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Entry
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- *191315 - NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1; NTRK1
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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">*191315</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/191315">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000198400;t=ENST00000524377" 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=4914" 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=191315" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000198400;t=ENST00000524377" 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_001007792,NM_001012331,NM_002529" 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_002529" 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=191315" 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=01869&isoform_id=01869_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/NTRK1" 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/339918,3869113,4585712,32815818,38566284,56118210,59889558,94730402,119573285,119573286,119573287,158254954,189053416,219841840,223459656,554505517,608785411,608785413,2505219720" 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/P04629" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4914" 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=ENSG00000198400;t=ENST00000524377" 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=NTRK1" 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=NTRK1" 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+4914" 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/NTRK1" 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:4914" 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/4914" 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=chr1&hgg_gene=ENST00000524377.7&hgg_start=156815750&hgg_end=156881850&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:8031" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=191315[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=191315[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000198400" 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=NTRK1" 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=NTRK1" 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=NTRK1" 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="http://www.molgen.ua.ac.be/CMTMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NTRK1&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/PA31817" 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:8031" 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://www.mousephenotype.org/data/genes/MGI:97383" 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/NTRK1#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:97383" 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/4914/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=4914" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-980526-118" 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="mimCellLines">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:191315" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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">
|
|
<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:4914" 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=NTRK1&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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|
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
|
<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 62985007<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
191315
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
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NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1; NTRK1
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
|
</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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
TYROSINE KINASE RECEPTOR; TRK<br />
|
|
TYROSINE KINASE RECEPTOR A; TRKA
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
TRK ONCOGENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
NTRK1/TPM3 FUSION GENE, INCLUDED<br />
|
|
NTRK1/TFG FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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|
|
<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NTRK1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NTRK1</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/1/1269?start=-3&limit=10&highlight=1269">1q23.1</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:156815750-156881850&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'})">1:156,815,750-156,881,850</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1269?start=-3&limit=10&highlight=1269">
|
|
1q23.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Insensitivity to pain, congenital, with anhidrosis
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/256800"> 256800 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The NTRK1 gene encodes the neurotrophic tyrosine kinase-1 receptor and belongs to a family of nerve growth factor receptors whose ligands include neurotrophins. Neurotrophins and their receptors play an important role in regulating development of both the central and the peripheral nervous systems. <a href="#3" class="mim-tip-reference" title="Bothwell, M. <strong>p75(NTR): a receptor after all.</strong> Science 272: 506-507, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8614797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8614797</a>] [<a href="https://doi.org/10.1126/science.272.5261.506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8614797">Bothwell (1996)</a>, <a href="#5" class="mim-tip-reference" title="Carter, B. D., Lewin, G. R. <strong>Neurotrophins live or let die: does p75(NTR) decide?</strong> Neuron 18: 187-190, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9052790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9052790</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80259-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9052790">Carter and Lewin (1997)</a>, and <a href="#1" class="mim-tip-reference" title="Bibel, M., Barde, Y.-A. <strong>Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system.</strong> Genes Dev. 14: 2919-2937, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11114882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11114882</a>] [<a href="https://doi.org/10.1101/gad.841400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11114882">Bibel and Barde (2000)</a> reviewed neurotrophins and their receptors. Nerve growth factor receptor (NGFR; <a href="/entry/162010">162010</a>) is also referred to as p75(NTR) due to its molecular mass and its ability to bind at low affinity not only NGF (<a href="/entry/162030">162030</a>, <a href="/entry/162030">162030</a>), but also other neurotrophins, including brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>), neurotrophin-3 (NTF3; <a href="/entry/162660">162660</a>), and neurotrophin-4 (NTF4; <a href="/entry/162662">162662</a>). Higher affinity binding of NGFR can achieved by association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases, TRKA (NTRK1), TRKB (NTRK2; <a href="/entry/600456">600456</a>), and TRKC (NTRK3; <a href="/entry/191316">191316</a>). TRKA, TRKB, and TRKC are specific for or 'preferred by' NGF, NTF4 and BDNF, and NTF3, respectively (<a href="#24" class="mim-tip-reference" title="Ip, N. Y., Stitt, T. N., Tapley, P., Klein, R., Glass, D. J., Fandl, J., Greene, L. A., Barbacid, M., Yancopoulos, G. D. <strong>Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells.</strong> Neuron 10: 137-149, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7679912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7679912</a>] [<a href="https://doi.org/10.1016/0896-6273(93)90306-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7679912">Ip et al., 1993</a>). NTF3 also binds to TRKA and TRKB, but with significantly lower affinity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8614797+9052790+11114882+7679912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#32" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Sztriha, L., Frossard, P., Moosa, A., Ismail, E. A. R., Macaya, A., Andria, G., Toscano, E., Gibson, W., Graham, G. E., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.</strong> Am. J. Hum. Genet. 64: 1570-1579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330344</a>] [<a href="https://doi.org/10.1086/302422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330344">Mardy et al. (1999)</a> reported cloning of the full-length human TRKA gene, which was predicted to encode a 790- or 796-residue protein with a single transmembrane domain. The extracellular domain is important for specific NGF binding and contains 2 immunoglobulin-like domains. The intracellular domain contains a juxtamembrane region, a tyrosine kinase domain, and a short C terminal tail. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330344" 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>NTRK1/TPM3 Fusion Gene</em></strong></p><p>
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Martin-Zanca et al. (<a href="#33" class="mim-tip-reference" title="Martin-Zanca, D., Hughes, S. H., Barbacid, M. <strong>A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences.</strong> Nature 319: 743-748, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2869410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2869410</a>] [<a href="https://doi.org/10.1038/319743a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2869410">1986</a>, <a href="#34" class="mim-tip-reference" title="Martin-Zanca, D., Mitra, G., Long, L. K., Barbacid, M. <strong>Molecular characterization of the human trk oncogene.</strong> Cold Spring Harbor Symp. Quant. Biol. 51: 983-992, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472772</a>] [<a href="https://doi.org/10.1101/sqb.1986.051.01.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472772">1986</a>) identified a biologically active cDNA of a transforming gene in a human colon carcinoma cell line. The gene, referred to as the TRK protooncogene, is a chimera containing sequences of both tropomyosin-3 (TPM3; <a href="/entry/191030">191030</a>) and a tyrosine kinase. The TRK protooncogene was predicted to encode a 641-amino acid transmembrane tyrosine kinase expressed in neural tissues. The protein was identified by its ability to transform rodent cells in gene transfer assays. <a href="#34" class="mim-tip-reference" title="Martin-Zanca, D., Mitra, G., Long, L. K., Barbacid, M. <strong>Molecular characterization of the human trk oncogene.</strong> Cold Spring Harbor Symp. Quant. Biol. 51: 983-992, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472772</a>] [<a href="https://doi.org/10.1101/sqb.1986.051.01.112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472772">Martin-Zanca et al. (1986)</a> suggested that the chimeric gene was likely formed by a somatic rearrangement between the 2 genes, resulting in the replacement of the extracellular domain of a putative transmembrane receptor with the first 221 amino acids of the tropomyosin-3 molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2869410+3472772" 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="#38" class="mim-tip-reference" title="Mitra, G., Martin-Zanca, D., Barbacid, M. <strong>Identification and biochemical characterization of p70(TRK), product of the human TRK oncogene.</strong> Proc. Nat. Acad. Sci. 84: 6707-6711, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3477801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3477801</a>] [<a href="https://doi.org/10.1073/pnas.84.19.6707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3477801">Mitra et al. (1987)</a> expressed the entire coding sequence of the TRK oncogene in E. coli. Antisera raised against these bacteria-synthesized TRK polypeptides were used to identify the gene product of the TRK oncogene as a 70-kD protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3477801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#16" class="mim-tip-reference" title="Greco, A., Villa, R., Pierotti, M. A. <strong>Genomic organization of the human NTRK1 gene.</strong> Oncogene 13: 2463-2466, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8957089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8957089</a>]" pmid="8957089">Greco et al. (1996)</a> determined that the human NTRK1 gene contains 17 exons spanning 25 kb of DNA, of which exon 9 is alternatively spliced. The 5-prime untranslated region lacks a TATA box but has putative binding sites for the transcription factors Sp1 (<a href="/entry/189906">189906</a>), AP1 (<a href="/entry/165160">165160</a>), AP2 (<a href="/entry/107580">107580</a>), AP3, ATF (<a href="/entry/123803">123803</a>), and GCF (<a href="/entry/189901">189901</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8957089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#36" class="mim-tip-reference" title="Miozzo, M., Pierotti, M. A., Sozzi, G., Radice, P., Bongarzone, I., Spurr, N. K., Della Porta, G. <strong>Human TRK proto-oncogene maps to chromosome 1q32-q41.</strong> Oncogene 5: 1411-1414, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2216464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2216464</a>]" pmid="2216464">Miozzo et al. (1990)</a> mapped the TRK protooncogene to chromosome 1q32-q41 by means of Southern analysis of a panel of human-rodent somatic cell hybrids and subsequent in situ hybridization of human metaphase chromosomes. <a href="#41" class="mim-tip-reference" title="Morris, C. M., Hao, Q. L., Heisterkamp, N., Fitzgerald, P. H., Groffen, J. <strong>Localization of the TRK proto-oncogene to human chromosome bands 1q23-1q24.</strong> Oncogene 6: 1093-1095, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1829807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1829807</a>]" pmid="1829807">Morris et al. (1991)</a> localized the TRK oncogene to a more proximal location, 1q23-q24, by in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1829807+2216464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By use of computer-assisted microscopy and a method of fluorescence in situ hybridization involving selection of human genomic P1 clones with large DNA inserts, <a href="#53" class="mim-tip-reference" title="Weier, H.-U. G., Rhein, A. P., Shadravan, F., Collins, C., Polikoff, D. <strong>Rapid physical mapping of the human trk protooncogene (NTRK1) to human chromosome 1q21-q22 by P1 clone selection, fluorescence in situ hybridization (FISH), and computer-assisted microscopy.</strong> Genomics 26: 390-393, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7601468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7601468</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80226-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7601468">Weier et al. (1995)</a> mapped the NTRK1 gene to 1q21-q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7601468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#18" class="mim-tip-reference" title="Hempstead, B. L., Martin-Zanca, D., Kaplan, D. R., Parada, L. F., Chao, M. V. <strong>High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor.</strong> Nature 350: 678-683, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1850821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1850821</a>] [<a href="https://doi.org/10.1038/350678a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1850821">Hempstead et al. (1991)</a> found that high affinity binding of NGF required coexpression of the TRK gene and the low-affinity NGF receptor. NGF stimulated phosphorylation of the TRK protein in neural cell lines and in embryonic dorsal root ganglia. <a href="#25" class="mim-tip-reference" title="Kaplan, D. R., Hempstead, B. L., Martin-Zanca, D., Chao, M. V., Parada, L. F. <strong>The trk proto-oncogene product: a signal transducing receptor for nerve growth factor.</strong> Science 252: 554-558, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1850549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1850549</a>] [<a href="https://doi.org/10.1126/science.1850549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1850549">Kaplan et al. (1991)</a> likewise identified the TRK gene product as an NGF receptor, thus indicating that the protein participates in the primary signal transduction mechanism of NGF. <a href="#29" class="mim-tip-reference" title="Loeb, D. M., Maragos, J., Martin-Zanca, D., Chao, M. V., Parada, L. F., Greene, L. A. <strong>The trk proto-oncogene rescues NGF responsiveness in mutant NGF-nonresponsive PC12 cell lines.</strong> Cell 66: 961-966, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1653650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1653650</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90441-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1653650">Loeb et al. (1991)</a> presented results indicating that TRK was necessary for functional nerve growth factor signal transduction. <a href="#7" class="mim-tip-reference" title="Cordon-Cardo, C., Tapley, P., Jing, S., Nanduri, V., O'Rourke, E., Lamballe, F., Kovary, K., Klein, R., Jones, K. R., Reichardt, L. F., Barbacid, M. <strong>The trk tyrosine protein kinase mediates the mitogenic properties of nerve growth factor and neurotrophin-3.</strong> Cell 66: 173-183, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1649007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1649007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=1649007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90149-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1649007">Cordon-Cardo et al. (1991)</a> presented evidence that the product of the TRK protooncogene was sufficient to mediate signal transduction processes induced by nerve growth factor and neurotrophin-3. <a href="#12" class="mim-tip-reference" title="Ehrhard, P. B., Ganter, U., Stalder, A., Bauer, J., Otten, U. <strong>Expression of functional trk protooncogene in human monocytes.</strong> Proc. Nat. Acad. Sci. 90: 5423-5427, 1993. Note: Erratum: Proc. Nat. Acad. Sci. 91: 1193 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8390664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8390664</a>] [<a href="https://doi.org/10.1073/pnas.90.12.5423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8390664">Ehrhard et al. (1993)</a> reported that TRK is expressed in monocytes; this finding as well as others suggested that nerve growth factor is an immunoregulatory cytokine acting on monocytes in addition to its neurotrophic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1653650+8390664+1649007+1850821+1850549" 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="Chuang, H., Prescott, E. D., Kong, H., Shields, S., Jordt, S.-E., Basbaum, A. I., Chao, M. V., Julius, D. <strong>Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.