https://doi.org/10.1126/science.1061891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486090">Marin et al. (2001)</a> demonstrated that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin-3A and semaphorin-3F (<a href="/entry/601124">601124</a>). Migrating interneurons expressing neuropilins, receptors for semaphorins, are directed to the cortex; those lacking them go to the striatum. Loss of neuropilin function increases the number of interneurons that migrate into the striatum. <a href="#12" class="mim-tip-reference" title="Marin, O., Yaron, A., Bagri, A., Tessier-Lavigne, M., Rubenstein, J. L. R. <strong>Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions.</strong> Science 293: 872-875, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11486090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11486090</a>] [<a href="https://doi.org/10.1126/science.1061891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11486090">Marin et al. (2001)</a> concluded that their observations reveal a mechanism by which neuropilins mediate sorting of distinct neuronal populations into different brain structures, and provide evidence that, in addition to guiding axons, these receptors also control neuronal migration in the central nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11486090" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a COS cell-based morphologic assay, <a href="#17" class="mim-tip-reference" title="Takahashi, T., Strittmatter, S. M. <strong>PlexinA1 autoinhibition by the plexin sema domain.</strong> Neuron 29: 429-439, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239433</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00216-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239433">Takahashi and Strittmatter (2001)</a> showed that Plexa1 or Plexa2 activity mediated Sema3 signaling in combination with neuropilins, resulting in cell contraction, growth cone collapse, and neurite outgrowth inhibition. Truncation analysis revealed that the intracellular domain of Plexa1 mediated signaling activity and that the transmembrane region was required for this activity. The conserved sema domain in the Plexa1 extracellular segment bound to the remainder of the PlexA1 extracellular region, inhibited Plexa1 activity, and prevented Plexa1 from participating in Sema3a signaling. Furthermore, the Plexa1 sema domain and the remainder of the Plexa1 extracellular domain interacted with Nrp1 at sites distinct from the Sema3a binding site of Nrp1 and enhanced Sema3a binding to Nrp1. Sema3a binding to Nrp1 induced a conformational change in the Nrp1/Plexa1 complex nd dissociated the sema domain from the remainder of the Plexa1 ectodomain, thereby activating Plexa1 and causing cell contraction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Serini, G., Valdembri, D., Zanivan, S., Morterra, G., Burkhardt, C., Caccavari, F., Zammataro, L., Primo, L., Tamagnone, L., Logan, M., Tessier-Lavigne, M., Taniguchi, M., Puschel, A. W., Bussolino, F. <strong>Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.</strong> Nature 424: 391-397, 2003. Note: Erratum: Nature 424: 974 only, 2003. Expression of Concern: Nature 627: E7, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879061</a>] [<a href="https://doi.org/10.1038/nature01784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879061">Serini et al. (2003)</a> demonstrated that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulated integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonized integrin activation. Misexpression of dominant-negative SEMA3 receptors in chick embryo endothelial cells locked integrins in an active conformation, and severely impaired vascular remodeling. Sema3a-null mice showed vascular defects as well. <a href="#15" class="mim-tip-reference" title="Serini, G., Valdembri, D., Zanivan, S., Morterra, G., Burkhardt, C., Caccavari, F., Zammataro, L., Primo, L., Tamagnone, L., Logan, M., Tessier-Lavigne, M., Taniguchi, M., Puschel, A. W., Bussolino, F. <strong>Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.</strong> Nature 424: 391-397, 2003. Note: Erratum: Nature 424: 974 only, 2003. Expression of Concern: Nature 627: E7, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879061</a>] [<a href="https://doi.org/10.1038/nature01784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879061">Serini et al. (2003)</a> concluded that during angiogenesis, endothelial SEMA3 proteins endow the vascular system with the plasticity required for reshaping by controlling integrin function. Note that an Expression of Concern was published for the article by <a href="#15" class="mim-tip-reference" title="Serini, G., Valdembri, D., Zanivan, S., Morterra, G., Burkhardt, C., Caccavari, F., Zammataro, L., Primo, L., Tamagnone, L., Logan, M., Tessier-Lavigne, M., Taniguchi, M., Puschel, A. W., Bussolino, F. <strong>Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.</strong> Nature 424: 391-397, 2003. Note: Erratum: Nature 424: 974 only, 2003. Expression of Concern: Nature 627: E7, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12879061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12879061</a>] [<a href="https://doi.org/10.1038/nature01784" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12879061">Serini et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12879061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Wu, K. Y., Hengst, U., Cox, L. J., Macosko, E. Z., Jeromin, A., Urquhart, E. R., Jaffrey, S. R. <strong>Local translation of RhoA regulates growth cone collapse. (Letter)</strong> Nature 436: 1020-1024, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16107849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16107849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16107849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16107849">Wu et al. (2005)</a> showed that transcripts for RhoA (<a href="/entry/165390">165390</a>), a small GTPase that regulates the actin cytoskeleton, are localized in developing axons and growth cones, and that this localization is mediated by an axonal targeting element located in the RhoA 3-prime untranslated region. Sema3A induces intraaxonal translation of RhoA mRNA, and this local translation of RhoA is necessary and sufficient for Sema3A-mediated growth cone collapse. <a href="#20" class="mim-tip-reference" title="Wu, K. Y., Hengst, U., Cox, L. J., Macosko, E. Z., Jeromin, A., Urquhart, E. R., Jaffrey, S. R. <strong>Local translation of RhoA regulates growth cone collapse. (Letter)</strong> Nature 436: 1020-1024, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16107849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16107849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16107849[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature03885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16107849">Wu et al. (2005)</a> concluded that their studies indicate that local RhoA translation regulates the neuronal cytoskeleton and identify a new mechanism for the regulation of RhoA signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16107849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunohistochemistry, <a href="#11" class="mim-tip-reference" title="Lepelletier, Y., Smaniotto, S., Hadj-Slimane, R., Villa-Verde, D. M. S., Nogueira, A. C., Dardenne, M., Hermine, O., Savino, W. <strong>Control of human thymocyte migration by neuropilin-1/semaphorin-3A-mediated interactions.</strong> Proc. Nat. Acad. Sci. 104: 5545-5550, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17369353[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0700705104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369353">Lepelletier et al. (2007)</a> found that NP1 and SEMA3A were expressed in thymic epithelial cells (TECs) and CD4 (<a href="/entry/186940">186940</a>)/CD8 (see <a href="/entry/186910">186910</a>) thymocytes. Both IL7 (<a href="/entry/146660">146660</a>), which is constitutively secreted by TECs, and T-cell receptor (TCR) engagement upregulated NP1 expression in thymocytes. SEMA3A blocked adhesion of NP1-positive thymocytes to TECs and induced thymocyte repulsive migration, partially by inhibiting binding of very late antigens (see ITGA4; <a href="/entry/192975">192975</a>) to laminin (see LAMA1; <a href="/entry/150320">150320</a>). <a href="#11" class="mim-tip-reference" title="Lepelletier, Y., Smaniotto, S., Hadj-Slimane, R., Villa-Verde, D. M. S., Nogueira, A. C., Dardenne, M., Hermine, O., Savino, W. <strong>Control of human thymocyte migration by neuropilin-1/semaphorin-3A-mediated interactions.</strong> Proc. Nat. Acad. Sci. 104: 5545-5550, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17369353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17369353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17369353[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0700705104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17369353">Lepelletier et al. (2007)</a> concluded that NP1 and SEMA3A interactions are important in regulation of migration and adhesion of thymocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17369353" 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="#8" class="mim-tip-reference" title="Imai, T., Yamazaki, T., Kobayakawa, R., Kobayakawa, K., Abe, T., Suzuki, M., Sakano, H. <strong>Pre-target axon sorting establishes the neural map topography.