</strong> Nature 411: 957-962, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11418861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11418861</a>] [<a href="https://doi.org/10.1038/35082088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11418861">Chuang et al. (2001)</a> demonstrated that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo required expression of VR1 (TRPV1; <a href="/entry/602076">602076</a>), a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5,bisphosphate levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma (<a href="/entry/172420">172420</a>) to TRK-alpha was essential for NGF-mediated potentiation of channel activity, and biochemical studies suggested that VR1 associates with this complex. <a href="#6" class="mim-tip-reference" title="Chuang, H., Prescott, E. D., Kong, H., Shields, S., Jordt, S.-E., Basbaum, A. I., Chao, M. V., Julius, D. <strong>Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.</strong> Nature 411: 957-962, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11418861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11418861</a>] [<a href="https://doi.org/10.1038/35082088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11418861">Chuang et al. (2001)</a> concluded that their studies delineated a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signaling systems regulates other members of the TRP channel family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11418861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Kuruvilla, R., Zweifel, L. S., Glebova, N. O., Lonze, B. E., Valdez, G., Ye, H., Ginty, D. D. <strong>A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling.</strong> Cell 118: 243-255, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15260993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15260993</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15260993">Kuruvilla et al. (2004)</a> found that the related neurotrophins NGF and NT3, acting through a common TRKA receptor, were required for sequential stages of sympathetic axon growth and innervation of target fields. Yet, whereas NGF supported TRKA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT3 could not. Final target-derived NGF promoted expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT3. <a href="#26" class="mim-tip-reference" title="Kuruvilla, R., Zweifel, L. S., Glebova, N. O., Lonze, B. E., Valdez, G., Ye, H., Ginty, D. D. <strong>A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling.</strong> Cell 118: 243-255, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15260993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15260993</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15260993">Kuruvilla et al. (2004)</a> proposed that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TRKA internalization, trafficking, and retrograde axonal signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15260993" 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>Neurotrophins (NTFs) act as survival and differentiation factors in the nervous system and have been detected in the developing rodent testis. To determine whether neurotrophins could influence development and maturation of the human fetal testis, <a href="#46" class="mim-tip-reference" title="Robinson, L. L. L., Townsend, J., Anderson, R. A. <strong>The human fetal testis is a site of expression of neurotrophins and their receptors: regulation of the germ cell and peritubular cell population.</strong> J. Clin. Endocr. Metab. 88: 3943-3951, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915691</a>] [<a href="https://doi.org/10.1210/jc.2003-030196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915691">Robinson et al. (2003)</a> examined the cell-specific expression and distribution of several members of the neurotrophin family and their receptors during the second trimester, with particular emphasis on NT4 and TRKB. They detected expression of mRNA for nerve growth factor (NGF; <a href="/entry/162030">162030</a>), NTF3 (<a href="/entry/162660">162660</a>) and NTF4 (<a href="/entry/162662">162662</a>), brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>), the high-affinity receptors TRKA, TRKB (<a href="/entry/600456">600456</a>), and TRKC (<a href="/entry/191316">191316</a>), and the low-affinity p75 receptor NGFR in the human testis between 14 and 19 weeks' gestation. NT4 mRNA and protein were predominantly localized to the peritubular cells. These cells were also the site of expression of p75. By contrast, NGF and NT3 were mainly expressed in Sertoli and interstitial cells. The authors concluded that these data demonstrate the expression of neurotrophins and their receptors in the human fetal testis during the second trimester and indicate possible roles in the regulation of proliferation and survival of germ cells and peritubular cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915691" 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>Cholinergic projection neurons of the basal forebrain nucleus basalis (NB) express NGF receptors p75(NTR) and TrkA, which promote cell survival. These same cells undergo extensive degeneration in Alzheimer disease (AD; <a href="/entry/104300">104300</a>). <a href="#9" class="mim-tip-reference" title="Counts, S. E., Nadeem, M., Wuu, J., Ginsberg, S. D., Saragovi, H. U., Mufson, E. J. <strong>Reduction of cortical TrkA but not p75-NTR protein in early-stage Alzheimer's disease.</strong> Ann. Neurol. 56: 520-531, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15455399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15455399</a>] [<a href="https://doi.org/10.1002/ana.20233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15455399">Counts et al. (2004)</a> found an approximately 50% average reduction in TrkA levels in 4 cortical brain regions of 15 patients with AD, compared to 18 individuals with no cognitive impairment (NCI) and 16 with mild/moderate cognitive impairment (MCI). By contrast, cortical p75(NTR) levels were stable across the diagnostic groups. Scores on the Mini-Mental State Examination (MMSE) correlated with TrkA levels in the anterior cingulate, superior frontal, and superior temporal cortices. <a href="#9" class="mim-tip-reference" title="Counts, S. E., Nadeem, M., Wuu, J., Ginsberg, S. D., Saragovi, H. U., Mufson, E. J. <strong>Reduction of cortical TrkA but not p75-NTR protein in early-stage Alzheimer's disease.</strong> Ann. Neurol. 56: 520-531, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15455399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15455399</a>] [<a href="https://doi.org/10.1002/ana.20233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15455399">Counts et al. (2004)</a> suggested that reduced TrkA levels may be the cause or result of abnormal NB cholinergic function in AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15455399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The AML1 (RUNX1; <a href="/entry/151385">151385</a>)/ETO (CBFA2T1; <a href="/entry/133435">133435</a>) fusion protein results from a t(8;21) chromosomal translocation and is a potent transcriptional modulator associated with acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>). <a href="#42" class="mim-tip-reference" title="Mulloy, J. C., Jankovic, V., Wunderlich, M., Delwel, R., Cammenga, J., Krejci, O., Zhao, H., Valk, P. J. M., Lowenberg, B., Nimer, S. D. <strong>AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34(+) cells, allowing nerve growth factor-induced expansion.</strong> Proc. Nat. Acad. Sci. 102: 4016-4021, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15731354[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.0404701102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731354">Mulloy et al. (2005)</a> transduced CD34 (<a href="/entry/142230">142230</a>)-positive cells with a retrovirus carrying the AML1/ETO fusion transcript and found that AML1/ETO expression upregulated NTRK1. Physiologic concentrations of NGF increased the proliferation of AML1/ETO-transduced cells. Furthermore, NGF and IL3 (<a href="/entry/147740">147740</a>) synergistically promoted the expansion of ALM1/ETO-expressing cells, but not control CD34-positive cells, in liquid culture. <a href="#42" class="mim-tip-reference" title="Mulloy, J. C., Jankovic, V., Wunderlich, M., Delwel, R., Cammenga, J., Krejci, O., Zhao, H., Valk, P. J. M., Lowenberg, B., Nimer, S. D. <strong>AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34(+) cells, allowing nerve growth factor-induced expansion.</strong> Proc. Nat. Acad. Sci. 102: 4016-4021, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15731354/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15731354</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15731354[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.0404701102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15731354">Mulloy et al. (2005)</a> examined a large number of AML bone marrow or peripheral blood samples and found those containing the t(8;21) translocation expressed significantly higher levels of NTRK1 mRNA than samples without the translocation. They concluded that the NGF/NTRK1 signaling pathway may be involved in the development of AML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15731354" 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>Keratoconus is a common corneal dystrophy that leads to severe visual impairment. Since NGF is involved in trophism and corneal wound healing, <a href="#27" class="mim-tip-reference" title="Lambiase, A., Merlo, D., Mollinari, C., Bonini, P., Rinaldi, A. M., D'Amato, M., Micera, A., Coassin, M., Rama, P., Bonini, S., Garaci, E. <strong>Molecular basis for keratoconus: lack of TrkA expression and its transcriptional repression by Sp3.</strong> Proc. Nat. Acad. Sci. 102: 16795-16800, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16275928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16275928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16275928[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.0508516102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16275928">Lambiase et al. (2005)</a> investigated alterations in the NGF pathway in keratoconus-affected corneas and found a total absence of TRKA expression and decreased expression of NGF and p75(NTR). The absence of TRKA expression was associated with a strong increase in expression of the short isoforms of SP3 (<a href="/entry/601804">601804</a>), which is involved in gene repression, and lack of the long SP3 isoform, which is involved in gene activation. Furthermore, expression of short SP3 isoforms in human corneal keratocyte primary cultures resulted in downregulation of TRKA expression. <a href="#27" class="mim-tip-reference" title="Lambiase, A., Merlo, D., Mollinari, C., Bonini, P., Rinaldi, A. M., D'Amato, M., Micera, A., Coassin, M., Rama, P., Bonini, S., Garaci, E. <strong>Molecular basis for keratoconus: lack of TrkA expression and its transcriptional repression by Sp3.</strong> Proc. Nat. Acad. Sci. 102: 16795-16800, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16275928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16275928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16275928[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.0508516102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16275928">Lambiase et al. (2005)</a> hypothesized that an imbalance in SP transcription factor isoforms may play a role in controlling NGF signaling, thus contributing to the pathogenesis of keratoconus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16275928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Mutoh, T., Tachi, M., Yano, S., Mihara, T., Yamamoto, H. <strong>Impairment of Trk-neurotrophin receptor by the serum of a patient with subacute sensory neuropathy.</strong> Arch. Neurol. 62: 1612-1615, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16216947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16216947</a>] [<a href="https://doi.org/10.1001/archneur.62.10.1612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16216947">Mutoh et al. (2005)</a> reported an 86-year-old Japanese man with a history of non-Hodgkin lymphoma who developed sensory axonal neuropathy and autonomic dysfunction. Detailed laboratory investigations identified a paraneoplastic autoantibody to Trk. Serum from the patient inhibited NGF-induced neurite outgrowth and Trk autophosphorylation in rat pheochromocytoma cells, suggesting that the autoantibody was responsible for the clinical symptoms. Treatment with intravenous human immunoglobulin resulted in clinical improvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16216947" 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="Deppmann, C. D., Mihalas, S., Sharma, N., Lonze, B. E., Niebur, E., Ginty, D. D. <strong>A model for neuronal competition during development.</strong> Science 320: 369-373, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323418</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18323418[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1152677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18323418">Deppmann et al. (2008)</a> reported that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived NGF (<a href="/entry/162030">162030</a>) promoted expression of its own receptor TrkA in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>) and neurotrophin-4 (NT4; <a href="/entry/162662">162662</a>), which, through the receptor p75, can kill neighboring neurons with low retrograde NGF-TrkA signaling, whereas neurons with high NGF-TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. <a href="#10" class="mim-tip-reference" title="Deppmann, C. D., Mihalas, S., Sharma, N., Lonze, B. E., Niebur, E., Ginty, D. D. <strong>A model for neuronal competition during development.</strong> Science 320: 369-373, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18323418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18323418</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18323418[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1152677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18323418">Deppmann et al. (2008)</a> suggested that 3 target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18323418" 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="Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., and 20 others. <strong>A Spaetzle-like role for nerve growth factor-beta in vertebrate immunity to Staphylococcus aureus.</strong> Science 346: 641-646, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359976</a>] [<a href="https://doi.org/10.1126/science.1258705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359976">Hepburn et al. (2014)</a> found that stimulation of macrophages with Staphylococcus aureus, but not with other bacteria or staphylococcal species, resulted in secretion of both pro-NGF and mature NGFB, but not other neurotrophins. S. aureus strains that triggered lower levels of NGFB, possibly due to differences in both host and bacterial proteases, were associated with increased all-cause mortality. Macrophages, neutrophils, and TRKA-transfected HeLa cells responded to NGFB with sustained calcium signaling. Cells expressing a TRKA mutant (G517E; <a href="#0015">191315.0015</a>) associated with hereditary sensory and autonomic neuropathy IV (HSAN4, CIPA; <a href="/entry/256800">256800</a>) had reduced calcium signaling, whereas activation of wildtype TRKA led to enhanced phagocytosis, proinflammatory cytokine release, phagosomal superoxide generation, and destruction of S. aureus. Studies in zebrafish suggested that NGFB-TRKA signaling is an evolutionarily conserved component of vertebrate immunity to S. aureus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25359976" 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>NTRK1/TPM3 Fusion Gene</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Coulier, F., Martin-Zanca, D., Ernst, M., Barbacid, M. <strong>Mechanism of activation of the human TRK oncogene.</strong> Molec. Cell. Biol. 9: 15-23, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2538716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2538716</a>] [<a href="https://doi.org/10.1128/mcb.9.1.15-23.1989" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2538716">Coulier et al. (1989)</a> found that the only change leading to the transforming capacity of the TRK oncogene was replacement of the extracellular domain of NTRK1 by sequences coding for the 221 amino-terminal residues of TPM3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2538716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By transfection assay, <a href="#2" class="mim-tip-reference" title="Bongarzone, I., Pierotti, M. A., Monzini, N., Mondellini, P., Manenti, G., Donghi, R., Pilotti, S., Grieco, M., Santoro, M., Fusco, A., Vecchio, G., Della Porta, G. <strong>High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma.</strong> Oncogene 4: 1457-1462, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2594368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2594368</a>]" pmid="2594368">Bongarzone et al. (1989)</a> found that the TRK oncogene was activated in tumor cells, both primary tumor and/or metastasis, in 4 of 16 patients with papillary thyroid carcinoma (see <a href="/entry/188550">188550</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2594368" 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>Chromosomal rearrangements are responsible for the generation of 2 different oncogenes in papillary thyroid carcinoma: RET/PTC (<a href="/entry/164761">164761</a>) and NTRK1/TPM3 (TRK). Both of these oncogenes result from the fusion of the tyrosine kinase domain of a membrane receptor protein (RET and NTRK1, respectively) with 5-prime unrelated sequences, yielding chimeric proteins with ectopic, constitutive tyrosine kinase activity. <a href="#15" class="mim-tip-reference" title="Greco, A., Mariani, C., Miranda, C., Pagliardini, S., Pierotti, M. A. <strong>Characterization of the NTRK1 genomic region involved in chromosomal rearrangements generating TRK oncogenes.</strong> Genomics 18: 397-400, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288244</a>] [<a href="https://doi.org/10.1006/geno.1993.1482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288244">Greco et al. (1993)</a> established that the oncogenic rearrangement of the NTRK1 gene detected in thyroid tumors involved 3 different genes: the TPM3 gene was fused to the NTRK1 tyrosine kinase domain in 3 cases; the TPR gene (<a href="/entry/189940">189940</a>) was involved in 3 cases; and the TAG gene (TFG; <a href="/entry/602498">602498</a>) was involved in the rearrangement in 1 case. <a href="#15" class="mim-tip-reference" title="Greco, A., Mariani, C., Miranda, C., Pagliardini, S., Pierotti, M. A. <strong>Characterization of the NTRK1 genomic region involved in chromosomal rearrangements generating TRK oncogenes.</strong> Genomics 18: 397-400, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288244</a>] [<a href="https://doi.org/10.1006/geno.1993.1482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288244">Greco et al. (1993)</a> found that the rearrangements creating all the TRK oncogenes fell within a 2.9-kb XbaI/SmaI restriction fragment of the NTRK1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288244" 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 3 of 8 papillary thyroid carcinomas, <a href="#4" class="mim-tip-reference" title="Butti, M. G., Bongarzone, I., Ferraresi, G., Mondellini, P., Borrello, M. G., Pierotti, M. A. <strong>A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas.</strong> Genomics 28: 15-24, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590742</a>] [<a href="https://doi.org/10.1006/geno.1995.1100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590742">Butti et al. (1995)</a> found that replacement of the extracellular domain of the NTRK1 gene by sequences coding for the 221 amino-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation. In all of them, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8. Therefore, due to the displacing mechanism, all of the TPM3/NTRK1 gene fusions encoded an invariable transcript and the same chimeric protein of 70 kD, which was constitutively phosphorylated on tyrosine. In 2 of the 3 tumors, the simultaneous presence of the reciprocal products of the TPM3/NTRK1 recombination (5-prime TPM3/3-prime NTRK1 and 5-prime NTRK1/3-prime TPM3) and the previously demonstrated localization of both genes on 1q led <a href="#4" class="mim-tip-reference" title="Butti, M. G., Bongarzone, I., Ferraresi, G., Mondellini, P., Borrello, M. G., Pierotti, M. A. <strong>A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas.</strong> Genomics 28: 15-24, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590742</a>] [<a href="https://doi.org/10.1006/geno.1995.1100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590742">Butti et al. (1995)</a> to suggest that an intrachromosomal inversion was responsible for their recombination. In these recombinant regions, they found some recombinogenic elements as well as palindromes, direct and inverted repeats, and Alu family sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7590742" 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 3-dimensional structural analysis and a protein-protein interaction system, <a href="#52" class="mim-tip-reference" title="Wehrman, T., He, X., Raab, B., Dukipatti, A., Blau, H., Garcia, K. C. <strong>Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.</strong> Neuron 53: 25-38, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17196528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17196528</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.09.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17196528">Wehrman et al. (2007)</a> found no evidence of TRKA and p75 heterodimerization. Instead, TRKA formed a crab-shaped homodimer after interaction with NGF, and p75 existed on the cell surface as a preformed oligomer that was not dissociated by NGF. <a href="#52" class="mim-tip-reference" title="Wehrman, T., He, X., Raab, B., Dukipatti, A., Blau, H., Garcia, K. C. <strong>Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.</strong> Neuron 53: 25-38, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17196528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17196528</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.09.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17196528">Wehrman et al. (2007)</a> proposed that TRKA and NGFR do not interact directly, but that they likely communicate through convergence of downstream signaling pathways and/or shared adaptor molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17196528" 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 engineered embryonic stem cells, <a href="#44" class="mim-tip-reference" title="Nikoletopoulou, V., Lickert, H., Frade, J. M., Rencurel, C., Giallonardo, P., Zhang, L., Bibel, M., Barde, Y.-A. <strong>Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not.</strong> Nature 467: 59-63, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20811452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20811452</a>] [<a href="https://doi.org/10.1038/nature09336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20811452">Nikoletopoulou et al. (2010)</a> demonstrated that the neurotrophin receptors TRKA and TRKC (<a href="/entry/191316">191316</a>) instruct developing neurons to die, both in vitro and in vivo. By contrast, TRKB (<a href="/entry/600456">600456</a>), a closely related receptor primarily expressed in the central nervous system, does not. These results indicated that TRKA and TRKC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic factor-dependent for survival. <a href="#44" class="mim-tip-reference" title="Nikoletopoulou, V., Lickert, H., Frade, J. M., Rencurel, C., Giallonardo, P., Zhang, L., Bibel, M., Barde, Y.-A. <strong>Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not.</strong> Nature 467: 59-63, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20811452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20811452</a>] [<a href="https://doi.org/10.1038/nature09336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20811452">Nikoletopoulou et al. (2010)</a> suggested that the expansion of the TRK gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20811452" 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>NTRK1/TFG Fusion Gene</em></strong></p><p>
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In one papillary thyroid carcinoma tumor, <a href="#14" class="mim-tip-reference" title="Greco, A., Mariani, C., Miranda, C., Lupas, A., Pagliardini, S., Pomati, M., Pierotti, M. A. <strong>The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain.</strong> Molec. Cell Biol. 15: 6118-6127, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7565764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7565764</a>] [<a href="https://doi.org/10.1128/MCB.15.11.6118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7565764">Greco et al. (1995)</a> found a chimeric oncogene, which they designated TRKT3, in which 1,412 nucleotides of NTRK1 were fused to 598 nucleotides from the TRK-fused gene (TFG; <a href="/entry/602498">602498</a>). <a href="#14" class="mim-tip-reference" title="Greco, A., Mariani, C., Miranda, C., Lupas, A., Pagliardini, S., Pomati, M., Pierotti, M. A. <strong>The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain.</strong> Molec. Cell Biol. 15: 6118-6127, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7565764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7565764</a>] [<a href="https://doi.org/10.1128/MCB.15.11.6118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7565764">Greco et al. (1995)</a> determined that the TRKT3 gene encodes a predicted 592-amino acid chimeric protein that forms multimeric complexes in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7565764" 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 7 families with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), <a href="#32" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Sztriha, L., Frossard, P., Moosa, A., Ismail, E. A. R., Macaya, A., Andria, G., Toscano, E., Gibson, W., Graham, G. E., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.</strong> Am. J. Hum. Genet. 64: 1570-1579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330344</a>] [<a href="https://doi.org/10.1086/302422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330344">Mardy et al. (1999)</a> identified 11 novel mutations of the TRKA gene: 6 missense mutations, 2 frameshift mutations, 1 nonsense mutation, and 2 splice site mutations. Mendelian inheritance of the mutations in this autosomal recessive disorder was confirmed in 6 families for which parent samples were available. The mutations were distributed in an extracellular domain, involved in nerve growth factor binding, as well as the intracellular signal transduction domain. Two mutations were linked (on the same chromosome) to arg85 to ser (<a href="#0006">191315.0006</a>) and to his598 to tyr;gly607 to val (<a href="#0005">191315.0005</a>); hence, they probably represented double and triple mutations. Triple mutation is rare and has been reported in Gaucher disease; see <a href="/entry/230800#0009">230800.0009</a>. Double mutations have been reported more often, e.g., in the HEXA gene causing Tay-Sachs disease (<a href="/entry/272800#0036">272800.0036</a>), and in the LDLR gene causing familial hypercholesterolemia (<a href="/entry/143890#0055">143890.0055</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10330344" 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="#40" class="mim-tip-reference" title="Miura, Y., Mardy, S., Awaya, Y., Nihei, K., Endo, F., Matsuda, I., Indo, Y. <strong>Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families.</strong> Hum. Genet. 106: 116-124, 2000. Note: Erratum: Hum. Genet. 106: 575 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982191</a>] [<a href="https://doi.org/10.1007/s004390051018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982191">Miura et al. (2000)</a> studied the NTRK1 gene in 46 CIPA chromosomes derived from 23 unrelated Japanese CIPA families, including 3 that had previously been reported, and identified 11 novel mutations. Four were missense mutations that resulted in amino acid substitutions at positions conserved in the TRK family. Three frameshift and 3 nonsense mutations were found. One was an intronic branch-site mutation (<a href="#0007">191315.0007</a>), causing aberrant splicing in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10982191" 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="#47" class="mim-tip-reference" title="Shatzky, S., Moses, S., Levy, J., Pinsk, V., Hershkovitz, E., Herzog, L., Shorer, Z., Luder, A., Parvari, R. <strong>Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.</strong> Am. J. Med. Genet. 92: 353-360, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861667</a>] [<a href="https://doi.org/10.1002/1096-8628(20000619)92:5<353::aid-ajmg12>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861667">Shatzky et al. (2000)</a> identified 2 novel mutations in the NTRK1 gene in consanguineous Israeli-Bedouins with CIPA: a 1926insT (<a href="#0010">191315.0010</a>) in most of the patients of the southern Israeli-Negev, and a pro689-to-leu mutation (<a href="#0011">191315.0011</a>) in a different Bedouin isolate in northern Israel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861667" 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="#39" class="mim-tip-reference" title="Miura, Y., Hiura, M., Torigoe, K., Numata, O., Kuwahara, A., Matsunaga, M., Hasegawa, S., Boku, N., Ino, H., Mardy, S., Endo, F., Matsuda, I., Indo, Y. <strong>Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis.</strong> Hum. Genet. 107: 205-209, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071380</a>] [<a href="https://doi.org/10.1007/s004390000369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071380">Miura et al. (2000)</a> reported the second case of paternal uniparental disomy (UPD) for chromosome 1 in a male patient with congenital insensitivity to pain with anhidrosis, who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation (1726delC; <a href="#0001">191315.0001</a>) at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Nonmaternity was excluded by analyses of autosomes other than chromosome 1. The findings further supported the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor.</strong> Hum. Molec. Genet. 10: 179-188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159935</a>] [<a href="https://doi.org/10.1093/hmg/10.3.179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159935">Mardy et al. (2001)</a> introduced various CIPA-causing mutations into TRKA cDNA and examined NGF-stimulated autophosphorylation in neuronal and nonneuronal cells. Two mutations in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Five mutations in the tyrosine kinase domain, including gly571 to arg (<a href="#0003">191315.0003</a>), were processed as wildtype TRKA but showed significantly diminished autophosphorylation in both neuronal and nonneuronal cells. In contrast, arg85 to ser (<a href="#0006">191315.0006</a>) and his598 to tyr; gly607 to val (<a href="#0005">191315.0005</a>), detected previously as double and triple mutations, are possibly polymorphisms in a particular ethnic background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11159935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Indo, Y. <strong>Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.</strong> Hum. Mutat. 18: 462-471, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11748840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11748840</a>] [<a href="https://doi.org/10.1002/humu.1224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11748840">Indo (2001)</a> reviewed mutations and polymorphisms in the NTRK1 gene. Thirty-seven different mutations had been identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11748840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Indo, Y., Mardy, S., Miura, Y., Moosa, A., Ismail, E. A. R., Toscano, E., Andria, G., Pavone, V., Brown, D. L., Brooks, A., Endo, F., Matsuda, I. <strong>Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency.</strong> Hum. Mutat. 18: 308-318, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11668614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11668614</a>] [<a href="https://doi.org/10.1002/humu.1192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11668614">Indo et al. (2001)</a> reported 8 novel mutations in the TRKA gene in patients with CIPA, detected in either homozygous or heterozygous state in 9 families from 5 countries. In 1 family, paternal uniparental disomy for chromosome 1 was thought to be the cause of reduction to homozygosity of the TRKA gene mutation. A Hispanic patient from the United States had 2 autosomal genetic disorders, CIPA and pyruvate kinase (PK) deficiency (<a href="/entry/266200">266200</a>), whose genetic loci map to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR (<a href="/entry/609712">609712</a>) genes, respectively, from the homozygous proband. Thus, concordant occurrence of 2 disorders was ascribed to a combination of 2 separate mutant genes, not to a contiguous gene syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11668614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#48" class="mim-tip-reference" title="Smeyne, R. J., Klein, R., Schnapp, A., Long, L. K., Bryant, S., Lewin, A., Lira, S. A., Barbacid, M. <strong>Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene.</strong> Nature 368: 246-249, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8145823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8145823</a>] [<a href="https://doi.org/10.1038/368246a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8145823">Smeyne et al. (1994)</a> found that mice lacking the gene for Trka shared dramatic features of congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), including loss of responses to painful stimuli, although anhidrosis is not apparent in the animals. This prompted <a href="#22" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. <strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong> Nature Genet. 13: 485-488, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696348</a>] [<a href="https://doi.org/10.1038/ng0896-485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696348">Indo et al. (1996)</a> to consider the human TRKA homolog as a candidate for the CIPA gene. In 3 unrelated CIPA patients who had consanguineous parents, they detected a deletion (<a href="#0001">191315.0001</a>), a splice site aberration (<a href="#0002">191315.0002</a>), and a missense mutation (<a href="#0003">191315.0003</a>) in the tyrosine kinase domain of the TRKA gene. The findings suggested to <a href="#22" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. <strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong> Nature Genet. 13: 485-488, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696348</a>] [<a href="https://doi.org/10.1038/ng0896-485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696348">Indo et al. (1996)</a> that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception system as well as establishment of thermoregulation via sweating in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8145823+8696348" 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="#51" class="mim-tip-reference" title="Ugolini, G., Marinelli, S., Covaceuszach, S., Cattaneo, A., Pavone, F. <strong>The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain.</strong> Proc. Nat. Acad. Sci. 104: 2985-2990, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17301229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17301229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17301229[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.0611253104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17301229">Ugolini et al. (2007)</a> found that MNAC13, an anti-TrkA antibody with known neutralizing properties, induced analgesia in mouse models of both acute inflammatory and chronic neuropathic pain. Treatment with MNAC13 resulted in a long-lasting effect in the neuropathic model and resulted in significant functional recovery in mice with sciatic nerve ligation. Moreover, treatment with MNAC13 potentiated the analgesic effects of subthreshold doses of opiates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17301229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The naked mole rat is a subterranean rodent that lacks several pain behaviors found in humans, rats, and mice, including failure of NGF to produce thermal hyperalgesia. <a href="#45" class="mim-tip-reference" title="Omerbasic, D., Smith, E. St. J., Moroni, M., Homfeld, J., Eigenbrod, O., Bennett, N. C., Reznick, J., Faulkes, C. G., Selbach, M., Lewin, G. R. <strong>Hypofunctional TrkA accounts for the absence of pain sensitization in the African naked mole rat.</strong> Cell Rep. 17: 748-758, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27732851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27732851</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27732851[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.celrep.2016.09.035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27732851">Omerbasic et al. (2016)</a> found that naked mole rat cells possessed the necessary signaling components for Trpv1 sensitization, a necessary component of NGF-induced hyperalgesia. Moreover, naked mole rat Trpv1 channels were capable of being sensitized by NGF when expressed in sensory neurons from Trpv1 -/- mice. However, naked mole rat Trpv1 ion channels were not sensitized by NGF in isolated naked mole rat sensory neurons due to hypofunctional Trka that was less efficient at engaging downstream signal transduction pathways. Sequence and functional analyses of Trka from various species revealed that 1 to 3 amino acids changes in the conserved intracellular kinase domain of naked mole rat Trka rendered it unable to participate in nociceptor sensitization. Electron microscopic analysis showed that hypofunctional Trka resulted in naked mole rat pups with more C fibers in their peripheral nerves compared with adults. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27732851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Li, Z., Meyers, C. A., Chang, L., Lee, S., Li, Z., Tomlinson, R., Hoke, A., Clemens, T. L., James, A. W. <strong>Fracture repair requires TrkA signaling by skeletal sensory nerves.</strong> J. Clin. Invest. 129: 5137-5150, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31638597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31638597</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31638597[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI128428" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31638597">Li et al. (2019)</a> showed that inhibition of Trka within skeletal sensory nerves in mice led to reduced innervation, vascularization, and osteoblastic activity within the stress fracture site and impaired fracture healing. Chemotherapy-induced peripheral neuropathy in mice recapitulated the key features of Trka inhibition during stress fracture. The authors concluded that TRKA is required for sensory nerve regeneration and normal fracture repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31638597" 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 patient with congenital insensitivity to pain (CIPA; <a href="/entry/256800">256800</a>), <a href="#22" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. <strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong> Nature Genet. 13: 485-488, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696348</a>] [<a href="https://doi.org/10.1038/ng0896-485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696348">Indo et al. (1996)</a> found deletion of a single base C at nucleotide 1726 in exon C of the NTRK1 gene. The deletion occurred in a region encoding the tyrosine kinase domain, causing a frameshift and premature termination codons downstream. The proband and her parents were homozygous and heterozygous for the deletion, respectively. In a note added in proof, <a href="#22" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. <strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong> Nature Genet. 13: 485-488, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696348</a>] [<a href="https://doi.org/10.1038/ng0896-485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696348">Indo et al. (1996)</a> indicated that they had discovered another patient homozygous for the same single-base deletion in exon C. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696348" 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="#40" class="mim-tip-reference" title="Miura, Y., Mardy, S., Awaya, Y., Nihei, K., Endo, F., Matsuda, I., Indo, Y. <strong>Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families.</strong> Hum. Genet. 106: 116-124, 2000. Note: Erratum: Hum. Genet. 106: 575 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982191</a>] [<a href="https://doi.org/10.1007/s004390051018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982191">Miura et al. (2000)</a> found that the 1726delC mutation was present in 20 of 40 CIPA chromosomes studied. In 6 families, the mutation was homozygous in affected individuals; in 8 families it was heterozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10982191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The 1726delC mutation causes a frameshift and premature termination codon after amino acid arg548 in exon 14. In the case of paternal uniparental isodisomy for chromosome 1 reported by <a href="#39" class="mim-tip-reference" title="Miura, Y., Hiura, M., Torigoe, K., Numata, O., Kuwahara, A., Matsunaga, M., Hasegawa, S., Boku, N., Ino, H., Mardy, S., Endo, F., Matsuda, I., Indo, Y. <strong>Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis.</strong> Hum. Genet. 107: 205-209, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11071380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11071380</a>] [<a href="https://doi.org/10.1007/s004390000369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11071380">Miura et al. (2000)</a>, the father was heterozygous for the mutation, and the mother was homozygous for the wildtype allele. The mutation was on the chromosome 1 derived from the paternal grandmother. Neither maternal grandparent carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11071380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs914061514 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs914061514;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/rs914061514?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=rs914061514" 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=rs914061514" 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=RCV000013095" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013095" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013095</a>
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<p>In 2 Ecuadorian brothers with congenital insensitivity to pain with anhidrosis (GM08382 and GM08383) (CIPA; <a href="/entry/256800">256800</a>), <a href="#22" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. <strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong> Nature Genet. 13: 485-488, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696348</a>] [<a href="https://doi.org/10.1038/ng0896-485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696348">Indo et al. (1996)</a> found a deletion of exon D (nucleotides 1872-2112) on 1 allele of the NTRK1 gene. Part of the same exon (nucleotides 1966-2112) was deleted on the other allele, indicating the presence of RNA splicing errors. The partial exon deletion was apparently due to activation of a cryptic splice donor site. Sequencing of genomic DNA revealed that the 5-prime splice site of an intron between exons D and E contained an A-to-C transversion in the third position. Such mutations are known to result in skipping of the preceding exon. No substitution was found in exon D and the flanking exon/intron junctions. Restriction digestion analysis demonstrated that GM08382 and GM08383 (identification numbers for cell lines in the NIGMS cell bank) were homozygous for the A-to-C transversion and that the parents were heterozygous. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000013096" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013096" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013096</a>
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<p>In a patient with congenital insensitivity to pain and anhidrosis (CIPA; <a href="/entry/256800">256800</a>), <a href="#22" class="mim-tip-reference" title="Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. <strong>Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis.</strong> Nature Genet. 13: 485-488, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696348</a>] [<a href="https://doi.org/10.1038/ng0896-485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696348">Indo et al. (1996)</a> found a G-to-C transversion at nucleotide 1795 in exon C that caused a gly571-to-arg (G571R) substitution. The patient and parents were homozygous and heterozygous for this mutation, respectively. The authors noted that G571 is located in the tyrosine kinase domain and is conserved among 14 receptor tyrosine kinases, including human TRKB (<a href="/entry/600456">600456</a>) and TRKC (<a href="/entry/191316">191316</a>), suggesting that it is important for enzyme activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696348" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<p>In an Italian patient with congenital insensitivity to pain and anhidrosis (CIPA; <a href="/entry/256800">256800</a>), <a href="#17" class="mim-tip-reference" title="Greco, A., Villa, R., Tubino, B., Romano, L., Penso, D., Pierotti, M. A. <strong>A novel NTRK1 mutation associated with congenital insensitivity to pain with anhidrosis. (Letter)</strong> Am. J. Hum. Genet. 64: 1207-1210, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10090906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10090906</a>] [<a href="https://doi.org/10.1086/302319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10090906">Greco et al. (1999)</a> identified homozygosity for a G-to-C transversion at nucleotide 2405 in exon 17, predicting an arg774-to-pro (R774P) substitution. Other members of the family were heterozygous; indeed, the R774P mutation was present in both maternal grandparents, who had no documented consanguinity but were from the same village. Biologic and biochemical studies were consistent with a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10090906" 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 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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NTRK1, GLN9TER, HIS598TYR, AND GLY607VAL
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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> rs6336 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6336;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/rs6336?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=rs6336" 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=rs6336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs6339 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6339;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/rs6339?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=rs6339" 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=rs6339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80356673 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356673;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/rs80356673?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=rs80356673" 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=rs80356673" 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=RCV000013100 OR RCV000013101 OR RCV000030667 OR RCV000030674 OR RCV000031916 OR RCV000031917 OR RCV000127263 OR RCV000592514 OR RCV000712453 OR RCV000712454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013100, RCV000013101, RCV000030667, RCV000030674, RCV000031916, RCV000031917, RCV000127263, RCV000592514, RCV000712453, RCV000712454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013100...</a>
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<p>In an Italian patient with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), <a href="#32" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Sztriha, L., Frossard, P., Moosa, A., Ismail, E. A. R., Macaya, A., Andria, G., Toscano, E., Gibson, W., Graham, G. E., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.</strong> Am. J. Hum. Genet. 64: 1570-1579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330344</a>] [<a href="https://doi.org/10.1086/302422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330344">Mardy et al. (1999)</a> found homozygosity for a triple mutation in exons 1 and 15 in the NTRK1 gene, leading to 1 nonsense mutation (gln9 to ter; Q9X) and 2 missense mutations (his598 to tyr and gly607 to val). <a href="#32" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Sztriha, L., Frossard, P., Moosa, A., Ismail, E. A. R., Macaya, A., Andria, G., Toscano, E., Gibson, W., Graham, G. E., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.</strong> Am. J. Hum. Genet. 64: 1570-1579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330344</a>] [<a href="https://doi.org/10.1086/302422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330344">Mardy et al. (1999)</a> suggested that the Q9X mutation was the most likely cause of CIPA in this family. The missense mutations were later determined to have no effect on autophosphorylation of NTRK1 (<a href="#31" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor.</strong> Hum. Molec. Genet. 10: 179-188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159935</a>] [<a href="https://doi.org/10.1093/hmg/10.3.179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159935">Mardy et al., 2001</a>), and are thus likely to be polymorphisms in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11159935+10330344" 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>.0006 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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NTRK1, IVS4, G-C, -1 AND ARG85SER
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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> rs543320028 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs543320028;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/rs543320028?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=rs543320028" 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=rs543320028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs748672380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs748672380;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/rs748672380?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=rs748672380" 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=rs748672380" 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=RCV000013098 OR RCV000789505 OR RCV000789673 OR RCV000986439 OR RCV001329488 OR RCV001585661 OR RCV002424729 OR RCV004798874" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013098, RCV000789505, RCV000789673, RCV000986439, RCV001329488, RCV001585661, RCV002424729, RCV004798874" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013098...</a>
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<p>In a male patient with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>) from the United Arab Emirates, <a href="#32" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Sztriha, L., Frossard, P., Moosa, A., Ismail, E. A. R., Macaya, A., Andria, G., Toscano, E., Gibson, W., Graham, G. E., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor.</strong> Am. J. Hum. Genet. 64: 1570-1579, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330344</a>] [<a href="https://doi.org/10.1086/302422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330344">Mardy et al. (1999)</a> found homozygosity for a double mutation in the NTRK1 gene: a G-to-C transversion in the first position of exon 4 (IVS4-1G-C), and a C-to-A transversion at nucleotide 337 in exon 2 causing an arg85-to-ser (R85S) substitution. The latter mutation was later determined to have no effect on autophosphorylation of NTRK1 (<a href="#31" class="mim-tip-reference" title="Mardy, S., Miura, Y., Endo, F., Matsuda, I., Indo, Y. <strong>Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor.</strong> Hum. Molec. Genet. 10: 179-188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11159935/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11159935</a>] [<a href="https://doi.org/10.1093/hmg/10.3.179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11159935">Mardy et al., 2001</a>), and is thus likely to be a polymorphism in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11159935+10330344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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NTRK1, IVS7AS, T-A, -33
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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> rs80356674 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356674;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/rs80356674?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=rs80356674" 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=rs80356674" 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=RCV000020471 OR RCV000190819 OR RCV002468974" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020471, RCV000190819, RCV002468974" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020471...</a>
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<p>In a Japanese patient with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), <a href="#40" class="mim-tip-reference" title="Miura, Y., Mardy, S., Awaya, Y., Nihei, K., Endo, F., Matsuda, I., Indo, Y. <strong>Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families.</strong> Hum. Genet. 106: 116-124, 2000. Note: Erratum: Hum. Genet. 106: 575 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10982191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10982191</a>] [<a href="https://doi.org/10.1007/s004390051018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10982191">Miura et al. (2000)</a> identified an intronic branch-site mutation, IVS7AS-33 T-A, causing aberrant splicing in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10982191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 THYROID CARCINOMA, FAMILIAL MEDULLARY</strong>
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NTRK1, TYR604HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964867 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964867;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=rs121964867" 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=rs121964867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs6336 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6336;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/rs6336?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=rs6336" 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=rs6336" 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=RCV000013100 OR RCV000030667 OR RCV000030674 OR RCV000592514 OR RCV000712453" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013100, RCV000030667, RCV000030674, RCV000592514, RCV000712453" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013100...</a>
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<p>By SSCP analysis of 31 sporadic medullary thyroid carcinomas (<a href="/entry/155240">155240</a>), <a href="#13" class="mim-tip-reference" title="Gimm, O., Greco, A., Hoang-Vu, C., Dralle, H., Pierotti, M. A., Eng, C. <strong>Mutation analysis reveals novel sequence variants in NTRK1 in sporadic human medullary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 84: 2784-2787, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10443680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10443680</a>] [<a href="https://doi.org/10.1210/jcem.84.8.5901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10443680">Gimm et al. (1999)</a> detected variants in 5 exons (exons 4 and 14-17) of the NTRK1 gene. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (C1810T/Y604H) and codon 613 (G1838T/V613G; <a href="#0009">191315.0009</a>) of exon 15 always occurred together, possibly representing linkage disequilibrium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10443680" 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>.0009 THYROID CARCINOMA, FAMILIAL MEDULLARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs6339 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6339;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/rs6339?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=rs6339" 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=rs6339" 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=RCV000013101 OR RCV000030667 OR RCV000031916 OR RCV000127263 OR RCV000712454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013101, RCV000030667, RCV000031916, RCV000127263, RCV000712454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013101...</a>