</strong> Science 325: 585-590, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19589963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19589963</a>] [<a href="https://doi.org/10.1126/science.1173596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19589963">Imai et al. (2009)</a> analyzed the pre-target axon sorting for olfactory map formation in mice. In olfactory sensory neurons, an axon guidance receptor, neuropilin-1 (NPN1; <a href="/entry/602069">602069</a>), and its repulsive ligand, semaphorin-3A, are expressed in a complementary manner. <a href="#8" class="mim-tip-reference" title="Imai, T., Yamazaki, T., Kobayakawa, R., Kobayakawa, K., Abe, T., Suzuki, M., Sakano, H. <strong>Pre-target axon sorting establishes the neural map topography.</strong> Science 325: 585-590, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19589963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19589963</a>] [<a href="https://doi.org/10.1126/science.1173596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19589963">Imai et al. (2009)</a> found that expression levels of neuropilin-1 determined both pre-target sorting and projection sites of axons. Olfactory sensory neuron-specific knockout of semaphorin-3A perturbed axon sorting and altered the olfactory map topography. Thus, <a href="#8" class="mim-tip-reference" title="Imai, T., Yamazaki, T., Kobayakawa, R., Kobayakawa, K., Abe, T., Suzuki, M., Sakano, H. <strong>Pre-target axon sorting establishes the neural map topography.</strong> Science 325: 585-590, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19589963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19589963</a>] [<a href="https://doi.org/10.1126/science.1173596" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19589963">Imai et al. (2009)</a> concluded that pre-target axon sorting plays an important role in establishing the topographic order based on the relative levels of guidance molecules expressed by axons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19589963" 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="#18" class="mim-tip-reference" title="Tran, T. S., Rubio, M. E., Clem, R. L., Johnson, D., Case, L., Tessier-Lavigne, M., Huganir, R. L., Ginty, D. D., Kolodkin, A. L. <strong>Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS.</strong> Nature 462: 1065-1069, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20010807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20010807</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20010807[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08628" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20010807">Tran et al. (2009)</a> found that a Sema3A-Npn1/PlexA4 (<a href="/entry/604280">604280</a>) signaling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. In contrast, they demonstrated that the secreted semaphorin Sema3F (<a href="/entry/601124">601124</a>) is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F and its holoreceptor components neuropilin-2 (NPN2; <a href="/entry/602070">602070</a>) and plexin A3 (PLEXA3; <a href="/entry/300022">300022</a>) exhibit increased dentate gyrus granule cell and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn2-null brain slices cortical layer V and dentate gyrus granule cells exhibit increased miniature excitatory postsynaptic current frequency. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn2 to apical dendrites and of Npn1 to all dendrites of cortical pyramidal neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20010807" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Hayashi, M., Nakashima, T., Taniguchi, M., Kodama, T., Kumanogoh, A., Takayanagi, H. <strong>Osteoprotection by semaphorin 3A.</strong> Nature 485: 69-74, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22522930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22522930</a>] [<a href="https://doi.org/10.1038/nature11000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22522930">Hayashi et al. (2012)</a> showed that Sema3a exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited RANKL (<a href="/entry/602642">602642</a>)-induced osteoclast differentiation by inhibiting ITAM (<a href="/entry/608740">608740</a>) and RhoA signaling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/beta-catenin signaling pathway (see <a href="/entry/116806">116806</a>). The osteopenic phenotype in Sema3a-null mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22522930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#3" class="mim-tip-reference" title="Fukuda, T., Takeda, S., Xu, R., Ochi, H., Sunamura, S., Sato, T., Shibata, S., Yoshida, Y., Gu, Z., Kimura, A., Ma, C., Xu, C., and 9 others. <strong>Sema3A regulates bone-mass accrual through sensory innervations.</strong> Nature 497: 490-493, 2013. Note: Erratum: Nature 500: 612 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23644455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23644455</a>] [<a href="https://doi.org/10.1038/nature12115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23644455">Fukuda et al. (2013)</a> showed that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3A-null mice had a low bone mass due to decreased bone formation. <a href="#3" class="mim-tip-reference" title="Fukuda, T., Takeda, S., Xu, R., Ochi, H., Sunamura, S., Sato, T., Shibata, S., Yoshida, Y., Gu, Z., Kimura, A., Ma, C., Xu, C., and 9 others. <strong>Sema3A regulates bone-mass accrual through sensory innervations.</strong> Nature 497: 490-493, 2013. Note: Erratum: Nature 500: 612 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23644455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23644455</a>] [<a href="https://doi.org/10.1038/nature12115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23644455">Fukuda et al. (2013)</a> created osteoblast-specific Sema3A-null mice using Col1a1 (<a href="/entry/120150">120150</a>)-Cre mice and osterix (<a href="/entry/606633">606633</a>)-Cre mice (Sema3a(col1)-null and Sema3a(osx)-null mice, respectively), and neuron-specific Sema3A-null mice using synapsin-1 (<a href="/entry/313440">313440</a>)-Cre mice and nestin (<a href="/entry/600915">600915</a>)-Cre mice (Sema3a(synapsin)-null and Sema3a(nestin)-null mice, respectively). The osteoblast-specific Sema3A-deficient mice had normal bone mass even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons had low bone mass similar to Sema3a-null mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3a(synapsin)-null mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wildtype mice, whereas it did not reduce the low bone mass in Sema3a(nestin)-null mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a-null mice, such as olfactory development, were identified in Sema3a(synapsin)-null mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a-null mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. <a href="#3" class="mim-tip-reference" title="Fukuda, T., Takeda, S., Xu, R., Ochi, H., Sunamura, S., Sato, T., Shibata, S., Yoshida, Y., Gu, Z., Kimura, A., Ma, C., Xu, C., and 9 others. <strong>Sema3A regulates bone-mass accrual through sensory innervations.</strong> Nature 497: 490-493, 2013. Note: Erratum: Nature 500: 612 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23644455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23644455</a>] [<a href="https://doi.org/10.1038/nature12115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23644455">Fukuda et al. (2013)</a> concluded that Sema3A regulates bone remodeling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23644455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Molofsky, A. V., Kelley, K. W., Tsai, H.-H., Redmond, S. A., Chang, S. M., Madireddy, L., Chan, J. R., Baranzini, S. E., Ullian, E. M., Rowitch, D. H. <strong>Astrocyte-encoded positional cues maintain sensorimotor circuit integrity.</strong> Nature 509: 189-194, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24776795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776795">Molofsky et al. (2014)</a> showed that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded SEMA3A is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a leads to dysregulated alpha-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of alpha-motor but not of adjacent gamma-motor neurons. In addition, a subset of Trka (<a href="/entry/191315">191315</a>)-positive sensory afferents projects to ectopic ventral positions. <a href="#13" class="mim-tip-reference" title="Molofsky, A. V., Kelley, K. W., Tsai, H.-H., Redmond, S. A., Chang, S. M., Madireddy, L., Chan, J. R., Baranzini, S. E., Ullian, E. M., Rowitch, D. H. <strong>Astrocyte-encoded positional cues maintain sensorimotor circuit integrity.</strong> Nature 509: 189-194, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24776795[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776795">Molofsky et al. (2014)</a> concluded that these findings demonstrated that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggested that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24776795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Uesaka, N., Uchigashima, M., Mikuni, T., Nakazawa, T., Nakao, H., Hirai, H., Aiba, A., Watanabe, M., Kano, M. <strong>Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain.</strong> Science 344: 1020-1023, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24831527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24831527</a>] [<a href="https://doi.org/10.1126/science.1252514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24831527">Uesaka et al. (2014)</a> identified semaphorins, a family of versatile cell recognition molecules, as retrograde signals for elimination of redundant climbing fiber to Purkinje cell synapses in developing mouse cerebellum. Knockdown of Sema3a, a secreted semaphorin, in Purkinje cells or its receptor in climbing fibers accelerated synapse elimination during postnatal day 8 (P8) to P18. Conversely, knockdown of Sema7a (<a href="/entry/607961">607961</a>), a membrane-anchored semaphorin, in Purkinje cells or either of its 2 receptors in climbing fibers impaired synapse elimination after P15. The effect of Sema7a involves signaling by metabotropic glutamate receptor-1 (GRM1; <a href="/entry/604473">604473</a>), a canonical pathway for climbing fiber synapse elimination. <a href="#19" class="mim-tip-reference" title="Uesaka, N., Uchigashima, M., Mikuni, T., Nakazawa, T., Nakao, H., Hirai, H., Aiba, A., Watanabe, M., Kano, M. <strong>Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain.</strong> Science 344: 1020-1023, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24831527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24831527</a>] [<a href="https://doi.org/10.1126/science.1252514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24831527">Uesaka et al. (2014)</a> concluded that their findings defined how semaphorins retrogradely regulate multiple processes of synapse elimination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24831527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Lee, H., Macpherson, L. J., Parada, C. A., Zuker, C. S., Ryba, N. J. P. <strong>Rewiring the taste system.</strong> Nature 548: 330-333, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28792937[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792937">Lee et al. (2017)</a> showed that bitter and sweet taste receptor cells provide instructive signals to bitter and sweet target neurons via different guidance molecules, SEMA3A and SEMA7A, respectively. <a href="#10" class="mim-tip-reference" title="Lee, H., Macpherson, L. J., Parada, C. A., Zuker, C. S., Ryba, N. J. P. <strong>Rewiring the taste system.</strong> Nature 548: 330-333, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28792937[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792937">Lee et al. (2017)</a> demonstrated that targeted expression of SEMA3A or SEMA7A in different classes of taste receptor cells produces peripheral taste systems with miswired sweet or bitter cells. They engineered mice with bitter neurons that responded to sweet tastants, sweet neurons that responded to bitter, or sweet neurons that responded to sour stimuli. <a href="#10" class="mim-tip-reference" title="Lee, H., Macpherson, L. J., Parada, C. A., Zuker, C. S., Ryba, N. J. P. <strong>Rewiring the taste system.</strong> Nature 548: 330-333, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28792937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28792937</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28792937[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature23299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28792937">Lee et al. (2017)</a> concluded that their results uncovered the basic logic of the wiring of the taste system at the periphery, and illustrated how a labeled-line sensory circuit preserves signaling integrity despite rapid and stochastic turnover of receptor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28792937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Hypogonadotropic Hypogonadism 16 with or without Anosmia</em></strong></p><p>
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In 2 sibs and their father with Kallmann syndrome (HH16; <a href="/entry/614897">614897</a>), <a href="#21" class="mim-tip-reference" title="Young, J., Metay, C., Bouligand, J., Tou, B., Francou, B., Maione, L., Tosca, L., Sarfati, J., Brioude, F., Esteva, B., Briand-Suleau, A., Brisset, S., Goossens, M., Tachdjian, G., Guiochon-Mantel, A. <strong>SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development.</strong> Hum. Reprod. 27: 1460-1465, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22416012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22416012</a>] [<a href="https://doi.org/10.1093/humrep/des022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22416012">Young et al. (2012)</a> identified heterozygosity for a 213-kb deletion in the SEMA3A gene (<a href="#0001">603961.0001</a>). Sequencing of the nondeleted SEMA3A allele and of 12 known HH-associated genes in affected members of the family did not reveal any other mutations. <a href="#21" class="mim-tip-reference" title="Young, J., Metay, C., Bouligand, J., Tou, B., Francou, B., Maione, L., Tosca, L., Sarfati, J., Brioude, F., Esteva, B., Briand-Suleau, A., Brisset, S., Goossens, M., Tachdjian, G., Guiochon-Mantel, A. <strong>SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development.</strong> Hum. Reprod. 27: 1460-1465, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22416012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22416012</a>] [<a href="https://doi.org/10.1093/humrep/des022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22416012">Young et al. (2012)</a> concluded that SEMA3A plays a role in anosmic hypogonadotropic hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22416012" 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>Because mutant mice lacking a functional Sema3a-binding domain in the NRP1 gene have a Kallmann syndrome (KS)-like phenotype (anosmic HH), <a href="#5" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> sequenced the SEMA3A gene in 386 unrelated patients with anosmic HH, 88 (23%) of whom were known to carry a heterozygous mutation in 1 of 5 previously tested KS-associated genes (KAL1, <a href="/entry/300836">300836</a>; FGFR1, <a href="/entry/136350">136350</a>; PROKR2, <a href="/entry/607123">607123</a>; PROK2, <a href="/entry/607002">607002</a>; and FGF8, <a href="/entry/600483">600483</a>). Heterozygosity for 8 different nonsynonymous mutations in SEMA3A were identified in 24 patients (see, e.g., <a href="#0002">603961.0002</a> and <a href="#0003">603961.0003</a>), including 5 patients already known to carry a mutation in another KS-associated gene (KAL1; FGFR1; PROKR2; and PROK2). The 7 missense mutations in the SEMA3A gene were all located at highly conserved residues and 6 were shown to be loss-of-function mutations; all 7 had been reported in the Exome Variant Server database, and 3 were also detected in the sample of 386 controls. Based on the seemingly normal reproductive phenotype of Sema3a +/- mice, <a href="#5" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> suggested that monoallelic mutations in SEMA3A are not sufficient to induce the abnormal phenotype in patients, but contribute to the pathogenesis of KS through synergistic effects with mutant alleles of other disease-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 Chinese patients with HH without anosmia (patients 1 and 2), <a href="#2" class="mim-tip-reference" title="Dai, W., Li, J.-D., Zhao, Y., Wu, J., Jiang, F., Chen, D.-N., Zheng, R., Men, M. <strong>Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.</strong> Clin. Genet. 97: 696-703, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32060892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32060892</a>] [<a href="https://doi.org/10.1111/cge.13723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32060892">Dai et al. (2020)</a> identified heterozygous missense mutations in the SEMA3A gene (R197Q, <a href="#0004">603961.0004</a> and R617Q, <a href="#0006">603961.0006</a>, respectively). In a Chinese patient with anosmic HH (patient 2), they identified a heterozygous V458I mutation in the SEMA3A gene (<a href="#0005">603961.0005</a>). Transfection of a plasmid containing SEMA3A with the R197Q or R617Q mutation showed normal secretion but absence of FAK phosphorylation in GN11 cells and failure to stimulate GN11 cell migration; transfection with the V458I mutation showed abnormal secretion, failure to phosphorylate FAK in GN11 cells, and failure to stimulate GN11 cell migration. Patient 2 also had heterozygous mutations in the CCDC141 (<a href="/entry/616031">616031</a>) and PROKR2 (<a href="/entry/607123">607123</a>) genes, leading <a href="#2" class="mim-tip-reference" title="Dai, W., Li, J.-D., Zhao, Y., Wu, J., Jiang, F., Chen, D.-N., Zheng, R., Men, M. <strong>Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.</strong> Clin. Genet. 97: 696-703, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32060892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32060892</a>] [<a href="https://doi.org/10.1111/cge.13723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32060892">Dai et al. (2020)</a> to consider oligogenic inheritance in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32060892" 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 an association between variation in the SEMA3A gene and crypt frequency in the iris, see <a href="/entry/610744">610744</a>.</p>
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<p><a href="#1" class="mim-tip-reference" title="Behar, O., Golden, J. A., Mashimo, H., Schoen, F. J., Fishman, M. C. <strong>Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.</strong> Nature 383: 525-528, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8849723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8849723</a>] [<a href="https://doi.org/10.1038/383525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8849723">Behar et al. (1996)</a> generated mice mutant in semaphorin III using embryonic stem cells in which they replaced the first coding exon with 'neo' cassettes. Heterozygous mice appeared normal. The cerebral cortex of homozygous mutant mice showed a paucity of neuropil and abnormally oriented neuronal processes, especially of the large pyramidal neurons. Certain embryonic bones and cartilaginous structures developed abnormally, with vertebral fusions and partial rib duplications. The few mice that survived more than a few days postnatally manifested pronounced and selective hypertrophy of the right ventricle of the heart and dilation of the right atrium. <a href="#1" class="mim-tip-reference" title="Behar, O., Golden, J. A., Mashimo, H., Schoen, F. J., Fishman, M. C. <strong>Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.</strong> Nature 383: 525-528, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8849723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8849723</a>] [<a href="https://doi.org/10.1038/383525a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8849723">Behar et al. (1996)</a> thus concluded that semaphorin III may serve as a signal that restrains growth in several developing organs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8849723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kaneko, S., Iwanami, A., Nakamura, M., Kishino, A., Kikuchi, K., Shibata, S., Okano, H. J., Ikegami, T., Moriya, A., Konishi, O., Nakayama, C., Kumagai, K., Kimura, T., Sato, Y., Goshima, Y., Taniguchi, M., Ito, M., He, Z., Toyama, Y., Okano, H. <strong>A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.</strong> Nature Med. 12: 1380-1389, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17099709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17099709</a>] [<a href="https://doi.org/10.1038/nm1505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17099709">Kaneko et al. (2006)</a> found that adult rats with transection of the spinal cord showed considerable functional recovery after being treated with a Sema3A inhibitor, SM-216289, derived from the fermentation broth of a fungal strain. With SM-216289 treatment, the injured rats showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, decreased number of apoptotic cells, and marked enhancement of angiogenesis compared to untreated rats. <a href="#9" class="mim-tip-reference" title="Kaneko, S., Iwanami, A., Nakamura, M., Kishino, A., Kikuchi, K., Shibata, S., Okano, H. J., Ikegami, T., Moriya, A., Konishi, O., Nakayama, C., Kumagai, K., Kimura, T., Sato, Y., Goshima, Y., Taniguchi, M., Ito, M., He, Z., Toyama, Y., Okano, H. <strong>A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.</strong> Nature Med. 12: 1380-1389, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17099709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17099709</a>] [<a href="https://doi.org/10.1038/nm1505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17099709">Kaneko et al. (2006)</a> concluded that Sema3A is an inhibitor of axonal regeneration and other regenerative responses after spinal cord injury. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17099709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunofluorescence microscopy, <a href="#7" class="mim-tip-reference" title="Ieda, M., Kanazawa, H., Kimura, K., Hattori, F., Ieda, Y., Taniguchi, M., Lee, J.-K., Matsumura, K., Tomita, Y., Miyoshi, S., Shimoda, K., Makino, S., Sano, M., Kodama, I., Ogawa, S., Fukuda, K. <strong>Sema3a maintains normal heart rhythm through sympathetic innervation patterning.</strong> Nature Med. 13: 604-612, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17417650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17417650</a>] [<a href="https://doi.org/10.1038/nm1570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17417650">Ieda et al. (2007)</a> analyzed the distribution of sympathetic nerves in mouse heart. Sema3a was abundantly expressed in the trabecular layer in early-stage embryos, but it was restricted to Purkinje fibers after birth. Sema3a -/- mice lacked a cardiac sympathetic innervation gradient and exhibited stellate ganglia malformation, leading to marked sinus bradycardia due to sympathetic dysfunction. Overexpression of Sema3a in hearts of transgenic mice led to reduced sympathetic innervation and attenuation of the epicardial-to-endocardial innervation gradient. Sema3a-overexpressing mice succumbed to sudden death and showed susceptibility to ventricular tachycardia due to catecholamine supersensitivity and prolongation of action potential duration. <a href="#7" class="mim-tip-reference" title="Ieda, M., Kanazawa, H., Kimura, K., Hattori, F., Ieda, Y., Taniguchi, M., Lee, J.-K., Matsumura, K., Tomita, Y., Miyoshi, S., Shimoda, K., Makino, S., Sano, M., Kodama, I., Ogawa, S., Fukuda, K. <strong>Sema3a maintains normal heart rhythm through sympathetic innervation patterning.</strong> Nature Med. 13: 604-612, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17417650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17417650</a>] [<a href="https://doi.org/10.1038/nm1570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17417650">Ieda et al. (2007)</a> concluded that normal sympathetic innervation mediated by SEMA3A is important for maintenance of arrhythmia-free hearts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17417650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a brother and sister and their father with Kallmann syndrome (HH16; <a href="/entry/614897">614897</a>), <a href="#21" class="mim-tip-reference" title="Young, J., Metay, C., Bouligand, J., Tou, B., Francou, B., Maione, L., Tosca, L., Sarfati, J., Brioude, F., Esteva, B., Briand-Suleau, A., Brisset, S., Goossens, M., Tachdjian, G., Guiochon-Mantel, A. <strong>SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development.</strong> Hum. Reprod. 27: 1460-1465, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22416012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22416012</a>] [<a href="https://doi.org/10.1093/humrep/des022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22416012">Young et al. (2012)</a> identified heterozygosity for a 213-kb deletion involving exon 6 through exon 17 of the SEMA3A gene. No mutation was found on the nondeleted allele, and no mutations were found in other known HH-associated genes. <a href="#21" class="mim-tip-reference" title="Young, J., Metay, C., Bouligand, J., Tou, B., Francou, B., Maione, L., Tosca, L., Sarfati, J., Brioude, F., Esteva, B., Briand-Suleau, A., Brisset, S., Goossens, M., Tachdjian, G., Guiochon-Mantel, A. <strong>SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development.</strong> Hum. Reprod. 27: 1460-1465, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22416012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22416012</a>] [<a href="https://doi.org/10.1093/humrep/des022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22416012">Young et al. (2012)</a> concluded that loss of function of SEMA3A played a role in the patients' phenotype. <a href="#5" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> stated that their findings did not support mere autosomal dominant mendelian inheritance in this family, and suggested that variation in another gene combined with SEMA3A haploinsufficiency produced the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22416012+22927827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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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> rs147436181 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147436181;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/rs147436181?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=rs147436181" 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=rs147436181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 16 patients with anosmic hypogonadotropic hypogonadism (HH16; <a href="/entry/614897">614897</a>), <a href="#5" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> identified heterozygosity for a G-A transition in exon 11 of the SEMA3A gene, resulting in a val435-to-ile (V435I) substitution at a highly conserved residue in the SEMA domain. Transfection studies in COS-7 cells demonstrated defective secretion of the mutant protein, which was not detected in the conditioned medium. The V435I mutation had been reported in the Exome Variant Server database with an allele frequency in the European American population of 1.3%, and was also detected in 13 of 772 control chromosomes. Three of the patients with V435I were known to also carry heterozygous mutations in 3 other HH-associated genes, including a man with a missense mutation in FGFR1 (<a href="/entry/136350">136350</a>), a man with a missense mutation in PROKR2 (<a href="/entry/607123">607123</a>), and a woman with a frameshift mutation in PROK2 (<a href="/entry/607002">607002</a>). <a href="#5" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> suggested that monoallelic mutations in SEMA3A contribute to the pathogenesis of anosmic HH through synergistic effects with other mutant alleles of disease-associated genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a man with anosmic hypogonadotropic hypogonadism (HH16; <a href="/entry/614897">614897</a>), <a href="#5" class="mim-tip-reference" title="Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. <strong>SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.</strong> PLoS Genet. 