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<p>For discussion of the val613-to-gly (V613G) mutation in the NTRK1 gene that was found in compound heterozygous state in 31 sporadic medullary thyroid carcinomas (<a href="/entry/155240">155240</a>) by <a href="#13" class="mim-tip-reference" title="Gimm, O., Greco, A., Hoang-Vu, C., Dralle, H., Pierotti, M. A., Eng, C. <strong>Mutation analysis reveals novel sequence variants in NTRK1 in sporadic human medullary thyroid carcinoma.</strong> J. Clin. Endocr. Metab. 84: 2784-2787, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10443680/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10443680</a>] [<a href="https://doi.org/10.1210/jcem.84.8.5901" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10443680">Gimm et al. (1999)</a>, see <a href="#0008">191315.0008</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10443680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356676;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=rs80356676" 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=rs80356676" 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=RCV000020469 OR RCV000479042" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020469, RCV000479042" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020469...</a>
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<p>In patients with congenital insensitivity to pain (CIPA; <a href="/entry/256800">256800</a>) from 16 Bedouin families from the southern Israeli-Negev, <a href="#47" class="mim-tip-reference" title="Shatzky, S., Moses, S., Levy, J., Pinsk, V., Hershkovitz, E., Herzog, L., Shorer, Z., Luder, A., Parvari, R. <strong>Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.</strong> Am. J. Med. Genet. 92: 353-360, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861667</a>] [<a href="https://doi.org/10.1002/1096-8628(20000619)92:5<353::aid-ajmg12>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861667">Shatzky et al. (2000)</a> identified a 1-bp insertion (1926insT) in the NTRK1 gene. The mutation was used for prenatal diagnosis in 6 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0011 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121964868 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964868;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/rs121964868?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=rs121964868" 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=rs121964868" 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=RCV000013103" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013103" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013103</a>
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<p>In patients from a Bedouin isolate Bedouins in northern Israel with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), <a href="#47" class="mim-tip-reference" title="Shatzky, S., Moses, S., Levy, J., Pinsk, V., Hershkovitz, E., Herzog, L., Shorer, Z., Luder, A., Parvari, R. <strong>Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies.</strong> Am. J. Med. Genet. 92: 353-360, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861667/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861667</a>] [<a href="https://doi.org/10.1002/1096-8628(20000619)92:5<353::aid-ajmg12>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861667">Shatzky et al. (2000)</a> identified a pro689-to-leu (P689L) mutation in the NTRK1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964869 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964869;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=rs121964869" 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=rs121964869" 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=RCV000013104 OR RCV000789504" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000013104, RCV000789504" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000013104...</a>
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<p><a href="#20" class="mim-tip-reference" title="Houlden, H., King, H. M., Hashemi-Nejad, A., Wood, N. W., Mathias, C. J., Reilly, M., Thomas, P. K. <strong>A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.</strong> Ann. Neurol. 49: 521-525, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310631</a>]" pmid="11310631">Houlden et al. (2001)</a> described a boy, from a consanguineous Pakistani family, with recurrent pyrexial episodes from early life who sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons. <a href="#20" class="mim-tip-reference" title="Houlden, H., King, H. M., Hashemi-Nejad, A., Wood, N. W., Mathias, C. J., Reilly, M., Thomas, P. K. <strong>A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.</strong> Ann. Neurol. 49: 521-525, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310631</a>]" pmid="11310631">Houlden et al. (2001)</a> concluded that the pathologic findings were most consistent with hereditary sensory and autonomic neuropathy type V (HSAN5; <a href="/entry/608654">608654</a>); HSAN V is distinguished from the usual congenital insensitivity to pain with anhidrosis (CIPA or HSAN4; <a href="/entry/256800">256800</a>) by the selective loss of small myelinated fibers (<a href="#30" class="mim-tip-reference" title="Low, P. A., Burke, W. J., McLeod, J. G. <strong>Congenital sensory neuropathy with selective loss of small myelinated fibers.</strong> Ann. Neurol. 3: 179-182, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/77656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">77656</a>] [<a href="https://doi.org/10.1002/ana.410030215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="77656">Low et al., 1978</a>; <a href="#11" class="mim-tip-reference" title="Donaghy, M., Hakin, R. N., Bamford, J. M., Garner, A., Kirkby, G. R., Noble, B. A., Tazir-Melboucy, M., King, R. H. M., Thomas, P. K. <strong>Hereditary sensory neuropathy with neurotrophic keratitis: description of an autosomal recessive disorder with a selective reduction of small myelinated nerve fibres and a discussion of the classification of the hereditary sensory neuropathies.</strong> Brain 110: 563-583, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3472625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3472625</a>] [<a href="https://doi.org/10.1093/brain/110.3.563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3472625">Donaghy et al., 1987</a>). Because the Pakistani patient was homozygous for a tyr359-to-cys missense mutation in exon 8 of the NTRK1 gene, <a href="#20" class="mim-tip-reference" title="Houlden, H., King, H. M., Hashemi-Nejad, A., Wood, N. W., Mathias, C. J., Reilly, M., Thomas, P. K. <strong>A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.</strong> Ann. Neurol. 49: 521-525, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310631</a>]" pmid="11310631">Houlden et al. (2001)</a> concluded that HSAN IV and V are not distinct disorders but different manifestations of mutations in the NTRK1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3472625+11310631+77656" 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="#50" class="mim-tip-reference" title="Toscano, E., Simonati, A., Indo, Y., Andria, G. <strong>No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V.</strong> Ann. Neurol. 52: 224-227, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210794</a>] [<a href="https://doi.org/10.1002/ana.10245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12210794">Toscano et al. (2002)</a> suggested that the patient reported by <a href="#20" class="mim-tip-reference" title="Houlden, H., King, H. M., Hashemi-Nejad, A., Wood, N. W., Mathias, C. J., Reilly, M., Thomas, P. K. <strong>A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.</strong> Ann. Neurol. 49: 521-525, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310631</a>]" pmid="11310631">Houlden et al. (2001)</a> had HSAN4, not HSAN5, and noted that <a href="#20" class="mim-tip-reference" title="Houlden, H., King, H. M., Hashemi-Nejad, A., Wood, N. W., Mathias, C. J., Reilly, M., Thomas, P. K. <strong>A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V.</strong> Ann. Neurol. 49: 521-525, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310631</a>]" pmid="11310631">Houlden et al. (2001)</a> had based their diagnosis mainly on the pathologic findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12210794+11310631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121964870 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121964870;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=rs121964870" 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=rs121964870" 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 large family with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), which came from a small remote island in the southern part of Japan and had many consanguineous marriages, <a href="#54" class="mim-tip-reference" title="Yotsumoto, S., Setoyama, M., Hozumi, H., Mizoguchi, S., Fukumaru, S., Kobayashi, K., Saheki, T., Kanzaki, T. <strong>A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis.</strong> J. Invest. Derm. 112: 810-814, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10233776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10233776</a>] [<a href="https://doi.org/10.1046/j.1523-1747.1999.00569.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10233776">Yotsumoto et al. (1999)</a> identified a met581-to-val (M581V) mutation, occurring within subdomain V (beta-5 strand) of the NTRK1 tyrosine kinase domain. The amino acid substitution resulted from an A-to-G transition at nucleotide 1825 in exon 14 of the NTRK1 gene. The 3 affected individuals were adults and displayed milder clinical symptoms compared with other CIPA patients, including normal temperature sensation and a relatively long survival. Two patients were homozygous for the M581V mutation. <a href="#37" class="mim-tip-reference" title="Miranda, C., Selleri, S., Pierotti, M. A., Greco, A. <strong>The M581V mutation, associated with a mild form of congenital insensitivity to pain with anhidrosis, causes partial inactivation of the NTRK1 receptor.</strong> J. Invest. Derm. 119: 978-979, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12406349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12406349</a>] [<a href="https://doi.org/10.1046/j.1523-1747.2002.00140.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12406349">Miranda et al. (2002)</a> demonstrated that the M581V mutation causes a reduction of activity of the NTRK1 receptor in transfected COS-1 and NIH 3T3 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10233776+12406349" 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>.0014 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs398122810 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122810;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/rs398122810?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=rs398122810" 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=rs398122810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sibs with congenital insensitivity to pain with anhidrosis (CIPA; <a href="/entry/256800">256800</a>), whose unrelated Israeli parents were of Moroccan Jewish descent, <a href="#49" class="mim-tip-reference" title="Suriu, C., Khayat, M., Weiler, M., Kfir, N., Cohen, C., Zinger, A., Aslanidis, C., Schmitz, G., Falik-Zaccai, T. C. <strong>Skoura--a genetic island for congenital insensitivity to pain and anhidrosis among Moroccan Jews, as determined by a novel mutation in the NTRK1 gene.</strong> Clin. Genet. 75: 230-236, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19250380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19250380</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01143.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19250380">Suriu et al. (2009)</a> identified a homozygous 2-bp deletion (207delTG) in exon 1 of the NTRK1 gene, resulting in a frameshift and premature termination at codon 86. Each unaffected parent was heterozygous for the mutation. This mutation was identified in the heterozygous state in a carrier from a second unrelated family of Moroccan Jewish origin in which 2 individuals had CIPA and died. The mutation was not found in 600 control chromosomes. Haplotype analysis indicated shared markers surrounding the mutant allele. Both families originated from Skoura, a small oasis village along the Valley of a Thousand Kasbahs in southern Morocco. Most members of the Jewish families residing there had immigrated to Israel in the 1950s. The common ancestry suggested that 207delTG may be a founder mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19250380" 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> rs606231467 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231467;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/rs606231467?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=rs606231467" 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=rs606231467" 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=RCV000148946" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000148946" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000148946</a>
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<p>In affected members of a Caucasian family with HSAN4 (CIPA; <a href="/entry/256800">256800</a>), <a href="#19" class="mim-tip-reference" title="Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., and 20 others. <strong>A Spaetzle-like role for nerve growth factor-beta in vertebrate immunity to Staphylococcus aureus.</strong> Science 346: 641-646, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359976</a>] [<a href="https://doi.org/10.1126/science.1258705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359976">Hepburn et al. (2014)</a> identified compound heterozygous mutations in the NTRK1 gene: a c.1550G-A transition, resulting in a gly517-to-glu (G517E) substitution, and an A-to-T transversion in intron 6 (c.717+4A-T; <a href="#0016">191315.0016</a>), resulting in a splicing defect. <a href="#19" class="mim-tip-reference" title="Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., and 20 others. <strong>A Spaetzle-like role for nerve growth factor-beta in vertebrate immunity to Staphylococcus aureus.</strong> Science 346: 641-646, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359976</a>] [<a href="https://doi.org/10.1126/science.1258705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359976">Hepburn et al. (2014)</a> found that the G517E mutation was associated with reduced calcium signaling following stimulation with NGFB (<a href="/entry/162030">162030</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25359976" 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">rs606231466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231466;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=rs606231466" 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=rs606231466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splice site mutation in intron 6 of the NTRK1 gene (c.717+4A-T) that was found in compound heterozygous state in a patient with HSAN4 (CIPA; <a href="/entry/256800">256800</a>) by <a href="#19" class="mim-tip-reference" title="Hepburn, L., Prajsnar, T. K., Klapholz, C., Moreno, P., Loynes, C. A., Ogryzko, N. V., Brown, K., Schiebler, M., Hegyi, K., Antrobus, R., Hammond, K. L., Connolly, J., and 20 others. <strong>A Spaetzle-like role for nerve growth factor-beta in vertebrate immunity to Staphylococcus aureus.</strong> Science 346: 641-646, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25359976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25359976</a>] [<a href="https://doi.org/10.1126/science.1258705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25359976">Hepburn et al. (2014)</a>, see <a href="#0015">191315.0015</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25359976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Martin-Zanca1989" class="mim-tip-reference" title="Martin-Zanca, D., Oskam, R., Mitra, G., Copeland, T., Barbacid, M. <strong>Molecular and biochemical characterization of the human TRK proto-oncogene.</strong> Molec. Cell. Biol. 9: 24-33, 1989.">Martin-Zanca et al. (1989)</a>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<a id="50" class="mim-anchor"></a>
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<a id="Toscano2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Toscano, E., Simonati, A., Indo, Y., Andria, G.
|
|
<strong>No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V.</strong>
|
|
Ann. Neurol. 52: 224-227, 2002.
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|
|
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12210794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12210794</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12210794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10245" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="51" class="mim-anchor"></a>
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<a id="Ugolini2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Ugolini, G., Marinelli, S., Covaceuszach, S., Cattaneo, A., Pavone, F.
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|
<strong>The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain.</strong>
|
|
Proc. Nat. Acad. Sci. 104: 2985-2990, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17301229/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17301229</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17301229[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=17301229" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0611253104" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Wehrman2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
|
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Wehrman, T., He, X., Raab, B., Dukipatti, A., Blau, H., Garcia, K. C.
|
|
<strong>Structural and mechanistic insights into nerve growth factor interactions with the TrkA and p75 receptors.</strong>
|
|
Neuron 53: 25-38, 2007.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17196528/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17196528</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17196528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2006.09.034" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Weier1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weier, H.-U. G., Rhein, A. P., Shadravan, F., Collins, C., Polikoff, D.
|
|
<strong>Rapid physical mapping of the human trk protooncogene (NTRK1) to human chromosome 1q21-q22 by P1 clone selection, fluorescence in situ hybridization (FISH), and computer-assisted microscopy.</strong>
|
|
Genomics 26: 390-393, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7601468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7601468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7601468" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0888-7543(95)80226-c" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="54" class="mim-anchor"></a>
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<a id="Yotsumoto1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yotsumoto, S., Setoyama, M., Hozumi, H., Mizoguchi, S., Fukumaru, S., Kobayashi, K., Saheki, T., Kanzaki, T.
|
|
<strong>A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis.</strong>
|
|
J. Invest. Derm. 112: 810-814, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10233776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10233776</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10233776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1046/j.1523-1747.1999.00569.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 04/17/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
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Paul J. Converse - updated : 12/3/2014<br>Cassandra L. Kniffin - updated : 12/3/2014<br>Paul J. Converse - updated : 3/28/2013<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Ada Hamosh - updated : 9/27/2010<br>Cassandra L. Kniffin - updated : 8/14/2008<br>Ada Hamosh - updated : 6/17/2008<br>Cassandra L. Kniffin - updated : 4/27/2007<br>Cassandra L. Kniffin - updated : 7/14/2006<br>Patricia A. Hartz - updated : 12/21/2005<br>Patricia A. Hartz - updated : 4/18/2005<br>Cassandra L. Kniffin - updated : 1/20/2005<br>John A. Phillips, III - updated : 10/6/2004<br>Stylianos E. Antonarakis - updated : 8/18/2004<br>Cassandra L. Kniffin - updated : 5/17/2004<br>Gary A. Bellus - updated : 2/11/2003<br>Victor A. McKusick - updated : 2/22/2002<br>Victor A. McKusick - updated : 2/15/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Ada Hamosh - updated : 6/20/2001<br>Paul J. Converse - updated : 5/15/2001<br>George E. Tiller - updated : 4/16/2001<br>Victor A. McKusick - updated : 10/3/2000<br>Victor A. McKusick - updated : 6/7/2000<br>John A. Phillips, III - updated : 6/6/2000<br>Victor A. McKusick - updated : 2/17/2000<br>Victor A. McKusick - updated : 5/27/1999<br>Victor A. McKusick - updated : 4/9/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
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Creation Date:
|
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</span>
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Victor A. McKusick : 6/21/1991
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/20/2023
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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mgross : 05/05/2020<br>mgross : 04/17/2020<br>joanna : 05/14/2019<br>alopez : 08/31/2015<br>carol : 8/21/2015<br>mcolton : 8/14/2015<br>carol : 2/6/2015<br>mcolton : 2/5/2015<br>mgross : 12/4/2014<br>mcolton : 12/3/2014<br>ckniffin : 12/3/2014<br>carol : 9/17/2013<br>mgross : 4/5/2013<br>terry : 3/28/2013<br>carol : 11/14/2012<br>terry : 11/13/2012<br>terry : 9/7/2012<br>carol : 4/18/2012<br>ckniffin : 4/11/2012<br>alopez : 9/27/2010<br>terry : 9/27/2010<br>wwang : 10/22/2009<br>ckniffin : 8/22/2008<br>carol : 8/20/2008<br>carol : 8/20/2008<br>ckniffin : 8/14/2008<br>alopez : 6/20/2008<br>alopez : 6/20/2008<br>terry : 6/17/2008<br>wwang : 5/9/2007<br>ckniffin : 4/27/2007<br>carol : 7/19/2006<br>ckniffin : 7/14/2006<br>wwang : 1/24/2006<br>wwang : 12/21/2005<br>carol : 11/18/2005<br>terry : 6/28/2005<br>mgross : 4/18/2005<br>terry : 4/18/2005<br>tkritzer : 2/1/2005<br>ckniffin : 1/20/2005<br>alopez : 10/6/2004<br>mgross : 8/18/2004<br>ckniffin : 5/24/2004<br>carol : 5/21/2004<br>ckniffin : 5/17/2004<br>alopez : 2/11/2003<br>alopez : 2/11/2003<br>alopez : 1/8/2003<br>carol : 3/11/2002<br>cwells : 3/5/2002<br>terry : 2/22/2002<br>carol : 2/21/2002<br>cwells : 2/20/2002<br>terry : 2/15/2002<br>carol : 12/27/2001<br>terry : 12/27/2001<br>alopez : 6/21/2001<br>terry : 6/20/2001<br>mgross : 5/15/2001<br>cwells : 5/9/2001<br>cwells : 4/25/2001<br>cwells : 4/16/2001<br>mcapotos : 10/12/2000<br>mcapotos : 10/9/2000<br>terry : 10/3/2000<br>carol : 6/9/2000<br>terry : 6/7/2000<br>alopez : 6/6/2000<br>alopez : 2/29/2000<br>terry : 2/17/2000<br>mgross : 6/8/1999<br>mgross : 6/2/1999<br>terry : 5/27/1999<br>carol : 4/12/1999<br>terry : 4/9/1999<br>dkim : 10/1/1998<br>dkim : 10/1/1998<br>terry : 7/24/1998<br>alopez : 4/1/1997<br>jamie : 10/23/1996<br>jamie : 10/16/1996<br>mark : 8/8/1996<br>mark : 8/7/1996<br>terry : 7/30/1996<br>mark : 8/16/1995<br>terry : 7/28/1995<br>carol : 3/9/1995<br>carol : 11/30/1993<br>carol : 10/2/1992<br>supermim : 3/16/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 191315
|
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</span>
|
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</h3>
|
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</div>
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<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
NEUROTROPHIC TYROSINE KINASE, RECEPTOR, TYPE 1; NTRK1
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
|
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
|
</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
TYROSINE KINASE RECEPTOR; TRK<br />
|
|
TYROSINE KINASE RECEPTOR A; TRKA
|
|
</span>
|
|
</h4>
|
|
</div>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<div>
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
TRK ONCOGENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
NTRK1/TPM3 FUSION GENE, INCLUDED<br />
|
|
NTRK1/TFG FUSION GENE, INCLUDED
|
|
</span>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: NTRK1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
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<p>
|
|
<span class="mim-text-font">
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|
<strong>SNOMEDCT:</strong> 62985007;
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 1q23.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 1:156,815,750-156,881,850 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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|
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
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|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
1q23.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Insensitivity to pain, congenital, with anhidrosis
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
256800
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
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|
</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
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<p>The NTRK1 gene encodes the neurotrophic tyrosine kinase-1 receptor and belongs to a family of nerve growth factor receptors whose ligands include neurotrophins. Neurotrophins and their receptors play an important role in regulating development of both the central and the peripheral nervous systems. Bothwell (1996), Carter and Lewin (1997), and Bibel and Barde (2000) reviewed neurotrophins and their receptors. Nerve growth factor receptor (NGFR; 162010) is also referred to as p75(NTR) due to its molecular mass and its ability to bind at low affinity not only NGF (162030, 162030), but also other neurotrophins, including brain-derived neurotrophic factor (BDNF; 113505), neurotrophin-3 (NTF3; 162660), and neurotrophin-4 (NTF4; 162662). Higher affinity binding of NGFR can achieved by association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases, TRKA (NTRK1), TRKB (NTRK2; 600456), and TRKC (NTRK3; 191316). TRKA, TRKB, and TRKC are specific for or 'preferred by' NGF, NTF4 and BDNF, and NTF3, respectively (Ip et al., 1993). NTF3 also binds to TRKA and TRKB, but with significantly lower affinity. </p>
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<strong>Cloning and Expression</strong>
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<p>Mardy et al. (1999) reported cloning of the full-length human TRKA gene, which was predicted to encode a 790- or 796-residue protein with a single transmembrane domain. The extracellular domain is important for specific NGF binding and contains 2 immunoglobulin-like domains. The intracellular domain contains a juxtamembrane region, a tyrosine kinase domain, and a short C terminal tail. </p><p><strong><em>NTRK1/TPM3 Fusion Gene</em></strong></p><p>
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Martin-Zanca et al. (1986, 1986) identified a biologically active cDNA of a transforming gene in a human colon carcinoma cell line. The gene, referred to as the TRK protooncogene, is a chimera containing sequences of both tropomyosin-3 (TPM3; 191030) and a tyrosine kinase. The TRK protooncogene was predicted to encode a 641-amino acid transmembrane tyrosine kinase expressed in neural tissues. The protein was identified by its ability to transform rodent cells in gene transfer assays. Martin-Zanca et al. (1986) suggested that the chimeric gene was likely formed by a somatic rearrangement between the 2 genes, resulting in the replacement of the extracellular domain of a putative transmembrane receptor with the first 221 amino acids of the tropomyosin-3 molecule. </p><p>Mitra et al. (1987) expressed the entire coding sequence of the TRK oncogene in E. coli. Antisera raised against these bacteria-synthesized TRK polypeptides were used to identify the gene product of the TRK oncogene as a 70-kD protein. </p>
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<strong>Gene Structure</strong>
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<p>Greco et al. (1996) determined that the human NTRK1 gene contains 17 exons spanning 25 kb of DNA, of which exon 9 is alternatively spliced. The 5-prime untranslated region lacks a TATA box but has putative binding sites for the transcription factors Sp1 (189906), AP1 (165160), AP2 (107580), AP3, ATF (123803), and GCF (189901). </p>
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<strong>Mapping</strong>
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<p>Miozzo et al. (1990) mapped the TRK protooncogene to chromosome 1q32-q41 by means of Southern analysis of a panel of human-rodent somatic cell hybrids and subsequent in situ hybridization of human metaphase chromosomes. Morris et al. (1991) localized the TRK oncogene to a more proximal location, 1q23-q24, by in situ hybridization. </p><p>By use of computer-assisted microscopy and a method of fluorescence in situ hybridization involving selection of human genomic P1 clones with large DNA inserts, Weier et al. (1995) mapped the NTRK1 gene to 1q21-q22. </p>
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<strong>Gene Function</strong>
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<p>Hempstead et al. (1991) found that high affinity binding of NGF required coexpression of the TRK gene and the low-affinity NGF receptor. NGF stimulated phosphorylation of the TRK protein in neural cell lines and in embryonic dorsal root ganglia. Kaplan et al. (1991) likewise identified the TRK gene product as an NGF receptor, thus indicating that the protein participates in the primary signal transduction mechanism of NGF. Loeb et al. (1991) presented results indicating that TRK was necessary for functional nerve growth factor signal transduction. Cordon-Cardo et al. (1991) presented evidence that the product of the TRK protooncogene was sufficient to mediate signal transduction processes induced by nerve growth factor and neurotrophin-3. Ehrhard et al. (1993) reported that TRK is expressed in monocytes; this finding as well as others suggested that nerve growth factor is an immunoregulatory cytokine acting on monocytes in addition to its neurotrophic function. </p><p>Chuang et al. (2001) demonstrated that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo required expression of VR1 (TRPV1; 602076), a heat-activated ion channel on sensory neurons. Diminution of plasma membrane phosphatidylinositol-4,5,bisphosphate levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma (172420) to TRK-alpha was essential for NGF-mediated potentiation of channel activity, and biochemical studies suggested that VR1 associates with this complex. Chuang et al. (2001) concluded that their studies delineated a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signaling systems regulates other members of the TRP channel family. </p><p>Kuruvilla et al. (2004) found that the related neurotrophins NGF and NT3, acting through a common TRKA receptor, were required for sequential stages of sympathetic axon growth and innervation of target fields. Yet, whereas NGF supported TRKA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT3 could not. Final target-derived NGF promoted expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT3. Kuruvilla et al. (2004) proposed that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TRKA internalization, trafficking, and retrograde axonal signaling. </p><p>Neurotrophins (NTFs) act as survival and differentiation factors in the nervous system and have been detected in the developing rodent testis. To determine whether neurotrophins could influence development and maturation of the human fetal testis, Robinson et al. (2003) examined the cell-specific expression and distribution of several members of the neurotrophin family and their receptors during the second trimester, with particular emphasis on NT4 and TRKB. They detected expression of mRNA for nerve growth factor (NGF; 162030), NTF3 (162660) and NTF4 (162662), brain-derived neurotrophic factor (BDNF; 113505), the high-affinity receptors TRKA, TRKB (600456), and TRKC (191316), and the low-affinity p75 receptor NGFR in the human testis between 14 and 19 weeks' gestation. NT4 mRNA and protein were predominantly localized to the peritubular cells. These cells were also the site of expression of p75. By contrast, NGF and NT3 were mainly expressed in Sertoli and interstitial cells. The authors concluded that these data demonstrate the expression of neurotrophins and their receptors in the human fetal testis during the second trimester and indicate possible roles in the regulation of proliferation and survival of germ cells and peritubular cells. </p><p>Cholinergic projection neurons of the basal forebrain nucleus basalis (NB) express NGF receptors p75(NTR) and TrkA, which promote cell survival. These same cells undergo extensive degeneration in Alzheimer disease (AD; 104300). Counts et al. (2004) found an approximately 50% average reduction in TrkA levels in 4 cortical brain regions of 15 patients with AD, compared to 18 individuals with no cognitive impairment (NCI) and 16 with mild/moderate cognitive impairment (MCI). By contrast, cortical p75(NTR) levels were stable across the diagnostic groups. Scores on the Mini-Mental State Examination (MMSE) correlated with TrkA levels in the anterior cingulate, superior frontal, and superior temporal cortices. Counts et al. (2004) suggested that reduced TrkA levels may be the cause or result of abnormal NB cholinergic function in AD. </p><p>The AML1 (RUNX1; 151385)/ETO (CBFA2T1; 133435) fusion protein results from a t(8;21) chromosomal translocation and is a potent transcriptional modulator associated with acute myeloid leukemia (AML; 601626). Mulloy et al. (2005) transduced CD34 (142230)-positive cells with a retrovirus carrying the AML1/ETO fusion transcript and found that AML1/ETO expression upregulated NTRK1. Physiologic concentrations of NGF increased the proliferation of AML1/ETO-transduced cells. Furthermore, NGF and IL3 (147740) synergistically promoted the expansion of ALM1/ETO-expressing cells, but not control CD34-positive cells, in liquid culture. Mulloy et al. (2005) examined a large number of AML bone marrow or peripheral blood samples and found those containing the t(8;21) translocation expressed significantly higher levels of NTRK1 mRNA than samples without the translocation. They concluded that the NGF/NTRK1 signaling pathway may be involved in the development of AML. </p><p>Keratoconus is a common corneal dystrophy that leads to severe visual impairment. Since NGF is involved in trophism and corneal wound healing, Lambiase et al. (2005) investigated alterations in the NGF pathway in keratoconus-affected corneas and found a total absence of TRKA expression and decreased expression of NGF and p75(NTR). The absence of TRKA expression was associated with a strong increase in expression of the short isoforms of SP3 (601804), which is involved in gene repression, and lack of the long SP3 isoform, which is involved in gene activation. Furthermore, expression of short SP3 isoforms in human corneal keratocyte primary cultures resulted in downregulation of TRKA expression. Lambiase et al. (2005) hypothesized that an imbalance in SP transcription factor isoforms may play a role in controlling NGF signaling, thus contributing to the pathogenesis of keratoconus. </p><p>Mutoh et al. (2005) reported an 86-year-old Japanese man with a history of non-Hodgkin lymphoma who developed sensory axonal neuropathy and autonomic dysfunction. Detailed laboratory investigations identified a paraneoplastic autoantibody to Trk. Serum from the patient inhibited NGF-induced neurite outgrowth and Trk autophosphorylation in rat pheochromocytoma cells, suggesting that the autoantibody was responsible for the clinical symptoms. Treatment with intravenous human immunoglobulin resulted in clinical improvement. </p><p>Deppmann et al. (2008) reported that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived NGF (162030) promoted expression of its own receptor TrkA in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain-derived neurotrophic factor (BDNF; 113505) and neurotrophin-4 (NT4; 162662), which, through the receptor p75, can kill neighboring neurons with low retrograde NGF-TrkA signaling, whereas neurons with high NGF-TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. Deppmann et al. (2008) suggested that 3 target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects. </p><p>Hepburn et al. (2014) found that stimulation of macrophages with Staphylococcus aureus, but not with other bacteria or staphylococcal species, resulted in secretion of both pro-NGF and mature NGFB, but not other neurotrophins. S. aureus strains that triggered lower levels of NGFB, possibly due to differences in both host and bacterial proteases, were associated with increased all-cause mortality. Macrophages, neutrophils, and TRKA-transfected HeLa cells responded to NGFB with sustained calcium signaling. Cells expressing a TRKA mutant (G517E; 191315.0015) associated with hereditary sensory and autonomic neuropathy IV (HSAN4, CIPA; 256800) had reduced calcium signaling, whereas activation of wildtype TRKA led to enhanced phagocytosis, proinflammatory cytokine release, phagosomal superoxide generation, and destruction of S. aureus. Studies in zebrafish suggested that NGFB-TRKA signaling is an evolutionarily conserved component of vertebrate immunity to S. aureus. </p><p><strong><em>NTRK1/TPM3 Fusion Gene</em></strong></p><p>