8: e1002896, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927827</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22927827[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002896" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927827">Hanchate et al. (2012)</a> identified heterozygosity for a 14-bp deletion (1613_1626del) in exon 14 of the SEMA3A gene, predicted to cause a frameshift within the PSI domain resulting in a premature termination codon (Asp538fsTer31). Transfection studies in COS-7 cells demonstrated defective secretion of the mutant protein, which was not detected in the conditioned medium. The mutation was not found in the Exome Variant Server database or in 386 unrelated Caucasian controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1404070020 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1404070020;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=rs1404070020" 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=rs1404070020" 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 man with hypogonadotropic hypogonadism without anosmia (HH16; <a href="/entry/614897">614897</a>), <a href="#2" class="mim-tip-reference" title="Dai, W., Li, J.-D., Zhao, Y., Wu, J., Jiang, F., Chen, D.-N., Zheng, R., Men, M. <strong>Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.</strong> Clin. Genet. 97: 696-703, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32060892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32060892</a>] [<a href="https://doi.org/10.1111/cge.13723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32060892">Dai et al. (2020)</a> identified a heterozygous c.590G-A transition in the SEMA3A gene, resulting in an arg197-to-gln (R197Q) substitution at a conserved residue in the sema domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's mother was heterozygous for the mutation. The mutation was not present in the gnomAD database or in a database of 2,019 Chinese controls. Transfection of a plasmid containing SEMA3A with the R197Q mutation showed that normal secretion but failure to phosphorylate FAK in GN11 cells and failure to stimulate GN11 cell migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32060892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HYPOGONADOTROPIC HYPOGONADISM 16 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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SEMA3A, VAL458ILE
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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> rs553661856 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs553661856;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/rs553661856?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=rs553661856" 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=rs553661856" 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=RCV001785417 OR RCV004591567 OR RCV004749740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001785417, RCV004591567, RCV004749740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001785417...</a>
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<p>In a man with anosmic hypogonadotropic hypogonadism (HH16; <a href="/entry/614897">614897</a>), <a href="#2" class="mim-tip-reference" title="Dai, W., Li, J.-D., Zhao, Y., Wu, J., Jiang, F., Chen, D.-N., Zheng, R., Men, M. <strong>Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.</strong> Clin. Genet. 97: 696-703, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32060892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32060892</a>] [<a href="https://doi.org/10.1111/cge.13723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32060892">Dai et al. (2020)</a> identified a heterozygous c.1372G-A transition in the SEMA3A gene, resulting in a val458-to-ile (V458I) substitution at a conserved residue in the sema domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father, who had normal fertility, was heterozygous for the mutation. The mutation was present in the gnomAD database at a frequency of 0.000053 and was not identified in a database of 2,019 Chinese controls. Transfection of a plasmid containing SEMA3A with the V458I mutation showed abnormal secretion, failure to phosphorylate FAK in GN11 cells, and failure to stimulate GN11 cell migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32060892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs919402688 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs919402688;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/rs919402688?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=rs919402688" 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=rs919402688" 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 man with hypogonadotropic hypogonadism without anosmia (HH16; <a href="/entry/614897">614897</a>), <a href="#2" class="mim-tip-reference" title="Dai, W., Li, J.-D., Zhao, Y., Wu, J., Jiang, F., Chen, D.-N., Zheng, R., Men, M. <strong>Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.</strong> Clin. Genet. 97: 696-703, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32060892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32060892</a>] [<a href="https://doi.org/10.1111/cge.13723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32060892">Dai et al. (2020)</a> identified a heterozygous c.1850G-A transition in the SEMA3A gene, resulting in an arg617-to-gln (R617Q) substitution at a conserved residue in the Ig domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's mother was heterozygous for the mutation. The mutation was present in the gnomAD database at a frequency of 0.0000041 and was not identified in a database of 2,019 Chinese controls. Transfection of a plasmid containing SEMA3A with the R617Q mutation showed normal secretion but failure to phosphorylate FAK in GN11 cells and failure to stimulate GN11 cell migration. The patient also had heterozygous mutations in the CCDC141 (<a href="/entry/616031">616031</a>) and PROKR2 (<a href="/entry/607123">607123</a>), leading <a href="#2" class="mim-tip-reference" title="Dai, W., Li, J.-D., Zhao, Y., Wu, J., Jiang, F., Chen, D.-N., Zheng, R., Men, M. <strong>Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.</strong> Clin. Genet. 97: 696-703, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32060892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32060892</a>] [<a href="https://doi.org/10.1111/cge.13723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32060892">Dai et al. (2020)</a> to consider oligogenic inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32060892" 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>Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.</strong>
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Nature 383: 525-528, 1996.
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Tran, T. S., Rubio, M. E., Clem, R. L., Johnson, D., Case, L., Tessier-Lavigne, M., Huganir, R. L., Ginty, D. D., Kolodkin, A. L.
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<strong>Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS.</strong>
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Nature 462: 1065-1069, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20010807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20010807</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20010807[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=20010807" 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/nature08628" target="_blank">Full Text</a>]
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</p>
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<a id="19" class="mim-anchor"></a>
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<a id="Uesaka2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Uesaka, N., Uchigashima, M., Mikuni, T., Nakazawa, T., Nakao, H., Hirai, H., Aiba, A., Watanabe, M., Kano, M.
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<strong>Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain.</strong>
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Science 344: 1020-1023, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24831527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24831527</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24831527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1252514" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Wu2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, K. Y., Hengst, U., Cox, L. J., Macosko, E. Z., Jeromin, A., Urquhart, E. R., Jaffrey, S. R.
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<strong>Local translation of RhoA regulates growth cone collapse. (Letter)</strong>
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Nature 436: 1020-1024, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16107849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16107849</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16107849[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=16107849" 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/nature03885" target="_blank">Full Text</a>]
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</p>
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<a id="21" class="mim-anchor"></a>
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<a id="Young2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Young, J., Metay, C., Bouligand, J., Tou, B., Francou, B., Maione, L., Tosca, L., Sarfati, J., Brioude, F., Esteva, B., Briand-Suleau, A., Brisset, S., Goossens, M., Tachdjian, G., Guiochon-Mantel, A.