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Coulier et al. (1989) found that the only change leading to the transforming capacity of the TRK oncogene was replacement of the extracellular domain of NTRK1 by sequences coding for the 221 amino-terminal residues of TPM3. </p><p>By transfection assay, Bongarzone et al. (1989) found that the TRK oncogene was activated in tumor cells, both primary tumor and/or metastasis, in 4 of 16 patients with papillary thyroid carcinoma (see 188550). </p><p>Chromosomal rearrangements are responsible for the generation of 2 different oncogenes in papillary thyroid carcinoma: RET/PTC (164761) and NTRK1/TPM3 (TRK). Both of these oncogenes result from the fusion of the tyrosine kinase domain of a membrane receptor protein (RET and NTRK1, respectively) with 5-prime unrelated sequences, yielding chimeric proteins with ectopic, constitutive tyrosine kinase activity. Greco et al. (1993) established that the oncogenic rearrangement of the NTRK1 gene detected in thyroid tumors involved 3 different genes: the TPM3 gene was fused to the NTRK1 tyrosine kinase domain in 3 cases; the TPR gene (189940) was involved in 3 cases; and the TAG gene (TFG; 602498) was involved in the rearrangement in 1 case. Greco et al. (1993) found that the rearrangements creating all the TRK oncogenes fell within a 2.9-kb XbaI/SmaI restriction fragment of the NTRK1 gene. </p><p>In 3 of 8 papillary thyroid carcinomas, Butti et al. (1995) found that replacement of the extracellular domain of the NTRK1 gene by sequences coding for the 221 amino-terminal residues of the TPM3 gene was responsible for the oncogenic NTRK1 activation. In all of them, the illegitimate recombination involved the 611-bp NTRK1 intron placed upstream of the transmembrane domain and the TPM3 intron located between exons 7 and 8. Therefore, due to the displacing mechanism, all of the TPM3/NTRK1 gene fusions encoded an invariable transcript and the same chimeric protein of 70 kD, which was constitutively phosphorylated on tyrosine. In 2 of the 3 tumors, the simultaneous presence of the reciprocal products of the TPM3/NTRK1 recombination (5-prime TPM3/3-prime NTRK1 and 5-prime NTRK1/3-prime TPM3) and the previously demonstrated localization of both genes on 1q led Butti et al. (1995) to suggest that an intrachromosomal inversion was responsible for their recombination. In these recombinant regions, they found some recombinogenic elements as well as palindromes, direct and inverted repeats, and Alu family sequences. </p><p>Using 3-dimensional structural analysis and a protein-protein interaction system, Wehrman et al. (2007) found no evidence of TRKA and p75 heterodimerization. Instead, TRKA formed a crab-shaped homodimer after interaction with NGF, and p75 existed on the cell surface as a preformed oligomer that was not dissociated by NGF. Wehrman et al. (2007) proposed that TRKA and NGFR do not interact directly, but that they likely communicate through convergence of downstream signaling pathways and/or shared adaptor molecules. </p><p>Using engineered embryonic stem cells, Nikoletopoulou et al. (2010) demonstrated that the neurotrophin receptors TRKA and TRKC (191316) instruct developing neurons to die, both in vitro and in vivo. By contrast, TRKB (600456), a closely related receptor primarily expressed in the central nervous system, does not. These results indicated that TRKA and TRKC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic factor-dependent for survival. Nikoletopoulou et al. (2010) suggested that the expansion of the TRK gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control. </p><p><strong><em>NTRK1/TFG Fusion Gene</em></strong></p><p>
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In one papillary thyroid carcinoma tumor, Greco et al. (1995) found a chimeric oncogene, which they designated TRKT3, in which 1,412 nucleotides of NTRK1 were fused to 598 nucleotides from the TRK-fused gene (TFG; 602498). Greco et al. (1995) determined that the TRKT3 gene encodes a predicted 592-amino acid chimeric protein that forms multimeric complexes in vivo. </p>
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<strong>Molecular Genetics</strong>
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<p>In 7 families with congenital insensitivity to pain with anhidrosis (CIPA; 256800), Mardy et al. (1999) identified 11 novel mutations of the TRKA gene: 6 missense mutations, 2 frameshift mutations, 1 nonsense mutation, and 2 splice site mutations. Mendelian inheritance of the mutations in this autosomal recessive disorder was confirmed in 6 families for which parent samples were available. The mutations were distributed in an extracellular domain, involved in nerve growth factor binding, as well as the intracellular signal transduction domain. Two mutations were linked (on the same chromosome) to arg85 to ser (191315.0006) and to his598 to tyr;gly607 to val (191315.0005); hence, they probably represented double and triple mutations. Triple mutation is rare and has been reported in Gaucher disease; see 230800.0009. Double mutations have been reported more often, e.g., in the HEXA gene causing Tay-Sachs disease (272800.0036), and in the LDLR gene causing familial hypercholesterolemia (143890.0055). </p><p>Miura et al. (2000) studied the NTRK1 gene in 46 CIPA chromosomes derived from 23 unrelated Japanese CIPA families, including 3 that had previously been reported, and identified 11 novel mutations. Four were missense mutations that resulted in amino acid substitutions at positions conserved in the TRK family. Three frameshift and 3 nonsense mutations were found. One was an intronic branch-site mutation (191315.0007), causing aberrant splicing in vitro. </p><p>Shatzky et al. (2000) identified 2 novel mutations in the NTRK1 gene in consanguineous Israeli-Bedouins with CIPA: a 1926insT (191315.0010) in most of the patients of the southern Israeli-Negev, and a pro689-to-leu mutation (191315.0011) in a different Bedouin isolate in northern Israel. </p><p>Miura et al. (2000) reported the second case of paternal uniparental disomy (UPD) for chromosome 1 in a male patient with congenital insensitivity to pain with anhidrosis, who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation (1726delC; 191315.0001) at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Nonmaternity was excluded by analyses of autosomes other than chromosome 1. The findings further supported the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. </p><p>Mardy et al. (2001) introduced various CIPA-causing mutations into TRKA cDNA and examined NGF-stimulated autophosphorylation in neuronal and nonneuronal cells. Two mutations in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Five mutations in the tyrosine kinase domain, including gly571 to arg (191315.0003), were processed as wildtype TRKA but showed significantly diminished autophosphorylation in both neuronal and nonneuronal cells. In contrast, arg85 to ser (191315.0006) and his598 to tyr; gly607 to val (191315.0005), detected previously as double and triple mutations, are possibly polymorphisms in a particular ethnic background. </p><p>Indo (2001) reviewed mutations and polymorphisms in the NTRK1 gene. Thirty-seven different mutations had been identified. </p><p>Indo et al. (2001) reported 8 novel mutations in the TRKA gene in patients with CIPA, detected in either homozygous or heterozygous state in 9 families from 5 countries. In 1 family, paternal uniparental disomy for chromosome 1 was thought to be the cause of reduction to homozygosity of the TRKA gene mutation. A Hispanic patient from the United States had 2 autosomal genetic disorders, CIPA and pyruvate kinase (PK) deficiency (266200), whose genetic loci map to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR (609712) genes, respectively, from the homozygous proband. Thus, concordant occurrence of 2 disorders was ascribed to a combination of 2 separate mutant genes, not to a contiguous gene syndrome. </p>
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<strong>Animal Model</strong>
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<p>Smeyne et al. (1994) found that mice lacking the gene for Trka shared dramatic features of congenital insensitivity to pain with anhidrosis (CIPA; 256800), including loss of responses to painful stimuli, although anhidrosis is not apparent in the animals. This prompted Indo et al. (1996) to consider the human TRKA homolog as a candidate for the CIPA gene. In 3 unrelated CIPA patients who had consanguineous parents, they detected a deletion (191315.0001), a splice site aberration (191315.0002), and a missense mutation (191315.0003) in the tyrosine kinase domain of the TRKA gene. The findings suggested to Indo et al. (1996) that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception system as well as establishment of thermoregulation via sweating in humans. </p><p>Ugolini et al. (2007) found that MNAC13, an anti-TrkA antibody with known neutralizing properties, induced analgesia in mouse models of both acute inflammatory and chronic neuropathic pain. Treatment with MNAC13 resulted in a long-lasting effect in the neuropathic model and resulted in significant functional recovery in mice with sciatic nerve ligation. Moreover, treatment with MNAC13 potentiated the analgesic effects of subthreshold doses of opiates. </p><p>The naked mole rat is a subterranean rodent that lacks several pain behaviors found in humans, rats, and mice, including failure of NGF to produce thermal hyperalgesia. Omerbasic et al. (2016) found that naked mole rat cells possessed the necessary signaling components for Trpv1 sensitization, a necessary component of NGF-induced hyperalgesia. Moreover, naked mole rat Trpv1 channels were capable of being sensitized by NGF when expressed in sensory neurons from Trpv1 -/- mice. However, naked mole rat Trpv1 ion channels were not sensitized by NGF in isolated naked mole rat sensory neurons due to hypofunctional Trka that was less efficient at engaging downstream signal transduction pathways. Sequence and functional analyses of Trka from various species revealed that 1 to 3 amino acids changes in the conserved intracellular kinase domain of naked mole rat Trka rendered it unable to participate in nociceptor sensitization. Electron microscopic analysis showed that hypofunctional Trka resulted in naked mole rat pups with more C fibers in their peripheral nerves compared with adults. </p><p>Li et al. (2019) showed that inhibition of Trka within skeletal sensory nerves in mice led to reduced innervation, vascularization, and osteoblastic activity within the stress fracture site and impaired fracture healing. Chemotherapy-induced peripheral neuropathy in mice recapitulated the key features of Trka inhibition during stress fracture. The authors concluded that TRKA is required for sensory nerve regeneration and normal fracture repair. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>16 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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NTRK1, 1-BP DEL, 1726C
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SNP: rs80356675,
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gnomAD: rs80356675,
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ClinVar: RCV000020468
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<p>In a patient with congenital insensitivity to pain (CIPA; 256800), Indo et al. (1996) found deletion of a single base C at nucleotide 1726 in exon C of the NTRK1 gene. The deletion occurred in a region encoding the tyrosine kinase domain, causing a frameshift and premature termination codons downstream. The proband and her parents were homozygous and heterozygous for the deletion, respectively. In a note added in proof, Indo et al. (1996) indicated that they had discovered another patient homozygous for the same single-base deletion in exon C. </p><p>Miura et al. (2000) found that the 1726delC mutation was present in 20 of 40 CIPA chromosomes studied. In 6 families, the mutation was homozygous in affected individuals; in 8 families it was heterozygous. </p><p>The 1726delC mutation causes a frameshift and premature termination codon after amino acid arg548 in exon 14. In the case of paternal uniparental isodisomy for chromosome 1 reported by Miura et al. (2000), the father was heterozygous for the mutation, and the mother was homozygous for the wildtype allele. The mutation was on the chromosome 1 derived from the paternal grandmother. Neither maternal grandparent carried the mutation. </p>
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<span class="mim-font">
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<strong>.0002 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
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NTRK1, IVSDS, A-C, +3
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SNP: rs914061514,
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gnomAD: rs914061514,
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ClinVar: RCV000013095
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<span class="mim-text-font">
|
|
<p>In 2 Ecuadorian brothers with congenital insensitivity to pain with anhidrosis (GM08382 and GM08383) (CIPA; 256800), Indo et al. (1996) found a deletion of exon D (nucleotides 1872-2112) on 1 allele of the NTRK1 gene. Part of the same exon (nucleotides 1966-2112) was deleted on the other allele, indicating the presence of RNA splicing errors. The partial exon deletion was apparently due to activation of a cryptic splice donor site. Sequencing of genomic DNA revealed that the 5-prime splice site of an intron between exons D and E contained an A-to-C transversion in the third position. Such mutations are known to result in skipping of the preceding exon. No substitution was found in exon D and the flanking exon/intron junctions. Restriction digestion analysis demonstrated that GM08382 and GM08383 (identification numbers for cell lines in the NIGMS cell bank) were homozygous for the A-to-C transversion and that the parents were heterozygous. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
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NTRK1, GLY571ARG
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|
<br />
|
|
|
|
SNP: rs121964866,
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|
|
|
|
gnomAD: rs121964866,
|
|
|
|
|
|
ClinVar: RCV000013096
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient with congenital insensitivity to pain and anhidrosis (CIPA; 256800), Indo et al. (1996) found a G-to-C transversion at nucleotide 1795 in exon C that caused a gly571-to-arg (G571R) substitution. The patient and parents were homozygous and heterozygous for this mutation, respectively. The authors noted that G571 is located in the tyrosine kinase domain and is conserved among 14 receptor tyrosine kinases, including human TRKB (600456) and TRKC (191316), suggesting that it is important for enzyme activity. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
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|
<span class="mim-font">
|
|
<strong>.0004 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
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NTRK1, ARG774PRO
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<br />
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|
|
SNP: rs35669708,
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gnomAD: rs35669708,
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|
|
ClinVar: RCV000013097
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|
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|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an Italian patient with congenital insensitivity to pain and anhidrosis (CIPA; 256800), Greco et al. (1999) identified homozygosity for a G-to-C transversion at nucleotide 2405 in exon 17, predicting an arg774-to-pro (R774P) substitution. Other members of the family were heterozygous; indeed, the R774P mutation was present in both maternal grandparents, who had no documented consanguinity but were from the same village. Biologic and biochemical studies were consistent with a loss-of-function effect. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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|
</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
NTRK1, GLN9TER, HIS598TYR, AND GLY607VAL
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs6336, rs6339, rs80356673,
|
|
|
|
|
|
gnomAD: rs6336, rs6339, rs80356673,
|
|
|
|
|
|
ClinVar: RCV000013100, RCV000013101, RCV000030667, RCV000030674, RCV000031916, RCV000031917, RCV000127263, RCV000592514, RCV000712453, RCV000712454
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Italian patient with congenital insensitivity to pain with anhidrosis (CIPA; 256800), Mardy et al. (1999) found homozygosity for a triple mutation in exons 1 and 15 in the NTRK1 gene, leading to 1 nonsense mutation (gln9 to ter; Q9X) and 2 missense mutations (his598 to tyr and gly607 to val). Mardy et al. (1999) suggested that the Q9X mutation was the most likely cause of CIPA in this family. The missense mutations were later determined to have no effect on autophosphorylation of NTRK1 (Mardy et al., 2001), and are thus likely to be polymorphisms in this population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, IVS4, G-C, -1 AND ARG85SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs543320028, rs748672380,
|
|
|
|
|
|
gnomAD: rs543320028, rs748672380,
|
|
|
|
|
|
ClinVar: RCV000013098, RCV000789505, RCV000789673, RCV000986439, RCV001329488, RCV001585661, RCV002424729, RCV004798874
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient with congenital insensitivity to pain with anhidrosis (CIPA; 256800) from the United Arab Emirates, Mardy et al. (1999) found homozygosity for a double mutation in the NTRK1 gene: a G-to-C transversion in the first position of exon 4 (IVS4-1G-C), and a C-to-A transversion at nucleotide 337 in exon 2 causing an arg85-to-ser (R85S) substitution. The latter mutation was later determined to have no effect on autophosphorylation of NTRK1 (Mardy et al., 2001), and is thus likely to be a polymorphism in this population. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, IVS7AS, T-A, -33
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80356674,
|
|
|
|
|
|
gnomAD: rs80356674,
|
|
|
|
|
|
ClinVar: RCV000020471, RCV000190819, RCV002468974
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese patient with congenital insensitivity to pain with anhidrosis (CIPA; 256800), Miura et al. (2000) identified an intronic branch-site mutation, IVS7AS-33 T-A, causing aberrant splicing in vitro. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 THYROID CARCINOMA, FAMILIAL MEDULLARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, TYR604HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964867, rs6336,
|
|
|
|
|
|
gnomAD: rs6336,
|
|
|
|
|
|
ClinVar: RCV000013100, RCV000030667, RCV000030674, RCV000592514, RCV000712453
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>By SSCP analysis of 31 sporadic medullary thyroid carcinomas (155240), Gimm et al. (1999) detected variants in 5 exons (exons 4 and 14-17) of the NTRK1 gene. All variants were also present in the corresponding germline DNA. Interestingly, the sequence variants at codon 604 (C1810T/Y604H) and codon 613 (G1838T/V613G; 191315.0009) of exon 15 always occurred together, possibly representing linkage disequilibrium. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 THYROID CARCINOMA, FAMILIAL MEDULLARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, VAL613GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs6339,
|
|
|
|
|
|
gnomAD: rs6339,
|
|
|
|
|
|
ClinVar: RCV000013101, RCV000030667, RCV000031916, RCV000127263, RCV000712454
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the val613-to-gly (V613G) mutation in the NTRK1 gene that was found in compound heterozygous state in 31 sporadic medullary thyroid carcinomas (155240) by Gimm et al. (1999), see 191315.0008. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, 1-BP INS, 1926T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80356676,
|
|
|
|
|
|
|
|
ClinVar: RCV000020469, RCV000479042
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients with congenital insensitivity to pain (CIPA; 256800) from 16 Bedouin families from the southern Israeli-Negev, Shatzky et al. (2000) identified a 1-bp insertion (1926insT) in the NTRK1 gene. The mutation was used for prenatal diagnosis in 6 cases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, PRO689LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964868,
|
|
|
|
|
|
gnomAD: rs121964868,
|
|
|
|
|
|
ClinVar: RCV000013103
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In patients from a Bedouin isolate Bedouins in northern Israel with congenital insensitivity to pain with anhidrosis (CIPA; 256800), Shatzky et al. (2000) identified a pro689-to-leu (P689L) mutation in the NTRK1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, TYR359CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964869,
|
|
|
|
|
|
|
|
ClinVar: RCV000013104, RCV000789504
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Houlden et al. (2001) described a boy, from a consanguineous Pakistani family, with recurrent pyrexial episodes from early life who sustained a painless ankle injury and was found to have a calcaneus fracture and, later, neuropathic joint degeneration of the tarsus. Examination revealed distal loss of pain and temperature sensation and widespread anhidrosis. Sural nerve biopsy demonstrated severe reduction in small-caliber myelinated fiber density but only modest reduction in unmyelinated axons. Houlden et al. (2001) concluded that the pathologic findings were most consistent with hereditary sensory and autonomic neuropathy type V (HSAN5; 608654); HSAN V is distinguished from the usual congenital insensitivity to pain with anhidrosis (CIPA or HSAN4; 256800) by the selective loss of small myelinated fibers (Low et al., 1978; Donaghy et al., 1987). Because the Pakistani patient was homozygous for a tyr359-to-cys missense mutation in exon 8 of the NTRK1 gene, Houlden et al. (2001) concluded that HSAN IV and V are not distinct disorders but different manifestations of mutations in the NTRK1 gene. </p><p>Toscano et al. (2002) suggested that the patient reported by Houlden et al. (2001) had HSAN4, not HSAN5, and noted that Houlden et al. (2001) had based their diagnosis mainly on the pathologic findings. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, MET581VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121964870,
|
|
|
|
|
|
|
|
ClinVar: RCV000013105
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large family with congenital insensitivity to pain with anhidrosis (CIPA; 256800), which came from a small remote island in the southern part of Japan and had many consanguineous marriages, Yotsumoto et al. (1999) identified a met581-to-val (M581V) mutation, occurring within subdomain V (beta-5 strand) of the NTRK1 tyrosine kinase domain. The amino acid substitution resulted from an A-to-G transition at nucleotide 1825 in exon 14 of the NTRK1 gene. The 3 affected individuals were adults and displayed milder clinical symptoms compared with other CIPA patients, including normal temperature sensation and a relatively long survival. Two patients were homozygous for the M581V mutation. Miranda et al. (2002) demonstrated that the M581V mutation causes a reduction of activity of the NTRK1 receptor in transfected COS-1 and NIH 3T3 cells. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
NTRK1, 2-BP DEL, 207TG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398122810,
|
|
|
|
|
|
gnomAD: rs398122810,
|
|
|
|
|
|
ClinVar: RCV000022807
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with congenital insensitivity to pain with anhidrosis (CIPA; 256800), whose unrelated Israeli parents were of Moroccan Jewish descent, Suriu et al. (2009) identified a homozygous 2-bp deletion (207delTG) in exon 1 of the NTRK1 gene, resulting in a frameshift and premature termination at codon 86. Each unaffected parent was heterozygous for the mutation. This mutation was identified in the heterozygous state in a carrier from a second unrelated family of Moroccan Jewish origin in which 2 individuals had CIPA and died. The mutation was not found in 600 control chromosomes. Haplotype analysis indicated shared markers surrounding the mutant allele. Both families originated from Skoura, a small oasis village along the Valley of a Thousand Kasbahs in southern Morocco. Most members of the Jewish families residing there had immigrated to Israel in the 1950s. The common ancestry suggested that 207delTG may be a founder mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</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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NTRK1, GLY517GLU
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<br />
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SNP: rs606231467,
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gnomAD: rs606231467,
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ClinVar: RCV000148946
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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 affected members of a Caucasian family with HSAN4 (CIPA; 256800), Hepburn et al. (2014) identified compound heterozygous mutations in the NTRK1 gene: a c.1550G-A transition, resulting in a gly517-to-glu (G517E) substitution, and an A-to-T transversion in intron 6 (c.717+4A-T; 191315.0016), resulting in a splicing defect. Hepburn et al. (2014) found that the G517E mutation was associated with reduced calcium signaling following stimulation with NGFB (162030). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS</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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NTRK1, IVS6DS, A-T, +4
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<br />
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SNP: rs606231466,
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ClinVar: RCV000148945
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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>For discussion of the splice site mutation in intron 6 of the NTRK1 gene (c.717+4A-T) that was found in compound heterozygous state in a patient with HSAN4 (CIPA; 256800) by Hepburn et al. (2014), see 191315.0015. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
|
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Martin-Zanca et al. (1989)
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<p class="mim-text-font">
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Li, Z., Meyers, C. A., Chang, L., Lee, S., Li, Z., Tomlinson, R., Hoke, A., Clemens, T. L., James, A. W.
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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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Bao Lige - updated : 04/17/2020<br>Paul J. Converse - updated : 12/3/2014<br>Cassandra L. Kniffin - updated : 12/3/2014<br>Paul J. Converse - updated : 3/28/2013<br>Cassandra L. Kniffin - updated : 4/11/2012<br>Ada Hamosh - updated : 9/27/2010<br>Cassandra L. Kniffin - updated : 8/14/2008<br>Ada Hamosh - updated : 6/17/2008<br>Cassandra L. Kniffin - updated : 4/27/2007<br>Cassandra L. Kniffin - updated : 7/14/2006<br>Patricia A. Hartz - updated : 12/21/2005<br>Patricia A. Hartz - updated : 4/18/2005<br>Cassandra L. Kniffin - updated : 1/20/2005<br>John A. Phillips, III - updated : 10/6/2004<br>Stylianos E. Antonarakis - updated : 8/18/2004<br>Cassandra L. Kniffin - updated : 5/17/2004<br>Gary A. Bellus - updated : 2/11/2003<br>Victor A. McKusick - updated : 2/22/2002<br>Victor A. McKusick - updated : 2/15/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Ada Hamosh - updated : 6/20/2001<br>Paul J. Converse - updated : 5/15/2001<br>George E. Tiller - updated : 4/16/2001<br>Victor A. McKusick - updated : 10/3/2000<br>Victor A. McKusick - updated : 6/7/2000<br>John A. Phillips, III - updated : 6/6/2000<br>Victor A. McKusick - updated : 2/17/2000<br>Victor A. McKusick - updated : 5/27/1999<br>Victor A. McKusick - updated : 4/9/1999
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Victor A. McKusick : 6/21/1991
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alopez : 03/20/2023<br>mgross : 05/05/2020<br>mgross : 04/17/2020<br>joanna : 05/14/2019<br>alopez : 08/31/2015<br>carol : 8/21/2015<br>mcolton : 8/14/2015<br>carol : 2/6/2015<br>mcolton : 2/5/2015<br>mgross : 12/4/2014<br>mcolton : 12/3/2014<br>ckniffin : 12/3/2014<br>carol : 9/17/2013<br>mgross : 4/5/2013<br>terry : 3/28/2013<br>carol : 11/14/2012<br>terry : 11/13/2012<br>terry : 9/7/2012<br>carol : 4/18/2012<br>ckniffin : 4/11/2012<br>alopez : 9/27/2010<br>terry : 9/27/2010<br>wwang : 10/22/2009<br>ckniffin : 8/22/2008<br>carol : 8/20/2008<br>carol : 8/20/2008<br>ckniffin : 8/14/2008<br>alopez : 6/20/2008<br>alopez : 6/20/2008<br>terry : 6/17/2008<br>wwang : 5/9/2007<br>ckniffin : 4/27/2007<br>carol : 7/19/2006<br>ckniffin : 7/14/2006<br>wwang : 1/24/2006<br>wwang : 12/21/2005<br>carol : 11/18/2005<br>terry : 6/28/2005<br>mgross : 4/18/2005<br>terry : 4/18/2005<br>tkritzer : 2/1/2005<br>ckniffin : 1/20/2005<br>alopez : 10/6/2004<br>mgross : 8/18/2004<br>ckniffin : 5/24/2004<br>carol : 5/21/2004<br>ckniffin : 5/17/2004<br>alopez : 2/11/2003<br>alopez : 2/11/2003<br>alopez : 1/8/2003<br>carol : 3/11/2002<br>cwells : 3/5/2002<br>terry : 2/22/2002<br>carol : 2/21/2002<br>cwells : 2/20/2002<br>terry : 2/15/2002<br>carol : 12/27/2001<br>terry : 12/27/2001<br>alopez : 6/21/2001<br>terry : 6/20/2001<br>mgross : 5/15/2001<br>cwells : 5/9/2001<br>cwells : 4/25/2001<br>cwells : 4/16/2001<br>mcapotos : 10/12/2000<br>mcapotos : 10/9/2000<br>terry : 10/3/2000<br>carol : 6/9/2000<br>terry : 6/7/2000<br>alopez : 6/6/2000<br>alopez : 2/29/2000<br>terry : 2/17/2000<br>mgross : 6/8/1999<br>mgross : 6/2/1999<br>terry : 5/27/1999<br>carol : 4/12/1999<br>terry : 4/9/1999<br>dkim : 10/1/1998<br>dkim : 10/1/1998<br>terry : 7/24/1998<br>alopez : 4/1/1997<br>jamie : 10/23/1996<br>jamie : 10/16/1996<br>mark : 8/8/1996<br>mark : 8/7/1996<br>terry : 7/30/1996<br>mark : 8/16/1995<br>terry : 7/28/1995<br>carol : 3/9/1995<br>carol : 11/30/1993<br>carol : 10/2/1992<br>supermim : 3/16/1992
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