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<strong>SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development.</strong>
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Hum. Reprod. 27: 1460-1465, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22416012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22416012</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22416012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/humrep/des022" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/22/2021
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 01/14/2020<br>Bao Lige - updated : 01/06/2020<br>Ada Hamosh - updated : 01/29/2018<br>Ada Hamosh - updated : 07/09/2014<br>Ada Hamosh - updated : 5/30/2014<br>Ada Hamosh - updated : 7/10/2013<br>Marla J. F. O'Neill - updated : 10/23/2012<br>Ada Hamosh - updated : 9/20/2012<br>Marla J. F. O'Neill - updated : 9/12/2011<br>Ada Hamosh - updated : 4/15/2010<br>Ada Hamosh - updated : 9/1/2009<br>Paul J. Converse - updated : 6/12/2007<br>Paul J. Converse - updated : 5/16/2007<br>Cassandra L. Kniffin - updated : 1/4/2007<br>Ada Hamosh - updated : 9/15/2005<br>Ada Hamosh - updated : 8/5/2003<br>Patricia A. Hartz - updated : 7/15/2003<br>Ada Hamosh - updated : 8/27/2001<br>Ada Hamosh - updated : 4/5/2000<br>Stylianos E. Antonarakis - updated : 10/25/1999
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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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Patti M. Sherman : 7/1/1999
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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carol : 04/16/2024
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<span class="mim-text-font">
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carol : 04/15/2024<br>carol : 11/22/2021<br>carol : 04/07/2020<br>mgross : 01/14/2020<br>mgross : 01/06/2020<br>alopez : 01/29/2018<br>carol : 10/27/2017<br>alopez : 07/09/2014<br>alopez : 5/30/2014<br>alopez : 10/28/2013<br>alopez : 10/2/2013<br>alopez : 7/10/2013<br>carol : 10/23/2012<br>terry : 10/23/2012<br>alopez : 9/24/2012<br>terry : 9/20/2012<br>carol : 9/13/2011<br>terry : 9/12/2011<br>alopez : 4/15/2010<br>terry : 9/1/2009<br>mgross : 6/12/2007<br>mgross : 5/16/2007<br>mgross : 5/16/2007<br>wwang : 1/25/2007<br>ckniffin : 1/4/2007<br>alopez : 9/16/2005<br>terry : 9/15/2005<br>carol : 8/28/2003<br>alopez : 8/6/2003<br>terry : 8/5/2003<br>mgross : 7/15/2003<br>alopez : 8/31/2001<br>terry : 8/27/2001<br>alopez : 4/5/2000<br>terry : 4/5/2000<br>mgross : 10/25/1999<br>psherman : 7/1/1999
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<strong>*</strong> 603961
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<h3>
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SEMAPHORIN 3A; SEMA3A
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<br />
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<em>Alternative titles; symbols</em>
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SEMAPHORIN III<br />
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SEMAPHORIN D; SEMAD<br />
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COLLAPSIN 1; COLL1
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<strong><em>HGNC Approved Gene Symbol: SEMA3A</em></strong>
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Cytogenetic location: 7q21.11
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:83,955,777-84,492,725 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Inheritance
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7q21.11
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{Hypogonadotropic hypogonadism 16 with or without anosmia}
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<span class="mim-font">
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614897
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Mapping</strong>
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<p>Gross (2020) mapped the SEMA3A gene to chromosome 7q21.11 based on an alignment of the SEMA3A sequence (GenBank AK289954) with the genomic sequence (GRCh38).</p>
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<strong>Gene Function</strong>
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<p>Takahashi et al. (1999) found that the 2 semaphorin-binding proteins, plexin-1 (PLXN1; 601055) and neuropilin-1 (NP1, or NRP1; 602069), form a stable complex. PLXN1 alone did not bind semaphorin-3A (SEMA3A), but the NRP1/PLXN1 complex had a higher affinity for SEMA3A than did NRP1 alone. While SEMA3A binding to NRP1 did not alter nonneuronal cell morphology, SEMA3A interaction with NRP1/PLXN1 complexes induced adherent cells to round up. Expression of a dominant-negative PLXN1 in sensory neurons blocked SEMA3A-induced growth cone collapse. SEMA3A treatment led to the redistribution of growth cone NRP1 and PLXN1 into clusters. Thus, the authors concluded that physiologic SEMA3A receptors consist of NRP1/PLXN1 complexes. </p><p>Polleux et al. (2000) demonstrated that the growth of apical dendrites toward the pial surface is regulated by a diffusible chemoattractant present at high levels near the marginal zone. A major component of the signal is SEMA3A, which was previously characterized as a chemorepellent for cortical axons. Soluble guanylate cyclase is asymmetrically localized to the developing apical dendrite, and is required for the chemoattractive effect of SEMA3A. Thus, the asymmetric localization of soluble guanylate cyclase confers distinct SEMA3A responses to axons and dendrites. Polleux et al. (2000) concluded that these observations reveal a mechanism by which a single chemotropic signal can pattern both axons and dendrites during development. </p><p>Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. Marin et al. (2001) demonstrated that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin-3A and semaphorin-3F (601124). Migrating interneurons expressing neuropilins, receptors for semaphorins, are directed to the cortex; those lacking them go to the striatum. Loss of neuropilin function increases the number of interneurons that migrate into the striatum. Marin et al. (2001) concluded that their observations reveal a mechanism by which neuropilins mediate sorting of distinct neuronal populations into different brain structures, and provide evidence that, in addition to guiding axons, these receptors also control neuronal migration in the central nervous system. </p><p>Using a COS cell-based morphologic assay, Takahashi and Strittmatter (2001) showed that Plexa1 or Plexa2 activity mediated Sema3 signaling in combination with neuropilins, resulting in cell contraction, growth cone collapse, and neurite outgrowth inhibition. Truncation analysis revealed that the intracellular domain of Plexa1 mediated signaling activity and that the transmembrane region was required for this activity. The conserved sema domain in the Plexa1 extracellular segment bound to the remainder of the PlexA1 extracellular region, inhibited Plexa1 activity, and prevented Plexa1 from participating in Sema3a signaling. Furthermore, the Plexa1 sema domain and the remainder of the Plexa1 extracellular domain interacted with Nrp1 at sites distinct from the Sema3a binding site of Nrp1 and enhanced Sema3a binding to Nrp1. Sema3a binding to Nrp1 induced a conformational change in the Nrp1/Plexa1 complex nd dissociated the sema domain from the remainder of the Plexa1 ectodomain, thereby activating Plexa1 and causing cell contraction. </p><p>Serini et al. (2003) demonstrated that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulated integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonized integrin activation. Misexpression of dominant-negative SEMA3 receptors in chick embryo endothelial cells locked integrins in an active conformation, and severely impaired vascular remodeling. Sema3a-null mice showed vascular defects as well. Serini et al. (2003) concluded that during angiogenesis, endothelial SEMA3 proteins endow the vascular system with the plasticity required for reshaping by controlling integrin function. Note that an Expression of Concern was published for the article by Serini et al. (2003). </p><p>Wu et al. (2005) showed that transcripts for RhoA (165390), a small GTPase that regulates the actin cytoskeleton, are localized in developing axons and growth cones, and that this localization is mediated by an axonal targeting element located in the RhoA 3-prime untranslated region. Sema3A induces intraaxonal translation of RhoA mRNA, and this local translation of RhoA is necessary and sufficient for Sema3A-mediated growth cone collapse. Wu et al. (2005) concluded that their studies indicate that local RhoA translation regulates the neuronal cytoskeleton and identify a new mechanism for the regulation of RhoA signaling. </p><p>Using immunohistochemistry, Lepelletier et al. (2007) found that NP1 and SEMA3A were expressed in thymic epithelial cells (TECs) and CD4 (186940)/CD8 (see 186910) thymocytes. Both IL7 (146660), which is constitutively secreted by TECs, and T-cell receptor (TCR) engagement upregulated NP1 expression in thymocytes. SEMA3A blocked adhesion of NP1-positive thymocytes to TECs and induced thymocyte repulsive migration, partially by inhibiting binding of very late antigens (see ITGA4; 192975) to laminin (see LAMA1; 150320). Lepelletier et al. (2007) concluded that NP1 and SEMA3A interactions are important in regulation of migration and adhesion of thymocytes. </p><p>Imai et al. (2009) analyzed the pre-target axon sorting for olfactory map formation in mice. In olfactory sensory neurons, an axon guidance receptor, neuropilin-1 (NPN1; 602069), and its repulsive ligand, semaphorin-3A, are expressed in a complementary manner. Imai et al. (2009) found that expression levels of neuropilin-1 determined both pre-target sorting and projection sites of axons. Olfactory sensory neuron-specific knockout of semaphorin-3A perturbed axon sorting and altered the olfactory map topography. Thus, Imai et al. (2009) concluded that pre-target axon sorting plays an important role in establishing the topographic order based on the relative levels of guidance molecules expressed by axons. </p><p>Tran et al. (2009) found that a Sema3A-Npn1/PlexA4 (604280) signaling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. In contrast, they demonstrated that the secreted semaphorin Sema3F (601124) is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F and its holoreceptor components neuropilin-2 (NPN2; 602070) and plexin A3 (PLEXA3; 300022) exhibit increased dentate gyrus granule cell and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn2-null brain slices cortical layer V and dentate gyrus granule cells exhibit increased miniature excitatory postsynaptic current frequency. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn2 to apical dendrites and of Npn1 to all dendrites of cortical pyramidal neurons. </p><p>Hayashi et al. (2012) showed that Sema3a exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited RANKL (602642)-induced osteoclast differentiation by inhibiting ITAM (608740) and RhoA signaling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/beta-catenin signaling pathway (see 116806). The osteopenic phenotype in Sema3a-null mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. </p><p>In mice, Fukuda et al. (2013) showed that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3A-null mice had a low bone mass due to decreased bone formation. Fukuda et al. (2013) created osteoblast-specific Sema3A-null mice using Col1a1 (120150)-Cre mice and osterix (606633)-Cre mice (Sema3a(col1)-null and Sema3a(osx)-null mice, respectively), and neuron-specific Sema3A-null mice using synapsin-1 (313440)-Cre mice and nestin (600915)-Cre mice (Sema3a(synapsin)-null and Sema3a(nestin)-null mice, respectively). The osteoblast-specific Sema3A-deficient mice had normal bone mass even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons had low bone mass similar to Sema3a-null mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3a(synapsin)-null mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wildtype mice, whereas it did not reduce the low bone mass in Sema3a(nestin)-null mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a-null mice, such as olfactory development, were identified in Sema3a(synapsin)-null mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a-null mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. Fukuda et al. (2013) concluded that Sema3A regulates bone remodeling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts. </p><p>Molofsky et al. (2014) showed that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded SEMA3A is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte-encoded Sema3a leads to dysregulated alpha-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of alpha-motor but not of adjacent gamma-motor neurons. In addition, a subset of Trka (191315)-positive sensory afferents projects to ectopic ventral positions. Molofsky et al. (2014) concluded that these findings demonstrated that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggested that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement. </p><p>Uesaka et al. (2014) identified semaphorins, a family of versatile cell recognition molecules, as retrograde signals for elimination of redundant climbing fiber to Purkinje cell synapses in developing mouse cerebellum. Knockdown of Sema3a, a secreted semaphorin, in Purkinje cells or its receptor in climbing fibers accelerated synapse elimination during postnatal day 8 (P8) to P18. Conversely, knockdown of Sema7a (607961), a membrane-anchored semaphorin, in Purkinje cells or either of its 2 receptors in climbing fibers impaired synapse elimination after P15. The effect of Sema7a involves signaling by metabotropic glutamate receptor-1 (GRM1; 604473), a canonical pathway for climbing fiber synapse elimination. Uesaka et al. (2014) concluded that their findings defined how semaphorins retrogradely regulate multiple processes of synapse elimination. </p><p>Lee et al. (2017) showed that bitter and sweet taste receptor cells provide instructive signals to bitter and sweet target neurons via different guidance molecules, SEMA3A and SEMA7A, respectively. Lee et al. (2017) demonstrated that targeted expression of SEMA3A or SEMA7A in different classes of taste receptor cells produces peripheral taste systems with miswired sweet or bitter cells. They engineered mice with bitter neurons that responded to sweet tastants, sweet neurons that responded to bitter, or sweet neurons that responded to sour stimuli. Lee et al. (2017) concluded that their results uncovered the basic logic of the wiring of the taste system at the periphery, and illustrated how a labeled-line sensory circuit preserves signaling integrity despite rapid and stochastic turnover of receptor cells. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Hypogonadotropic Hypogonadism 16 with or without Anosmia</em></strong></p><p>
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In 2 sibs and their father with Kallmann syndrome (HH16; 614897), Young et al. (2012) identified heterozygosity for a 213-kb deletion in the SEMA3A gene (603961.0001). Sequencing of the nondeleted SEMA3A allele and of 12 known HH-associated genes in affected members of the family did not reveal any other mutations. Young et al. (2012) concluded that SEMA3A plays a role in anosmic hypogonadotropic hypogonadism. </p><p>Because mutant mice lacking a functional Sema3a-binding domain in the NRP1 gene have a Kallmann syndrome (KS)-like phenotype (anosmic HH), Hanchate et al. (2012) sequenced the SEMA3A gene in 386 unrelated patients with anosmic HH, 88 (23%) of whom were known to carry a heterozygous mutation in 1 of 5 previously tested KS-associated genes (KAL1, 300836; FGFR1, 136350; PROKR2, 607123; PROK2, 607002; and FGF8, 600483). Heterozygosity for 8 different nonsynonymous mutations in SEMA3A were identified in 24 patients (see, e.g., 603961.0002 and 603961.0003), including 5 patients already known to carry a mutation in another KS-associated gene (KAL1; FGFR1; PROKR2; and PROK2). The 7 missense mutations in the SEMA3A gene were all located at highly conserved residues and 6 were shown to be loss-of-function mutations; all 7 had been reported in the Exome Variant Server database, and 3 were also detected in the sample of 386 controls. Based on the seemingly normal reproductive phenotype of Sema3a +/- mice, Hanchate et al. (2012) suggested that monoallelic mutations in SEMA3A are not sufficient to induce the abnormal phenotype in patients, but contribute to the pathogenesis of KS through synergistic effects with mutant alleles of other disease-associated genes. </p><p>In 2 Chinese patients with HH without anosmia (patients 1 and 2), Dai et al. (2020) identified heterozygous missense mutations in the SEMA3A gene (R197Q, 603961.0004 and R617Q, 603961.0006, respectively). In a Chinese patient with anosmic HH (patient 2), they identified a heterozygous V458I mutation in the SEMA3A gene (603961.0005). Transfection of a plasmid containing SEMA3A with the R197Q or R617Q mutation showed normal secretion but absence of FAK phosphorylation in GN11 cells and failure to stimulate GN11 cell migration; transfection with the V458I mutation showed abnormal secretion, failure to phosphorylate FAK in GN11 cells, and failure to stimulate GN11 cell migration. Patient 2 also had heterozygous mutations in the CCDC141 (616031) and PROKR2 (607123) genes, leading Dai et al. (2020) to consider oligogenic inheritance in this patient. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of an association between variation in the SEMA3A gene and crypt frequency in the iris, see 610744.</p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</h4>
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<p>Behar et al. (1996) generated mice mutant in semaphorin III using embryonic stem cells in which they replaced the first coding exon with 'neo' cassettes. Heterozygous mice appeared normal. The cerebral cortex of homozygous mutant mice showed a paucity of neuropil and abnormally oriented neuronal processes, especially of the large pyramidal neurons. Certain embryonic bones and cartilaginous structures developed abnormally, with vertebral fusions and partial rib duplications. The few mice that survived more than a few days postnatally manifested pronounced and selective hypertrophy of the right ventricle of the heart and dilation of the right atrium. Behar et al. (1996) thus concluded that semaphorin III may serve as a signal that restrains growth in several developing organs. </p><p>Kaneko et al. (2006) found that adult rats with transection of the spinal cord showed considerable functional recovery after being treated with a Sema3A inhibitor, SM-216289, derived from the fermentation broth of a fungal strain. With SM-216289 treatment, the injured rats showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, decreased number of apoptotic cells, and marked enhancement of angiogenesis compared to untreated rats. Kaneko et al. (2006) concluded that Sema3A is an inhibitor of axonal regeneration and other regenerative responses after spinal cord injury. </p><p>Using immunofluorescence microscopy, Ieda et al. (2007) analyzed the distribution of sympathetic nerves in mouse heart. Sema3a was abundantly expressed in the trabecular layer in early-stage embryos, but it was restricted to Purkinje fibers after birth. Sema3a -/- mice lacked a cardiac sympathetic innervation gradient and exhibited stellate ganglia malformation, leading to marked sinus bradycardia due to sympathetic dysfunction. Overexpression of Sema3a in hearts of transgenic mice led to reduced sympathetic innervation and attenuation of the epicardial-to-endocardial innervation gradient. Sema3a-overexpressing mice succumbed to sudden death and showed susceptibility to ventricular tachycardia due to catecholamine supersensitivity and prolongation of action potential duration. Ieda et al. (2007) concluded that normal sympathetic innervation mediated by SEMA3A is important for maintenance of arrhythmia-free hearts. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</h4>
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<span class="mim-font">
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<strong>.0001 HYPOGONADOTROPIC HYPOGONADISM 16 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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SEMA3A, 213-KB DEL
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<br />
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ClinVar: RCV000032920
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<span class="mim-text-font">
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<p>In a brother and sister and their father with Kallmann syndrome (HH16; 614897), Young et al. (2012) identified heterozygosity for a 213-kb deletion involving exon 6 through exon 17 of the SEMA3A gene. No mutation was found on the nondeleted allele, and no mutations were found in other known HH-associated genes. Young et al. (2012) concluded that loss of function of SEMA3A played a role in the patients' phenotype. Hanchate et al. (2012) stated that their findings did not support mere autosomal dominant mendelian inheritance in this family, and suggested that variation in another gene combined with SEMA3A haploinsufficiency produced the disease phenotype. </p>
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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>.0002 HYPOGONADOTROPIC HYPOGONADISM 16 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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SEMA3A, VAL435ILE
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<br />
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SNP: rs147436181,
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gnomAD: rs147436181,
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ClinVar: RCV000032921, RCV000059788, RCV000455242
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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 16 patients with anosmic hypogonadotropic hypogonadism (HH16; 614897), Hanchate et al. (2012) identified heterozygosity for a G-A transition in exon 11 of the SEMA3A gene, resulting in a val435-to-ile (V435I) substitution at a highly conserved residue in the SEMA domain. Transfection studies in COS-7 cells demonstrated defective secretion of the mutant protein, which was not detected in the conditioned medium. The V435I mutation had been reported in the Exome Variant Server database with an allele frequency in the European American population of 1.3%, and was also detected in 13 of 772 control chromosomes. Three of the patients with V435I were known to also carry heterozygous mutations in 3 other HH-associated genes, including a man with a missense mutation in FGFR1 (136350), a man with a missense mutation in PROKR2 (607123), and a woman with a frameshift mutation in PROK2 (607002). Hanchate et al. (2012) suggested that monoallelic mutations in SEMA3A contribute to the pathogenesis of anosmic HH through synergistic effects with other mutant alleles of disease-associated genes. </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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<h4>
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<span class="mim-font">
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<strong>.0003 HYPOGONADOTROPIC HYPOGONADISM 16 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SEMA3A, 14-BP DEL, NT1613
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<br />
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ClinVar: RCV000032922
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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 man with anosmic hypogonadotropic hypogonadism (HH16; 614897), Hanchate et al. (2012) identified heterozygosity for a 14-bp deletion (1613_1626del) in exon 14 of the SEMA3A gene, predicted to cause a frameshift within the PSI domain resulting in a premature termination codon (Asp538fsTer31). Transfection studies in COS-7 cells demonstrated defective secretion of the mutant protein, which was not detected in the conditioned medium. The mutation was not found in the Exome Variant Server database or in 386 unrelated Caucasian controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 HYPOGONADOTROPIC HYPOGONADISM 16 WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SEMA3A, ARG197GLN
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<br />
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SNP: rs1404070020,
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ClinVar: RCV001785416
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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 man with hypogonadotropic hypogonadism without anosmia (HH16; 614897), Dai et al. (2020) identified a heterozygous c.590G-A transition in the SEMA3A gene, resulting in an arg197-to-gln (R197Q) substitution at a conserved residue in the sema domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's mother was heterozygous for the mutation. The mutation was not present in the gnomAD database or in a database of 2,019 Chinese controls. Transfection of a plasmid containing SEMA3A with the R197Q mutation showed that normal secretion but failure to phosphorylate FAK in GN11 cells and failure to stimulate GN11 cell migration. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 HYPOGONADOTROPIC HYPOGONADISM 16 WITH ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SEMA3A, VAL458ILE
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<br />
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SNP: rs553661856,
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gnomAD: rs553661856,
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ClinVar: RCV001785417, RCV004591567, RCV004749740
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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 man with anosmic hypogonadotropic hypogonadism (HH16; 614897), Dai et al. (2020) identified a heterozygous c.1372G-A transition in the SEMA3A gene, resulting in a val458-to-ile (V458I) substitution at a conserved residue in the sema domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father, who had normal fertility, was heterozygous for the mutation. The mutation was present in the gnomAD database at a frequency of 0.000053 and was not identified in a database of 2,019 Chinese controls. Transfection of a plasmid containing SEMA3A with the V458I mutation showed abnormal secretion, failure to phosphorylate FAK in GN11 cells, and failure to stimulate GN11 cell migration. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 HYPOGONADOTROPIC HYPOGONADISM 16 WITHOUT ANOSMIA, SUSCEPTIBILITY TO</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SEMA3A, ARG617GLN
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<br />
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SNP: rs919402688,
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gnomAD: rs919402688,
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ClinVar: RCV001785418
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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 man with hypogonadotropic hypogonadism without anosmia (HH16; 614897), Dai et al. (2020) identified a heterozygous c.1850G-A transition in the SEMA3A gene, resulting in an arg617-to-gln (R617Q) substitution at a conserved residue in the Ig domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The patient's mother was heterozygous for the mutation. The mutation was present in the gnomAD database at a frequency of 0.0000041 and was not identified in a database of 2,019 Chinese controls. Transfection of a plasmid containing SEMA3A with the R617Q mutation showed normal secretion but failure to phosphorylate FAK in GN11 cells and failure to stimulate GN11 cell migration. The patient also had heterozygous mutations in the CCDC141 (616031) and PROKR2 (607123), leading Dai et al. (2020) to consider oligogenic inheritance. </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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<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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Behar, O., Golden, J. A., Mashimo, H., Schoen, F. J., Fishman, M. C.
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<strong>Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.</strong>
|
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Nature 383: 525-528, 1996.
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[PubMed: 8849723]
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donation now and again in the future. Donations are an important
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component of our efforts to ensure long-term funding to provide you the
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information that you need at your fingertips.
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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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